title: brentuximab vedotin and avd followed by involved-site

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Title: Brentuximab Vedotin and AVD followed by Involved-Site Radiotherapy in Early Stage, Unfavorable Risk Hodgkin Lymphoma Authors: Anita Kumar1, Carla Casulo2, Joachim Yahalom1, Heiko Schöder1, Paul M. Barr2, Philip Caron1, April Chiu1, Louis S. Constine2, Pamela Drullinsky1, Jonathan W. Friedberg2, John F. Gerecitano1, Audrey Hamilton1, Paul A. Hamlin1, Steven M. Horwitz1, Alexandra G. Jacob1, Matthew J. Matasar1, Gianna N. McArthur1, Susan J. McCall1, Alison J. Moskowitz1, Ariela Noy1, Maria L. Palomba1, Carol S. Portlock1, David J. Straus1, Nicholas VanderEls1, Stephanie L. Verwys1, Joanna Yang1, Anas Younes1, Andrew D. Zelenetz1, Zhigang Zhang1, and Craig H. Moskowitz1

Author Affiliations: 1Memorial Sloan Kettering Cancer Center, NY, NY 2Wilmot Cancer Institute, University of Rochester, Rochester, NY Corresponding Author: Anita Kumar, MD Memorial Sloan-Kettering Cancer Center 1275 York Avenue NY, New York 10065 Phone: 212-639-2668 Fax: 646-227-7257 Email: [email protected] Running head: Brentuximab Vedotin and CMT in Early Stage HL Previous presentation: Presented at the 56th American Society of Hematology, San Francisco, California, December 2014 and the 13th International Conference on Malignant Lymphoma, Lugano, Switzerland, June 2015 Abstract: 245 words Text: 3311 words Tables: 2 Figures: 4 Key Points:

• Brentuximab Vedotin and AVD followed by ISRT is well tolerated, without significant pulmonary toxicity

• Brentuximab Vedotin and AVD followed by ISRT is an effective therapy for unfavorable risk early stage HL, including bulky disease

Blood First Edition Paper, prepublished online July 25, 2016; DOI 10.1182/blood-2016-03-703470

Copyright © 2016 American Society of Hematology

For personal use only.on January 29, 2018. by guest www.bloodjournal.orgFrom

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Abstract:

This multicenter pilot study assessed the safety and efficacy of Brentuximab Vedotin (BV) and

AVD (adriamycin, vinblastine, and dacarbazine) followed by 30 Gray (Gy) involved site

radiation therapy (ISRT). Patients with newly diagnosed, early stage classical Hodgkin

lymphoma (HL) with unfavorable risk features were treated with 4 cycles of BV and AVD.

Patients who achieved a negative positron emission tomography (PET) scan (Deauville score of

1-3) received 30 Gy ISRT. Thirty patients received treatment and were assessable for toxicity.

Twenty-nine patients completed 4 cycles of BV+AVD and 25 patients BV+AVD+30Gy ISRT.

No clinically significant non-infectious pneumonitis was observed. Serious adverse events

(≥grade 3) were reported in 4 patients, including febrile neutropenia, peripheral neuropathy, and

hypertension. After 2 and 4 cycles of BV+AVD, 90% (26 of 29) and 93% (27 or 29) of patients

achieved a negative PET scan, respectively. Two patients with biopsy-proven primary refractory

HL were treated off-study. All 25 patients who completed BV+AVD+ISRT achieved a complete

response. With a median follow-up of 18.8 months, by intent to treat, the 1-year progression free

survival is 93.3% (95% CI 84-102). Overall, the treatment was well-tolerated with no evidence

of significant pulmonary toxicity. The majority of patients (≥90%) achieved negative interim

PET scans after 2 and 4 cycles of BV + AVD. Excluding the 2 primary refractory patients, all

patients are disease-free, suggesting this is a highly active treatment program even in patients

with substantial disease bulk. This study is registered at ClinicalTrials.gov as # NCT01868451.




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Introduction

The standard of care for patients with early stage, unfavorable risk Hodgkin lymphoma,

particularly patients with disease bulk, is chemotherapy in combination with radiation therapy

(RT).1 Although recent studies have demonstrated efficacy for chemotherapy-alone approaches

in selected early stage, unfavorable risk patients based on favorable interim PET-response, these

studies have generally excluded patients with bulky disease or systemic symptoms.2, 3 The

estimated 5-year progression free survival (PFS) for patients with early stage, unfavorable risk

disease treated with ABVD and involved-field radiotherapy is 80-85%, thus a significant

proportion of patients will relapse in this population.4-6

Due to an increased appreciation of long-term toxicities related to RT in HL survivors

who receive CMT, efforts have been made to reduce the doses and the extent of RT fields over

time.7, 8 Involved-nodal RT (INRT), applied in the EORTC/LYSA/FIL H10 study, involves a

markedly reduced RT field compared to its predecessor involved-field RT and encompasses only

the pre-chemotherapy disease volume with minimal margins.3, 9 Conceptually similar to INRT,

but with less strict pre-treatment imaging requirements, involved-site radiotherapy (ISRT) is now

the standard RT field for HL patients as recommended by the International Lymphoma Radiation

Oncology Group (ILROG) and the National Comprehensive Cancer Network (NCCN)

guidelines.10

Brentuximab Vedotin (BV; Seattle Genetics; Bothell, WAS, USA) is a novel antibody-

drug conjugate that is highly active in the treatment of patients with relapsed and refractory

HL.11-13 In a phase 1 study in the frontline setting, patients with advanced stage HL were treated

with BV at a dose of 1.2 mg/m2 in combination with AVD chemotherapy for up to 6 cycles.14, 15

For the 26 patients treated with BV+AVD, the treatment was found to be safe and the




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preliminary efficacy was promising with a 3-year failure-free survival and overall survival (OS)

of 96% and 100%, respectively.14, 15 With the aim of improving initial cure rates, many ongoing

studies are testing the combination of BV with AVD chemotherapy for the frontline treatment of

HL in various clinical settings.

Limited data exists on the administration and safety of BV in conjunction with CMT for

the frontline treatment of early stage HL. Pulmonary toxicity is a known of side effect of

bleomycin and radiation involving the mediastinum and lung fields.16-19 In addition, combining

BV with the bleomycin-containing ABVD arm in the phase 1 study resulted in significant

pulmonary toxicity and, analogously, when SGN-30 (naked anti-CD30 monoclonal antibody)

was combined with gemcitabine severe grade 3-5 pneumonitis led to premature study closure.14,

20 We hypothesized that BV may be associated with subclinical pulmonary toxicity that is only

unmasked when combined with an additional pulmonary insult, such as bleomycin or

radiotherapy.

We designed this pilot study to assess the safety and preliminary efficacy of the upfront

combination of BV with AVD chemotherapy followed by 30 Gy ISRT for patients with early

stage, unfavorable risk HL. The primary objective of this study was to evaluate the rate of

development of clinically significant pulmonary toxicity with the proposed treatment program.

The secondary objective was to evaluate the preliminary efficacy.

Methods

Study Population

Patients between the ages of 18 and 60 with biopsy proven CD30 positive classical HL

were enrolled. Eligible patients had untreated stage I/II, classical HL with any of the unfavorable




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risk factors as defined by German Hodgkin Study Group (GHSG) including bulky mediastinal

mass (≥1/3 maximum width of mass/maximum intrathoracic diameter on posterioranterior (PA)-

CXR or ≥10cm by CT imaging in transaxial plane), ESR≥50mm/h or ESR≥30mm/h in patients

with “B” symptoms, extranodal involvement, or >2 lymph node sites (as defined by GHSG).5 In

addition, patients with infradiaphragmatic disease were eligible. Stage IIB disease with disease

bulk (X) or extranodal involvement (E) were included. Patients had to have adequate organ

function (defined as a cardiac ejection fraction of >50%, hemoglobin-adjusted diffusing capacity

for carbon monoxide (DLCO(Hb)) ≥60% on pulmonary function testing (PFT), a serum

creatinine clearance ≥30mL/min, an absolute neutrophil count of >1,000/µl, a platelet count

>75,000/µl, and total bilirubin of <2.0 mg/dl in absence of a history of Gilbert’s disease).

Patients were excluded if pregnant or lactating, with baseline peripheral neuropathy > grade 1, or

receiving chronic steroid treatment. Patients were enrolled on study from June 2013 to February

2015.

This pilot study was conducted at Memorial Sloan Kettering Cancer Center (MSKCC)

and Wilmot Cancer Institute, University of Rochester (ClinicalTrials.gov, trial No.

NCT01868451). The institutional review board of each participating institution approved the

study and written informed consent was obtained for all patients before enrollment.

Study Design and Treatment

Patients were scheduled to receive a total of 4 cycles of BV and AVD chemotherapy. BV,

1.2 mg/kg, Doxorubicin 25 mg/m2, Vinblastine 6mg/m2, and Dacarbazine 375 mg/m2 was

administered on days 1 and 15 of each 28 day cycle. Prophylactic growth factor support

(Neupogen) was administered with each cycle, dosing and schedule per physician discretion.




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Patients with a PET-negative response after 4 cycles of BV and AVD chemotherapy or

PET-positive post-chemotherapy with subsequent biopsy negative for HL, received 30 Gy ISRT.

Patients with a positive PET-4 result and biopsy positive for lymphoma were subsequently

treated off study. The treatment schema is summarized in Figure 1.

ISRT was administered per standard guidelines and under the direction of lymphoma

radiation oncologists (J.Y. and L.S.C.).21 Typical ISRT fields were designed with consideration

of the pre-chemotherapy and post-chemotherapy gross tumor volume (GTV) information. The

resulting clinical target volume (CTV) was then reduced so that normal structures such as lungs

and heart, which were previously displaced by the GTV, were excluded. The CTV was expanded

0.5 – 1.0 cm to planning target volume to account for set-up error.10, 21

Study Assessments

All patients underwent standard staging tests including 18F-FDG PET, diagnostic CT

scans of neck (if evidence of disease in neck), chest, abdomen, and pelvis, PA and lateral chest

X-ray, and unilateral bone marrow biopsy if presence of B-symptoms, extranodal disease, or

mass>10cm.

PET scan was performed after 2 cycles and 4 cycles of BV+AVD, and again 8 weeks

after completion of BV + AVD + ISRT. All PET scans were reviewed by nuclear medicine

radiologists at MKSCC and Wilmot Cancer Institute and interpreted using the five-point

Deauville scale; a score of 1, 2, or 3 was negative.22 The interim PET after 2 cycles was

exploratory; treatment was not altered based on the result.

Safety assessments consisted of recordings of adverse events (AEs), physical

examination, PFTs, and routine laboratory tests. AEs were assessed per the Common

Terminology Criteria of Adverse Events (CTCAE v4.03). PFTs were obtained at baseline, post




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BV + AVD, post BV + AVD + ISRT, and 12 months post-treatment. PFTs were performed in

pulmonary laboratories and percent predicted DLCO(Hb) and FVC were determined using the

same references equations across all PFT studies.23, 24

Outcomes

The central study aim was to assess the safety and toxicities of the treatment regimen.

The primary objective was to evaluate the rate of the development of significant pulmonary

toxicity which was defined as the development of grade 2 or higher non-infectious pneumonitis

as defined by CTCAE v4.03. All patients with suspected pulmonary toxicity were evaluated by

an institutional pulmonary specialist who determined if the patient’s clinical picture was

consistent with non-infectious pneumonitis and adjudicated the grade.

The secondary objective was to evaluate the preliminary efficacy of the proposed

treatment plan, including response to therapy and 1-year PFS.

Statistical Analyses

Descriptive statistics were used to describe toxicities and response rates. The trial

included a stopping rule to declare unacceptable toxicity rates; if more than 1 out of the first 15,

or more than 3 out of the total 30 patients developed significant pulmonary toxicity, the trial

would have been stopped. PFS was estimated using the Kaplan-Meier method. The study

database was frozen in February 18, 2016.

Results

Patients




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From June 2013 to February 2015, 30 patients were enrolled. The median age of enrolled

patients was 31 years (range, 18-59) and all patients had stage II disease. With regard to

unfavorable risk features, 47% of patients had disease bulk by CT criteria >10cm, 57% had

disease bulk by ≥1/3 MMR on CXR, 67% had elevated ESR (ESR>50 or ESR >30 with B-

symptoms), 47% presented with B-symptoms, 47% had extranodal involvement, 67% had >2

involved lymph node sites, and 3% presented with infradiaphragmatic disease. Thirteen patients

had a bulky anterior mediastinal mass with a median maximal transverse diameter of 13cm,

range 10-16.9cm. Applying a novel MSKCC definition of disease bulk in early stage HL (>7cm

in maximal transverse diameter or >7cm in maximal coronal diameter), 23 (77%) patients had

disease bulk.25 Eleven patients (37%) had advanced stage disease by the GHSG criteria: 2 (7%)

with IIBX, 4 (13%) with IIBE, and 5 (17%) with IIBXE disease. Baseline patient characteristics

are shown in Table 1.

A flow chart of the study is shown in Figure 2. Of 30 patients, 29 were treated with 4

cycles of BV and AVD chemotherapy. One patient came off study due to toxicity after 1

treatment of BV+AVD. Four patients did not receive 30 Gy ISRT. Of these, 2 patients had

biopsy-confirmed refractory cHL, 1 patient elected to come off study and receive proton beam

RT to the mantle field, and 1 patient elected to come off study and received chemotherapy alone

with 2 additional cycles of ABVD after completing 4 cycles BV+AVD therapy.

After completing 4 cycles of BV+AVD, 25 patients received ISRT at a dose of 30.6 Gy

in 17 daily fractions. Sixty percent of patients (n=15) were simulated and treated using deep

inspiration breath hold to maximally spare normal lung and heart tissue. Ninety-six percent

(n=24) of patients received radiation to the neck and mediastinum and the median percentage of

lung volume receiving 20 Gy radiation was 18.5% (range 3-36%, Supplemental Figure 1). A




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single patient received conventional radiation to the left pelvis. Forty-four percent of patients

(n=11) received intensity-modulated radiation therapy for extensive bilateral local disease

involving the neck and chest. A remaining 13 patients (52%) received conventional radiation

therapy using AP-PA fields and a single patient received 3D-conformal radiation therapy.

Safety and Toxicity

Adverse events associated with BV+AVD were generally grade 1 or 2 and easily

managed; and the most common grade 3 or higher AE was the development of neutropenia (16

[53%] of 30 patients). As anticipated with the combination of BV and vinblastine, peripheral

neuropathy was observed in 40% of patients (12 of 30 patients), most grade 1 (10 [83%] of 12

patients) and less frequent grade 3 (2 [17%] of 12 patients). Serious adverse events occurred in 6

patients. Of these SAEs, 3 patients had febrile neutropenia (grade 3) and two patients were

admitted with fever without neutropenia (grade 1/2). One patient, after a single treatment of BV

+ AVD, developed hypertension (grade 3) and peripheral motor and sensory neuropathy (grade

3) and came off study.

All patients tolerated ISRT well with only grade 1-2 toxicity. The most common acute

toxicities were fatigue, which affected 88% of patients (n=22), followed by dermatitis (n=20),

dysphagia (n=20) and esophagitis (n=13). Of the 24 patients who received ISRT to the

mediastinum, 9 patients (38%) reported grade 1 cough and a single patient (4%) reported grade 1

dyspnea.

No clinically significant (grade 2 or higher) drug-related non-infectious pneumonitis was

observed. In most patients, there was an initial decline in DLCO(Hb) after 4 cycles of BV+AVD.

There was no change in forced vital capacity (FVC) related to treatment with BV, Figure 3B.

Administration of ISRT was not associated with a worsening of the DLCO(Hb). Changes in




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DLCO(Hb) were not accompanied by respiratory symptoms in most patients. Two patients were

evaluated by a pulmonary specialist. One patient was evaluated due to cough and dyspnea (grade

2) that developed after completion of 4 cycles of BV and AVD chemotherapy. PFTs showed an

initial decrease by 30% in DLCO(Hb) from baseline, but repeat PFTs one week later showed an

increase by 16%. The respiratory symptoms were attributed to an upper respiratory infection and

reactive airways disease, not drug-related, and resolved with antibiotics and supportive care. Of

note, this patient had normal repeat PFTs 12-months post-treatment. The second patient

evaluated by a pulmonary specialist had mild dyspnea on exertion (grade 1) and an initial

decrease in DLCO(Hb) by 57% after chemotherapy compared to baseline, however, this was

attributed to an upper respiratory infection and poor test effort, not related to BV+AVD.

DLCO(Hb) improved on repeat PFTs.

Interim PET response

Ninety percent of patients (26 of 29) achieved a negative PET scan after 2 cycles. Of

patients with disease bulk treated with 2 cycles of BV and AVD chemotherapy, 85% (11 of 13)

were PET-2 negative. Of the three patients with PET-2 positive scans, the scan became negative

after 4 cycles in two patients and one patient had biopsy-proven primary refractory Hodgkin

lymphoma. Ninety-three percent of patients (27 of 29) had a negative PET scan after 4 cycles of

chemotherapy. The two patients with a positive PET scan after 4 cycles had baseline tumor bulk

(measuring 13.0 and 13.6 cm in maximal transverse diameter on CT). Both had a positive biopsy

consistent with refractory Hodgkin lymphoma and were treated off study with ICE

chemotherapy, pre-transplantation radiation, and high-dose therapy and autologous stem cell

transplant. These patients continue in remission 7 and 13 months post-transplant.

End of Treatment Response




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All patients who completed the entire treatment program with BV + AVD followed by

ISRT (n=25) achieved a complete response. Two patients had a positive PET post treatment

(Deauville 4). For one patient, repeat PET scan remained positive, but subsequent biopsy

demonstrated granulomatous inflammation consistent with sarcoid. For the second patient, a

repeat PET scan after two months was negative (Deauville 3). Thus both patients achieved a

complete response.

The median follow-up time is 18.8 months. Of the 25 patients who have completed CMT

and achieved complete responses, no relapses have occurred to date. By intent-to-treat including

all 30 patients, the 1-year PFS is 93.3% (95% CI 84-102), see Figure 4.

Discussion

To our knowledge, this is the first publication describing the safety and tolerability of BV

in combination with chemoradiotherapy for the treatment of early stage Hodgkin lymphoma.

Overall the treatment program was well tolerated and associated with preliminary evidence of

promising efficacy with high rates of early PET-negativity and excellent 1-year PFS.

The study was designed to primarily assess if there was evidence of undue toxicity

associated with BV and CMT, with particular attention to pulmonary toxicity given the incidence

of fatal lung injury with the combination of BV and bleomycin.14 In this study, no significant

non-infectious pneumonitis occurred with the combination of BV and chemoradiotherapy.

Pulmonary function studies demonstrated a decrement in DLCO in majority of patients after 4

cycles of BV and AVD chemotherapy. We hypothesize that this decrease is DLCO can be

attributed to brentuximab-mediated subclinical mild alveolar injury as AVD is not associated

with pulmonary toxicity and underlying intrathoracic disease burden was significantly reduced




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after chemotherapy. Further, there was evidence of interval improvement in FVC after BV+AVD

which demonstrates an absence of significant drug-related restrictive lung injury and likely

reflects reduction in mediastinal disease burden after treatment. In addition, no clinically

significant drug-related pulmonary toxicity was observed. For the two patients referred to a

pulmonologist, their respiratory symptoms and transient PFT abnormalities were attributed to

upper respiratory infections. Similarly, in the phase 1 experience of BV+AVD, no patients

experienced pulmonary toxic effects.14 In the current study, despite the fact that most patients

received RT to the mediastinum, radiotherapy did not worsen lung diffusing capacity, FVC, or

give rise to clinically significant respiratory symptoms. In addition, 12-month PFTs showed

improvement in mean DLCO(Hb) and FVC even higher than baseline likely due to resolution of

intrathoracic HL. This compares favorably with retrospective data for ABVD and mantle RT

which demonstrated decrement in DLCO and FVC at 12-15 months post-treatment.17, 18

Although interim PET negativity is an important prognostic factor in early stage Hodgkin

lymphoma, a robust historical benchmark to compare our interim PET-2 results does not exist

given the heterogeneity of early stage HL patient populations and variable definitions for disease

bulk and PET-negativity across studies.3, 26 The EORTC/LYSA/FIL H10 is the only prospective

study with interim PET-2 data and approximately 76% of early stage, unfavorable risk patients

(40% with EORTC defined disease bulk) had a negative PET scan after 2 cycles of ABVD

applying the now outdated International Harmonization Project Criteria (PET negative =

Deauville score 1 or 2).3, 27 In one of the largest retrospective series of interim PET in early stage

HL, 85% of patients (67/79) with early stage, unfavorable risk HL with EORTC-defined disease

bulk achieved a negative PET (Deauville 1-3) after 2 cycles of ABVD.28 In our pilot study

including early stage, unfavorable risk HL patients with 47% of patients meeting GHSG disease




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bulk criteria, 90% of patients achieved a negative PET (Deauville 1-3) after 2 cycles of BV +

AVD. In the phase 1 study of BV+AVD in advanced stage HL, a similar PET-negative rate (24

of 26 patients, 92%) was demonstrated.14 Preliminarily BV and AVD compares favorably to

standard ABVD in terms of early conversion to PET-negativity after 2 cycles, suggesting it is a

highly active treatment program in this group of ESHL patients with substantial tumor bulk and

extensive disease. Overall the reduced rate of PET-positivity with BV+AVD therapy is

encouraging as interim-PET positivity has been associated with inferior outcome in HL and in

risk-adapted protocols prompts further intensification of therapy.29

This study was not designed to definitively assess the efficacy of BV + AVD x 4 cycles

followed by 30Gy ISRT and we cannot formally compare our results to previous trials due to

differences in eligibility, type and number of cycles of chemotherapy, and radiotherapy field and

dose. Nevertheless, the 1-year PFS outcome for the current treatment program, 93% (95% CI

84-100), appears promising and is approximately equivalent to previously reported data for

combined modality therapy programs. For example, in the Intergroup E2496 trial that included

early stage HL patients with locally extensive, bulky mediastinal disease, among patients treated

with ABVD x 6-8 cycles + 36 Gy IFRT, the 1-year PFS was 94% (95% CI 90 - 98)

(communication with Dr. Ranjana Advani).6 Compared to the E2496 trial, our treatment program

uses fewer cycles of chemotherapy (4 vs. 6-8) and a smaller radiotherapy dose and field (30 Gy

ISRT vs. 36 Gy IFRT). Based on data from the GHSG HD11 and HD14 clinical trials, the 1-year

PFS for the ABVD x 4 cycles + 30Gy IFRT arms was 96.6% (95% CI 94.7 – 98.5) and 96.1%

(95% CI 94.7-97.5), respectively (communication with Drs. Engert and von Tresckow).5, 30

However, the patients included in the GHSG trials were more favorable as they did not include




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patients with IIBX, IIBE, or IIBXE disease (classified as advanced stage by GHSG criteria) and

in our study, 37% of patients met these criteria.

A limitation of this study is the small sample size that was adequate for assessing

toxicity, but inadequate for a robust efficacy assessment. To further explore efficacy, we have

expanded the current study to include an additional 29 patients who will receive a decreased dose

of ISRT, 20Gy. In addition, the median follow up time in this study is only 18.8 months although

our data fully captures the rate of primary refractory disease (<CR) which is a significant

concern among patients with bulky Hodgkin lymphoma.

In conclusion, BV in conjunction with AVD chemotherapy and ISRT is a well tolerated

regimen with no evidence of pulmonary toxicity. The early results from this study demonstrate

promising efficacy with high rates of PET-negativity and CR. Recent data from British Columbia

Cancer Agency reports excellent outcomes for HL patients with disease bulk who achieve a

negative PET scan after full-course ABVD without additional consolidative RT.31 Future studies

to test whether radiotherapy can be eliminated or its volume further reduced in PET-negative

bulky ESHL patients treated with BV and AVD chemotherapy are warranted.




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Acknowledgements:

The authors thank the participating patients and their families. The authors thank Seattle

Genetics for providing brentuximab vedotin for this study. The authors also thank the German

Hodgkin Study Group and ECOG investigators for providing 1-year PFS data for prior combined

modality therapy clinical trials in early stage HL.

Authorship Contributions:

AK, CC, JY, HS, PMB, PC, AC, LSC, PD, JWF, JFG, AH, PH, SMH, AGJ, MJM, GNM, SM,

AJM, AN, MLP, CSP, DJS, NV, SLV, JY, AY, ADZ, ZZ, and CHM contributed to the study

design, patient recruitment, data collection, and data analysis. The draft report was written by

AK and CHM and was commented upon and revised by all the authors.

Disclosure of Conflicts of Interest: PD, SM, and AJM served on an advisory board for Seattle

Genetics and received an honorarium. AY received an honorarium for Seattle Genetics and

Takeda Millennium. CHM and PMB have consulted for Seattle Genetics. CHM serves on the

scientific advisory board for Seattle Genetics. AK, AJM, and CHM receive research funding

from Seattle Genetics. JWF has received an honorarium from Bayer for Data Safety Monitoring

Board. All other authors declare no competing interests.




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Tables

Table 1. Patient Characteristics of Early Stage Hodgkin Lymphoma, N=30 Patients Characteristic No. % Age years, median [range] 30 31 [18-59] Gender Male 16 53 Female 14 47 Hodgkin Lymphoma Pathologic Features CD20+ 4 13 EBV+ (by EBER or LMP1), N = 27 3 11 Stage II 30 100 Unfavorable Risk Features B symptoms 14 47 ESR >50 or ESR > 30 with B-symptoms 20 67 Nodal sites >2 20 67 Extranodal involvement 14 47 Bulk ≥10cm on CT 14 47 Bulk ≥1/3 MMR on CXR 17 57 Anterior Mediastinal Mass >10 cm, N = 14, median size in cm [range]

13 [10-16.9]

Bulky by MSK Definition (>7 cm in MTD or >7cm in MCD), N=30

23 77

Advanced stage by GHSG criteria 11 37 IIBX 2 7 IIBE 4 13 IIBXE 5 17 Table 2. PET results after 2 and 4 cycles of BV + AVD chemotherapy and at the end of treatment (EOT), i.e. 8 weeks after completion of involved-site radiotherapy.

Deauville Score Post 2 cycles (n=29)

Post 4 cycles (n=29)

EOT / Post ISRT (n=25)

1* 3 (10%) 5 (20%) 2* 14 (48%) 21 (72%) 16 (64%) 3* 12 (41%) 3 (10%) 2 (8%) 4 3 (10%) 2 (7%) 2 (8%)†

5 *PET-negative response was defined as Deauville 1-3 †For one patient, repeat PET scan remained positive, but subsequent biopsy demonstrated granulomatous inflammation consistent with sarcoid. For the second patient, repeat PET after two months was negative (Deauville 3). Thus both patients achieved a complete response.




21

Figure Legends

Figure 1. Treatment Schema

Figure 2. Clinical Trial Flow Chart

Figure 3. Trend in hemoglobin-adjusted DLCO (A) and FVC (B) during the treatment program. Mean DLCO(Hb) baseline, pre-ISRT, post-ISRT, and 12-month post treatment are 91% (n=30), 82%

(n=29), 92% (n=23), and 98% (n=15), respectively (A). Trend in FVC during treatment program. Mean FVC baseline, pre-ISRT, post-ISRT, and 12-month post treatment are 91% (n=30), 97% (n=28), 99% (n=22), and 106% (n=15), respectively (B).

Figure 4. Progression Free Survival by Intent-to-Treat (N=30) with median follow up of 18.8 months.





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doi:10.1182/blood-2016-03-703470Prepublished online July 25, 2016;

Craig H. MoskowitzVanderEls, Stephanie L. Verwys, Joanna Yang, Anas Younes, Andrew D. Zelenetz, Zhigang Zhang and McCall, Alison J. Moskowitz, Ariela Noy, Maria L. Palomba, Carol S. Portlock, David J. Straus, NicholasA. Hamlin, Steven M. Horwitz, Alexandra G. Jacob, Matthew J. Matasar, Gianna N. McArthur, Susan J.

PaulLouis S. Constine, Pamela Drullinsky, Jonathan W. Friedberg, John F. Gerecitano, Audrey Hamilton, Anita Kumar, Carla Casulo, Joachim Yahalom, Heiko Schöder, Paul M. Barr, Philip Caron, April Chiu, early stage, unfavorable risk Hodgkin lymphomaBrentuximab vedotin and AVD followed by involved-site radiotherapy in

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title: brentuximab vedotin and avd followed by involved-site

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