f l a t h r e o f i ajho education resource · 2015-07-13 · out our heavy premed course load....

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lymphomaThe Role of PET Imaging in the Management of Patients With Hodgkin Lymphoma Craig Moskowitz, MD

leukemiaA Primer on Molecular Testing in Chronic Myeloid Leukemia (PCR for Poets)Jerald P. Radich, MD

ovarian cancerGenomic (“Precision”) Medicine in the Management of Ovarian CancerMaurie Markman, MD per: 9th annual international SympoSium on ovarian cancer and GynecoloGic maliGnancieS®

What Would Clinicians Do If BRCA or Lynch Positive?Medical Management, Insurance Discrimination, and Confidentiality

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H e m a t o l o g y /

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a peer-reviewed resource

for oncology education

cmeMedical Crossfire: Recent Advances in the Treatment of Metastatic Melanoma A CME-certified enduring material sponsored by Physicians’ Education Resource®, LLC

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Table of Contents

LYMPHOMA

The Role of PET Imaging in the Management of Patients With Hodgkin LymphomaCraig Moskowitz, MD

FDG-PET-CT revolutionized the management of Hodgkin lymphoma (HL) and is currently integrated into all aspects of HL management. As such, this review discusses the current role of PET imaging in the management of HL, including some of the basic “rules” for PET scanning and some of the controversies.

LEUKEMIA

A Primer on Molecular Testing in Chronic Myeloid Leukemia (PCR for Poets)Jerald P. Radich, MD

Tyrosine kinase inhibitor (TKI) therapy can yield sustained cytogenetic remissions in most patients with chronic phase chronic myeloid leukemia (CML.) Peripheral blood quantita-tive PCR monitoring of the chimeric BCR-ABL mRNA is a very sensitive method to measure disease burden in patients with cytogenetic remission. Molecular monitoring is a minimally invasive method to optimize treatment and outcome in CML.

OVARIAN CANCER

Genomic (“Precision”) Medicine in the Management of Ovarian Cancer Maurie Markman, MD

The virtual revolution in our understanding of specific driver molecular abnormalities present in a subset of cancers from patients with a variety of solid tumors has resulted in major favorable changes in how these diseases are routinely managed. However, despite substantial research effort, ovarian cancer has not seen any changes in its standard man-agement based on evidence of unique molecular alterations within individual tumors. This brief review will highlight both the past and current status of investigative efforts involving genomically based treatment of ovarian cancer and possible future approaches in this criti-cally important area.

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PER: 9TH ANNUAL INTERNATIONAL SYMPOSIUM ON OVARIAN CANCER AND GYNECOLOGIC MALIGNANCIES®

What Would Clinicians Do If BRCA or Lynch Positive? Medical Management, Insurance Discrimination, and Confidentiality Based on a presentation by Ellen Matloff, MS, CGC, director of the Yale Cancer Genetic Counseling Program at the Yale School of Medicine/Yale Cancer Center, in New Haven, Connecticut, at the 9th Annual International Symposium on Ovarian Cancer and Gyneco-logic Malignancies®, held in Philadelphia, Pennsylvania, on October 5, 2013 by Physicians’ Education Resource®, LLC.

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EditorAndrew Zelenetz, MD, PhD

Vice Chair, Medical Informatics, Department of Medicine Memorial Sloan-Kettering Cancer Center New York, NY

Associate EditorDavid Ilson, MD, PhD

Medical Oncologist Gastrointestinal Oncology Service Memorial Sloan-Kettering Cancer Center New York, NY

Director of Scientific AffairsDru S. Dace, PhD

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EDITORIAL STAFF

From the Editor

Thank you for engaging in the re-launch of The American Journal of Hematology/Oncology. In an era when medical information seems so ubiquitous, you may be asking yourself why we need another journal. I think this may be reflected in this journal’s subtitle, “A Peer-Reviewed Resource for Oncology Education.” In the winter of 2012-2013, a number of us participated in a survey of medical oncologists regarding their clinical experience and comfort levels with the 20 most recently approved antineoplastic agents.1 The survey found highly variable experience with new agents, and more importantly, a general lack of confidence in prescribing new agents. As the amount of new information about new therapies has begun to expand exponentially, it is often difficult for practitioners to access and absorb primary clinical data for many new agents. Furthermore, the rapid evolution of companion diagnostics and cancer genomics and their critical use in treatment selection has increased the challenge for the practicing medical oncologist to assimilate the neces-sary information to stay at the cutting edge of clinical practice.

The American Journal of Hematology/Oncology will help fill that knowledge gap by provid-ing peer-reviewed articles on cutting edge topics by leaders in the field in a way that makes the information accessible and useful in clinical practice. In this issue, Dr. Craig Moskow-itz illuminates the role of FDG-PET imaging in the management of patients with Hodgkin lymphoma. Dr. Jerald Radich has transformed the arcane subject of molecular monitoring in chronic myeloid leukemia into a practical and useful guide he terms “PCR for Poets,” harkening back to our college days when we were looking to find that gut course to round out our heavy premed course load. Finally, Dr. Markman provides a practical approach to the use of genomic or what he terms “precision” medicine in the management of ovarian cancer.

These are examples of the high quality reviews you can expect from The American Journal of Hematology/Oncology, which will be published quarterly. However, the journal will also provide up-to-date insights from recent meetings. In this issue, we have a guide from the 9th Annual International Symposium on Ovarian Cancer and Gynecologic Malignancies for clinicians facing the challenges of caring for patients with defined cancer syndrome, fo-cusing on implications beyond medical management to issues of insurance discrimination and balancing confidentiality versus appropriate disclosure to family members.

In future issues we will also include challenging cases from clinical practice that are dis-cussed by a panel of experts so that the practicing clinician can gain a greater understand-ing of the varying approaches taken by highly specialized experts in the field. This helps to illuminate differences in the understanding of current data and identified the gaps in our knowledge.

Importantly, we look forward to your contributions to this journal. These can be in the form of original research with a focus on the use of diagnostics and genomics in the selection of therapy, state of the art reviews that will help the general medical oncologist improve clinical care, and letters to the editor that involve informative cases from which we can all learn something new.

We are in the midst of an extremely exciting era in medical oncology. The therapies available to us range from highly targeted treatments aimed at specific gene-level defects, to therapies that harness the power of the immune system to recognize and eradicate tumors. However, we will only improve outcomes for patients if these novel therapies are well un-derstood and effectively utilized by practicing clinicians. This journal will provide a vehicle for the dissemination of that critical information, which can be utilized in a meaningful and practical way in our practices.

Andrew D. Zelenetz, MD, PhDEditor-in-Chief

1. Love N, Anderson KC, Flaherty K, et al. Medical oncologists’ clinical experience and comfort levels with 20 recently approved agents. J Clin Oncol. 2013;31(suppl; abstract e17570).

The rapid pace of discovery in the field of oncology presents practicing oncologists with the difficult challenge of implementing novel research findings into clinical practice. In order to accelerate the translation of academic advances to community-based practice, The American Journal of Hematology/Oncology provides a forum to facilitate an exchange between the oncologists who conduct state-of-the-art research and the oncologists who face the real-world challenges of applying these discoveries in the clinic.

Each issue of The American Journal of Hematology/Oncology will feature an academic perspective and a community-based perspective of current research and treatment trends in a specific disease state. Articles of particular interest include concise reviews, commentaries, and case studies of best practices.

ajho

T h e

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lymphomaThe Role of PET Imaging in the Management of Patients With Hodgkin Lymphoma Craig Moskowitz, MD

leukemiaA Primer on Molecular Testing in Chronic Myeloid Leukemia (PCR for Poets)Jerald P. Radich, MD

ovarian cancerGenomic (“Precision”) Medicine in the Management of Ovarian CancerMaurie Markman, MD per: 9th annual international SympoSium on ovarian cancer and GynecoloGic maliGnancieS®

What Would Clinicians Do If BRCA or Lynch Positive?Medical Management, Insurance Discrimination, and Confidentiality

A m e r i c a n

J o u r n a l

H e m a t o l o g y /

O n c o l o g y ®

a peer-reviewed resource

for oncology education

cmeMedical Crossfire: Recent Advances in the Treatment of Metastatic Melanoma A CME-certified enduring material sponsored by Physicians’ Education Resource®, LLC

www.AJHO.comwww.AJHO.com

All manuscripts will undergo peer review, and authors of accepted articles will receive an honorarium and will be required to sign an authorship form disclosing any possible conflicts of interest. To submit an article to The American Journal of Hematology/Oncology or if you wish to speak to an editor, please e-mail Dru Dace at [email protected]

Call for Papers

AJHO_CallForPapers.indd 5 2/11/14 11:11 AM

On behalf of Physicians’ Education Resource®, LLC, (PER), I would like to welcome and thank you for reading the inaugural issue of The American Journal of Hematology/Oncology (AJHO). This journal will present a series of concise reviews and clinical controversies from multiple areas in oncology, contributed by leading physicians in their field. Our goal is to establish this publication as a trusted and practical resource for community-based oncologists.

Each issue will include original articles from many physicians and researchers in oncology, including many of our faculty from our live PER conferences and symposia. Since PER is accredited by the ACCME to provide continuing medical education (CME) for phy-sicians, each issue will contain an accredited CME article.

AJHO is the official journal of PER, and this publication continues our mission and commitment to advancing cancer care through professional education. I hope you enjoy this inaugural issue, and please feel free to provide feedback and comments to me at [email protected].

Sincerely,

Dru S. Dace, PhDDirector of Scientific AffairsPER

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These activities are supported by educational grants from Celgene Corporation, Delcath Systems, Inc., Eisai Inc., Genentech, Lilly USA, LLC, Merck Sharp & Dohme Corporation, Novartis Pharmaceuticals Corporation, Onyx Pharmaceuticals, Provectus Pharmaceuticals, Inc and Seattle Genetics, Inc

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Join Drs. James Berenson, Jennifer Brown, Harry Erba, and Andre Goy as they discuss emerging clinical data regarding new agents and evolving strategies for the treatment of hematologic malignancies from the 17th Annual International Congress on Hematologic Malignancies®. Topics include maintenance therapy and novel agents for multiple myeloma, immunomodulatory agents and strategies for treating elderly patients with CLL, frontline therapy and monitoring response for CML, and current and emerging treatment options for poor-risk DLBCL and indolent lymphomas.

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The American Journal of Hematology online activity coming March 1, 2014!Earn up to 1.0 AMA PRA Category 1 Credits™

This activity will serve as an update on advances in the field and will focus on the clinical implications of metastatic melanoma and basal cell carcinoma, including novel treatment regimens for the management of advanced melanoma, including immunomodulatory antibodies, BRAF inhibitors, multiple tyrosine kinase inhibitors, antiangiogenic agents, and other novel agents in earlier phases of development.Physicians’ Education Resource®, LLC is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

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· LYMPHOMA ·

The Role of PET Imaging in the Management of Patients With Hodgkin Lymphoma

Craig Moskowitz, MD

FDG-PET-CT has revolutionized the way oncologists manage Hodgkin lymphoma (HL). FDG-PET-CT imaging is more sen-sitive and specific than either modality alone, and in 2014 all HL patients should have a combined FDG-PET-CT scan. It is also recommended that the CT component include IV and oral contrast, which can be helpful for patients requiring subsequent consolidative therapy. (Note: For the remainder of this review, PET scan will imply FDG-PET-CT.) Some of the basic “rules” in PET scanning for HL is that it is always abnormal at diagnosis, and normalization after therapy is highly predictive of a good outcome.

Some of the major controversies include: (1) what are the op-timal criteria to determine active disease via PET scan interpreta-tion because it is not uniform and the need for standardization is critical; (2) whether interim evaluation should be considered standard or investigational; (3) whether a negative PET scan is required for transplant-eligibility; and (4) whether PET scanning is indicated for surveillance once a patients achieves first or sec-ond remission.

STAGINGPET scanning identifies more extranodal sites of disease, includ-ing liver, spleen, and bone involvement. The advantage of PET over CT in the evaluation of the spleen and liver is the ability to identify both diffuse and focal involvement when the organ size is not enlarged. Similarly, PET detects FDG-avid lymph nodes that are normal-sized on CT, and PET scans are also superior for the detection of cutaneous and subcutaneous disease.1-3 Thus far, PET scanning is unreliable for the diagnosis of diffuse bone mar-row disease but clearly finds focal involvement.4 Initial staging of HL with PET scans commonly upstages patients from early to advanced stage, and can result in a change from combined modality therapy (CMT) to full-course chemotherapy.

The 2013 National Comprehensive Cancer Network

(NCCN) guidelines require that all patients with HL get a dedicated (contrast-enhanced) CT and PET scan as part of initial staging evaluation, both on and off clinical trials.5

END-OF-THERAPY RESPONSE ASSESSMENT HL is associated with a posttreatment residual mass in the major-ity of patients, including those patients who are deemed to have achieved a complete response (CR) based upon other imaging modalities. PET scanning is critical in distinguishing between persistent residual fibrosis and active HL. A residual mass that is negative by PET is considered a complete response based upon 2007 consensus criteria.6,7 The largest series confirming this observation is the German Hodgkin Study Group HD15 trial, where 5-year freedom from treatment failure was 92% in 540 patients with a negative PET scan after a full course of chemo-therapy. The larger issue is how the clinician manages patients with a positive PET scan at the end of initial treatment.8,9

Traditionally, a positive scan was defined as uptake greater than mediastinal blood pool, the IHP (international harmonization project) criteria. The nuclear medicine community has shifted to the five-point (5-PS) scale or Deauville criteria for interpretation of interim and end-of-treatment PET scans. In the 5-PS, a score of 1 indicates no residual uptake above the background level, 2 indicates residual uptake less than or equal to the mediastinum, 3 indicates residual uptake greater than the mediastinum but not greater than the liver, 4 indicates residual uptake moderately in-creased compared with the maximum standardized uptake value (SUV) in a large area of normal liver, and 5 indicates residual uptake markedly increased compared with the liver, or 2-3 times greater than the maximum SUV in the liver or new sites of dis-ease. These criteria are used for grading nodal and extranodal disease, with scores of 1–3 regarded as negative and scores of 4 and 5 regarded as positive.10-13

The current NCCN guidelines define potential clinical re-sponses for positive end-of-treatment PET scans, Deauville scores 4 or 5. A Deauville score of 4 requires significant clini-cal judgment, and three possible scenarios exist: the patient requires a biopsy to determine whether there is active HL; radiotherapy (RT) can be considered if there is a single FDG-avid nodal lesion; or the test can be repeated in 3 months to see if the activity resolves. In the final scenario, if there is persistent FDG avidity after 3 months, then a biopsy or RT is recommended. If the end-of-treatment PET scan is consistent with a Deauville score of 5, a biopsy is strongly encouraged.

AbstractFDG-PET-CT has revolutionized the way oncologists man-age Hodgkin lymphoma (HL), and is currently integrated into all aspects of HL management. FDG-PET-CT imaging is more sensitive and specific than either modality alone, and in 2014 all HL patients should have a combined FDG-PET-CT scan. This review will discuss the current role of PET imaging in HL, including some of the basic “rules” for PET scanning and some of the controversies.

VOL. 10, NO. 1 THE AMERICAN JOURNAL OF HEMATOLOGY/ONCOLOGY 7

THE ROLE OF PET IMAGING IN THE MANAGEMENT OF PATIENTS WITH HODGKIN LYMPHOMA

INTERIM EVALUATION The concept of interim (early) PET scans to predict the eventual result of treatment is relatively new. In most but not all studies, patients with a positive scan after 2-3 cycles of treatment have a poorer outcome than those with a negative scan. Proponents of interim PET (iPET) scans endorse the concept of response-adapted treatment escalation. With this approach, patients with a positive iPET might have their treatment intensified with the goal of improving their long-term survival. The value of chang-ing treatment on the basis of a positive iPET hinges upon the new treatment still curing those patients destined to do well with the initial regimen, and curing some of the patients likely to do poorly. Of course, the results could vary from one disease to another and with different initial treatment regimens. These are questions for randomized trials, not standard therapy, and several such trials have been reported, with some still in progress.

HL (UNTREATED DISEASE)Minimal residual uptake (MRU), defined as low-grade uptake of FDG (just above background) in a focus within an area of previ-ously noted disease on a iPET scan, is likely a false-positive result in patients with HL, especially in early-stage HL (ESHL), where 90% of patients are cured with standard therapy. MRU may cause more confusion in advanced-stage HL (ASHL), where the complete remission rate decreases significantly with an increase in the number of pretreatment clinical risk factors.14,15

EARLY-STAGE HL Approximately 40% of patients diagnosed with HL present with non-bulky stage I or II disease, and the cure rate is 90%-95% with combined modality therapy.16 The emphasis on clinical tri-als in this patient population is de-escalation of therapy while maintaining therapeutic efficacy. The focal point of most re-search studies is the elimination of consolidative RT. Although chemotherapy alone is a common management strategy in the United States, this option remains suspect by a variety of groups.

In the pre-PET era, the National Cancer Institute of Canada (NCIC) Clinical Trials Group/Eastern Cooperative Oncology Group (ECOG) HD6 trial demonstrated that approximately 50% of patients achieving a CR by CT scanning criteria after two cycles of ABVD chemotherapy (doxorubicin, bleomycin, vinblas-tine, dacarbazine) can be consolidated with only two more cycles of therapy, and have a >90% chance of long-term progression-free survival (PFS), compared with only 80% for patients who achieve only a partial response (PR) by CT scanning after two cycles of ABVD. In this group of patients, those with <CR on CT, the intriguing question would be whether or not iPET could identify those patients most likely to fail primary therapy.17

Zinzani and colleagues18 interrogated their HL PET database and recently reported the results of 147 early-stage HL patients: 131 (89.1%) were PET-negative at the end of treatment, with 126 patients progression-free after a median follow-up of 45 months. Among the 147 patients, iPET two-cycle scans were normal in

128, and 19 were abnormal; the 9-year PFS of these two cohorts were 94.7% and 31.3%, respectively. Similar retrospective data are available in the literature and have led to a number of large prospective studies; the most important of these being the H10 and RAPID trials.19,20

The first interim analysis of EORTC/GELA H10 study in early-stage HL favorable and unfavorable risk categories reported on 894 of 1097 recruited patients at the international HL confer-ence in Cologne, Germany, in 2010.19 Using IHP criteria, iPET was positive in 14% and 24% in the favorable and unfavorable categories, respectively. Risk-adapted therapy via the iPET two-cycle results was undertaken and clearly feasible in a cooperative group setting. Early results are difficult to interpret, and although there are more events in the non-RT arm, all groups of patients have done extremely well. However, the investigators concluded that chemotherapy alone would be unlikely to be noninferior to CMT in iPET-negative patients, and the chemotherapy-alone arm was discontinued.

The RAPID trial20 is powered based upon the premise that a PFS that is 7% inferior is acceptable in the observation arm (iPET-negative, no consolidative RT). The preliminary analysis of the RAPID trial was reported at American Society of Hematol-ogy (ASH) meeting in 2012. The RAPID study enrolled an inter-mediate group of patients with early-stage HL, stage I/II without B symptoms, or tumor bulk as defined as a 10-cm nodal mass. This is the first prospective multicenter study using the 5-PS in early-stage HL. Five hundred and seventy-one patients were en-rolled, and 72.7% had a negative iPET after two cycles of ABVD based on strict criteria (5-PS, 1 or 2). These patients were ran-domly assigned to no further therapy or consolidative RT. The intent-to-treat analysis on these 420 patients found a 3-year PFS of 94.5% for CMT versus 90.8% for chemotherapy alone, with a hazard ratio [HR] of 1.51 supporting the use of IFRT (P = .23).

iPET in early-stage HL successfully identifies candidate pa-tients for de-escalation of therapy to short-course chemotherapy alone. Although the results of these trials will generate great interest, it is very likely and expected that PFS will be slightly superior in the group of patients receiving consolidative RT com-pared with those assigned to ABVD alone. Clinicians must not merely conclude that CMT is the winner; clearly, ABVD alone can be administered to the majority of patients with curative in-tent. However, it must be understood that the type of salvage therapy in patients who receive only short-course chemotherapy is largely unknown.

ADVANCED-STAGE HL In advanced-stage HL, maximizing treatment efficacy takes prece-dence over minimizing therapy-related side effects since PFS with ABVD ranges from 60%-80% in a variety of published reports. The landmark studies by Gallamini et al21 and Hutchings et al22 have clearly shown that iPET imaging after two cycles of chemo-therapy is the most important clinical predictor of outcome. The research questions for the next few years include whether dose


· LYMPHOMA ·

escalation in patients with a positive iPET will improve outcome, and whether escalated BEACOPP chemotherapy (bleomycin, et-oposide, doxorubicin, cyclophosphamide, vincristine, procarba-zine, prednisone) can be de-escalated for the majority of patients with a negative iPET.

A number of studies are ongoing to see whether PFS is not reduced with de-escalation of standard therapy in those patients with an iPET-negative result. These studies include the HD18 trial by the GHSG, comparing six cycles versus four cycles of escalated BEACOPP, the RATHL study comparing ABVD with AVD (doxorubicin, vinblastine, dacarbazine), the GELA ASHL study comparing BEACOPP with standard ABVD, the HD 0607 and HD0801 trials by the Italian lymphoma study groups investi-gating RT versus no RT after six cycles of ABVD in patients with interim and final PET-negative results.23-29

The opposite research question is dose escalation in patients who are iPET-positive. A large phase II US intergroup study has completed accrual, and results were presented at the Interna-tional Lymphoma Conference in Lugano, Switzerland, in 2013. Patients with positive iPET two scans as defined by the 5-PS of 4 or 5 after ABVD have therapy changed to escalated BEACOPP. Although follow-up is still short, there is a clear improvement in PFS for these patients compared with historical controls.30 The RATHL study has a similar study design for patients with iPET-positive disease.31,32

A more rational study design is to incorporate pretreatment risk factors, either the international prognostic index (IPI) score, or possibly in the future an unfavorable gene profile based upon nanostring evaluation. Favorable patients can start with ABVD, and if iPET is negative, then a reduction of cycles of therapy can be done; if positive, then augmenting therapy makes sense either

to escalated BEACOPP or autologous stem cell transplantation (ASCT). Unfavorable patients can start with escalated BEACOPP, and if iPET is negative then risk-adapted therapy to ABVD may be warranted but if still positive, investigational therapy that includes ASCT can be explored; this approach has been championed by Dann and colleagues33 from an Israeli lymphoma consortium (Figure 1). Lastly, it is unclear whether brentuximab vedo-tin in combination with AVD, currently being evaluated as part of the ECHELON study, will change the above paradigm (Figure 2).

INTERIM PET DURING RESCUE TREATMENT FOR RELAPSED/REFRACTORY HLThe current, standard second-line treatment for relapsed or pri-mary refractory HL is a multistep process that includes salvage chemotherapy, typically platinum-based followed by high-dose chemoradiotherapy (HDT/ASCT), for patients with chemo-sensitive disease. Approximately 45%-55% of the patients who received transplants are cured, but this is definitely dependent upon pretreatment clinical risk factors including relapsed versus primary refractory disease, extranodal disease involvement, and active B symptoms.34,35

Moskowitz et al36 and others have reported that chemosensi-tive disease should be defined by pre-transplant PET status; those patients with a negative scan have a 5-year PFS of approxi-mately 75% compared with 30% for those patients with improve-ment of CT but with persistent PET positivity. Since second-line treatment employs a comprehensive approach, the post-salvage therapy PET in reality is an iPET. Reporting should be similar to that of untreated HL: scores 1-3 are negative via the 5-pt scale and 4 and 5 are positive. The question that investigators face is whether a patient who is deemed chemosensitive by CT but with an abnormal iPET should be excluded from curative therapy.

FIGURE 2.34 Advanced-Staged Hodgkin Lymphoma

ABVD, doxorubicin, bleomycin, vinblastine, dacarbazine; AVD, doxorubicin, vinblastine, dacarbazine; BV, brentuximab vedotin.

SCREENING

RANDOMIZATION

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ASSESSMENT

END

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Deauville Score:1-4

Continue protocol therapy:

A+AVDx4 cycles

ABVDx4 cycles

or

Deauville Score:5

Continueprotocoltherapy:

A+AVDx4 cycles

orABVD

x4 cycles

Initiatealternativetherapy:

Physician’sChoice

FIGURE 1.33 Israel H2 trial: Advanced Stages of HL

HL, Hodgkin lymphoma; ABVD, doxorubicin, bleomycin, vinblastine, dacar-bazine; BEACOPP, bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone; IPS, International Prognostic Score.

IPS 0-2 IPS 3-7

2 X ABVD

4 X ABVD

2 x BEA exc. (+ RT)

PETPositive PositiveNegativeNegative

NegativeNegative

2 X BEACOPP esc.

2 X BEACOPP esc.

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SalvageSalvage

2 X BEACOPP esc.

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PET

PET


THE ROLE OF PET IMAGING IN THE MANAGEMENT OF PATIENTS WITH HODGKIN LYMPHOMA

Thirty percent of patients are still cured as long as there is tumor shrinkage after one course of salvage therapy.37

Moskowitz et al37 recently reported the results of a large phase II, second-line treatment program where iPET was prospectively evaluated. Patients who achieved normalization of their post-ICE (ifosfamide, carboplatin, etoposide) PET scan underwent HDT/ASCT and had the expected 77% long-term PFS. Patients with cytoreduction to ICE but a persistently abnormal PET received a second, non–cross-resistant salvage treatment with GVD (gem-citabine, vinorelbine, liposomal doxorubicin). Interestingly, 50% of patients had a PET-negative response to four biweekly treatments, and these patients also had a 77% long-term PFS. Patients with a persistently positive PET scan after two-salvage chemotherapy program had 22% 5-year PFS (Figure 3).

In the opinion of Moskowitz et al, the goal of salvage chemo-therapy in the context of a comprehensive second-line approach should be a negative PET scan; if it takes up to two programs to achieve this, ASCT is still a reasonable treatment option. Investiga-tional therapy should be offered to patients, including a nonablative allogeneic transplant for patients with a persistently positive PET scan after two-salvage chemotherapy program. It must be stressed that patients with nodal-only HL at this point can still achieve a negative PET with involved- or extended-field RT—a reasonable approach in this patient population (MSKCC strategy).

MONITORINGAs stated previously, HDT/ASCT cures at least 50% of patients whose primary therapy fails; therefore, many clinicians assume that early detection of relapse will increase the cure rate of sec-ond-line treatment. However, one must remember that the ma-jority of relapses in HL are detected by the patient and not by the imaging. Ninety percent of patients with early-stage HL and 75% of those with advanced-stage HL were cured with primary treat-ment in the pre-PET imaging era. Therefore, most surveillance scans will be normal, and if positive, a false-positive PET scan is a real issue that leads to unnecessary biopsies, and in not-so-rare instances, treatment without documentation of active disease. NCCN guidelines recommend CT imaging at defined intervals for the first 3 years. At MSKCC, if there is evidence of progres-sion of disease on CT or if the patient has a new node on exam, then a PET scan is warranted.

CONCLUSIONThe current paradigm in HL is to not overtreat the patients very likely to do well with standard management and to not under-treat patients with high-risk disease. PET imaging is currently integrated into all aspects of HL management. The exciting re-sponse-adapted therapy phase III clinical trials will be reported within the next few years, and it is likely that the role of PET imaging will be expanded.

One important lesson that has been learned from studies in patients with diffuse large B cell lymphoma is the major difficul-

ty evaluating the iPET and deciding whether low-grade uptake (5-PS, 4 and sometimes 3) represents active disease. The conserva-tive approach, which the MSKCC group strongly recommends, is if there is a completely negative scan or a grossly positive scan, a decision can be made on the scan alone to risk-adapt therapy; however, if there is any doubt, biopsy confirmation of active HL is required.

Craig Moskowitz, MD, is clinical director, Division of Hematologic Oncology; attending physician, Lymphoma and Adult BMT Services; member, Memorial Sloan-Kettering Cancer Center; and professor of Medicine, Weill Medical College of Cornell University, New York City.

Disclosure: Dr. Moskowitz reports no relevant conflicts of inter-est to disclose.

REFERENCES1. Jerusalem G, Beguin Y, Fassotte MF, et al. Whole-body positron emission tomography using 18F-fluorodeoxyglucose compared to standard procedures for staging patients with Hodgkin’s disease. Haematologica. 2001;86(3):266-273. 2. Munker R, Glass J, Griffeth LK, et al. Contribution of PET imag-ing to the initial staging and prognosis of patients with Hodgkin’s disease. Ann Oncol. 2004;15(11):1699-1704. 3. Weihrauch MR, Re D, Bischoff S, et al. Whole-body positron emission tomography using 18F-fluorodeoxyglucose for initial stag-ing of patients with Hodgkin’s disease. Ann Hematol. 2002;81(1):20-25. 4. Pakos EE, Fotopoulos AD, Ioannidis JP. 18F-FDG PET for evalu-ation of bone marrow infiltration in staging of lymphoma: a meta-analysis. J Nucl Med. 2005;46(6):958-963.5. Hoppe RT, Advani RH, Ai WZ, et al. Hodgkin lymphoma, ver-sion 2.2012 featured updates to the NCCN guidelines. J Natl Compr Canc Netw. 2012;10(5):589-597.6. Cheson BD, Pfistner B, Juweid ME, et al. Revised response crite-ria for malignant lymphoma. J Clin Oncol. 2007;25(5):579-586. 7. Juweid ME, Stroobants S, Hoekstra OS, et al. Use of positron emission tomography for response assessment of lymphoma: consen-

FIGURE 3.37 Relasped/Refactory Disease: 2004 to Present

HDT/ASCT, high-dose therapy/autologous stem cell transplantation; MSKCC, Memorial Sloan-Kettering Cancer Center; ICE, ifosfamide, carboplatin, etoposide; GVD, gemcitabine, vinorelbine, liposomal doxorubicin.

Relapsed/Refractory

Second-line Chemo

HDT/ASCT

Risk Model

PET normalization


· LYMPHOMA ·

sus of the Imaging Subcommittee of International Harmonization Project in Lymphoma. J Clin Oncol. 2007;25(5):571-578. 8. Engert A, Haverkamp H, Kobe C, et al. Reduced-intensity che-motherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin’s lymphoma (HD15 trial): a randomised, open-label, phase 3 non-inferiority trial. Lancet. 2012;379(9828):1791-1799. 9. Terasawa T, Nihashi T, Hotta T, Nagai H. 18F-FDG PET for post-therapy assessment of Hodgkin’s disease and aggressive Non-Hodg-kin’s lymphoma: a systematic review. J Nucl Med. 2008;49(1):13-21. 10. Barrington SF, Qian W, Somer EJ, et al. Concordance between four European centres of PET reporting criteria designed for use in multicentre trials in Hodgkin lymphoma. Eur J Nucl Med Mol Imag-ing. 2010;37(10):1824-1833. 11. Meignan M, Gallamini A, Haioun C, Polliack A. Report on the Second International Workshop on interim positron emission to-mography in lymphoma held in Menton, France, April 8-9, 2010. Leuk Lymphoma. 2010;51(12):2171-2180. 12. Meignan M, Gallamini A, Itti E, et al. Report on the Third In-ternational Workshop on Interim Positron Emission Tomography in Lymphoma held in Menton, France, September 26-27, 2011 and Menton 2011 consensus. Leuk Lymphoma. 2012;53(10):1876-1881.13. Meignan M, Gallamini A, Haioun C. Report on the First Inter-national Workshop on Interim-PET-Scan in Lymphoma. Leuk Lym-phoma. 2009;50(8):1257-1260. 14. Connors JM Bernard F, Gascoyne RD, et al. FDG PET/CT scan guided treatment of limited stage Hodgkin lymphoma spares>80% of patients from radiotherapy while retaining excellent disease con-trol. Haematologica. 2010;95(s4):s15.15. Yeddes I MM, Bardet S, et al. Positive interim PET after 2 ABVD is more requested in patients with unfavourable stage I/II Hodgkin lymphoma and bulky mediastinum than in non-bulky. The EORTC-GELA-IIL H10 trial experience. Haematologica. 2010;95(s4):s49.16. Engert A, Plutschow A, Eich HT, et al. Reduced treatment inten-sity in patients with early-stage Hodgkin’s lymphoma. N Engl J Med. 2010;363(7):640-652.17. Meyer RM, Gospodarowicz MK, Connors JM, et al. ABVD alone versus radiation-based therapy in limited-stage Hodgkin’s lympho-ma. N Engl J Med. 2012;366(5):399-408.18. Zinzani PL, Rigacci L, Stefoni V, et al. Early interim 18F-FDG PET in Hodgkin’s lymphoma: evaluation on 304 patients. Eur J Nucl Med Mol Imaging. 2012;39(1):4-12. 19. Filippi AR Ciammela P, Piva C, et al. Image-guided intensity modulated radiotherapy vs standard 3D-conformal radiotherapy in early stage Hodgkin’s lymphoma. Haematologica. 2013;98(s2):14.20. Radford J Barrington S, Counsell N, et al. Prognostic perfor-mance of pre-treatment EORTC, AGHSG and IPI risk factors and post chemotherapy PET response in the UK NCRI RAPID trial in early stage Hodgkin lymphoma. Haematologica. 2013;98(s2):13.21. Gallamini A, Hutchings M, Rigacci L, et al. Early interim 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography is prognos-tically superior to international prognostic score in advanced-stage Hodgkin’s lymphoma: a report from a joint Italian-Danish study. J Clin Oncol. 2007;25(24):3746-3752. 22. Hutchings M, Loft A, Hansen M, et al. FDG-PET after two cycles of chemotherapy predicts treatment failure and progression-free survival in Hodgkin lymphoma. Blood. 2006;107(1):52-59. 23. Clinicaltrials.gov. Positron emission tomography (PET)-adapted

chemotherapy in advanced Hodgkin lymphoma (HL) (HD0607). http://clinicaltrials.gov/show/NCT00795613.24. Clinicaltrials.gov. Fludeoxyglucose F18-PET/CT imaging and combination chemotherapy wih or without additional chemothera-py and G-CSF in treating patients with stage III or stage IV Hodgkin lymphoma. http://clinicaltrials.gov/show/NCT00822120.25. Clinicaltrials.gov. Study of a treatment driven by early PET re-sponse to a treatment not monitored by early PETin patients with AA stage 3–4 or 2B HL (AHL2011). http://clinicaltrials.gov/ct2/show/NCT01358747. 26. Clinicaltrials.gov. Fludeoxyglucose F 18-PET/CT imaging in as-sessing response to chemotherapy in patients with newly diagnosed stage II, stage III, or stage IV Hodgkin lymphoma. http://www.clini-caltrials.gov/ct2/show/NCT00678327.27. Clinicaltrials.gov. HD18 for advanced stages in Hodgkin’s lym-phoma http://clinicaltrials.gov/ct2/show/NCT00515554. 28. Clinicaltrials.gov. High-dose chemotherapy and stem cell trans-plantation in patients PET-2 positive, after 2 courses of ABVD and comparison of RT versus no RT in PET-2 negative patients (HD0801). http://www.clinicaltrials.gov/ct2/show/NCT00784537.29. Clinicaltrials.gov. Tailored therapy for Hodgkin lymphoma using early interim therapy PET for therapy decision. http://clinicaltrials.gov/ct2/show/NCT00392314. 30. Press O, Li H, Schroder H, et al. Response adapted therapy of stage III-IV Hodgkin lymphoma based on interim PDG-PET imaging: early results of US Intergroup S0816. Haematologica. 2013;98(s2):36.31. Gallamini A, Rossi A, Patti C, et al. Early treatment intensifica-tion in advanced stage high-risk Hodgkin lymphoma patients with a positive FDG-PET scan after two ABVD courses--second interim analysis of the GITIL/FIL HD0607 clinical trial. Haematologica. 2013;98(s2):3.32. Johnson P, Federico M, Fossa, et al. Response rates and toxic-ity of response-adapted therapy in advanced Hodgkin lymphoma: initial results from the international RATHL study. Haematologica. 2013;98(s2):2.33. Dann EJ, Bairey O, Bar-Shalom R. Tailored therapy in Hodgkin lymphoma, based on pre-defined risk factors and early interim PET/CT. Israeli H2 protocol: preliminary report on 317 patients. Haema-tologica. 2013;98(s2):37.34. Moskowitz CH, Nimer SD, Zelenetz AD, et al. A 2-step com-prehensive high-dose chemoradiotherapy second-line program for relapsed and refractory Hodgkin disease: analysis by intent to treat and development of a prognostic model. Blood. 2001;97(3):616-623.35. Moskowitz CH, Yahalom J, Zelenetz AD, et al. High-dose chemo-radiotherapy for relapsed or refractory Hodgkin lymphoma and the significance of pre-transplant functional imaging. Br J Haematol. 2010;148(6):890-897. 36. Moskowitz AJ, Yahalom J, Kewalramani T, et al. Pretransplanta-tion functional imaging predicts outcome following autologous stem cell transplantation for relapsed and refractory Hodgkin lymphoma. Blood. 2010;116(23):4934-4937. 37. Moskowitz CH, Matasar MJ, Zelenetz AD, et al. Normalization of pre-ASCT, FDG-PET imaging with second-line, non-cross-resistant, chemotherapy programs improves event-free survival in patients with Hodgkin lymphoma. Blood. 2012;119(7):1665-1670.


· LEUKEMIA ·

A Primer on Molecular Testing in Chronic Myeloid Leukemia (PCR for Poets)

Jerald P. Radich, MD

BackgroundThe natural history of chronic myeloid leukemia (CML) has been forever changed by the advent of tyrosine kinase inhibitor (TKI) therapy. To summarize the salient points of CML therapy and monitoring, circa 2013:

1. The tyrosine kinase inhibitors (TKIs) are highly effective in chronic-phase CML. The majority of patients (~80%) who are treated in chronic phase achieve a complete cytogenetic response (CCyR), and these patients have an excellent survival (~90%).1

2. Nonetheless, some patients become resistant and progress. Approximately 60% of patients treated with imatinib mesylate (IM) in the IRIS trial remained in CCyR on IM after 6 years of therapy.2 Of those that did not remain on therapy, roughly one-third had primary resistance to IM therapy, one-third had toxicity, and one-third initially responded and either relapsed or progressed to advanced-phase disease. In roughly half of the resistance cases, a point mutation in the Abl tyrosine kinase domain has occurred, which affects TKI binding and Abl in-hibition. 3. Resistance is not futile. For those patients who fail front-line imatinib, salvage therapy with the second-generation TKIs (dasatinib, nilotinib) can yield a CCyR in 40%-50% of cases.3,4 For cases in which initial therapy with a second-generation TKI fails, salvage with another second-generation TKI, or a “third-generation” bosutinib or ponatinib, can yield major response and CCyR, but generally at a lower frequency. How-ever, cases that initially respond to second-line therapy often relapse, sometimes with a new mutation. Patients in this cat-egory can be treated with other TKIs (bosutinib, ponatinib),

but if one is looking for cure, allogeneic transplant remains the best bet for highly resistant disease. 4. Monitoring is easy and meaningful. The treatment end-point of a CCyR is a treatment endpoint clearly highly cor-related with long-term outcome. The use of PCR to deter-mine a major molecular remission (MMR) places the patient in a “safe harbor” where resistance and progression are very remote. The selection of patients with complete molecular remission (CMR) may pick candidates who can successfully discontinue therapy.

All therapies for CML work better in chronic- rather than ad-

vanced-phase disease; thus, early identification of relapse or pro-gression may increase the likelihood that alternative treatments will be effective. Hence, we have the rationale for frequent and sensitive monitoring.

In this short review we attempt to succinctly outline the types of tests available to detect CML, the rationale for using them, national guidelines for monitoring, and other issues that can confound the practicing physician.

Types of Tests for MonitoringThe basis for monitoring in CML is the unique t(9;22) reciprocal translocation forming the Philadelphia (Ph) chromosome. The Ph chromosome is found in all CML cells, but not in normal he-matopoietic cells. As a result, the Ph chromosome is a unique ge-netic fingerprint for the detection of CML. Conventional meta-phase cytogenetics looks for the Ph chromosome and can detect other chromosomal changes associated with advanced-phase dis-ease (Table 1). Cytogenetics can generally only be performed on bone marrow, and with regard to monitoring, is only useful if at least 20 metaphase preparations are evaluated.

Fluorescence in situ hybridization (FISH) is more sensitive than cytogenetics in detecting the BCR-ABL fusion and can be performed on bone marrow or peripheral blood. However, FISH cannot detect additional chromosomal changes unless those changes are anticipated and screened with specific probes (which is highly unlikely in most labs). Reverse transcription (RT)-PCR of the chimeric BCR-ABL mRNA is the most sensitive assay for detecting CML, and can detect one CML cell in approximately 100,000-1,000,000 cells. With PCR, most of the outcome data are based on peripheral blood, making it both the most conve-nient and sensitive test available for monitoring.

AbstractTyrosine kinase inhibitor (TKI) therapy can yield sustained cytogenetic remissions in most patients with chronic-phase chronic myeloid leukemia (CML). Peripheral blood real-time quantitative polymerase chain reaction (qPCR) monitoring of the chimeric BCR-ABL mRNA is a very sensitive method to measure disease burden in patients with cytogenetic remis-sion. The assay allows: (1) early (3-6 months after initiation of therapy) identification of cases at a high risk of progression; (2) detection of cases lacking response to TKI therapy; and (3) detection of cases with undetectable disease that could be eligible for TKI discontinuation trials. Molecular monitoring is a minimally invasive method to optimize treatment and outcome in CML.


THE ROLE OF PET IMAGING IN THE MANAGEMENT OF PATIENTS WITH HODGKIN LYPHOMA

Rationale for MonitoringA CCyR is the “gold standard” of response. In the IRIS trial, patients who did not achieve a CCyR had a risk of progression of approximately 25%, compared with <10% in patients who achieved a CCyR. Beyond CCyR, the molecular response as de-termined by PCR further mapped with outcome. At 54 months of follow-up, progression-free survival (PFS) for patients who nev-er achieved a CCyR, had a <3-log reduction in BCR-ABL at 12 months, or had a >3-log reduction at 12 months, was 72%, 89%, and 97%, respectively.5 For patients who achieved CCyR and a MMR at 18 months, no patient progressed to accelerated or blast phase by 60 months of follow-up.6 The rate of progression for those who had a CCyR and a <3 log reduction in BCR-ABL was only 3%. Subsequent studies have confirmed the IRIS PCR data and demonstrate that patients with a deeper molecular response at the time of initial CCyR, or a >3-log reduction of BCR-ABL during CCyR, have very low odds of progression and a superior

PFS compared with patients with an inferior response.7-11

Earlier responses after 3 to 6 months of TKI therapy may also be a predictor of long-term outcome. Several studies have shown that both overall survival (OS) and PFS are improved in patients who achieve a cytogenetic response at 3 or 6 months.12,13 In addi-tion, early molecular responses have also been shown to be asso-ciated with better outcome, as those patients who fail to achieve a 1-2 log reduction after 3 months of therapy are less likely to ever achieve a MMR.7-9

In a large study of chronic-phase cases, it was shown that the achievement of a MMR at 3, 6, and 12 months was highly cor-related with the duration of a CCyR. For example, for those patients who achieved a CCyR after 3 months of therapy, the subset that also achieved a MMR at that time had a 0% risk of relapse in the next 2 years, as compared with a 20% risk for those without a MMR. This trend held true for those in CCyR at 6 and 12 months, as well.8 The significance of a poor response at 3 months appears strongest for those patients who fail to achieve a reduction of BCR-ABL to <10% International Scale (IS); this as-sociation of poor initial response and CCyR, OS, and event-free survival (EFS) is evident in patients treated with both low- and high-dose imatinib, dasatinib, or nilotinib.14-16

For example, a large study of 483 newly diagnosed chronic-phase cases treated with imatinib showed that the EFS for cases with a BCR-ABL <10% at 3 months was 61%, compared with >95% in cases with a superior molecular response.17 Another study of dasatinib-treated patients demonstrated that BCR-ABL (IS) ≤10% at 3 months had had a 3-year PFS of 93% compared with 68% for cases with >10%.13 The same trend held true for patients treated with imatinib. In addition, transformation oc-curred in 3% of patients with BCR-ABL ≤10% at 3 months com-pared with 13.5% for those >10%.Mutation TestingResistance in CML is subdivided into primary (not meeting treat-ment milestones) and secondary (disease relapse after meeting treatment milestones). In general, resistance correlates with the disease phase, with the least amount in newly treated chronic phase with low Sokal score, and the highest in blast crisis.18-20 In

TABLE 2. Response Criteria in CML

Note: For cytogenetic response, at least 20 metaphases must be studied. Major cytogenetic response includes partial and complete responses. Complete molecular response requires a sample for which at least a 4.5-log depletion can be assessed.

CBC, complete blood count; Ph, Philadelphia chromosome; qPCR, real-time quantitative reverse transcription polymerase chain reaction.

Level of Response Definition

Complete hematologic response

Normal CBC and differential

Minor cytogenetic response 35%–90% Ph metaphases

Partial cytogenetic response 1%–34% Ph metaphases

Complete cytogenetic response

0% Ph-positive metaphases

Major molecular response ≥3-log reduction of BCR-ABL mRNA

Complete molecular remission Negativity by qPCR

TABLE 1. Methods to Detect Minimal Residual DIsease in CML

FISH, fluorescence in situ hybridization; qRT-PCR, real-time quantitative reverse transcription polymerase chain reaction; RT-PCR, real-time polymerase chain reaction.

Method Target Sensitivity Advantages Disadvantages

Metaphasechromosomecytogenetics

t(9;22) 1%-5% The gold standard, and detection of other chromosomal changes

Needs dividing cells, so generally only successful from bone marrow sample

FISH BCR-ABL DNA 0.1%-5% Can use peripheral blood or bone marrow

Relatively insensitive compared with RT-PCR

qRT-PCR BCR-ABL mRNA 0.001%-0.01% Very sensitive, and uses periph-eral blood

Not well standardized across labs


· LEUKEMIA ·

roughly 50% of secondary resistance, base pair mutations in the Abl kinase domain blunt the ability of the TKI to inhibit the aberrant BCR-ABL kinase activity. The acquisition of these mu-tations and the loss of response are associated with a heightened risk of progression to advanced-phase disease.18-20

The screening of mutations is limited by the sensitivity of the available assays. The most common method of direct nucleotide sequencing can detect an Abl tyrosine kinase domain mutation if it comprises 10% to 20% of the total BCR-ABL sampled popula-tion. The relatively poor sensitivity of these assays makes it dif-ficult to identify point mutations early in the course of therapy. For newly diagnosed chronic-phase disease, Abl mutations are quite rare, so testing is not needed. However, the monitoring of BCR-ABL during therapy can detect populations at a higher risk for relapse and mutation. Branford et al18 showed that 61% of patients with a > 2-fold increase in BCR-ABL had detectable mu-tations, compared with <1% of patients with stable or decreasing BCR-ABL. The caveat here is that few laboratories can equal this degree of precision, and the National Comprehensive Cancer Network (NCCN) guidelines suggest mutation testing for those cases where the BCR-ABL value increases >10-fold on two con-secutive tests. Thus, screening for mutations would be reason-able in any advanced-phase patient, chronic-phase patients not achieving cytogenetic milestones, and patients with rising BCR-ABL, especially those nearing or passing the MMR level.

It is unlikely that a continually rising BCR-ABL would sud-denly reverse course without some sort of remedy. In the case of a rising BCR-ABL, patient adherence should be investigated, as it is surprisingly poor.21 However, there is no evidence that early intervention of a rising BCR-ABL, before cytogenetic relapse, al-ters the long-term outcome of the patient. Thus, a steadily rising BCR-ABL with an accompanying mutation that predicts relative or absolute indifference to imatinib (eg, T315I or E255V) can reasonably trigger a change in treatment strategy, even before the patient crosses into cytogenetic relapse (Table 3).

Monitoring RecommendationsThe NCCN (www.nccn.org) and the European Leukemia Net-work (ELN; www.leukemia-net.org) have established online

treatment recommendations, which include monitoring guide-lines and robust treatment outcome endpoints (Table 4). For all practical purposes these guidelines are very similar. The NCCN guidelines recommend molecular monitoring with qPCR us-ing the IS with a sensitivity of ≥4.5 log reduction from the standardized baseline. Monitoring with qPCR every 3 months

TABLE 4. Monitoring Guidelines (based on NCCN and ELN guidelines)

CCyR, complete cytogenetic response; IS, international scale; MMR, major molecular response; PCyR, partial cytogenetic response; qRT-PCR, real-time quantitative reverse transcription polymerase chain reaction; TKI, tyrosine ki-nase inhibitor; NCCN, National Comprehensive Cancer Network; ELN, European Leukemia Network.

Test RecommendationBone marrowcytogenetics

At diagnosis to establish the disease phaseAt 3 months from initiation of therapy if

qPCR using IS is not available to assess response to TKI therapy

At 12 months from initiation of therapy, if CCyR or MMR is not achieved

At 18 months from initiation of therapy, if not in MMR or lack of CCyR at 12 months

If a 1-log increase in BCR ABL transcript levels without MMR

qRT-PCR of BCR-ABL

At diagnosisEvery 3 months when a patient is respond-

ing to treatmentAfter CCyR has been achieved, every 3

months for 3 years and every 3-6 months thereafter

If there is 1-log increase in transcript levels with MMR, qPCR analysis should be repeated in 1-3 months

BCR-ABL kinase domain mutation analysis

Chronic phaseIf there is inadequate initial response

(failure to achieve PCyR or 10% [IS] at 3 months or CCyR at 12 and 18 months)

Any sign of loss of response (defined as hematologic or cytogenetic relapse)

1-log increase in transcript levels and loss of MMR

Disease progression to accelerated or blast phase

TABLE 3. ABL Mutations and Treatment Options

HSCT, hematopoietic stem cell transplant.

Mutation Treatment Options

T315I Ponatinib, HSCT, omacetaxine, or clinical trial

V299L Nilotinib, ponatinib, HSCT, or omacetaxine

T315A Nilotinib, imatinib, bosutinib, ponatinib, HSCT, or omacetaxine

F317L/V/I/C Nilotinib, bosutinib, ponatinib, HSCT, or omacetaxine

Y253H, E255K/V, F359V/C/I Dasatinib, bosutinib, ponatinib, HSCT, or omacetaxine

Any other mutation Dasatinib, nilotinib, bosutinib, ponatinib, high-dose imatinib, HSCT, or omacetaxine


THE ROLE OF PET IMAGING IN THE MANAGEMENT OF PATIENTS WITH HODGKIN LYPHOMA

is recommended for patients who meet response milestones at 3, 6, 12, and 18 months (BCR-ABL transcripts ≤10% (IS) at 3 and 6 months, CCyR at 12 and 18 months). After CCyR has been achieved, molecular monitoring is recommended every 3 months for 3 years and every 3 to 6 months thereafter.

One perceived limitation of BCR-ABL transcript levels is the lack of standardization across different labs, which is a greater problem in the United States than in Europe, given the U.S. decentralized system of care. The ELN and NCCN guidelines assume that BCR-ABL is tested using the IS, which is a labora-tory-specific coefficient stemming from the IRIS definition of MMR as a 3-log reduction of BCR-ABL from the median of the aggregate of diagnostic BCR-ABL levels in that study. Using the IS, the baseline values defined in the IRIS trial are fixed to 100% IS value; CCyR is generally accomplished at the 1% IS level; and MMR, representing the 3-log reduction from the standardized baseline, is 0.10%.22 Not having the IS available is not an ex-cuse not to use PCR monitoring. If the IS is not available, it is acceptable to use the log reduction from the laboratory-specific standardized baseline to monitor molecular response. Indeed, the most recent Intergroup study used this approach because not all of the Intergroup central laboratories had a IS conversion fac-tor.23

There is a heightened interest and awareness of CMR since the surprising discovery that some patients who achieve a pro-longed CMR can have their TKI discontinued and not relapse. However, such a tactic should be done only in the context of a clinical trial since we do not know the long-term consequences of discontinuation. Another complicated issue is a negative test. A negative BCR-ABL PCR assay can arise from: (1) a poor and insensitive assay; (2) a degraded sample; or (3) actual disease bur-den below the level of detection, with an adequate sample. Only the latter should be graded a CMR, and a CMR should only be declared if the sample is adequate enough to detect at least a 4.5 reduction of tumor burden.

Conclusion and Practical Applications• With the IS scale, BCR-ABL values of >10% at 3 and 6 months

of therapy are associated with an inferior outcome. BCR-ABL of 1% IS roughly correlates with CCyR, and 0.1% with MMR.

• MMR is associated with a very low risk of resistance or relapse.• A rising BCR-ABL can be either biological (resistance) or non-

biological (poor adherence).• CMR can be determined only in the context of a highly sensi-

tive, reproducible PCR assay, and with adequate sample with regard to quality and quantity of material. A negative BCR-ABL test does not necessarily indicate CMR.

Jerald P. Radich, MD, is from the Fred Hutchinson Cancer Research Center, Seattle, WA. jradich@fhcrcDisclosure: Dr. Radich reports he has received grants from No-vartis and has served as a consultant or advisory board member

for Novartis, Ariad Pharmaceuticals, Inc., Bristol-Myers Squibb, and Pfizer Inc.

REFERENCES1. O’Brien SG, Deininger MW. Imatinib in patients with newly di-agnosed chronic-phase chronic myeloid leukemia. Semin Hematol. 2003;40(2 suppl):26-30.2. Druker BJ, Guilhot F, O’Brien S, Larson N, on behalf of the IRIS investigators. Long-term benefits of imatinib (IM) for patients newly diagnosed with chronic myelogenous leukemia in chronic phase (CML-CP): the 5-year update from the IRIS study. Proc Am Soc Clin Oncol. 2006;24(18S):338s.3. Hughes T, Saglio G, Branford S, et al. Impact of baseline BCR-ABL mutations on response to nilotinib in patients with chronic myeloid leukemia in chronic phase. J Clin Oncol. 2009;27(25):4204-4210.4. Muller MC, Cortes JE, Kim DW, et al. Dasatinib treatment of chronic-phase chronic myeloid leukemia: analysis of responses accord-ing to preexisting BCR-ABL mutations. Blood. 2009;114(24):4944-4953.5. Hughes TP, Kaeda J, Branford S, et al; for the International Ran-domised Study of Interferon versus STI571 (IRIS) Study Group. Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med. 2003;349(15):1423-1432.6. Druker BJ, Guilhot F, O’Brien SG, et al, for the IRIS investiga-tors. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355(23):2408-2417.7. Branford S, Rudzki Z, Harper A, et al. Imatinib produces signifi-cantly superior molecular responses compared to interferon alfa plus cytarabine in patients with newly diagnosed chronic myeloid leuke-mia in chronic phase. Leukemia. 2003;17(12):2401-2409.8. Cortes J, Talpaz M, O’Brien S, et al. Molecular responses in pa-tients with chronic myelogenous leukemia in chronic phase treated with imatinib mesylate. Clin Cancer Res. 2005;11(9):3425-3432.9. Marin D, Kaeda J, Szydlo R, et al. Monitoring patients in com-plete cytogenetic remission after treatment of CML in chronic phase with imatinib: patterns of residual leukaemia and prognostic factors for cytogenetic relapse. Leukemia. 2005;19(4):507-512.10. Press RD, Love Z, Tronnes AA, et al. BCR-ABL mRNA levels at and after the time of a complete cytogenetic response (CCR) pre-dict the duration of CCR in imatinib mesylate-treated patients with CML. Blood. 2006;107(11):4250-4256.11. Wang L, Pearson K, Ferguson JE, Clark RE. The early molecular response to imatinib predicts cytogenetic and clinical outcome in chronic myeloid leukaemia. Br J Haematol. 2003;120(6):990-999.12. Kantarjian H, Sawyers C, Hochhaus A, et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med. 2002;346(9):645-652.13. Marin D, Marktel S, Bua M, et al. Prognostic factors for pa-tients with chronic myeloid leukaemia in chronic phase treated with imatinib mesylate after failure of interferon alfa. Leukemia. 2003;17(8):1448-1453.14. Branford S, Kim DW, Soverini S, et al. Initial molecular response at 3 months may predict both response and event-free survival at 24 months in imatinib-resistant or -intolerant patients with Phila-


· LEUKEMIA ·

delphia chromosome-positive chronic myeloid leukemia in chronic phase treated with nilotinib. J Clin Oncol. 2012;30(35):4323-4329.15. Marin D, Gabriel IH, Ahmad S, et al. KIR2DS1 genotype pre-dicts for complete cytogenetic response and survival in newly di-agnosed chronic myeloid leukemia patients treated with imatinib. Leukemia. 2012;26(2):296-302.16. Marin D, Hedgley C, Clark RE, et al. Predictive value of early molecular response in patients with chronic myeloid leukemia treat-ed with first-line dasatinib. Blood. 2012;120(2):291-294.17. Jain P, Kantarjian H, Nazha A, et al. Early responses predict bet-ter outcomes in patients with newly diagnosed chronic myeloid leu-kemia: results with four tyrosine kinase inhibitor modalities. Blood. 2013;121(24):4867-4874.18. Branford S, Rudzki Z, Walsh S, et al. Detection of BCR-ABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the ATP phosphate-binding loop (P-loop) are associated with a poor progno-sis. Blood. 2003;102(1):276-283.19. Khorashad JS, de Lavallade H, Apperley JF, et al. Finding of kinase domain mutations in patients with chronic phase chronic myeloid leukemia responding to imatinib may identify those at high risk of disease progression. J Clin Oncol. 2008;26(29):4806-4813.20. Soverini S, Martinelli G, Rosti G, et al. ABL mutations in late chronic phase chronic myeloid leukemia patients with up-front cy-togenetic resistance to imatinib are associated with a greater likeli-hood of progression to blast crisis and shorter survival: a Study by the GIMEMA Working Party on Chronic Myeloid Leukemia. J Clin Oncol. 2005;23(18):4100-4109.21. Marin D, Bazeos A, Mahon FX, et al. Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib. J Clin Oncol. 2010;28(14):2381-2388.22. Hughes T, Deininger M, Hochhaus A, et al. Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: re-view and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood. 2006;108(1):28-37.23. Radich JP, Kopecky KJ, Appelbaum FR, et al. A randomized trial of dasatinib 100 mg versus imatinib 400 mg in newly diagnosed chronic-phase chronic myeloid leukemia. Blood. 2012;120(19):3898-3905.


· OVARIAN CANCER ·

Genomic (“Precision”) Medicine in the Management of Ovarian Cancer

Maurie Markman, MD

It is difficult to overstate the significance of our rapidly accel-erating basic understanding of unique molecular alterations in the development, progression, and resistance of individual can-cers.1,2 Further, the potential importance of this knowledge on clinically relevant endpoints has the realistic opportunity to re-sult in revolutionary changes in disease management. Consider, for example, how a newly diagnosed patient with advanced non-small cell lung cancer (NSCLC) or metastatic melanoma is rou-tinely managed today compared with how a similar individual would have been treated a mere 10 or even 5 years ago.

However, to date, the care of women with ovarian cancer has not experienced the changes evident in other solid cancers. The current lack of development of molecularly based therapy in this area is perhaps surprising, considering the central role played by the malignancy in the history of the establishment of new cyto-toxic antineoplastic agents in solid tumor oncology.

In fact, it was in the treatment of advanced ovarian cancer that a number of critically relevant drugs (cisplatin, carboplatin, pa-clitaxel, topotecan, pegylated liposomal doxorubicin) had their major initial success.3,4 Yet, today, the combination of a platinum agent (generally carboplatin) and a taxane (generally paclitaxel) remains the standard of care in the management of advanced ovarian cancer more than 16 years following the landmark Gyne-cologic Oncology Group study, which revealed the superiority of this two-drug combination compared with the previous standard of a platinum agent plus cyclophosphamide.5

Further, and in striking contrast to the situation with cancers of the breast, lung, colon, and metastatic melanoma, there are no molecularly defined subgroups of ovarian cancer that are cur-rently managed differently in routine clinical practice based on the presence of a specific molecular target.

This review briefly discusses the past history, current status, and future potential of molecularly based therapy in ovarian cancer.

Investigation of Targeted Molecularly Based Therapy of Ovarian CancerThere is no experience that better describes the fundamental difference in the development of molecularly targeted therapy of ovarian cancer, compared with other malignancies, than the reported exploration of the utility of anti-HER2 treatment in the malignancy.6

The primary role of such treatment in the management of breast cancer, and the relevance of molecularly typing an individ-ual cancer to determine whether it overexpresses the HER2 re-ceptor, are well established. It is interesting in this regard to note here that one of the seminal papers that described the negative prognostic impact of HER2 overexpression in breast cancer also included a detailed discussion regarding ovarian cancer, and it reached a similar conclusion.7 However, the subsequent develop-ment of an effective antineoplastic management strategy based on that observation in breast cancer has been strikingly different from what has occurred in ovarian cancer.

To be able to conduct even one single-arm, phase II trial of trastuzumab in patients with previously treated advanced ovar-ian cancer, based on the finding of overexpression of the HER2 receptor in individual cancers, required screening more than 800 patient samples (11.4% of ovarian tumors found to overex-press [+2 or +3 staining] this receptor). Considering the far lower incidence of ovarian cancer in the general population (compared with breast cancer) and the fact that the percentage of tumors that overexpressed this receptor was found to be substantially lower than what is observed in breast cancer, it is not difficult to appreciate the major difficulty associated with documenting or refuting the utility of this strategy in the pelvic malignancy. In addition, of the 41 patients who participated in the Gyne-cologic Oncology Group phase II trial and who were evaluable for response, an objective response rate (ORR) of only 7.3% (3

AbstractThe virtual revolution in our understanding of specific driver molecular abnormalities present in a subset of cancers from patients with a variety of solid tumors has resulted in major favorable changes in how these diseases are routinely managed. However, it is a rather striking observation that despite substantial research effort, ovar-ian cancer, the malignancy where the clinical utility of a number of our most effective cytotoxic antineoplastic agents was initially documented, has not seen any changes in its standard management based on evidence of unique molecular alterations within individual tumors. This brief review will highlight both the past and current status of investigative efforts involving genomically based treatment of ovarian cancer and possible future approaches in this critically important area.


GENOMIC (“PRECISION”) MEDICINE IN THE MANAGEMENT OF OVARIAN CANCER

patients) was observed.6 While a most disappointing result, one might argue that de-

spite the enormous effort undertaken to complete this trial, it still failed to adequately test the hypothesis that an anti-HER2 agent might be of clinical utility in ovarian cancer. This conclu-sion is reached as patients with both +2 and +3 overexpression were permitted study entry, and it remains possible that even a smaller subset of patients (perhaps <2%-3% of the total popula-tion) whose cancers strongly overexpress the receptor may be ap-propriate candidates for this therapeutic strategy. Unfortunately, even a single conventional phase II clinical trial to evaluate the utility of such therapy in this extremely small ovarian cancer pa-tient subset is most unlikely to ever be undertaken.

The potential major clinical relevance of small molecularly defined subsets in ovarian cancer is emphasized by the report of a second molecularly targeted agent studied in this setting.8

Gefitinib, a tyrosine kinase inhibitor (TKI) of epidermal growth-factor receptor (EGFR), has been shown to be an effective treat-ment in the management of patients with NSCLC if the tumor contains specific mutations in EGFR.

In a phase II trial of this agent in patients with ovarian cancer whose cancers were not specifically selected based on any pro-spectively defined molecular targets, a quite disappointing ORR of 4% (1 of 27 evaluable patients) was observed. However, it was retrospectively determined that the cancer in this single respond-ing individual contained a mutation in EGFR that would have predicted for potential activity of this agent in NSCLC. Again, while a most uncommon event in ovarian cancer (approximately 3% of a limited number of tumors evaluated in this report), if a molecular analysis of individual tumors in patients with ovarian cancer was routinely undertaken, it might be possible to find the rare malignancy where an anti-EGFR agent would be a relevant therapeutic option.

BRCA Mutations, BRCA-Like Ovarian Cancers, and PARP InhibitionIn striking contract to the experience to date with established molecularly targeted therapy in ovarian cancer, solid preclinical and increasingly strong clinical data support a major role for the administration of PARP inhibitors where the ovarian tumor is documented to possess a germ line or somatic mutation in BRCA, or where the tumor demonstrates a genetic profile sug-gesting that functionally the cancer lacks BRCA-related biologi-cal activity.9,10 As BRCA has been shown to have an important role in DNA repair, and PARP is also a critical element in this process, dual blockage of the repair process (absence of BRCA-related DNA repair activity and delivery of a PARP inhibitor) has been suggested to result in substantial tumor cell kill.

Single-agent phase II trials have revealed the impressive bio-logical and clinical activity for the PARP inhibitor olaparib in the second-line management of ovarian cancer.11 A randomized phase II trial comparing olaparib to placebo when employed as a single-agent maintenance approach in women with high-grade

serous ovarian cancers (shown to be “BRCA-like” in molecular analysis), who had either achieved an objective response or at-tained a stable clinical state to second-line platinum-based che-motherapy, revealed a most striking improvement in time to sub-sequent disease progression in favor of treatment with the PARP inhibitor (median progression-free survival [PFS], 8.4 months vs 4.8 months for placebo; hazard ratio [HR] = 0.35; P <.001).12 Fur-ther, when the investigators retrospectively analyzed subsequent PFS based on the presence (or absence) of a BRCA mutation within the study population, they found an even more impres-sive favorable impact of olaparib on outcome in the mutation-positive population (median PFS, 11.2 months vs 4.1 months for placebo; HR= 0.17; P <.001).13

Despite the unprecedented results of what might reasonably be labeled a landmark randomized phase II study (published in a premier peer-reviewed medical journal), and most distressing for a group of women with ovarian cancer, olaparib has yet to be ap-proved for routine clinical use in patients whose cancers possess a BRCA mutation or individuals with high-grade serous cancers.

A serious problem with randomized ovarian cancer studies over at least the past decade has been the inability to document that an improvement in PFS can be translated into a statistically significant improvement in overall survival. This dilemma al-most certainly results because patients with ovarian cancer who complete treatment on an evidence-based randomized trial will (and must) subsequently be offered treatment options that have previously been documented to have a favorable impact on out-come in the malignancy. Thus, while survival has been shown to improve substantially within the population of women with ovar-ian cancer over the past several decades,14 it is difficult to prove the survival superiority of a given regimen when patients on a tri-al’s control arm are treated with a variety of recognized beneficial antineoplastic agents when their studytreatment is complete.15

It is reasonable to hope that either the overall magnitude of the utility of olaparib demonstrated in this solidly evidence-based, randomized phase II ovarian cancer study or the future results of a recently activated phase III trial employing this agent will ultimately permit the drug to be available to appropriate pa-tients with this malignancy.

For completeness, it important to acknowledge the evolv-ing role of antiangiogenic therapy in ovarian cancer, where an increasing number of phase III trials have documented the fa-vorable impact associated with combining such agents with cytotoxic chemotherapy in the primary, recurrent potentially platinum-sensitive and platinum-resistant settings.9,16-20 Unfortu-nately, while antiangiogenic agents impact a relevant target in the malignancy, there remain no biomarkers (molecular or oth-erwise) that help define the specific cancers likely to respond.

The Future of Molecularly Based Chemotherapy in Ovarian CancerThe relatively recently reported results from The Cancer Ge-nome Atlas project involving ovarian cancers have helped to



clarify the magnitude of the problem associated with directing treatment to particular molecular targets in the malignancy.21 Other than the very common TP53 mutation in high-grade se-rous ovarian cancer (96% of cases) and the previously mentioned BRCA mutations (approximately 10%-12% of ovarian cancers), only a small overall percentage of tumors from patients with this malignancy will be found to possess a suggested specific individ-ual driver mutation. Further, with the current established/con-ventional cancer clinical trials paradigm, testing the relevance of these individual uncommon molecular abnormalities in ovarian cancer (as previously noted with the experience of trastuzumab in HER2-overexpressing cancers,6 or anti-EGFR therapy in mu-tation-positive tumors8) will be extremely difficult, if not realisti-cally impossible.

One option for the future of research in this area is the so-called “N of 1”strategy, where individual patients whose cancers have undergone broad-based somatic genetic profiling are treat-ed with a particular strategy based on the presence of unique, molecularly defined, actionable abnormalities.22 After patient de-identification, the details of these individual experiences (eg, prior therapy; objective positive or negative imaging or biomark-er response to treatment; documentation of subjective clinical improvement; time to subsequent disease progression; overall survival; toxicity) will be recorded in a secure publically acces-sible database, with the ultimate goal of obtaining sufficient data to document the utility (or lack thereof) of a specific antineoplas-tic approach in the presence of a specific molecular abnormality.Of course, this scenario is realistically only possible for antineo-plastic agents that are FDA-approved for use in another tumor type. One could envision, for example, a limited number of pa-tients with +3 HER2-overexpressing ovarian cancer whose experi-ence with trastuzumab could be included in such a public data-base, with the information available to assist clinicians, insurers, and patients in their future decision-making process.

An alternative approach would be to use data generated from retrospective analyses of previously collected tumor sam-ples where clinical outcomes are known (such as in the previ-ously noted randomized phase II trial of olaparib maintenance therapy12,13). For example, recent highly provocative data have revealed the impressive favorable impact on survival associated with the use of aspirin in patients with colon cancer, but this benefit only occurred when the tumor in question was shown to possess a mutation in PI3 kinase (approximately 15% of colon cancers).23,24 There was no benefit associated with aspirin intake in the presence of wild-type PI3 kinase. It is possible that future similarly designed research efforts employing retrospective analy-ses of ovarian cancers that have been maintained in a number of academic and industry tissue banks will provide useful clinical data.

It is important to acknowledge that whenever possible, it will also be valuable to examine in conventional clinical trials specific antineoplastic strategies/agents where preclinical evaluation or data in other clinical settings suggest that there may be relevance

in specific subtypes of ovarian cancer. For example, selumetinib, an inhibitor of MEK1/2, has been tested in a group of women with low-grade serous ovarian cancers, a setting where mutations within the MAPK pathway have been identified.25 While an ORR of only 15% (52 evaluable patients) was observed, 63% of treated individuals experienced PFS >6 months in duration. However, emphasizing the complexity of this type of research, there was no evidence in this study that response to the treat-ment program specifically correlated with any particular type of genetic alteration.

Another unique trial concept would be the so-called “basket trial,” where patients with multiple tumor types (including ovar-ian cancer) might be eligible for study entry if their cancer ex-pressed a relevant molecular target.

Finally, it is likely that the current focus on attempting to de-fine a driver mutation based on individual genetic abnormalities in a given cancer will be augmented in the near future with data focusing on patterns of gene expression or activation of specific networks/pathways within a given cancer. For example, a recent report has suggested the potential clinical utility of a unique 10-gene signature in advanced ovarian cancer that defines a group of tumors in patients with a particularly poor prognosis.26 However, of perhaps greatest interest, the genes identified in this report ap-pear to be regulated by a known signaling pathway (TGFbeta1), and a therapeutic strategy based on blocking this pathway has been shown to be effective in a preclinical model. Clinical trials based on this approach will be a logical next step to examine the potential utility of this novel concept.

Maurie Markman, MD, is from Cancer Treatment Centers of America, Philadelphia, PA, and Drexel University College of Medicine, Philadelphia, PA. [email protected] Disclosure: Dr. Markman has been a consultant or a member of a paid advisory board for Amgen Inc., Celgene Corporation, Caris Life Sciences, Ltd., Novartis Corporation, sanofi-aventis U.S., LLC., and Genentech, Inc.

REFERENCES1. Garraway LA. Genomics-driven oncology: framework for an emerging paradigm. J Clin Oncol. 2013;31(15):1806-1814.2. Collins FS, Hamburg MA. First FDA authorization for next-generation sequencer [perspective]. N Engl J Med. 2013;369:2369-2371.3. Hennessy BT, Coleman RL, Markman M. Ovarian cancer. Lancet. 2009;374(9698):1371-1382.4. Markman M, Bookman MA. Second-line treatment of ovarian cancer. Oncologist. 2000;5(1):26-35.5. McGuire WP, Hoskins WJ, Brady MF, et al. Cyclophospha-mide and cisplatin compared with paclitaxel and cisplatin in pa-tients with stage III and stage IV ovarian cancer. N Engl J Med. 1996;334(1):1-6.



6. Bookman MA, Darcy KM, Clarke-Pearson D, et al. Evaluation of monoclonal humanized anti-HER2 antibody, trastuzumab, in patients with recurrent or refractory ovarian or primary peritone-al carcinoma with overexpression of HER2: a phase II trial of the Gynecologic Oncology Group. J Clin Oncol. 2003;21(2):283-290.7. Slamon DJ, Godolphin W, Jones LA, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian can-cer. Science. 1989;244(4905):707-712.8. Schilder RJ, Sill MW, Chen X, et al. Phase II study of gefi-tinib in patients with relapsed or persistent ovarian or primary peritoneal carcinoma and evaluation of epidermal growth fac-tor receptor mutations and immunohistochemical expres-sion: a Gynecologic Oncology Group study. Clin Cancer Res. 2005;11(15):5539-5548.9. Kalachand R, Hennessy BT, Markman M. Molecular target-ed therapy in ovarian cancer: what is on the horizon? Drugs. 2011;71(8):947-967.10. Hennessy BT, Timms KM, Carey MS, et al. Somatic muta-tions in BRCA1 and BRCA2 could expand the number of pa-tients that benefit from poly (ADP ribose) polymerase inhibitors in ovarian cancer. J Clin Oncol. 2010;28(22):3570-3576.11. Fong PC, Yap TA, Boss DS, et al. Poly(ADP)-ribose poly-merase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval. J Clin On-col. 2010;28(15):2512-2519.12. Ledermann J, Harter P, Gourley C, et al. Olaparib mainte-nance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med. 2012;366(15):1382-1392.13. Ledermann J, Harter P, Gourley C, et al. Olaparib mainte-nance therapy in patients with platinum-sensitive relapsed serous ovarian cancer and a BRCA mutation. J Clin Oncol. 2013;31(sup-pl; abstr 5505). 14. Markman M. Ovarian cancer survival: steady improvement, despite rhetoric to the contrary. Curr Oncol Rep. 2013;15(5):433-435.15. Broglio KR, Berry DA. Detecting an overall survival benefit that is derived from progression-free survival. J Natl Cancer Inst. 2009;101(23):1642-1649.16. Burger RA, Brady MF, Bookman MA, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med. 2011;365(26):2473-2483.17. Perren TJ, Swart AM, Pfisterer J, et al. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med. 2011;365(26):2484-2496.18. Aghajanian C, Blank SV, Goff BA, et al. OCEANS: a ran-domized, double-blind-placebo-controlled phase III trial of che-motherapy with or without bevacizumab in patients with plat-inum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol. 2012;30(17):2039-2045.19. Pujade-Lauraine E, Hilpert F, Weber B, et al. AURELIA: a randomized phase III trial evaluating bevacizumab plus che-motherapy for platinum-resistant ovarian cancer. J Clin Oncol.

2012;30(suppl; abstr LBA 5002).20. DuBois A, Floquet A, Kim JW, et al. Randomized, double-blind, phase III trial of pazopanib versus placebo in women who have progressed after first-line chemotherapy for advanced epi-thelial ovarian, fallopian tube, or primary peritoneal cancer: re-sults of an international Intergroup trial (AGO-OVAR 16). J Clin Oncol. 2013;31(suppl; abstr LBA 5503). 21. The Cancer Genome Atlas Research Network. Integrated ge-nomic analyses of ovarian carcinoma. Nature. 2011;474(7353):609-615. Erratum in: Nature. 2012;490(7419):298.22. Von Hoff DD, Stephenson JJ Jr, Rosen P, et al. Pilot study using molecular profiling of patients’ tumors to find potential targets and select treatments for their refractory cancers. J Clin Oncol. 2010;28(33):4877-4883.23. Liao X, Lochhead P, Nishihara R, et al. Aspirin use, tumor PI3CA mutation, and colorectal-cancer survival. N Engl J Med. 2012;367(17):1596-1606.24. Domingo E, Church DN, Sieber O, et al. Evaluation of PI-3CA mutation as a predictor of benefit from nonsteroidal anti-inflammatory drug therapy in colorectal cancer. J Clin Oncol. 2013;31(34):4297-4305.25. Farley J, Brady WE, Vathipadiekal V, et al. Selumetinib in women with recurrent low-grade serous carcinoma of the ovary or peritoneum: an open-label, single-arm, phase 2 study. Lancet Oncol. 2013;14(2):134-140.26. Choen D-J, Tong Y, Sim M-S, et al. A collagen-remodeling gene signature regulated by TGFbeta signaling is associated with metastasis and poor survival in serous ovarian cancer [published online ahead of print November 11, 2013]. Clin Cancer Res. 2013. doi:10.1158/1078-0432.CCR-13-1256.


· CME ·

Medical Crossfire: Recent Advances in the Treatment of Metastatic Melanoma

A case-based discussion with Jeffrey S. Weber, MD, PhD, Jedd Wolchok, MD, PhD, and Keith T. Flaherty, MD

OverviewThis activity will serve as an update on advances in the field and will focus on the clinical implications of metastatic melanoma and basal cell carcinoma, including novel treatment regimens for the management of advanced melanoma, including immunomodulatory antibodies, BRAF inhibitors, multiple tyrosine kinase inhibitors, antiangiogenic agents, and other novel agents in earlier phases of development. Target Audience

Medical oncologists, fellows, surgical, radiation oncologists, who treat patients with skin and other cutaneous malignancies. Dermatologists, dermatopathologists and pathologists, nurse practitioners, nurses, physician assistants, pharmacists, researchers, and other health care professionals interested in the treatment of skin and other cutaneous malignancies will be invited to participate.

Learning Objectives

As a result of their participation in this activity, the target audience members should be better prepared to:1. Survey current standards of care in the treatment of patients with melanoma2. Evaluate the role of current and emerging immunotherapies in the treatment of melanoma3. Refer patients with melanoma to appropriate clinical trials based on patient and disease characteristics and the potential benefit of the investigational agent or regimen

Accreditation/Credit Designation


Physicians’ Education Resource®, LLC, designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Instructions for Participation/How to Receive AMA PRA Category 1 CreditTM

1. Read the article in its entirety.

2. Use the QR Code or type http://www.gotoper.com/LINK/73 into your Web browser to access the post-test.3. Complete and pass the post-test with a score of 70% or higher.4. Complete the evaluation and request for credit.Participants may immediately download a CME certificate upon successful completion of these steps.

No commercial support was received for this CME-certified activity.

Off-Label Disclosure and Disclaimer

This CME activity may or may not contain discussions of investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this CME activity is for continuing medical education purposes only and is not meant to substitute for the independent medical judgment of a physician relative to diagnostic and treatment options for a specific patient’s medical condition.

DisclaimerThe opinions expressed in the content are solely those of the individual faculty members and do not reflect those of Physicians’ Education Resource®, LLC.

Contact information for questions about the activity:Physicians’ Education Resource®, LLC666 Plainsboro Road, Suite 356Plainsboro, NJ 08536Phone: (888) 949-0045E-mail: [email protected]

Dates of Certification: February 15, 2014-February 15, 2015 | Medium (Print with online post-test, evaulation and request for credit)

Faculty Authors/PlannersKeith T. Flaherty, MDAssociate professor, Department of MedicineHarvard Medical SchoolDirector of Developmental Therapeutics, Cancer CenterMassachusetts General HospitalBoston, MADisclosure: Grant/Research Support (sanofi-aventis and Novartis Pharmaceuticals Corporation); Consultant (Roche/Genentech, GlaxoSmithKline, and Novartis Pharmaceuticals Corporation)

Jeffrey S. Weber, MD, PhDSenior member and directorDonald A. Adam Comprehensive Melanoma Research CenterMoffitt Cancer CenterTampa, FL Disclosure: Grant/Research Support (Bristol-Myers Squibb, Merck & Co, Inc, GlaxoSmithKline, and Genentech); Consultant (Bristol-Myers Squibb, Merck & Co, Inc, GlaxoSmithKline, and Genentech)

Jedd D. Wolchok, MD, PhDLloyd J. Old Chair for Clinical InvestigationMemorial Sloan-Kettering Cancer CenterNew York, NYDisclosure: Consultant (Bristol-Myers Squibb, Merck & Co, Inc, AstraZeneca, Medimmune, and GlaxoSmithKline)

Medical WriterCheryl Zigrand Disclosure: No relevant financial relationships with commercial interests. American Journal of Hematology/Oncology Editorial Board MemberAndrew Zelenetz, MD, PhDVice chair, Medical Informatics, Department of MedicineMemorial Sloan-Kettering Cancer CenterNew York, NYDisclosure: Research (Roche, GlaxoSmithKline, and Genentech); Consultant (Seattle Genetics, sanofi aventis USA, GlaxoSmithKline, Gilead, Cephalon, and Celgene); Scientific Advisor (Cancer Genetics)

Staff DisclosuresDru S. Dace, PhD has no relevant financial relationships with commercial interests to disclose.


RECENT ADVANCES IN THE TREATMENT OF METASTATIC MELANOMA

Over the past few years, treatment options for metastatic mela-noma have expanded dramatically. After decades with no major advances and no treatments with proven survival benefit, there are now two agents that have demonstrated an overall survival benefit compared with chemotherapy in randomized phase III trials: first, the anti-cytotoxic T-lymphocyte–associated anti-gen-4 (CTLA-4) monoclonal antibody ipilimumab, and now the BRAF inhibitor vemurafenib. In addition, in 2013, the FDA also approved the BRAF inhibitor da-brafenib and the mitogen-activated protein kinase (MEK) inhibitor trametinib, based on documented improvements in progression-free survival in large randomized trials.

There are also a number of investigational therapies and com-bination regimens that are showing promise in clinical trials. Al-though the addition of these agents provides more options and better care for patients with metastatic melanoma, the expansion of options has also introduced new clinical questions and chal-lenges. Jeffrey S. Weber, MD, PhD, senior member and director of the Donald A. Adam Comprehensive Melanoma Research Center at the Moffitt Cancer Center in Tampa, Florida, mod-erated the following Medical Crossfire with a panel including two other leading oncologists—Jedd Wolchok, MD, PhD, Lloyd J. Old Chair for Clinical Investigation at Memorial Sloan-Ketter-ing Cancer Center, New York City, and Keith T. Flaherty, MD, associate professor in the Department of Medicine at Harvard Medical School and director of Developmental Therapeutics at the Massachusetts General Hospital Cancer Center in Boston—to shed light on this important topic and to help community oncologists keep up-to-date on the latest advancements in meta-static melanoma treatment.

Checkpoint InhibitorsCTLA-4 Dr. Weber: What is the experience with the use of ipilimumab for metastatic melanoma? Dr. Wolchok: Ipilimumab can improve the overall survival of pa-tients with metastatic melanoma, whether in the upfront or the treatment-experienced setting.1 The number of patients who ben-efit in any way is probably about 20% to 25%, including objec-tive responses and long-term stable disease, which can translate into long-term survival for some patients, even though the scans do not show that the tumor has regressed to a significant extent. Dr. Weber: Can patients be told that they’re going to have long-term survival?Dr. Wolchok: It is certainly possible for patients to have long-term survival with immunotherapy. Approximately 3% to 5% of patients with melanoma treated with high-dose interleukin-2 (IL-2) had long-term survival.2 With ipilimumab, just over 20% of patients are living more than 3 years after ipilimumab thera-py.3 So, there are patients who can have very long-term survival. Some of the patients who were treated in the earliest phase I and phase II trials are still alive now, with 9 or 10 years of data behind them. We’re more focused on having patients live for an extended period of time than on quantifying the number of

patients with radiographic response.Dr. Weber: When should you re-treat with ipilimumab?Dr. Wolchok: Re-treatment is not part of its FDA label, but there are data from the phase III trial of ipilimumab that demonstrat-ed that patients who showed benefit from ipilimumab without severe toxicity could achieve remission upon re-treatment at the time of progression.1 In some cases, the remission that the pa-tients experience could be more impressive than their first re-sponse. Dr. Weber: Do you treat patients beyond progression?Dr. Wolchok: The response kinetics for ipilimumab are unlike more conventional anticancer therapies that target the tumor di-rectly (Figure), so it may be possible for patients to have a delayed response, and we believe that treating or observing past progres-sion is a reasonable thing to do with these patients.4 Dr. Weber: How do you handle the potential for immune-relat-ed side effects with ipilimumab and other immunotherapeutic antibodies?Dr. Wolchok: These are best classified as tissue-specific inflam-matory events. They most commonly involve the skin and the gastrointestinal tract in the form of dermatitis, pruritis, and enterocolitis (Table 1).1 And, as we became aware that this en-terocolitis could be serious, in fact fatal if not treated appropri-ately, we now pay particular attention to evolving gastrointestinal symptoms such as diarrhea, which, when recognized and treated appropriately, are quite easy to control.Dr. Weber: Do you think that there’s an interaction of chemo-therapy or radiation therapy with ipilimumab (the so-called “ab-scopal” effect)? Dr. Wolchok: Yes. We treated a patient in a phase II trial of ipilimumab whose disease slowed down but did not respond. It was slow progression of disease, which began to accelerate, not only with the index lesion enlarging and causing symp-

FIGURE. Response to Ipil imumab Therapy4

Figure courtesy Dr. Wolchok.

Radiographic progression of disease at week 12, followed by a clinical response and near complete resolution of disease following another course of ipilimumab induction therapy.

Pre-treatment Week 12 (10/06)

4 blind dosesipilimumab

4 10 mg/kg dose ipilimumab

No Drug


· CME ·

tomatic pain, but with many new lesions in the spleen. We suggested that the patient consult a radiation oncologist primarily for palliation of this one dominant lesion. We hoped that perhaps we would get some benefit from the abscopal ef-fect. The radiation therapy of one single tumor in this patient led to the regression of numer-ous untreated tumors, and this patient remains in a durable response today as a result of that. There are several documented cases of this phe-nomenon with ipilimumab or high-dose IL-2,5-7 which has led to several ongoing prospective clini-cal trials of radiation with ipilimumab and IL-2 to try to understand exactly how many patients ben-efit in this manner.8-10 Any therapies that cause the tumor to break down and die could lead to the re-lease of antigens and a change in the microenviron-ment that potentiates the effect of immunotherapy.

PD-1/PD-L1Dr. Weber: Will the emerging use of anti–pro-grammed cell death protein 1 (PD-1) and anti–PD-1-ligand 1 (PD-L1) antibodies (Table 2) replace ipi-limumab, or will they be used together?Dr. Wolchok: There’s an abundance of data now supporting the idea that blockade of the PD-1 pathway, which is another immune checkpoint, can lead to regressions in a significant number of patients with metastatic melanoma, even those who have progressed after ipilimumab.11,12 That is a great source of hope to our patients, because even if one type of immunotherapy does not provide therapeutic benefit, it does not mean that all im-munotherapies are written off the list of possible treatments for these patients. We recently showed that combining CTLA-4 and PD-1 blockade is fea-sible with an acceptable safety profile and is now being explored prospectively in phase II and III clinical trials to see if the blockade of both of these checkpoints concurrently is better than either one

alone.13-15 Dr. Weber: Do you see any issues for the adoption in the com-munity of concurrent blockade therapy?Dr. Wolchok: The side effects we saw in the phase I trial with concurrent therapy were not unlike what has been seen with ei-ther ipilimumab or the PD-1 or PD-L1 blocking antibodies by themselves (Table 3).13 More patients had multiple side effects, and that might be expected when you’re combining medicines together. But none of those side effects were beyond the skill set of a practicing oncologist.Dr. Weber: Can PD-1 or PD-L1 antibody treatment lead to late regression?

TABLE 2. PD-1/PD-L1 Antibodies in Development for Melanoma

Antibody Phase

Nivolumab (BMS-936558, MDX-1106, ONO-4538) III

Lambrolizumab (MD-3475) III

CT-011 II

MPDL3280A I

MEDI4736 I

AMP-514/MEDI0680 I

AMP-224 I

TABLE 1. Immune-Related Adverse Events With Ipil imumab1

Adapted from Hodi FS. N Engl J Med. 2010;363(8):711-723.

Adverse Event, n (%)

Ipilimumab Plus gp100 (n = 380)

Ipilimumab Alone (n = 131)

gp100 Alone (n = 132)

Total Total TotalAny immune-related event

221 (58.2) 80 (61.1) 42 (31.8)

Dermatologic 152 (40.0) 57 (43.5) 22 (16.7)

Pruritus 67 (17.6) 32 (24.4) 14 (10.6)

Rash 67 (17.6) 25 (19.1) 6 (4.5)

Vitiligo 14 (3.7) 3 (2.3) 1 (0.8)

Gastrointestinal 122 (32.1) 38 (29.0) 19 (14.4)

Diarrhea 115 (30.3) 36 (27.5) 18 (13.6)

Colitis 20 (5.3) 10 (7.6) 1 (0.8)

Endocrine 15 (3.9) 10 (7.6) 2 (1.5)

Hypothyroidism 6 (1.6) 2 (1.5) 2 (1.5)

Hypopituitarism 3 (0.8) 3 (2.3) 0

Hypophysitis 2 (0.5) 2 (1.5) 0

Adrenal insufficiency

3 (0.8) 2 (1.5) 0

Increase in serum thyrotropin level

2 (0.5) 1 (0.8) 0

Decrease in serum corticotropin level

0 2 (1.5) 0

Hepatic 8 (2.1) 5 (3.8) 6 (4.5)

Increase in alanine amino-transferase

3 (0.8) 2 (1.5) 3 (2.3)

Increase in aspartateaminotransferase

4 (1.1) 1 (0.8) 2 (1.5)

Hepatitis 2 (0.5) 1 (0.8) 0



Dr. Wolchok: We have certainly seen this pattern of immune-related responses with ipilimumab, responses that are delayed or that involve index lesions regressing while new lesions appear.1,4 We have now seen this with the PD-1 blocking antibodies and PD-L1 blocking antibodies as well.13,16,17

BRAF InhibitorsDr. Weber: Are there significant differences between the two ap-proved BRAF inhibitors dabrafenib and vemurafenib?Dr. Flaherty: The BRAF inhibitors look really similar in terms of efficacy, particularly their initial antitumor effect, but there

TABLE 3. Nivolumab Plus Ipil imumab in Advanced Melanoma: Highest Grade of Selected Treatment-Related Adverse Eventsa,13

Adapted from Wolchok JD, et al. N Engl J Med. 2013;369(2):122-133.aAEs that occurred in at least one of the patients who received the concurrent nivolumab/ipilimumab regimen.Cohort 1: 0.3 mg nivolumab per kg of body weight and 3 mg ipilimumab per kg.Cohort 2: 1 mg nivolumab per kg and 3 mg ipilimumab per kg; cohort 2a: 3 mg nivolumab per kg and 1 mg ipilimumab per kg.Cohort 3: 3 mg nivolumab per kg and 3 mg ipilimumab per kg.

Event, n (%) Cohort 1 (n = 14)

Cohort 2 (n = 17)

Cohort 2a (n = 16)

Cohort 3 (n = 6)

All Patients in Concurrent-Regimen Group (N = 53)

All Grades All Grades All Grades All Grades All GradesPneumonitis 1 (7) 2 (12) 0 0 3 (6)

Endocrinopathy 1 (7) 3 (18) 1 (6) 2 (33) 7 (13)

Hypothyroidism 0 2 (12) 0 0 2 (4)

Hypophysitis 0 1 (6) 0 1 (17) 2 (4)

Thyroiditis 0 1 (6) 1 (6) 1 (17) 3 (6)

Adrenal insufficiency 0 2 (12) 0 0 2 (4)

Hyperthyroidism 0 1 (6) 0 1 (17) 2 (4)

Thyroid function results abnormal

1 (7) 0 0 0 1 (2)

Hepatic disorder 4 (29) 5 (29) 2 (12) 1 (17) 12 (23)

Aspartate aminotransferase increased

4 (29) 4 (24) 2 (12) 1 (17) 11 (21)

Alanine aminotransferase increased

3 (21) 5 (29) 2 (12) 1 (17) 11 (21)

Gastrointestinal disorder 5 (36) 6 (35) 6 (38) 3 (50) 20 (38)

Diarrhea 5 (36) 5 (29) 5 (31) 3 (50) 18 (34)

Colitis 1 (7) 2 (12) 1 (6) 1 (17) 5 (9)

Renal disorder 1 (7) 1 (6) 1 (6) 0 3 (6)

Blood creatinine increased 1 (7) 1 (6) 1 (6) 0 3 (6)

Acute renal failure 0 1 (6) 1 (6) 0 2 (4)

Renal failure 0 1 (6) 0 0 1 (2)

Tubulointerstitial nephritis 1 (7) 0 0 0 1 (2)

Skin disorder 10 (71) 14 (82) 10 (62) 3 (50) 37 (70)

Rash 8 (57) 11 (65) 7 (44) 3 (50) 29 (55)

Pruritus 6 (43) 11 (65) 7 (44) 1 (17) 25 (47)

Urticaria 0 0 1 (6) 0 1 (2)

Blister 0 1 (6) 0 0 1 (2)

Infusion-related reaction 0 1 (6) 0 0 1 (2)


· CME ·

are differences in terms of the spectrum of kinases or enzymes inhibited beyond BRAF, which likely accounts for the differ-ence in side-effect profiles. Vemurafenib, for example, can cause photosensitivity, increasing risk of sunburn from relatively small amounts of sun exposure on some occasions.18 Dabrafenib doesn’t cause that so much, but it can cause fever in a fraction of patients treated for reasons that are still not entirely known, which doesn’t occur frequently with vemurafenib.18,19

Dr. Weber: Do you think that all eligible patients with BRAF-mutated melanoma should receive BRAF inhibitors as their first-line therapy?Dr. Flaherty: No, I wouldn’t say that we have the evidence that would really allow us to make that kind of statement. What we can say is that patients with metastatic disease can benefit from a BRAF inhibitor. Patients with BRAF mutations have multiple treatment options. One needs to think about what therapy to lead with and what therapy to use as a back-up.Dr. Weber: Does it make sense to give the drug to patients with high LDH [lactate dehydrogenase], rapid progressors, patients with high-bulk disease who are BRAF-mutated, but to use im-munotherapy for more indolent disease?Dr. Flaherty: I think so. The time of onset of a BRAF inhibitor is quite rapid, which is good for a patient with symptomatic, bur-densome disease, whereas ipilimumab, with its somewhat slower onset of action, may not be the best choice for that patient. I think it’s completely reasonable to think of leading with immune therapy in hopes of a durable treatment effect for a patient with lower disease burden, knowing that if you watch the patient closely you should still use a BRAF inhibitor effectively in the second-line setting.Dr. Weber: Would you ever use a BRAF inhibitor in a patient who is BRAF wild-type?Dr. Flaherty: No. The pathway in which BRAF sits is activated in a great many melanomas, but BRAF inhibitors actually don’t turn out to be very effective at controlling the pathway in tumors without a BRAF mutation. Dr. Weber: Do you think the combination of BRAF plus MEK inhibitors will replace single-agent BRAF inhibition?Dr. Flaherty: Yes. MEK inhibitors act in the same BRAF path-way in the tumor cell, which probably explains why MEK inhibi-tors look comparable to BRAF inhibitors in terms of efficacy. According to early clinical data, the two drugs together might even impair the tumor’s ability to work its way around and de-rive resistance to treatment.20 The early results clearly supported phase III development, but now we really need that phase III data to know if we’re meaningfully altering the natural history of disease.21 [Editor’s note: In January 2014, the FDA approved trametinib in combination with the BRAF inhibitor dabrafenib to treat patients with advanced melanoma that is unresectable or meta-static.22]Dr. Weber: How often do you monitor patients for the common adverse events associated with BRAF inhibitors?Dr. Flaherty: The most common vemurafenib-associated side ef-fects are rash, arthralgia, and photosensitivity (Table 4).18 Each

TABLE 4. Adverse Events in Trial of Vemurafenib18

Adverse Event, n (%) Vemurafenib (n = 336)a

Arthralgia

Grade 2 60 (18)

Grade 3 11 (3)

Rash

Grade 2 33 (10)

Grade 3 28 (8)

Fatigue

Grade 2 38 (11)

Grade 3 6 (2)

Cutaneous squamous cell carcinoma

Grade 3 40 (12)

Keratoacanthoma

Grade 2 7 (2)

Grade 3 20 (6)

Nausea

Grade 2 25 (7)

Grade 3 4 (1)

Alopecia

Grade 2 26 (8)

Pruritus

Grade 2 19 (6)

Grade 3 5 (1)

Hyperkeratosis

Grade 2 17 (5)

Grade 3 4 (1)

Diarrhea

Grade 2 16 (5)

Grade 3 2 (<1)

Headache

Grade 2 15 (4)

Grade 3 2 (<1)

Vomiting

Grade 2 9 (3)

Grade 3 4 (1)

Neutropenia

Grade 2 1 (<1)

Grade 3 0

Grade 4 1 (<1)

Grade 5 0

Adapted from Chapman PB, for the BRIM-3 Study Group. N Engl J Med. 2011; 364(26):2507-2516.

aIncludes all adverse events of grade ≥2 that were reported in more than 5% of patients.



of those is usually mild or moderate, without a major impact on quality of life. In some patients though, they can lead to dose interruption and re-institution of the same dose, or if it was really quite significant on first appearance, dose reduction may be needed to keep people on therapy, as was the case with about 40% of patients in vemurafenib clinical trials.18 Rash is the most common side effect with dabrafenib. Fever can occur in some, arthralgia also in others (Table 5).19 And, with those side effects, again, dose interruption and reduction seem to be the most plausible strategy. Cutaneous squamous cell carcinomas are commonly seen. No less than 10% maybe even 20% or 25% of patients experience the emergence of cutaneous squamous cell carcinomas early in the course of therapy.23

We have no doubt that those phenomena are treatment-re-lated, but in a patient with metastatic melanoma who develops that kind of well differentiated, noninvasive, or nonmetastatic lesion, the general algorithm is to treat those lesions but con-tinue the BRAF inhibitor-based therapy because the patient is facing a life-threatening underlying illness. A bigger concern is the possibility of other new malignancies. I find that partnering with a dermatologist before and during BRAF inhibitor-based therapy is a nice way of keeping a close eye on patients and being able to intervene when lesions are small and amenable to really minimally invasive maneuvers.

In trials, we scan patients just about every 6 or 8 weeks de-pending on the study. In practice, I follow roughly the same al-gorithm. While it is true that the vast majority of patients will move toward tumor regression early in the course of therapy, it is very hard to predict when the disease might become resistant to treatment. If this patient was receiving first-line BRAF inhibitor therapy and still has other therapy options ahead, particularly ipilimumab, it’s absolutely critical to know at the first moment when there is evidence of the disease working its way around treatment.Dr. Weber: Should BRAF inhibitors be continued beyond pro-gression?Dr. Flaherty: I can’t say that we really have good evidence of the benefit to patients. Yet, it did happen in clinical trials,18,19 so we have some accumulated experience there. If a patient has no other available treatment options and is still asymptomatic, if you don’t have another option, I think it’s acceptable to consider the idea of continuing treatment. But if the patient were to reach the point of symptomatic progression, it would be hard to make that argument.Dr. Weber: Does a rationale exist for discontinuous dosing of BRAF inhibitors?Dr. Flaherty: A rationale exists to support doing prospective clinical trials to investigate this regimen. It’s fairly clear in the midst of doing dose interruptions that you don’t tend to lose control of the disease during that time. So, I think it’s reasonable to look at the scientific evidence that suggests that we might be able to drag out the benefit of these therapies with on-treatment and off-treatment periods.24 Dr. Weber: What interval should be used between BRAF inhibi-tors and other melanoma therapy?

Dr. Wolchok: We should go with our clinical instincts. If you were considering how long to wait before initiating, for example, ipilimumab after a BRAF inhibitor, I don’t really think that there’s any evidence that you need to wait a certain period of time. In the preclinical setting, there’s actually reason to believe that both of those medicines help each other in some ways. The BRAF inhibitor has some ability to attract T-cells to the tumor site.25 There are also additional data that BRAF inhibitors can actually activate T-cells.26 But, we also know that in a small clini-cal trial of vemurafenib given concurrently with ipilimumab, the toxicities with the combination were unacceptable.27 Dabrafenib with ipilimumab is currently being investigated in the same type of concurrent dosing, and we eagerly await those results.28 My own practice would be to wait just a few days for vemurafenib (a few half-lives) before initiating ipilimumab therapy. Dr. Weber: What about the potential use of radiation, particu-larly in patients who develop brain metastases where we com-monly use stereotactic radiosurgery. Do you need to stop the drug for a day, several days, or could you simply continuously treat with the BRAF inhibitor?Dr. Flaherty: In trials, patients typically take a very brief inter-

TABLE 5. Dabrafenib Adverse Events a,19

Adverse Event Total, n (%)

Any event 86 (93)

Arthralgia 30 (33)

Hyperkeratosis 25 (27)

Pyrexia 22 (24)

Fatigue 20 (22)

Headache 19 (21)

Nausea 18 (20)

Skin papilloma 14 (15)

Vomiting 14 (15)

Pain in extremity 13 (14)

Cough 12 (13)

Decreased appetite 12 (13)

Alopecia 11 (12)

Anemia 11 (12)

Chills 11 (12)

Diarrhea 10 (11)

Back pain 9 (10)

Cutaneous squamous cell carcinomab 9 (10)

Hypophosphatemia 9 (10)

Pruritus 9 (10)

Adapted from Ascierto PA, et al. J Clin Oncol. 2013;31(26):3205-3211.

aThe majority of adverse events were Grade 1 or Grade 2 (data not shown).

bExperienced by at least 10% of patients in the trial group.


· CME ·

ruption right around the radiation course.18,19 So, if it was, for example, stereotactic radiotherapy, that would result in very few days, just maybe two days before, two days after. In my practice, I feel that a few days off therapy because of toxicity management or, in this case, to accommodate radiation treatment, really won’t jeopardize disease control a great deal. I’m cautious about concomitant therapy throughout.Dr. Weber: How should BRAF inhibitors and immunotherapies be sequenced?Dr. Wolchok: We simply don’t know yet. It’s very clear that us-ing a targeted therapy first for a patient with rapidly progressive, symptomatic, BRAF-mutated melanoma would provide the pa-tient with the initial benefit that they need.18,19 And then once the disease is controlled, you could consider switching to immu-notherapy. If a patient starts with ipilimumab with low-volume disease, even if it’s BRAF-mutated, and the ipilimumab doesn’t work, then I think obviously the next step would be to move to a BRAF inhibitor if the patient then has symptomatic progressive disease.Dr. Weber: How will the presence of brain metastases at baseline in a previously untreated patient influence choice of therapy?Dr. Flaherty: The available evidence, albeit from relatively small trials, suggests that both types of drug, BRAF inhibitor-based therapy and ipilimumab, can impact the brain and the brain metastases to a comparable degree as metastases elsewhere.29-31

Having said that, I think it’s really a matter of disease burden. If a patient doesn’t have a BRAF mutation and you’re looking at ipilimumab as the systemic approach, symptoms might force your hand. You’re going to want to deal with that brain metas-tasis with surgery or radiation, potentially stereotactic radiation, while you’re initiating ipilimumab or just before initiating ipili-mumab to allow the immune response to manifest.

For BRAF inhibitor-based treatment, the available evidence suggests that the upfront antitumor effect is comparable in brain metastases versus non-brain metastases.29,30 Based on those trial results, practitioners are becoming increasingly comfortable with foregoing local control measures of the brain metastases, at least for a time, to see if someone is going to have an excellent re-sponse to a BRAF inhibitor. That might spare you at least consid-ering whole-brain radiation, for example, and allow you to focus

on maneuvers like stereotactic radiation or, on occasion, surgery if there’s just one problematic brain metastasis that’s left after an initial response to treatment.

Dr. Weber: Do you feel comfortable foregoing stereotactic ra-diosurgery or surgery in a patient with oligometastatic central nervous system (CNS) disease and starting with ipilimumab or starting with a BRAF inhibitor?Dr. Wolchok: If the patient has a BRAF-mutated tumor, I’m comfortable foregoing radiation in a patient who is asymptom-atic from small-volume CNS disease. In patients without a BRAF mutation for whom ipilimumuab is being considered, more time will be needed for a response, and you don’t want the patient to become symptomatic. The combination of that scenario with the possibility of the abscopal effect with radiation really does influence me to deliver concomitant radiation and ipilimumab in patients with a BRAF wild-type tumor.Dr. Flaherty: I think a critical issue that we still don’t know much about is the impact of corticosteroids in the management of edema around brain metastases in the midst of the initial course of ipilimumab therapy. When patients are in the early course of ipilimumab treatment and have brain metastases, you really want to consider that part of this strategy is to avoid us-ing steroids. What limited clinical evidence we have is that these patients probably don’t have a great chance of benefiting from ipilimumab because either the steroid is interfering or because the brain metastases become a cause of morbidity, and even po-tentially mortality.31

Melanoma SubtypesDr. Weber: Do the immunotherapies have activity in acral len-tiginous, mucosal, and uveal melanomas?Dr. Wolchok: We know that ipilimumab is active in patients with mucosal melanoma, ocular melanoma, also called uveal melanoma, and acral melanoma.32-34 The response rates so far have been a bit lower than with cutaneous melanoma but they certainly are durable responders with all of those disease sub-types. The other important gene to look for is c-KIT, especially in the mucosal and the acral melanomas, where up to 30% of those patients can have a driver mutation in c-KIT which, in clinical trials, could be targeted with one of many medicines that can inhibit KIT, including imatinib or nilotinib.35 Dr. Weber: Would you use a chemotherapy adjuvant regimen in acral lentiginous or mucosal melanoma based on the latest published data?Dr. Wolchok: I think that the data from the adjuvant mucosal melanoma trial are very intriguing, showing the possibility of sub-stantial activity of combination chemotherapy in patients with mucosal melanoma.36 I think right now it remains a question for clinical trials. If patients have such sensitivity to chemotherapy in the adjuvant setting, then we would hope that combination chemotherapy could be used for metastatic disease as well.Dr. Weber: Would you choose a MEK inhibitor to treat ocu-lar melanoma based on the published data? Are there other ap-



proaches for this type of melanoma?Dr. Flaherty: We really lag behind in the ocular melanoma sub-population in terms of treatment advances. We know a lot less about its responsiveness to ipilimumab, although there can be some responsiveness. The available evidence suggests that a MEK inhibitor by itself in that disease—which really never has BRAF mutations and much more commonly has mutations that can activate the pathway in a very indirect fashion—has modest activ-ity in terms of tumor regression or disease control.37 I do think that MEK inhibitor-based combinations in clinical trials repre-sent the highest priority at the moment based on the emerging evidence.

Case Study, Presented by Dr. WolchokInitial Presentation

• 45-year-old woman• Biopsy-proven cutaneous melanoma • Seven 1-cm lung metastases• No brain metastases• Normal serum LDH• Asymptomatic• A stage II lesion was resected from her arm 3 years ago

Dr. Wolchok: There are many options to consider to manage this patient’s disease:

1. Start dacarbazine chemotherapy. 2. Genotype the patient’s tumor for a BRAF mutation. 3. Immediately initiate ipilimumab. 4. Initiate high dose interleukin-2. 5. Resect all of the distant metastases and start interferon alpha.

Dr. Flaherty: I would cross number 5 off. This number of le-sions, their distribution, and the extremely high likelihood that you would see new lesions appear within just a couple of months following a surgery like that for multiple metastatic lung lesions make that a difficult starting point. Among the other options, I think BRAF inhibitor–based therapy (if you test for the muta-tion), ipilimumab, and even high-dose IL-2 are all on the menu. I send for BRAF testing upfront no matter what. I may not wait for the results to come back before choosing between ipilimum-ab and IL-2 for a patient like this.Dr. Weber: I think every patient who presents with metastatic disease should get genetically profiled for BRAF mutation at the very least. I agree that resecting metastases would not seem rea-sonable. High-dose IL-2 is a truly niche drug that has significant toxicity and requires a dedicated unit with experienced nursing and other ancillary personnel. It’s not something you can do everywhere. We have better drugs than dacarbazine today. And, yes, you could initiate ipilimumab, but I’d certainly want to give the patient the option of being on either BRAF or a combina-tion BRAF trial. Since I’m at an academic institution, we use multiple drugs, never single-agent BRAF inhibition to try to over-

come resistance.Dr. Wolchok: I agree with you both completely. Dr. Wolchok: After being treated with ipilimumab and develop-ing fatigue and blurred vision at the time of the fourth dose, our options now are:

1. Refer to an ophthalmologist for what’s likely to be eye strain. 2. Start corticosteroids immediately for obvious hypothyroidism. 3. Proceed with dose four since many cancer patients have

fatigue and these other symptoms. 4. Obtain a brain MRI. 5. Treat with corticosteroid eye drops.

Dr. Weber: An ophthalmologist is not a bad idea, but there are bigger issues. The combination of headache and visual symp-toms points to immune/autoimmune pituitary/hypopituitarism and is a well-known complication both of ipilimumab and the PD-1 and PD-L1 antibodies. I would not start corticosteroids for hypothyroidism until the T4 and TSH results are in. And, even then I would give replacement. I wouldn’t necessarily give ste-roids unless uveitis is found. But I would get a brain MRI and I would look for an enlarged pituitary and, especially because of the optic chiasm being so close to the pituitary, I would look for an inhomogeneous pituitary that’s somewhat edematous. Dr. Flaherty: You can save the function of the pituitary gland in some cases if you recognize it and intervene quickly enough. And, while this may not be a life-threatening manifestation of au-toimmune toxicity, it can leave patients with a permanent need of additional medication and adrenal insufficiency, which can lead to infection. So, this really needs to be high on the clini-cian’s mind.

Case Study: Presented by Dr. FlahertyInitial Presentation

• 35-year-old man • Fairly invasive primary melanoma• Bulky lymph node involvement • Participated in an adjuvant therapy clinical trial• Restaging scans during the course of that study revealed

the emergence of metastatic disease• Multiple lesions present, 10 liver lesions with the largest

one measuring 3 cm, bilateral adrenal metastases• LDH elevated to four times the upper limit of normal• No symptoms of capsular distention or any other obvious

symptomatic complaint• Rising bilirubin• BRAF V600E mutation

Dr. Flaherty: Both the disease burden and the elevation in LDH, even in the absence of significant disease-related symp-toms, really push one to make a decision, in this case for BRAF inhibitor therapy, so the patient was initiated on vemurafenib


· CME ·

960 mg twice daily in a clinical trial. After one week of therapy, the patient noted significant sun sensitivity, with a severe burn on the back of his hands after just driving the car. Then, some pain in the wrists and knees manifested after 2 weeks, worsening by the fourth week, becoming intolerable to the patient, along with fatigue.

We interrupted treatment, and pretty quickly the side effects resolved, as they often do. Three, four days of interruption is usually the maximum needed, and then the patient restarted on 720 mg. The patient had had a history of really mild psoriasis, but that worsened in the third month of treatment. He was able to stay on therapy (720 mg) for 9 months. With this amount of disease burden, that was a pleasant surprise. At the time, we didn’t have as many options as we do now, and I think one won-ders, even in a case like this, whether one might think differently now about how long to treat with BRAF inhibitor therapy before considering ipilimumab, which unfortunately this patient never received.Dr. Weber: Do you think it was pre-ordained that this patient would progress relatively quickly?Dr. Flaherty: Yes. The patients with lower disease burden are the ones who have a chance of having longer-term responses.38 Disease control is probably not going to last beyond a year at the most for a patient who starts off with this kind of disease burden.Dr. Weber: Wasn’t it true in several of the randomized ipilim-umab trials that LDH and M1c status weren’t negative prognos-tic factors? Should this patient have had BRAF inhibitor induc-tion or a BRAF plus MEK inhibitor, and then, in spite of no relapse, be switched to an immunotherapy?Dr. Wolchok: You’re correct that in the clinical trials of ipilim-umab there was benefit across all of these different parameters.39

And, I do think that this might be a patient that once achieving a maximal response, you could consider the idea of switching over to immunotherapy with the goal of introducing more durability to the response. With that said, we know that when this has been tried by colleagues of ours, sometimes the patient will call after being off of the BRAF inhibitor for a few weeks and complain of returning symptoms. You can see the markers rising in terms of the LDH, and so your hands may be forced to go back on the medicine that was providing such a good benefit when you stopped it. There’s no clear answer yet.Dr. Weber: How long do you continue treatment past complete response?Dr. Flaherty: If you’re worried about microscopic disease existing elsewhere, you can’t lay eyes anymore on radiographic evidence of disease. We just don’t know whether BRAF inhibitor-based therapy significantly prolongs control or keeps those microscopic metastases hibernating, or could even potentially eradiate them. Absent the evidence from ongoing adjuvant trials, which thank-fully are being undertaken, I think it’s really difficult to say. And, in clinical trials, patients who had complete responses, generally speaking, stayed on treatment.

ConclusionsDr. Weber: With both BRAF inhibitor therapy and immuno-therapy, sometimes the best thing to do is to change nothing. Sometimes you have to fold, and you have to move on to another therapy. Dr. Flaherty: All patients should be tested for BRAF mutations in the metastatic setting, but that does not force your hand in terms of making a treatment decision. But, I think you need to act, at the moment, based on clinical characteristics and disease burden characteristics until we have more evidence.Dr. Wolchok: We have accomplished a significant amount with these therapies, but there still are far too many patients who are not having durable disease control; therefore, it’s extremely im-portant to continue to consider clinical trials to be a very high priority, and for colleagues in the community to make clinical trials available to their patients through cooperative groups or referral to academic centers. REFERENCES1. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711-723.2. Rosenberg SA, Yang JC, Topalian SL, et al. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA. 1994;271(12):907-913.3. Schadendorf D, Hodi FS, Robert C, et al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in metastatic or locally advanced, unresectable melanoma. Presented at: European Cancer Congress 2013 (ESMO-ECCO-ESTRO); Am-sterdam, The Netherlands; September 28, 2013. Abstract LBA24.4. Saenger YM, Wolchok JD. The heterogeneity of the kinetics of re-sponse to ipilimumab in metastatic melanoma: patient cases. Cancer Immun. 2008;8:1.5. Postow MA, Callahan MK, Barker CA, et al. Immunologic cor-relates of the abscopal effect in a patient with melanoma. N Engl J Med. 2012;366(10):925-931.6. Hiniker SM, Chen DS, Knox SJ. Abscopal effect in a patient with melanoma. N Engl J Med. 2012;366(21):2035; author reply 2035-2036.7. Okwan-Duodu D, Pollack BP, Lawson D, Khan MK. Role of ra-diation therapy as immune activator in the era of modern immuno-therapy for metastatic malignant melanoma [published online ahead of print May 2, 2013]. Am J Clin Oncol. 8. ClinicalTrials.gov. A pilot study of ipilimumab in subjects with stage IV melanoma receiving palliative radiation therapy. Clinical Trials Identifier NCT01449279. 9. ClinicalTrials.gov. Phase II randomized trial of ipilimumab versus ipilimumab and radiotherapy in metastatic melanoma. Clinical Tri-als Identifier NCT01689974.10. ClinicalTrials.gov. Radiotherapy as an immunological booster in patients with metastatic melanoma or renal cell carcinoma treated with high-dose interleukin-2: evaluation of biomarkers of immunologic and therapeutic response. Clinical Trials Identifier



NCT01884961.11. Merelli B, Massi D, Cattaneo L, Mandalà M. Targeting the PD1/PD-L1 axis in melanoma: biological rationale, clinical challenges and opportunities. Crit Rev Oncol Hematol. 2014;89(1):140-165. 12. Nivolumab is active in ipilimumab-refractory melanoma [pub-lished online ahead of print October 31, 2013]. Cancer Discov. 2013;3(12):1326. doi: 10.1158/2159-8290.CD-RW2013-240. 13. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369(2):122-133.14. ClinicalTrials.gov. Phase 2, randomized, double blinded, study of nivolumab (BMS-936558) in combination with ipilimumab vs ipi-limumab alone in subjects with previously untreated, unresectable or metastatic melanoma. Clinical Trials Identifier NCT01927419.15. ClinicalTrials.gov. A phase 3, randomized, double-blind study of nivolumab monotherapy or nivolumab combined with ipilimumab versus ipilimumab monotherapy in subjects with previously untreat-ed unresectable or metastatic melanoma. Clinical Trials Identifier NCT01844505.16. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443-2454.17. Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366(26):2455-2465.18. Chapman PB, Hauschild A, Robert C, et al, for the BRIM-3 Study Group. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364(26):2507-2516. 19. Ascierto PA, Minor D, Ribas A, et al. Phase II trial (BREAK-2) of the BRAF inhibitor dabrafenib (GSK2118436) in patients with metastatic melanoma. J Clin Oncol. 2013;31(26):3205-3211.20. Paraiso KH, Fedorenko IV, Cantini LP, et al. Recovery of phos-pho-ERK activity allows melanoma cells to escape from BRAF in-hibitor therapy. Br J Cancer. 2010;102(12):1724-1730.21. Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367(18):1694-1703.22. FDA News Release. FDA approves Mekinist in combination with Tafinlar for advanced melanoma. http://www.fda.gov/News-Events/Newsroom/PressAnnouncements/ucm381159.htm. Janu-ary 10, 2014. Accessed January 16, 2014.23. Vin H, Ojeda SS, Ching G, et al. BRAF inhibitors suppress apoptosis through off-target inhibition of JNK signaling. Elife. 2013;2:e00969.24. Thakur MD, Fisher R, Salangsang F, et al. Modeling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance. Presented at: the AACR Annual Meeting 2013; April 6-10, 2013; Washington, DC. Abstract LB-144. 25. Liu C, Peng W, Xu C, Lou Y, et al. BRAF inhibition increases tumor infiltration by T cells and enhances the antitumor activity of adoptive immunotherapy in mice. Clin Cancer Res. 2013;19(2):393-403. 26. Koya RC, Mok S, Otte N, et al. BRAF inhibitor vemurafenib

improves the antitumor activity of adoptive cell immunotherapy. Cancer Res. 2012;72(16):3928-3937.27. Ribas A, Hodi FS, Callahan M, Konto C, Wolchok J. Hepato-toxicity with combination of vemurafenib and ipilimumab. N Engl J Med. 2013;368(14):1365-1366. 28. ClinicalTrials.gov. A sequential safety and biomarker study of BRAF-MEK inhibition on the immune response in the context of CTLA-4 blockade for BRAF mutant melanoma. Clinical Trials Iden-tifier NCT01940809.29. Dummer R, Goldinger SM, Turtschi CP, et al. Vemurafenib in patients with BRAFV600 mutation-positive melanoma with symp-tomatic brain metastases: final results of an open-label pilot study. Eur J Cancer. 2013;pii: S0959-8049(13)00979-9. 30. Long GV, Trefzer U, Davies MA, et al. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13(11):1087-1095.31. Margolin K. Ipilimumab in a phase II trial of melanoma patients with brain metastases. Oncoimmunology. 2012;1(7):1197-1199.32. Del Vecchio M, Di Guardo L, Ascierto PA, et al. Efficacy and safety of ipilimumab 3 mg/kg in patients with pretreated, metastatic, mucosal melanoma. Eur J Cancer. 2014;50(1):121-127.33. Luke JJ, Callahan MK, Postow MA, et al. Clinical activity of ipilimumab for metastatic uveal melanoma: a retrospective review of the Dana-Farber Cancer Institute, Massachusetts General Hospital, Memorial Sloan-Kettering Cancer Center, and University Hospital of Lausanne experience. Cancer. 2013;119(20):3687-3695.34. Wilgenhof S, Du Four S, Everaert H, Neyns B. Patterns of re-sponse in patients with pretreated metastatic melanoma who re-ceived ipilimumab 3 mg/kg in a European expanded access program: five illustrative case reports. Cancer Invest. 2012;30(10):712-720.35. Abu-Abed S, Pennell N, Petrella T, et al. KIT gene mutations and patterns of protein expression in mucosal and acral melanoma. J Cutan Med Surg. 2012;16(2):135-142.36. Lian B, Si L, Cui C, et al. Phase II randomized trial compar-ing high-dose IFN-α2b with temozolomide plus cisplatin as systemic adjuvant therapy for resected mucosal melanoma. Clin Cancer Res. 2013;19(16):4488-4498.37. Carvajal RD, Sosman JA, Quevedo F, et al. Phase II study of se-lumetinib versus temozolomide in GNAQ/GNA11 mutation uveal melanoma. Presented at: 2013 American Society of Clinical Oncolo-gy Annual Meeting; June 1, 2013; Chicago, IL. Abstract CRA9003.38. Ribas A, Kim KB, Schuchter L, et al. BRIM 2: an open-label, multicenter phase II study of vemurafenib (PLX4032, RG7204) in previously treated patients with BRAFV600E mutation-positive metastatic melanoma. J Clin Oncol. 2011;29(15 suppl; abstr 8509).39. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus da-carbazine for previously untreated metastatic melanoma. N Engl J

Med. 2011;364(26):2517-2526.


WHAT WOULD CLINICIANS DO IF BRCA OR LYNCH POSITIVE?· 9TH ANNUAL INTERNATIONAL SYMPOSIUM ON OVARIAN CANCER AND GYNECOLOGIC MALIGNANCIES ·

What Would Clinicians Do If BRCA or Lynch Positive?Medical Management, Insurance Discrimination,

and Confidentiality

Over the last decade, clinically-based genetic testing has become commonplace. Two of the most well-established tests are for mu-tations within the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2 (BRCA 1/2) and the Lynch syndrome (he-reditary nonpolyposis colon cancer, or HNPCC) genes, which predispose patients to colorectal, uterine and ovarian cancers.1

Inherited mutations are thought to account for 5% to 10% of female breast cancers; most alterations occur in the BRCA1 and BRCA 2 genes.1 Lynch syndrome accounts for 2% to 4% of all colorectal cancer cancer cases.2

Patients at risk of carrying these genetic alterations face sev-eral sometimes difficult decisions regarding testing, including whether to be tested in the first place and what to do with the information gained from the testing. Management options that might be considered include earlier and heightened surveillance programs, prophylactic surgery, or chemoprevention. Addition-ally, a host of psychosocial, emotional, and medical/scientific factors must be considered during the decision-making process.

Well-informed clinicians can help their patients explore these issues. In the late 1990s, the commercial availability of tests for BRCA 1/2 and Lynch syndrome genes preceded long-term clini-cal data on their use and the efficacy of subsequent management options. In 1998, a team led by Ellen Matloff, MS, CGC, direc-tor of the Yale Cancer Genetic Counseling Program at the Yale School of Medicine/Yale Cancer Center, in New Haven, Con-necticut, conducted a study to explore what cancer genetic test-ing specialists would do if they themselves were faced with being tested or had been tested.3

The landscape of genetic testing and cancer care has changed-dramatically since that study was published in 2000.3 More data and clinical experience have been gained with genetic counsel-ing and testing, surveillance, prevention, and management. “We chose to repeat our study to examine how specialists’ perspec-

tives have changed over the past 14 years,” said Matloff during a presentation of the study results at the 9th Annual International Symposium on Ovarian Cancer and Gynecologic Malignan-cies, held in Philadelphia, Pennsylvania, on October 5, 2013 by Physicians’ Education Resource, LLC.

Matloff discussed the changes in the perspectives of active members of the National Society of Genetic Counselors Special Interest Group in Cancer (n = 216) on cancer genetic testing, prophylactic surgery, confidentiality, and insurance discrimina-tion between 1998 and 2012. Data for the updated study were collected via an email-based, computer questionnaire. Overall, the investigators noted some dramatic shifts in opinion over the last decade and a half.

According to Matloff, the take-home messages learned from this study that are most relevant to conference attendees include:

•Mostofthesespecialists—whoworkinthefieldanddealwiththeseissueseveryday—believethatgenetictestingforBRCA and Lynch syndrome is a safe and reasonable mea-sure to take

•Patientswhohaveconcernsaboutgenetictesting,includ-ing confidentiality and insurance billing, can be counseled that they do not have to use an alias and that they can feel comfortable billing their health insurance company for the tests

From a scientific perspective, Matloff said, “We now have long-term data showing that we understand the penetrance of BRCA and Lynch Syndrome; we understand our surveillance, chemoprevention, and prophylactic options. And we have long-term data indicating that those are helpful options to carriers and can reduce their cancer risks.”

Commenting on the study results, published in the July 13, 2013 issue of the Journal of Genetic Counseling,4 medical oncolo-gist/hematologist Karen Tedesco, MD, director of the Heredi-tary Cancer Risk Assessment Program at New York Oncology Hematology in Albany, New York, said, “These results suggest that the extensive data regarding strategies for cancer risk reduc-tion and early detection in high-risk populations that has be-come available since the late 1990s has led to important changes in practice patterns, which hopefully lead to better patient care and outcomes.”

Based on a presentation by Ellen Matloff, MS, CGC, director of the Yale Cancer Genetic Counseling Program at the Yale School of Medicine/Yale Cancer Center, in New Haven, Connecticut at the 9th Annual International Symposium on Ovarian Cancer and Gynecologic Malignancies®, held in Philadelphia, Pennsyl-vania, on October 5, 2013 by Physicians’ Education Resource®, LLC.


WHAT WOULD CLINICIANS DO IF BRCA OR LYNCH POSITIVE?

BRCA Mutations Responders were asked whether they would undergo genetic test-ing if their own risk of carrying a BRCA mutation was 50%. In 1998, 85% (n = 136) of the professionals answered yes. “That number significantly changed in 2012 when 99% (n = 214; P = .0006) said they would pursue testing,” said Matloff. The main reasons respondents would pursue testing were that the in-formation would change medical management (98%) or be help-ful to their family members (81%), that testing would lessen their uncertainty (67%), or they would do it for the 50% probability that it would be negative.4 The two cancer genetic specialists who answered no cited their reasons as fear of genetic discrimination (n = 1) or that it would not affect medical management (n = 1).

No significant change in response rate was observed between 1998 and 2012 regarding the decision to have prophylactic oo-phorectomy in the event of a positive BRCA test result. In 2012, most specialists who would opt to have their ovaries removed said it was because they lacked confidence in ovarian cancer sur-veillance and treatment (90%).

The trending opinion regarding bilateral prophylactic mastec-tomy shifted considerably, however. Nearly 60% of the specialists (n = 126) would opt for a prophylactic bilateral mastectomy if they tested positive for a BRCA mutation at age 35. That was a significant increase from the approximately 25% (n = 39; P = .0001) who said yes in the 1998 study.3

Matloff called this, “An unforeseen trend that occurred even though we have had a major improvement in breast imaging since 1998; we have seen the advent of breast MRI, which as you know is very sensitive.” Furthermore, she said, “We have chemo-preventive options, for example, tamoxifen and raloxifene, and even aromatase inhibitors, which can be used in healthy women who carry a mutation to reduce their risk of developing breast cancer.”

Those who would opt to have their breasts removed said it would be to decrease their risk of cancer development (58%), avoid fear and worry (49%), and because they had a lack of confi-dence in surveillance (12%). Reasons respondents cited in 2012 for indicating they would not opt for prophylactic breast surgery (n = 90) were confidence in surveillance (33%, n = 72), negative impact of surgery on body image and sexuality (22%, n = 48), would not completely reduce risk (11%, n = 23), and chemopre-vention preference (9%, n = 19).

Tedesco remarked on these study results, “Oncologists are feeling more comfortable now, compared to several years ago, advising appropriate patients to undergo genetic testing now that we are better able to interpret the results and support our recom-mendations for surveillance and prophylaxis with pertinent data. These results are what I would have expected based on the body of knowledge that has become available since the genes were dis-covered.”

Mutations in Genes Associated With Lynch SyndromeLynch syndrome increases risk for cancers of the colon, uterus, and ovaries, as well as other types of cancer. One option for patients who test positive for a deleterious Lynch mutation is prophylactic colectomy. In contrast to the results for prophy-lactic mastectomy, the number of specialists who would opt for colectomy decreased over the last 14 years from 17.4% to 7% (P = .0002).

The reasons cited by 2012 respondents who would not opt for prophylactic colectomy related to their confidence in colonos-copy (88%, n = 189), lowered quality of life after surgery (80%, n = 173), desire to postpone surgery until after detection of le-sion (58%, n = 125), or lowered body image (32%, n = 70). For the few that did say they would opt for surgery, it was to reduce risk or avoid routine colonoscopies.

“I think that this question shows us that there wasn’t an in-creased uptake of every prophylactic surgery, just of some,” Mat-loff said during her presentation.

On the other hand, the number of specialists who, if faced with a positive test for a deleterious Lynch mutation at age 35, would have their uterus removed prophylactically, rose from 54% in 1998 to nearly 80% in 2012 (P = .0057). Reasons for favoring uterus removal were: a reduction of cancer risk (79%, n = 170), organ no longer needed (62%, n = 133), or would not alter life-style or body image (51%, n = 110). Those who wouldn’t opt for surgery cited the following reasons: they would postpone surgery until after menopause (11%, n = 23), lack of evidence of sur-vival benefit (9%, n = 19), endometrial cancer is treatable (7%, n = 16), cancer risk is not high enough to justify surgery (6%, n = 13), or screening is adequate (6%, n = 12).

The number of specialists who would have their ovaries re-moved prophylactically if they tested positive for a deleterious Lynch mutation at age 35 increased from about 52% in 1998 to 78% in 2012 (P = .0090). Among those that would have the sur-gery, there was a belief that ovarian cancer surveillance is inad-equate (77%, n = 166), that there would be a reduction of cancer risks (72%, n = 156), or that it would not alter lifestyle or body image to have ovaries removed (39%, n = 84). For those who wouldn’t have the surgery, they cited that they would delay the surgery until a later age (13%, n = 28) or that they did not think risk for ovarian cancer associated with Lynch syndrome was high enough to warrant this surgery (13%, n = 28).

Insurance and ConfidentialityIn the 2012 survey, 95% of specialists said they would bill their insurance company for genetic testing, as opposed to 23% who answered yes to this question in 1998 (P < .0001). “For those of you who were doing this work at that time, you may remember that people were using aliases, paying for tests with cash, and were very concerned about confidentiality,” said Matloff.


· 9TH ANNUAL INTERNATIONAL SYMPOSIUM ON OVARIAN CANCER AND GYNECOLOGIC MALIGNANCIES ·

Why the change in opinion? More than 80% (n = 176) of those who answered yes said it was because they would want prophy-lactic surgery later if they received a positive test result and that their insurance would need to know about it. Other reasons in-cluded confidence in legislation to protect them (80%, n = 173) or residence in a country with socialized medicine (7%, n = 15).

“The Genetic Information Nondiscrimination Act (GINA) was signed in 2008 and provided greater protection against dis-crimination so a lot of people felt confidence just in that alone,” said Matloff. The few that replied no (5%, n = 11) didn’t feel ex-isting laws provide adequate protection and were worried about insurability and discrimination.

Approximately one-fourth of the specialists surveyed in 1998 responded that they would use an alias if they underwent genetic testing. That number dropped to about 3% in 2012 (P < .0001). Specialists who would not use an alias felt that the information is important to their medical record (88%, n = 190), that their insurance would need that information in order to pay for it (81%, n = 174), that confidentiality measures are adequate, or were uncomfortable using an alias (38%, n = 83). Concerns about discrimination and confidentiality were cited by the very few who answered yes.

“Patients often ask whether health insurance discrimination is something they need to be concerned about when pursuing genetic testing. Now with several years of experience, we can advise patients that there have not been cases like that, and in-form them that GINA prohibits health insurance discrimination based on genetic predisposition,” said Tedesco. “The results of this study suggest that this barrier that existed many years ago has largely been removed.”

Speaking to the applicability of these results to her own medi-cal oncology/hematology practice, Tedesco said, “As the chair-man of our hereditary cancer risk assessment program, I see patients referred by non-oncologists to undergo assessment for testing based on family history. The majority of patients referred to our program for testing are patients from our practice who have a cancer diagnosis already and genetic testing is requested due to risk for second cancers, concern for family members, etc.”

Compared with the status of the field in 1998, genetic test-ing is now well established. Clinicians and the general public are more familiar with genetic testing, BRCA, and Lynch syn-drome. “Many of us have patients who carry mutations and can see the natural progression of disease, as well as what it is like for patients who have the mutation to go through surveillance, or chemoprevention, or the diagnosis of cancer over time,” said Matloff.

References1. American Cancer Society. Cancer Facts & Figures 2013. Atlanta: American Cancer Society; 2013.2. National Comprehensive Cancer Network. NCCN Clinical Prac-tice Guidelines in Oncology (NCCN Guidelines): Colorectal Can-cer Screening. Version 2.2013. July 1, 2013. Available at: http://www.nccn.org/professionals/physician_gls/pdf/colorectal_screen-ing.pdf. Accessed January 20, 2014.3. Matloff ET, Shappell H, Brierley K, Bernhardt BA, McKinnon W, Peshkin BN. What would you do? Specialists’ perspectives on cancer genetic testing, prophylactic surgery, and insurance discrimination. J Clin Oncol. 2000;19:2484-2492.4. Matloff ET, Bonadies DC, Moyer A, Brierley KL. Changes in spe-cialists’ perspectives on cancer genetic testing, prophylactic surgery, and insurance discrimination: then and now. J Genet Counsel. 2013 Jul 13. [epub ahead of print].

Online CME Activities

Earn AMA PRA Category 1 Credits™

Hematologic Malignancies Edition

Your go-to source for online CME!


These activities are supported by educational grants from Celgene Corporation, Delcath Systems, Inc., Eisai Inc., Genentech, Lilly USA, LLC, Merck Sharp & Dohme Corporation, Novartis Pharmaceuticals Corporation, Onyx Pharmaceuticals, Provectus Pharmaceuticals, Inc and Seattle Genetics, Inc

Community Practice Connections: 17th Annual International Congress on Hematologic Malignancies®: Focus on Leukemias, Lymphomas and MyelomaEarn up to 3.0 AMA PRA Category 1 Credits™

Join Drs. James Berenson, Jennifer Brown, Harry Erba, and Andre Goy as they discuss emerging clinical data regarding new agents and evolving strategies for the treatment of hematologic malignancies from the 17th Annual International Congress on Hematologic Malignancies®. Topics include maintenance therapy and novel agents for multiple myeloma, immunomodulatory agents and strategies for treating elderly patients with CLL, frontline therapy and monitoring response for CML, and current and emerging treatment options for poor-risk DLBCL and indolent lymphomas.

Community Practice Connections: Challenges in Multiple MyelomaEarn up to 3.0 AMA PRA Category 1 Credits™

Join Drs. Sagar Lonial, Sundar Jagannath, and David H. Vesole as they provide insight and commentary on emerging data, established guidelines, and latest advances in the field of multiple myeloma, with a focus on clinical applications. Topics include factors in deciding on frontline therapy, the role of transplant in the era of novel agents, incorporating targeted therapy into current treatment paradigms, and the role of maintenance therapy.

American Journal of Hematology online activity coming March 1, 2014!Earn up to 1.0 AMA PRA Category 1 Credits™

This activity will serve as an update on advances in the field and will focus on the clinical implications of metastatic melanoma and basal cell carcinoma, including novel treatment regimens for the management of advanced melanoma, including immunomodulatory antibodies, BRAF inhibitors, multiple tyrosine kinase inhibitors, antiangiogenic agents, and other novel agents in earlier phases of development.Physicians’ Education Resource®, LLC is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

CME_HEMCancer_Asize.indd 1 2/11/14 1:33 PM


INSTRUCTIONS FOR AUTHORSINSTRUCTIONS FOR AUTHORS

Mission & Scope:The American Journal of Hematology/Oncology is a quarterly, peer-reviewed publication that provides research reviews, clinical con-troversies, and commentary that address cutting-edge develop-ments in genomics, targeted therapies, molecular diagnostics, and pathways. As the official publication of Physicians’ Educa-tion Resource (PER), the journal’s mission is to advance cancer care through professional education. The journal aims to provide practical interpretations of the lat-est advances in medical and hematologic oncology and to help practicing oncologists gain a better understanding of how these advances have changed the treatment landscape for both solid and hematologic malignancies. Articles published in the journal will illustrate successes and failures in clinical practice and pro-vide practical insights into the myriad decisions oncologists face in everyday clinical practice.

Readership:The American Journal of Hematology/Oncology circulates to 10,000 practicing oncologists across the country. Our audience includes medical oncologists, hematologists, pathologists, dermatologists, radiation oncologists, and surgical oncologists.

Submitting Manuscripts:Requirements for all submissions generally conform to the “Uni-form Requirements for Manuscripts Submitted to Biomedical Journals.”1 Our peer review process is blinded, so all identifying information (ie, author names, affiliations, etc) must be removed from the manuscript file before submission. Manuscripts submitted for publication in The American Journal of Hematology/Oncology must not have been published previously (either in whole or in part) nor currently be submitted elsewhere in either identical or similar form. Material posted on the In-ternet or disseminated in any other electronic form constitutes prior publication and may not be considered. Previous publica-tion of a small fraction of the content of a manuscript does not necessarily preclude its being published in The American Journal

of Hematology/Oncology, but the editors need information about previous publication when deciding how to use space in the jour-nal efficiently. These restrictions on prior publication, however, do not ap-ply to abstracts or poster presentations published in connection with scientific meetings or to working papers that have been posted on the Web to facilitate peer feedback. Authors must indicate in the cover letter whether any por-tion of the manuscript has been previously published and are re-quired to submit copies of related publications (either published, in preparation, or submitted), as well as any manuscripts cited as “in press” to the editors for review. Duplicate, redundant, and/or fragmented publications are not permitted. Refer to Chapter 5 of the American Medical Association (AMA) Manual of Style for further information on duplicate publication.2 Authors should also include a statement in the body of the paper that indicates whether the study was approved by an institutional review board. For all papers (when appropriate), a statement confirming that the informed consent of study subjects was obtained should be included in the manuscript.

Articles of Interest:The editors are pleased to consider manuscripts on a wide range of topics related to the journal’s mission. Authors should write for a sophisticated general audience and recognize that many of The American Journal of Hematology/Oncology readers are not re-searchers. In addition to evaluating articles for scientific merit, the editors will also assess the overall relevance of the work to the journal’s audience. If you are uncertain of an article’s appropriateness for The American Journal of Hematology/Oncology, we encourage authors to send an abstract or outline of an article to the Editorial Office ([email protected]) to facilitate a pre-submission review with the Editor-in-Chief. Submissions generally fall into one of the following categories: (1) original research; (2) research reviews; (3) clinical controver-sies; or (4) commentaries.

The American Journal of Hematology/Oncology


INSTRUCTIONS FOR AUTHORS

Original research articles should employ a clear research ques-tion and an appropriate research design to report the clinical or economic outcomes of a specific intervention or regulation. Articles should be 2000-2500 words (excluding abstract, refer-ences, tables, etc) and contain no more than 5 graphic elements. Supplemental data (extra tables, figures, or appendices) will be made available on the journal’s website at the time of publica-tion. Authors should indicate what material is intended as Web-only content and include the appropriate reference or callout in the text to these Web-exclusive elements.Research reviews should provide concise, up-to-date reviews of novel therapies and treatment strategies. Authors should present real-world examples and discussion of the inherent challenges of incorporating new therapeutics, new treatment strategies, and new diagnostic tools into clinical practice. The same length re-strictions for academic perspectives (2000-2500 words; no more than 5 graphic elements) apply to these clinical reviews.Clinical controversies are brief (<1200 words) opinion pieces that discuss relevant and controversial issues in oncology (eg, maintenance rituximab and its role in indolent lymphoma, should DCIS be considered a cancer, when to intervene in pros-tate cancer, what is the quality of life impact of PFS vs OS im-provements, etc).Case studies should provide descriptive data or case analyses that illustrate best practices in providing high-quality cancer care to patients in the community. Case studies should be <1500 words and contain no more than 2 graphic elements.

Authorship:Only persons who have made a direct contribution to the con-tent of a paper should be listed as authors. The number of au-thors listed with the manuscript should not exceed 10; more than 10 requires written justification and approval from the Editor-in-Chief. The American Journal of Hematology/Oncology uses the criteria provided by the “Uniform Requirements for Manuscripts Sub-mitted to Biomedical Journals”1 to determine authorship. Each author should have participated sufficiently in the work to take public responsibility for the content. Authorship credit should be based only on substantial contributions to (a) conception and design, or analysis and interpretation of data; and to (b) draft-ing the article or revising it critically for important intellectual content; and on (c) final approval of the version to be published. Conditions (a), (b), and (c) must all be met.1 Individuals who have contributed to a paper but who do not meet the criteria for authorship should be acknowledged.

Disclosures:It is our policy to have all authors disclose relationships with any commercial interest that may present a conflict of interest if: (a) the relationship is financial and occurred within the past 12

months; and (b) the author discusses products or services of that commercial interest. Relevant financial relationships are those relationships in which the author (and/or the author’s spouse or partner) benefits in any dollar amount by receiving a salary, royalty, intellectual property rights, consulting fee, honoraria, ownership interest (eg, stocks, stock options, or other ownership interests, excluding diversified mutual funds), or other financial benefit. Financial benefits are usually associated with roles, such as employment, management position, independent contractor (including contracted research), consulting, speaking and teach-ing, membership on advisory committees or review panels, board membership, and/or other activities for which remuneration is received or expected. In addition, authors are required to report all financial and material support for their research, which in-cludes (but is not limited to) grant support and funding sources and any provision of equipment or supplies. To this end, all au-thors must read and sign the journal’s Author Disclosure Form.

The name of the organization funding or initiating a research project should be made explicit on the title page (eg, “This study was funded by the XYZ Corporation.”). Relevant financial rela-tionships (whether direct to the authors or through a third party) for research and/or writing, including funding, grants, hono-raria, etc, must also be named on the title page. If the funding organization had any role in the collection of data, its analysis and interpretation, and/or in the right to approve or disapprove publication of the finished manuscript, this must be noted in the cover letter and described in the text. The editorial staff may inquire further about financial disclosure after the manuscript is submitted. If the manuscript is accepted for publication, disclo-sure statements will be printed as part of the published paper.

Manuscript Specifications:Manuscript components (cover letter, text, tables, figures, related papers, etc) must be included as part of the submission process. All manuscripts should include the following components:

Cover Letter: A cover letter must accompany each submission and include any background information about the submission (ie, how it contributes to the existing literature, whether any por-tion has been previously presented or published, etc) that would aid in the editors’ initial evaluation. Include a statement that the manuscript has been read and approved by all authors.

Titles. Titles should be concise (fewer than 10 words) and stim-ulate reader interest. Provide a brief running title in addition to the main article title. The title page should include the following information:

•thecompletemanuscripttitleandsubtitle,ifany•the fullnamesof eachauthor, followedby theirhighest

academic degree•thename,address,telephone,fax,ande-mailinformation

of the corresponding author•theinstitutionalaffiliationsforeachauthoratthetimethe

INSTRUCTIONS FOR AUTHORS


INSTRUCTIONS FOR AUTHORSINSTRUCTIONS FOR AUTHORS

work was completed•aconcisesummaryofthearticletoappearinthetableof

contents (ie, no more than 25 words) •practicalapplicationofyourwork(ie,abulletedlistthat

highlights the real-world impact of your work)•indicationofthesourceoffunding(includinggrantnum-

bers, grant agencies, corporations, or sponsors)•thenumberofpages,references,figures,andtables•awordcount(excludingreferences,tables,andfigures)

Abstract. An abstract is required for all manuscript submis-sions. The abstract should not exceed 250 words and should summarize the salient data and the principal conclusion of the piece.

Text. All text should be double-spaced, including the acknowl-edgments, references, tables, and legends. Cite references, tables, and figures in sequential order in the body of the paper. Mea-surements of length, height, weight, and volume should be re-ported in metric units. Temperatures should be given in degrees Celsius. Blood pressures should be listed in millimeters of mer-cury. Except for units of measure, abbreviations are discouraged.

Any abbreviation or acronym must be spelled out in full when it first appears in the text, followed by its abbreviation in paren-theses. State the generic name (not the trade name) for all drug names.

Permissions: Data and/or figures reproduced from another pub-lished source must be properly cited and acknowledged. Authors are required to obtain written permission from the appropriate author and/or copyright holder to reproduce previously pub-lished or copyrighted material. Authors must also obtain per-mission from at least 1 author when citing unpublished data, “in-press” articles, and/or personal communications. Copies of permission statements should be included with manuscript sub-missions.

Acknowledgments. Include a list of acknowledgments, if appro-priate. Refer to the “Authorship” section for an explanation of what constitutes authorship and for guidance in distinguishing contributions that warrant an acknowledgment. The correspond-ing author must affirm that he/she has received permission to list the individuals in the acknowledgment section (see bottom of Authorship Form).

References. Begin the reference section on a new page and dou-ble-space both within and between reference citations. Number references sequentially in the order cited in the text—do not al-phabetize. Provide the names of all authors when there are six or fewer; if there are more than six authors, list only the first three authors followed by “et al.” All references must be verified by the authors and should conform to the AMA Manual of Style.2

References cited only in table or figure legends should be numbered in accordance with the sequence established by the first mention of the particular table or figure in the text.

References to papers accepted but not yet published should be designated as “in press” and included in the reference sec-

tion. Information from manuscripts submitted but not accepted should be cited in the text as “unpublished observations” with written permission from the source. (Include copies of any “in press” and “submitted” manuscripts [ie, papers under consider-ation at other journals] for the editors’ evaluation as part of your submission.)

Avoid citing “personal communication” unless it provides es-sential information not available from a public source, in which case the name of the person, his or her degree, and the date of communication should be cited in parentheses in the text. Authors should obtain written permission and confirmation of accuracy from the source of a personal communication (see “Permissions” section). Note the format and punctuation in the following sample references:1. Cortes JE, Kim DW, Kantarjian HM, et al. Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leuke-mia: results from the BELA trial [published online ahead of print September 4, 2012]. J Clin Oncol. 2012;30(28):3486-3492.2. Wierda WG, O’Brien S. Chronic lymphoblastic leukemia. In: DeVita VT Jr, Lawrence TS, Rosenberg SA, eds. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology, 9th ed. Philadelphia: Lippincott Williams & Wilkins; 2011.3. American Cancer Society. Cancer Facts and Figures 2012. http://www.cancer.org/acs/groups/content/@epidemiologysur-veilance/documents/document/acspc-031941.pdf Accessed Octo-ber 5, 2012.

Graphic Elements. Judicious use of graphic elements is strongly encouraged, as space in the journal is limited. The American Jour-nal of Hematology/Oncology will print only essential tables and figures—no more than 5 graphic elements. All supplemental data (eg, appendices and lengthy tables) will be posted on the journal’s Web site at the time of publication. Authors should indicate what material is intended for Web-exclusive content and include the appropriate reference or callout in the text to these Web-exclusive elements.

Tables. Place each table on a new page. Number tables sequen-tially in the order they are cited in the text. Include a title for each table. Special characters, abbreviations, and symbols must be explained in a footnote to the table.

Figures. Figures are generally redrawn by our production team. Avoid the use of shading in bar graphs or pie charts—use color or crosshatch patterns instead. Number all figures in the order they are mentioned in the text. Any previously published figures must be accompanied by written permission from the publisher and/or copyright holder (see “Permissions” section).

Legends. Legends should be double-spaced and include the fig-ure number and a brief description of the illustration. Identify all abbreviations used in the figure at the end of each legend.

Peer Review:Each manuscript is sent to the Editor-in-Chief for an internal evaluation to determine its appropriateness. Manuscripts that do

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not meet the journal’s criteria for overall appropriateness, rel-evance, originality, and scientific merit will be returned promptly (usually within 2 weeks) so that authors may pursue alternate avenues for publication.

Although reviewer selection is ultimately the decision of the editors, authors may provide the names and e-mail informa-tion of preferred and nonpreferred peer reviewers. Manuscripts deemed appropriate for The American Journal of Hematology/On-cology will be sent to external peer reviewers. Typically, a manu-script will be sent to a minimum of two reviewers who will be asked to provide feedback on the scientific merit of the paper.

The Editorial Office contacts reviewers in advance and asks them to complete their evaluation of a manuscript within two weeks. Reviewers are asked to treat manuscripts as confidential communications and not to share their content with anyone (ex-cept colleagues whom they ask to assist in reviewing) or to use the content for their own purposes. We do not send a manuscript to a reviewer who is affiliated with the same institution as any of the authors and ask reviewers to declare any potential conflicts of interest, such as personal ties to an organization with a vested interest in the topic of the manuscript.

Editorial Decisions:We judge manuscripts on the interest and importance of the topic, the intellectual and scientific strength, the clarity of the presentation, and relevance to our readers. We also consider the strength of the paper compared with other papers under review and the number of accepted and previously published papers in the paper’s category. Authors of original research and review articles should take pains to describe exactly how their findings add to the existing literature. The Editorial Office is committed to providing prompt pro-cessing times and to communicating timely decisions to authors. While the Editorial Office makes every effort to notify authors and keep them informed of any delays, most authors can expect a first decision on their manuscript in approximately 4 to 6 weeks. We communicate editorial decisions on acceptance or rejection only to the corresponding author. Almost all papers that we ac-cept require some editorial revision before publication.

Accepted Papers:Page proofs are e-mailed to the corresponding author (PDFs) be-fore publication. Authors can expect to receive proofs approxi-mately 3 to 4 weeks before the scheduled issue date. All proofs must be returned to the Editorial Office within 48 hours.

References1. International Committee of Medical Journal Editors. Uni-form requirements for manuscripts submitted to biomedical jour-nals: writing and editing for biomedical publication. [Updated April 2010.] http://www.icmje.org/urm_full.pdf. Accessed October 5, 2012.2. Iverson C, ed. Ethical and legal considerations. In: American Medical Association Manual of Style. 10th ed. New York, NY: Oxford University Press; 2007:125-300.

Editorial offices are located at:The American Journal of Hematology/OncologyOffice Center at Princeton Meadows, Bldg 400Plainsboro, New Jersey 08536

E-mail: [email protected]

March 15, 2014Crowne Plaza® Times Square - ManhattanNew York, NY


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Daniel P. Petrylak, MD Professor of Medicine (Medical Oncology) and Urology

Co-Director, Signal Transduction Research Program

Yale Cancer Center New Haven, CT

Leonard G. Gomella, MD, FACS The Bernard W. Godwin Professor of Prostate Cancer

Thomas Jefferson UniversityJefferson Medical CollegeChairman, Department of UrologyAssociate DirectorKimmel Cancer CenterPhiladelphia, PA

A. Oliver Sartor, MD Laborde Professor of Cancer Research Medicine and Urology Departments Tulane University School of Medicine New Orleans, LA

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