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M A N A G E DSUPPLEMENT TO

CareCare

Volume 18, No.11Supplement 9

November 2009

MYELODYSPLASTIC SYNDROMES (MDS)New Approaches to Achieve Best Practices in Treating MDSManaged Care Clinical Oncology Expert RoundtableDallas, July 31, 2009

HIGHLIGHTS

• Current MDS Landscape

• Emerging Therapies, Survival, and Alternative Outcomes

• Alternative Dosing Schedules for Methylation Inhibitors

• Role of Specialty Pharmacy

• Health Care Management Considerations

This publication issponsored by Celgene Corp.

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CareM A N A G E D

Care

CareM A N A G E D

CareMYELODYSPLASTIC SYNDROMES (MDS)

New Approaches to Achieve Best Practices In Treating MDS

Managed Care Clinical Oncology Expert Roundtable

FACULTY PRESENTATIONS AND DISCUSSIONS

Myelodysplastic Syndromes (MDS): the Current Landscape ..........................................................................2STEVEN R. PESKIN, MD, MBAExecutive Vice President and Chief Medical OfficerMediMedia USA

Myelodysplastic Syndromes: Emerging Therapies, Survival, and Alternative Outcomes.....................................................................4BART L. SCOTT, MDAssistant Professor and Assistant MemberUniversity of Washington Medical Center

Alternative Dosing Schedules for Methylation Inhibitors in MDS Treatment ...............................................................................15DAVID FRAME, PHARMDAssistant Professor, Pharmacy and Clinical Hematology/Oncology/BMT SpecialistUniversity of Michigan Comprehensive Cancer Center

The Role of Specialty Pharmacy in the Treatment of Myelodysplastic Syndromes...........................................................21KIRBY ENG, RPH

Director, Oncology Management Services, CVS Caremark

Myelodysplastic Syndromes: Health Care Management Considerations.........................................25ALLAN JAY KOGAN, MD, MSS, ABFP, FAAFP, CPEMedical Director – West Region, CIGNA/Great-West HealthcareJEFFREY D. DUNN, PHARMD, MBAFormulary and Contract Manager, SelectHealth

S U P P L E M E N T T O

November 2009

Dallas, July 31, 2009

The treatment of myelodysplastic syndromes (MDS)has gained substantial attention in the last few years withthe development of novel therapies capable of alteringthe natural history of the disease. Prior to 2001,there was a limited collection of epidemiologicdata, but the addition of these stem cell malig-nancies to the North American Association ofCentral Cancer Registries has led to a better un-derstanding of the extent and impact of the dis-ease and a greater interest in therapeutic in-tervention (Rollison 2008).

A disease predominantly of older adults,with more than 70 percent of diagnoses oc-curring after age 50, treatment has long con-sisted of palliative care — many of these pa-tients were considered too old to tolerate thetreatments for myeloproliferative disorders, dose-inten-sive chemotherapy, and bone marrow transplantation(HMDS 2009, Hellström-Lindberg 1999, Silverman2001).Yet, MDS is a deadly disease, with 36 percent to 50percent of patients dying of infectious complications orbleeding within 3 to 4 years, and 35 percent to 40 percentprogressing to acute myelogenous leukemia (Hoffman2000, Kantarjian 2002, Kurzrock 2002, Silverman 2001).It has been estimated that 9,700 new cases of MDS are

diagnosed each year in the United States, with higherrates occurring among men and among whites and non-Hispanics; the median survival is 2 to 3 years (Rollison

2008). Because of the heterogeneous nature ofMDS — it comprises a group of hematologicdisorders marked by ineffective hematopoiesis,peripheral blood cytopenias, and bone mar-row failure — the disease burden is likely un-derestimated. Goldberg (2008) performed aretrospective analysis of new primary MDS di-agnoses filed in the Medicare Standard Ana-lytical File 5 percent (SAF5%) claims databasein 2003 (excluding patients with myeloidleukemia or anemias of known causes in theprevious year) and reports quite different num-bers (Table). Goldberg estimated an incidence

of more than 76,000 adults with MDS rather than the10,300 anticipated based on Surveillance Epidemiologyand End Results data (Rollison 2008). Clearly, this is acondition that calls out for effective treatment.

As a disease of hematopoietic dysfunction, a numberof hematologic therapies have been tested with variablebenefit. Growth factors are a logical choice to stimulate

INTRODUCTION

Myelodysplastic Syndromes (MDS):The Current LandscapeSTEVEN R. PESKIN, MD, MBA, FACPExecutive Vice President and Chief Medical Officer

MediMedia USA

STEVEN R. PESKIN, MD, MBA

Steven R. Peskin, MD, MBA, FACP, is executive vice president andchief medical officer, MediMedia USA. Prior to joining the com-pany, Peskin served as chief executive officer of PharmaceuticalResearch Plus (PRP), a clinical trials support company. He alsofounded and was president and chief operating officer of NelsonManaged Solutions, a division of Publicis Healthcare Group, thelargest global healthcare marketing services corporation. Peskinalso has held executive positions with PacifiCare Health Systems,CIGNA Healthcare, and John Hancock. He received his medicaldegree from Emory University School of Medicine, Atlanta, andcompleted his residency in internal medicine at Saint Elizabeth’sMedical Center, Boston. He received his MBA with a concentra-tion in health care from The Sloan School of Management at MIT.Peskin has held faculty appointments at Tufts University Schoolof Medicine, University of Texas, and University of Oklahoma,and is currently a clinical preceptor at The University of Medicineand Dentistry of New Jersey.

2 MANAGED CARE / SUPPLEMENT

TABLE MDS incidence in the Medicare population in 2003 – ICD-9-CM code 238.70

Median age at diagnosis, 76 years; incidence by age,per 100,000

Age (years) Medicare data SEER data*

<60 92 7.460-69 138 1670-79 199 34>80 261 37

Total: 76,600 10,300

• Bone marrow documentation in 53% of population;higher incidence in men.

*Rollison 2008 MDS=myelodysplastic syndromes, SEER=Surveillance Epidemiologyand End Results.Source: Goldberg 2008

blood cell production, but may simultaneously induceproliferation and survival of preleukemic cells (Gordon1999). In clinical trials, patients with low serum ery-thropoietin levels and minimal need for red cell trans-fusion have been found to benefit from erythropoietintreatment, but other MDS patients respond poorly (Sil-verman 2001). Neutrophil, platelet, and pleiotropicgrowth factors have been examined as hematopoieticsupport, but these approaches have failed to increasesurvival in MDS and may be associated with substantialtreatment-related toxicity (Demetri 2001, Gordon 1999,Silverman 2001). Response rates with standard inductionchemotherapy (anthracycline and cytarabine) are im-pressive, but relapse is rapid, occurring within a medianduration of less than 1 year (Silverman 2001) and with-out an increase in survival.

The hypomethylating agents azacitidine and deci -tabine have provided new hope for MDS patients. Bymitigating methylation of DNA, these agents allow thehealthy reproduction of previously quiescent genes. Inearly clinical trials, they produced promising results, in-cluding hematologic improvement, delayed disease pro-gression, and clinical remissions (Cheson 1998, Kizaki1992, Saba 2005, Silverman 1994, Silverman 2001, Sil-verman 2002), and with azacitidine, overall survival (Fe-naux 2007, Silverman 2002). As a result of these out-comes, patients today are more likely to be identifiedearlier in the course of the disease, referred to academiccenters for novel therapy, and offered multiple treat-ment options. We also can hope to realize the goals ofcancer therapy — delayed progression, prolonged sur-vival, and improved quality of life.

With new treatments come increasing challenges forhealth care plans and providers. Each advance in themedical management of disease necessitates that new in-tegrative delivery and financing systems be adapted, spe-cialty pharmacies be updated, and clinicians be keptabreast of how a new state-of-the-art medication willalter patient care. These changes also will affect the re-sources of managed care organizations, making it es-sential that payers and providers collaborate to developrational strategies for coverage and reimbursement andredefine protocols to maximize patient outcomes andminimize treatment costs.

The articles in this publication are based on the Man-aged Care Clinical Oncology Expert Roundtable held inDallas in July 2009. The authors address current MDS is-sues and how changing approaches to MDS treatment,and in particular higher-risk MDS, will affect all healthcare stakeholders — providers, patients, and healthplans. They offer potential strategies for merging treat-

ment benefit with the limited resources of health careplans to achieve best practices in treating MDS. Eachpresentation by an Expert Panel member is followed bya Q&A discussion. Our intent in sharing this dialoguewith our readers is to provide a better understanding ofMDS and to promote collaboration among health carestakeholders to ensure optimal patient outcomes.

ReferencesCheson BD. Standard and low-dose chemotherapy for the treat-

ment of myelodysplastic syndromes. Leuk Res. 1998;22:S17–S21.

Demetri GD. Targeted approaches for the treatment of thrombo-cytopenia. Oncologist. 2001;6(suppl 5):15–23.

Fenaux P, Mufti GJ, Santini V, et al. Azacitidine treatment pro-longs overall survival in higher-risk MDS patients com-pared with conventional care regimens: results of the AZA-001 phase III study. Blood. 2007;110:817.

Goldberg SL, Mody-Patel N, Chen ER. Clinical and economicconsequences of myelodysplastic syndromes in the UnitedStates: an analysis of the Medicare database. ASH AnnualMeeting Abstracts. Blood. 2008;112:636.

Gordon MS. Advances in supportive care of myelodysplasticsyndromes. Semin Hematol. 1999;36(suppl 6):21–24.

HMDS (Haematologic Malignancy Diagnostic Service). Themyelodysplastic syndromes. «http://www.hmds.org.uk/mds.html». Accessed Oct. 13, 2009.

Hellström-Lindberg E. Treatment of adult myelodysplastic syn-dromes. Int J Hematol. 1999;70:141–154.

Hoffman R, Benz E, Shattil S, et al. Hematology: Basic Principlesand Practice. 5th ed. Philadelphia: Churchill Livingstone.2009.

Kantarjian HM, Cortes JE, Rowe JM, Kurzrock R. Future clinicalimplications for farnesyltransferase inhibitors in hemato-logic malignancies. Semin Hematol. 2002;39(3 suppl 2):36–38.

Kizaki M, Koeffler HP. Differentiation-inducing agents in thetreatment of myelodysplastic syndromes. Semin Oncol.1992;19:95–105.

Kurzrock R. Myelodysplastic syndrome overview. Semin Hematol.2002;39(3 suppl 2):18–25.

Rollison DE, Howlader N, Smith MT, et al. Epidemiology ofmyelodysplastic syndromes and chronic myeloproliferativedisorders in the United States, 2001–2004, using data fromthe NAACCR and SEER programs. ASH Annual MeetingAbstracts. Blood. 2008;112:45–52.

Saba H, Wijermans PW. Decitabine in myelodysplastic syn-dromes. Semin Hematol. 2005;42:S23–S31.

Silverman LR. Targeting hypomethylation of DNA to achievecellular differentiation in myelodysplastic syndromes(MDS). Oncologist. 2001;6:8–14.

Silverman LR, Demakos EP, Peterson EL, et al. Randomized con-trolled trial of azacitidine in patients with the myelo dys-plastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol. 2002;20:2429–2440.

Silverman LR, Holland JF, Demakos EP, et al. Azacytidine (aza C)in myelodysplastic syndromes (MDS): CALGb studies 8421and 8921. Ann Hematol. 1994;68:A12.

SUPPLEMENT / MYELODYSPLASTIC SYNDROMES 3

Disclosure: Steven R. Peskin, MD, MBA, states that he has no realor apparent conflicts of interest with respect to companies, or-ganizations, or proprietary products mentioned in this supple-ment.


KEY POINTS• Novel therapeutics, such as hypomethylating

agents, growth factors, immunotherapeu-tics, and biologic response modifiers, are improving outcomes in patients with MDS.

• The hypomethylating agents azacitidine anddecitabine slow disease progression, andazacitidine has been shown to prolong sur-vival.

• Early diagnosis and classification of MDS isnecessary to best utilize the range of thera-pies now available.

• MCO decision makers should evaluate allavailable data on agents proven effective intreating MDS to define a treatment protocol.

The myelodysplastic syndromes (MDS) are a group ofclonally derived hematologic disorders characterized bymorphologic abnormalities of myeloid pluripotent stemcells, ineffective hematopoiesis, and resultant blood dys-plasias (Buckner 2008, Rollison 2008). Patients generallyare identified via the presence of peripheral cytopeniasand their common symptoms — anemia, heart failure,infection, bruising, and hemorrhage. The most frequentpresenting feature is anemia, often macrocytic in na-ture, but abnormalities of neutrophils, monocytes, andplatelets also may be observed (Cazzola 2005, HMDS2009, NCCN 2009). In some patients with specific sub-types, circulating blasts are present (HMDS 2009). Thenatural history generally progresses from peripheral cy-topenia to transfusion dependency, with approximately

30 percent of patients advancing to acute myeloidleukemia (AML) (Disperati 2006, Rollison 2008).

MDS are primarily disorders of the elderly; the medianage at diagnosis is approximately 70 years, and 70 percentof patients are age 50 or older (HMDS 2009). The inci-dence increases with advancing age, and the rate hasbeen shown to be 5 times higher among subjects age 80or older compared to those age 60 to 69 years (Buckner2009) and is highest among white and non-Hispanicmen (HMDS 2009, Rollison 2008).

Treatment of MDS has improved substantially in thelast decade. Whereas patients with MDS were generallytreated with a wait-and-see approach and allogeneicstem cell transplantation when needed, now biologicand chemotherapeutic treatments are proving effectivein controlling symptoms and preventing disease pro-gression. Novel therapeutics such as hypomethylatingagents, growth factors, immunotherapeutics, and biologicresponse modifiers have improved outcome in patientswith lower-risk MDS (Buckner 2009), and the hypo -methylating agent azacitidine, in particular, has beenshown to prolong survival in patients with higher-riskdisease (Fenaux 2009). Thus, for oncologists, it is im-portant to diagnose and classify MDS early and to strate-gize to best utilize the range of treatments available. Fur-ther, in the current managed care environment, theoutcome and survival benefits, patient expectations, andtreatment protocols must be balanced with the need tomanage costs.

In this article, I discuss the increasing success of noveltherapeutics in slowing the progression of and improv-ing the hematologic defects observed in higher-risk MDSand the issues that managed care organizations face re-garding the role of these new agents in their institutionalprotocols and formularies.

Clinical features and diagnostic evaluationMDS are disorders of blood; therefore, assessment is

focused on hematologic analyses (Table 1). A completeblood count with examination of peripheral blood smearand platelet count is standard if MDS is suspected, par-ticularly when looking for enlarged erythrocytes (treat-

Myelodysplastic Syndromes: Emerging Therapies, Survival, and Alternative OutcomesBART L. SCOTT, MDAssistant Professor and Assistant MemberUniversity of Washington Medical Center, Seattle

Bart L. Scott, MD, is assistant professor and assistant member atthe University of Washington Medical Center in Seattle. He re-ceived his medical degree from the University of South Alabamaand an MS in epidemiology from the University of Washington.Scott has held various faculty positions, including research asso-ciate and associate in clinical research at the Fred HutchinsonCancer Research Center in Seattle. He has published widely andis a reviewer for the Journal of the National Comprehensive Can-cer Network.

ing with replacement therapy to rule out folate or vita-min B12 deficiency) or peripheral blasts suggestive ofchronic myelomonocytic leukemia (CMML) (NCCN2009). Measures for serum iron, total iron-binding ca-pacity, ferritin, and folic acid also are recommended toevaluate for other potential causes of anemia, and lactatedehydrogenase, haptoglobin, reticulocyte count, andCoombs’ tests are needed to rule out an underlying he-molytic process. A baseline serum erythropoietin valueshould be determined, and this assessment should drivethe appropriate use of growth factor therapy.

Bone marrow evaluation, i.e., bone marrow aspirateand biopsy, is crucial to establish the diagnosis of MDS(NCCN 2009). In fact, a final diagnosis must be con-firmed based on morphologic criteria available only frommarrow examination. Marrow features alsoplay a role in treatment planning. A bone mar-row biopsy is the only means to measure cel-lularity, which can influence the selection oftherapy, and is prognostic of disease outcomes.A biopsy also will reveal the presence ofmyelofibrosis or atypical localization of im-mature precursors. A marrow aspirate can beexamined for evidence of hematopoietic cellmaturation abnormalities, excessive marrowblasts (>5 percent), and the presence of ironsuggestive of ring sideroblasts, and the samplecan be used for testing in flow cytometry, cy-togenetics, and fluorescence in situ hybridization testing(NCCN 2009).

Cytogenetic studies are important to determine diseaseprognosis, International Prognostic Scoring System(IPSS) risk, which is associated with the risk of AML, andsurvival — all of which factor into selecting the most ap-propriate therapy for a patient. In addition, specific ge-netic mutations can suggest patient prognosis; some mu-tations have been shown to predict disease progression,

whereas other genetic derangements may suggest sensi-tivity to specific medications (Apperley 2002, Magnus-son 2002, NCCN 2009, Ogata 2002, Szpurka 2006, Wells2003). Haase (2007) documented the reliability and prog-nostic significance of cytogenetic analyses. The investi-gators reported that among 2,124 patients in Austria andGermany on whom they carried out cytogenetic testing,97.6 percent were successfully analyzed. They also ob-served that about half of the subjects had normal geneticprofiles, but mutation profiles allowed for the separationof the rest of the subjects into good, intermediate, or poorprognostic categories.

Classification of MDS. The development of a classi-fication system for MDS based on cellular morphology,etiology, and clinical presentation is an important step in

MDS management, allowing clinicians to an-ticipate the likelihood of transformation toAML, forecast response to different therapies,and predict survival (Mufti 2008a).

The original classification guidelines — theFrench-American-British (FAB) system devel-oped in 1976 — were based on the percentageof blasts and specific morphological dysplasticfeatures, such as ring sideroblasts or Auer rods(Bennett 1982). However, this tool has provenunreliable in predicting survival or AML risk,due in large part to the absence of cytogeneticdetails and the inclusion of diseases with fea-

tures that overlap other diagnostic categories, althoughit is still used in some clinical trials and in the drug ap-proval process. After two decades of relying solely onthe FAB system, researchers began to investigate alter-native risk-based stratification schemas to improve prog-nostic and diagnostic ability.

In 2001, the World Health Organization (WHO) re-vised the FAB morphologic approach, lowering the blastthreshold for AML from 30 percent to 20 percent, whichsubstantially altered the classification categorizations(Brunning 2001). Another important change is thatrefactory anemia with excess blasts in transformationnow falls within the AML with multilineage dysplasia di-agnosis, and CMML is reclassified as a myelodysplas-tic/myeloproliferative disorder (Brunning 2001, Mufti2008a). A new category also was added: Refractory ane-mia with multilineage dysplasia with or without ringsideroblasts was broken out from the refractory anemiawith ringed sideroblasts category for cases with ≥10 per-cent of dysplasia in at least two cells lines. The challengethat has arisen with these changes is that health plan re-imbursements depend on disease classification; therefore,it is essential that clinicians be clear on whether treatmentapprovals for their patients are based on FAB or WHOclassifications.

The IPSS and WPPS scoring systems. The IPSS is themost extensively used prognostic system to determine the


TABLE 1Hematologic analyses are key to the identification of MDS

• CBC with differential, platelet count• Serum FE, TIBC, ferritin, folic acid, B12• LDH, haptoglobin, reticulocyte count, Coomb’s tests• Baseline serum erythropoietin in the event growth

factor therapy is considered• Bone marrow studies

•• Aspirate•• Biopsy•• Cytogenetics

CBC=complete blood count, FE=iron, LDH=lactate dehydrogenase,MDS=myelodysplastic syndromes,TIBC=total iron-binding capacity.Source: NCCN 2009

BART L. SCOTT,MD


associated risk for AML (Greenberg 1997, Mufti 2008a).This predictive model defines cytogenetic subgroups atdiagnosis that, when combined with percentage of bonemarrow blasts and number of cytopenias, designatesgood, intermediate, and poor risk for evolution to AML,and defines low, intermediate 1, intermediate 2, andhigher-risk subgroups for survival, indicating progres-sively greater mortality risk (Table 2). Stratification forage further improves the prognostic significance of IPSSrisk categories for survival. Based on these criteria, ap-proximately 70 percent of patients will have low or in-termediate 1 MDS at diagnosis, and 30 percent will haveintermediate 2 or higher-risk disease and the associatedrisk for AML and reduced survival (Figure 1).

An alternative to the IPSS is the WHO-Based Prog-

nostic Scoring System (WPPS),which takes into account redblood count (RBC) transfusionrequirements rather than cy-topenias to determine survivalrisk categories, making it a func-tional rather than laboratory as-sessment (Malcovati 2007). Theinclusion of transfusion burdenin the WPPS acknowledges animportant step in the naturalhistory of the disease and pro-vides a means to follow patientsfor treatment response or dis-ease progression, although theabsence of criteria for thrombo-cytopenia limits the usefulnessof this tool.

IPSS features can be used asguidelines in selecting treatment.

Lenalidomide (Revlimid), for example, is approved forsubjects with transfusion-dependent anemia due to lowand intermediate 1 MDS associated with del 5q cytoge-netic abnormality with or without additional cytoge-netic abnormalities, whereas the hypomethylating agentsazacitidine (Vidaza) and decitabine (Dacogen) are indi-cated for low, intermediate, and higher-risk disease. Cy-togenetic findings used in this prognosis classificationscheme are also proving valuable in directing therapy; forexample, MDS patients with deletion 5q mutation con-sistently respond to lenalidomide, making it the treat-ment of choice, and those with trisomy 8 have beenshown to be sensitive to antithymocyte globulin (Galili2007, NCCN 2009), whereas azacitidine, compared withthe conventional care regimen, appears to work partic-

ularly well in patients with dele-tion 7q mutation (Mufti 2008b).Fenaux (2009) found that for pa-tients with deletion 7q mutation,the median Kaplan-Meier overallsurvival (OS) increased from 4.6months on conventional care(n=27) to 13.1 months with azac-itidine therapy (n=30).

Treatment guidelinesIn recommending treatment for

clinically significant cytopenia(s),the National Comprehensive Can-cer Network (NCCN) recognizestwo major patient categories: Pa-tients who are in the IPSS low andintermediate 1 categories, andthose who are in the IPSS inter-mediate 2 and higher-risk cate-

FIGURE 1Survival and evolution to AML by IPSS classification

TABLE 2International Prognostic Scoring System (IPSS)

Score value

0 0.5 1.0 1.5 2.0

Prognostic variableBone marrow blasts <5% 5%–10% — 11%–20% 21%–30%Karotype* Good Intermediate Poor — —Cytopenias† 0/1 2/3 — — —

Total score

0 0.5 1.0 1.5 2.0 ≥2.5

Risk Low Intermediate 1 Intermediate 2 HighMedian survival, y 5.7 3.5 1.2 0.4

*Good=normal, -Y, del(5q), del(20q); Intermediate=other karyotypic abnormalities; Poor=complex (≥3 abnormalities) or chromosome 7 abnormalities.

†Hgb <10 g/dL; ANC <1800/µL; platelets <100,000/µL.Source: Greenberg 1997

From diagnosis in untreated patients. Kaplan Meier curves.

AML=acute myeloid leukemia, Int=intermediate, IPSS=International Prognostic Scoring System..Source: Adapted from Greenberg 1997 with permission.

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

Time from diagnosis (years)

Survival AML Evolution

Time from diagnosis (years)

100

90

80

70

60

50

40

30

20

10

0

Perc

ent

100

90

80

70

60

50

40

30

20

10

0

Perc

ent

Low 267 patients

Int-1 314 patients

Int-2 179 patients

High 56 patients

Low 235 patients

Int-1 295 patients

Int-2 171 patients

High 58 patients

gories. In this article, I focus on the latter group and onallogeneic hematopoietic stem cell transplantation(HSCT); the hypomethylating agents azacitidine anddecitabine, which are proving effective in treating higher-risk MDS; and on additional approaches under investi-gation.

HSCT. HSCT from a human leukocyte antigen-matched sibling donor is the only potential cure for pa-tients with intermediate 2 or higher-risk MDS, althoughnot all patients are candidates for this procedure. (An-derson 1997, Demuynck 1996, NCCN 2009, Nevill 1998,Scott 2006). Without HSCT, median survival after diag-nosis of MDS is 4.6 years for patients under 60 years andsignificantly lower for those diagnosed after age 60(Greenberg 1997). With HSCT, long-term survival ratesas high as 70 percent have been reported (Cutler 2004,DeWitte 2000); however, because HSCT carries sub-stantial risk for morbidity and mortality, including ap-proximately 20 percent first-year mortality, it must beused with extreme caution, particularly in patients overage 60.

Cutler (2004) used a Markov model to determine bestoutcomes from three different timing strategies forHSCT in patients with MDS: 1) transplantation at di-agnosis; 2) transplantation at progression to AML; and3) transplantation at a fixed time in between. Analyseswere carried out for all four IPSS stratification cate-gories. The investigators found that optimal timing forHSCT depended on IPSS category. Because of the risk formorbidity and mortality with HSCT, patients with IPSSlow or intermediate 1 MDS realized maximal life ex-pectancy when transplantation was delayed but per-formed prior to the onset of AML. Among patients withIPSS intermediate 2 and higher-risk disease, performingtransplantation at the time of diagnosis yielded bestoverall survival results, probably due to the advancedstage and higher risk for rapid progres-sion associated with this status. There-fore, early and aggressive interventionwith HSCT should be considered foreligible patients with higher-risk dis-ease.

Hypomethylating agents. One of themechanisms that may contribute to thedevelopment of MDS is the methyla-tion of critical DNA sites involved incellular transcription secondary to ge-netic damage, thereby blocking differ-entiation and maturation of the abnor-mal cells (Silverman 2001). It is thoughtthat this process protects against the re-production of damaged cells, but it hasbeen proposed to inhibit tumor sup-pressor genes as well, thereby eliminat-ing their protective capability. As a per-

son ages, the amount of methylated DNA increases, buta reduction in tumor suppressor function means a si-multaneous escape and multiplication of defective cells.Azacitidine and decitabine are two different cytosineanalogues, but both with a nitrogen in place of the car-bon grouping position 5 that prevents methylation. Theyare preferentially incorporated into DNA, and with azac-itidine, also into RNA. Incorporation into DNA inacti-vates the methyl transferase enzyme and halts methyla-tion of the gene, which allows previously inactivatedDNA, now with unmethylated cytosine residues, to beginto be transcribed with restored tumor suppressor func-tion and programmed apoptosis.

The U. S. Food and Drug Administration has approvedazacitidine (Vidaza 2009) and decitabine (Dacogen 2009)for intermediate 2 and higher-risk MDS. Azacitidine isgiven on an outpatient basis at 75 mg/m²/day for 7 daysand repeated every 28 days as a subcutaneous (SC) in-jection or a 10- to 40 minute intravenous (IV) infusion.Decitabine is approved for use as a 15 mg/m2 IV infusiondelivered over 3 hours every 8 hours for days 1-3 of every6-week cycle, necessitating hospitalization for infusionduring each treatment cycle.

Azacitidine. Fenaux (2009) recently evaluated azaci-tidine and compared its efficacy at 75 mg/m²/day givensubcutaneously for 7 days and repeated every 28 dayswith three other conventional care regimens used to treatMDS — best supportive care (BSC), low-dose cytarabine,and intensive chemotherapy (the comparator option wasselected by individual investigator choice) — in the treat-ment of 358 patients with higher-risk MDS. Because ofthe advanced age of the population (mean, 76 years)more subjects received BSC (n=105) or cytarabine(n=49) than the intensive chemotherapy regimen(n=25). The primary endpoint of the trial was OS (pa-tients followed until death or study closure to ensure


FIGURE 2Azacitidine significantly improves overall patient survival

0 5 10 15 20 25 30 35 40

Time (months) from randomization

1.00.90.80.70.60.50.40.30.20.10.0

Log-rank P=0.0001HR=0.58 (95% CI: 0.43 -0.77)

CCR=conventional care response, CI=confidence interval, HR=hazard ratio.Source: Fenaux 2009

Pro

po

rtio

n s

urv

ivin

g

24.5 months

azacitidine

CCR15 months

maximal response); secondary endpoints included timeto AML or death, infections requiring IV antimicrobials,transfusion independence, and hematologic responseand safety. At the time of analysis, the patients had beenfollowed for a median 21.1 months, with an observed me-dian OS of 24.5 months in the azacitidine group and 15.0months in the conventional care group (stratified logrank P=.0001) (Figure 2, page 7). The survival advantagebegan early as the Kaplan-Meier survival curves separatedpermanently after only 3 months. At 2 years, 50.8 percentof azacitidine-treated patients were alive vs. 26.2 per-cent of those in the conventional care group (P<.0001).This significant benefit for azacitidine was consistentacross all MDS cytogenetic subtypes and all IPSS sub-groups. In addition, the proportion of subjects withcomplete response (CR) or partial response (PR) was sig-nificantly greater with azacitidine therapy than with con-ventional care. Time to disease progression, rates of re-lapse after complete or partial remission, and death ratesalso were significantly better in the azacitidine group, aswere proportions of erythroid and platelet improvements.There was no significant difference in the frequency ofmajor neutrophil improvement between the two treat-ment groups. Peripheral blood cytopenias were the mostcommon grade 3-4 adverse events in all treatment groups.These results substantiated a benefit for azacitidine interms of increased overall survival and improved clinicaland laboratory markers compared with conventionalstandards of care in patients with higher-risk MDS.

For patients who respond to azacitidine, treatmentshould be continued until there is evidence of diseaseprogression or unacceptable toxicities develop. Also, it isimportant to note that responsesto azacitidine may improve withcontinued treatment.

Decitabine. In a combinedEORTC leukemia and GermanMDS Study Group randomizedphase 3 trial (Wijermans 2008),investigators followed responsesto low-dose decitabine (15mg/m2 IV over 4 hours every 8hours for the first 3 days of anevery 6-week cycle, maximum 8cycles) versus supportive care in233 patients aged ≥60 years withintermediate 2 or higher-riskMDS or CMML. Patients on sup-portive care returned for re-sponse monitoring every 24weeks and patients who had anyresponse to decitabine were re-assigned to two more cycles oftherapy and then discontinued.Patients with progressive disease

at the time of assessment were discontinued. The groupswere well balanced for age, performance status, FAB cri-teria, cytogenetics, and IPSS classification. The mediannumber of cycles administered was four, and 40 percentof patients received two cycles or less. The overall re-sponse rate was 34.5 percent, and progression-free sur-vival (PFS) was significantly prolonged with decitabinetherapy (0.55 vs. 0.25 years, P=.004), but median OStimes with decitabine did not improve significantly, at0.84 years versus 0.71 years with supportive care (logrank 2-sided, P=.38). The Kaplan-Meier OS curves areshown in Figure 3. The time to AML or death was not sig-nificantly different between groups (P=0.24). Toxicitieswere primarily hematologic, including grade 3-4 febrileneutropenia in 26 percent of decitabine-treated patientsand 7 percent of the supportive care group. Grade 3-4 in-fections occurred in 59 percent and 47 percent of sub-jects, respectively.

Survival benefit. Overall, available data with hy-pomethylating agents indicate a survival benefit withazacitidine that has not been duplicated with decitabine.In Wijermans’ study (2008), the failure to achieve sig-nificant benefit in terms of OS with decitabine is con-sistent with the findings of a previous trial (Kantarjian2006). This survival distinction, observed in clinical tri-als with the two agents, may suggest a preference forazacitidine in the treatment of MDS IPSS class interme-diate 2 or higher-risk. MCOs should interpret data oncost, clinical benefit, survival, and quality of life (QoL)to make formulary and protocol decisions in line with in-stitutional requirements and internally defined stan-dards of care.


FIGURE 3Overall survival with decitabine versus supportive care in higher-riskMDS or CMML - Kaplan Meier curve

Median (months): 10.1 vs. 8.5HR = 0.88 , 95% CI (0.66, 1.17)Logrank test: P=0.38

Decitabine

Supportive care

0 6 12 18 24 30 36 42

100%

90%

80%

70%

60%

50%

40%

30%

20%

10%

0

CI=confidence interval, CMML=chronic myelomonocytic leukemia, HR=hazard ratio, MDS=myelodysplastic syndromes. Source: Wijermans 2008

(months)

Other treatments. The NCCN (2009) recommendshigh-intensity chemotherapy regimens for patients withhigher-risk MDS for whom a stem cell donor cannot befound or for those eligible for HSCT but who requireblast reduction prior to the procedure. Due to the sub-stantial morbidity and mortality associated with theseregimens, the NCCN recommends that they be admin-istered in the setting of a clinical trial. Comparative tri-als have not revealed any significant difference in out-comes with regimens based on idarubicin, cytarabine,fludarabine, or topotecan (Estey 2001). Furthermore,there is a strong likelihood of multidrug resistance in ad-vanced MDS, leading to poorer response rates and ab-breviated response durations (Estey 2001, Sonneveld1993). Ongoing clinical trials also are examining the po-tential of multidrug resistance modulators, and may de-fine a role for these agents in the future.

Future therapeutic directionsSeveral therapeutic methods to achieve better out-

comes in higher-risk MDS are currently in the researchphase. Combination therapy, long-term maintenanceregimens, and such novel agents as clofarabine areamong the more promising.

Maintenance therapy. Despite a 50 percent responserate to induction chemotherapy among patients withhigher-risk MDS, response duration generally is shortand survival brief. To assess the benefit and risks of ex-tending hypomethylating therapy for long-term main-tenance therapy, the Nordic MDS Group in Sweden(Grövdal 2008) carried out a prospective multicenterphase 2 study delivering low-dose azacitidine (meandose, 54.3 mg/m2) administered for 5 of 28 days (untilrelapse or unacceptable toxicity) to 23 of 60 patientswith higher-risk MDS (n=23) or AML (n=37) and whoachieved a CR after induction therapy with daunorubicinand cytarabine, also known as ara-C. Subjects were in-eligible for stem cell transplantation. With maintenancetherapy for a median of 13.5 months, the median OS was20 months, and 11 of 24 patients experienced no adverseevents. At last follow-up, three patients were still in CR.The most commonly reported side effect was mild rashat the injection site. These results suggest that mainte-nance therapy with azacitidine can prolong survival inpatients with higher-risk MDS.

Combination therapy. Resistance to hypomethylatingagents is an emerging clinical concern. In phase 1/2 clin-ical studies, histone deacetylase inhibitors appeared toimprove the activity of hypomethylating agents whengiven in combination. In a recent phase 3 trial, however,the combination of decitabine plus valproic acid offeredno significant response benefit over decitabine alone inthe treatment of 72 patients with MDS or AML (Issa2008).

On the other hand, early results are promising for the

combination of azacitidine plus vorinostat, an alterna-tive histone deacetylase inhibitor. In a phase 1 study bySilverman (2008), azacitidine (55 or 75 mg/m2 SC) plusvorinostat (200 or 300 mg by mouth) was administeredin eight different dosage and schedule combinations to23 patients with MDL or AML. A minimum of four 28-day cycles was scheduled. At analysis, 50 percent of sub-jects had achieved CR and 11 percent CR with incompleteblood count recovery, which is superior to results re-ported with either agent alone and to other hypomethy-lating agent/histone deacetylase inhibitor combinations.The overall response rate (ORR) was 83.3 percent. Fa-tigue was related to duration of vorinostat exposure andnot to total daily dose. These results suggested the com-bination was safe and effective, and it is now scheduledfor phase 2 investigation.

In addition, the complementary benefits of a combi-nation of lenalidomide, which has immunomodulatory,anti-angiogenic, and cytotoxic properties, and azaciti-dine, with cytotoxic effects and hypomethylating activ-ity, have been examined in 19 patients with MDS, andearly data suggest that the combination appeared to bewell-tolerated, with efficacy superior to either agents’single-agent activity in higher-risk MDS (Sekeres 2008).

Clofarabine. Clofarabine (Clolar), a second-genera-tion purine analog FDA-approved for treating acute lym-phoblastic leukemia, is also now being used to treat MDS.It has demonstrated high response rates as first-line ther-apy for patients over age 60 with AML (ORR: 46 percent;CR: 38 percent), and proven active in patients over age70 with poor-risk cytogenetics and poor performancestatus (Erba 2008). It is currently being studied in bothIV (15 mg/m2 vs. 30 mg/m2/day for 5 days every 4 to 6weeks) and oral (40 mg/m2/day for 5 days, reduced to 30mg/m2/day after first 6 patients had been treated on thehigher dose) formulations for the treatment of patientswith ≥5 percent blasts and higher-risk MDS (Faderl2008). Early results presented at the 2008 American So-ciety of Hematology meeting reveal ORRs approaching50 percent with both oral and low-dose IV formulationswith efficacy in one quarter to one third of patients whofailed hypomethylating therapy (Faderl 2008). Liver com-plications may be a concern and patients warrant regu-lar testing.

Alternative outcomesA number of additional factors can influence the nat-

ural history of MDS, and the success and cost of therapyhave been identified and should be taken into account inmaking decisions regarding treatment protocols and for-mulary approval for the available medications for inter-mediate 2 and higher-risk MDS patients. These factorsare discussed below.

Transfusion requirement. A high transfusion bur-den (≥2 transfusion events in an 8-week period) is a rec-


ognized marker of disease severity and worse prognosisin MDS. Malcovati (2006) showed that increased trans-fusion burden can be directly correlated with risk for dis-ease progression and survival. The investigators reportedthat increasing transfusion dependency predicted agreater risk for transition to leukemia and decreased sur-vival. It is not clear whether the increased death is due di-rectly to more severe MDS, to the underlying anemia, orto a consequence of regular transfusions (e.g., iron ac-cumulation), but it is likely a combination of the three.This relationship, however, formed the basis for theWPSS prognostic schema (Greenburg 1997, Mufti2008a).

Importantly, effective hypomethylating therapy mayinduce transfusion independence and reduce morbidityand mortality risk in patients with higher-risk MDS. Fe-naux (2009) reported that 45 percent of patients who re-quired RBC transfusions on enrollment became RBCtransfusion independent while receiving azacitidine ther-apy; among subjects receiving conventional care, only11.4 percent achieved RBC transfusion independence(P<.0001). Even more compelling, it was noted thatamong patients who did not require transfusions onentry, 85.3 percent of azacitidine-treated patients main-tained RBC transfusion independence over the course ofthe trial compared to 56.9 percent receiving conven-tional therapeutic approaches. In a study by Kantarjian(2006) involving decitabine therapy, RBC transfusionindependence increased progressively with each cycle ofdecitabine therapy, while the RBC transfusion require-ment did not change significantly among patients treatedwith supportive care.

RBC transfusion is a generally a well-tolerated proce-dure that effectively increases the oxygen-carrying ca-pacity of the blood. The most significant risks associatedwith this technique are volume overload, iron overload,infection, and, in immunocompromised patients, a smallrisk for graft-versus-host disease. Once a patient requiresplatelet transfusion, however, the prognosis worsens.Platelets, unlike RBCs, are highly immunogenic, leadingto antibody development and self-destruction of infusedplatelets if human leukocyte antigen-matched donorcells are not used. Spontaneous and difficult to controlbleeding can arise, and death usually occurs within ayear.

Treatment-related cytopenias. Anemia, neutropenia,and thrombocytopenia may be worsened early in thecourse of hypomethylating agent therapy. With azaciti-dine therapy, in most cases cytopenias will resolve afterone or two cycles of therapy, although this has not beenshown with decitabine. In later cycles, the rates of thesecytopenias diminish substantially, and therapy can becontinued with few or no symptoms (Fenaux 2009).

Infection. The cytopenias associated with MDS placea patient at increased risk for infection, requiring in-

creased resources and greater cost. Complications likebacterial pneumonia and skin abscess are not uncom-mon. Infection may be a frequent cause of death amongpatients with MDS, and in one study (Pomeroy 1991) ac-counted for more deaths than acute leukemia.As a result,aggressive treatment with antimicrobial therapy shouldbe administered either prophylactically or at the first signof infection to minimize the risk for severe, life-threat-ening complications. Treatment with azacitidine appearsto reduce the risk for infection requiring IV anti -microbials by 33 percent compared with conventionalcare approaches (Figure 4). When measured as the rateof infection requiring IV antimicrobial therapy in pa-tient-years of care, azacitidine had a 0.16 risk comparedwith 0.24 (P=.0032) for conventional interventions (Fe-naux 2009). Comparable data do not exist for decitabine.

Hospitalization. In a French observational study todetermine the daily practices for care of patients withMDS, Kelaidi (2008) reported the characteristics of 919patients seen over a 1-week period in 74 centers in France:13 percent of subjects were hospitalized, 4.5 percent forinfections or bleeding and 8.5 percent for “active” treat-ment. In addition, 46 percent were being seen in day care(outpatient) facilities, predominantly for transfusions(40 percent). Only 40 percent of higher-risk patients werereceiving EPAs. The authors concluded that active treat-ments are underprescribed in this population.

Several preventive or proactive interventions may helpto reduce the need for hospitalization or acute day careand their associated high costs in patients with MDS.First, use of growth factor support or EPA at the first signof neutropenia or anemia could prevent later need forhospitalization (Stasi 2005). Similarly, prophylactic anti -biotics may prevent or diminish infection or pneumoniarisk. When transfusion is necessary, if undertaken earlyit might be accomplished in the outpatient department,


FIGURE 4Azacitidine reduces the risk for infectionrequiring intravenous antimicrobials

Azacitidine

Rate

per

pat

ien

t-ye

ar

CCR

.16

.24.30

.25

.20

.15

.10

.05

0

CCR=conventional care response, CI=confidence interval,HR=hazard ratio.Source: Fenaux 2009

A 33% reduction (HR, 0.67; 95% CI: 0.35–1.20)

with a relative reduction in cost compared with an in-patient procedure. In addition, there is a need to studyrevised regimens for active treatment that could reducemedical costs without impacting patient benefit. Azaci-tidine, for one, is being studied (Lyons 2009) as an on-going 5-day regimen for lower-risk MDS that may reducethe need for weekend care and may have the simultane-ous benefit of decreasing clinic and hospitalization fees.If significant efficacy and survival benefit also is estab-lished, these improvements may prove one agent morecost-effective than another.

ConclusionFor patients classified as intermediate 2 or higher-

risk MDS, early diagnosis and treatment initiation areimportant factors for deterring disease progression andprolonging survival. A clinical and hematologic labora-tory diagnosis should be confirmed with bone marrowmorphologic studies. HSCT should be considered at di-agnosis for optimal outcomes in patients with interme-diate 2 and higher-risk MDS who are appropriate can-didates for HSCT. Patients with lower-risk disease dobetter when transplant is delayed, as long as it is under-taken before progression to AML. The hypomethylatingagents azacitidine and decitabine have been shown toalter some of the hematologic defects of the disease in pa-tients with higher-risk MDS, and azacitidine has shownsurvival benefit.

Ongoing maintenance therapy may be essential tolong-term disease control in these patients, unless thereare signs of disease progression, and this approach isunder investigation in clinical trials. Early results of stud-ies undertaken suggest that long-term maintenance ther-apy with azacitidine after response to inductionchemotherapy improves survival in patients with higher-risk MDS. Regimens that combine agents with differentmechanisms also are being studied as a means to prolongresponses and sustain survival in MDS patients. Thecost of therapy can be contained through a concerted ef-fort to focus on outpatient treatment, manage cytopeniasand infections quickly, and minimize hospitalizations.

MCO decision makers should evaluate all availabledata on agents proven effective in treating higher-riskMDS within the context of their institutional guidelinesand standards of care to define a treatment protocol.Their assessment should consider clinical benefit (interms of transfusion burden, need for antimicrobials,and hospitalization rate), survival outcomes, and QoLas well as cost. Medication choice requires a well- orchestrated collaboration among patient, physician,and payer to maximize outcome within reasonable costboundaries.

ReferencesAnderson JE, Thomas ED. The Seattle experience with bone

marrow transplantation for MDS. Leuk Res. 1997;21:S51.Apperley JF, Gardembas M, Melo JV, et al. Response to imatinib

mesylate in patients with chronic myeloproliferative dis-eases with rearrangements of the platelet-derived growthfactor receptor beta. N Engl J Med. 2002;347:481–487.

Bennett JM, Catovsky D, Daniel MT, et al. Proposals for the clas-sification of the myelodysplastic syndromes. Br J Haematol.1982;51:189–199.

Brunning RD, Matute E, Harris NL, et al.: Acute myeloidleukemia with multilineage dysplasia. In: Jaffe ES, HarrisNL, Stein H, et al., eds. Pathology and Genetics of Tumours ofHaematopoietic and Lymphoid Tissues. Lyon, France: IARCPress. 2001:88–89.

Buckner D. Advances in the treatment of myelodysplastic syn-dromes. A report from the 2008 American Society ofHematology Meeting. «http://www.oncoed.com/conference_main.aspx?id=43091». Accessed Oct. 15, 2009.

Cazzola M, Malcovati L. Myelodysplastic syndromes – copingwith ineffective hematopoiesis. N Engl J Med. 2005;352:536–538.

Chesson BD, Bennett JM, Kantarjian H, et al. Report of an inter-national working group to standardize response criteria formyelodysplastic syndromes. Blood. 2000;96:3671–3674.

Cutler C, Lee SJ, Greenberg P, et al. A decision analysis of allo-geneic bone marrow transplantation for the myelodysplas-tic syndromes: delayed transplantation for low-riskmyelodysplasia is associated with improved outcome.Blood. 2004;104:579–585.

Dacogen (Decitabine). [Prescribing Information] MGI PharmInc., Bloomington, Minn. 2006.

Demuynck H, Verhoef GE, Zachee P, et al. Treatment of patientswith myelodysplastic syndromes with allogeneic bone mar-row transplantation from genotypically HLA-identical sib-ling and alternative donors. Bone Marrow Transplant.1996;17:745–751.

DeWitte T, Hermans J, Vossen J, et al. Haematopoietic stem celltransplantation for patients with myelo-dysplastic syn-dromes and secondary acute myeloid leukaemias: a reporton behalf of the Chronic Leukaemia Working Party of theEuropean Group for Blood and Marrow Transplantation(EBMT). Br J Haematol. 2000;110:620–630.

Disperati P, Ichim CV, Tkachuk D, et al. Progression ofmyelodysplasia to acute lymphoblastic leukaemia: implica-tions for disease biology. Leuk Res. 2006;30:233–239.

Erba HP, Kantarjian H, Claxton DF, et al. Phase II study of singleagent clofarabine in previously untreated older adult pa-tients with acute myelogenous leukemia (AML) unlikely tobenefit from standard induction chemotherapy. ASH An-nual Meeting Abstracts. Blood. 2008;112:558.

Estey EH, Thall PF, Cortes JE, et al. Comparison of idarubicin +ara-C-, fludarabine + ara-C-, and topotecan + ara-C-basedregimens in treatment of newly diagnosed acute myeloidleukemia, refractory anemia with excess blasts in transfor-mation, or refractory anemia with excess blasts. Blood.2001;98:3575–3583.

Faderl S, Garcia-Manero G, Ravandi F, et al. Oral (po) and intra-venous (iv) clofarabine for patients (pts) with myelodys-plastic syndrome (MDS). ASH Annual Meeting Abstracts.Blood. 2008;112:222.

Fenaux P, Mufti GJ, Hellström-Lindberg E, et al. Efficacy of aza-citidine compared with that of conventional care regimensin the treatment of higher-risk myelodysplastic syndromes:a randomised, open-label, phase III study. Lancet Oncol.2009;10:223–232.


Galili N, Cerny J, Raza A. Current treatment options: impact ofcytogenetics on the course of myelodysplasia. Curr TreatOptions Oncol. 2007;8:117–128.

Greenberg P, Cox C, LeBeau MM, et al. International scoring sys-tem for evaluating prognosis in myelodysplastic syndromes.Blood. 1997;89:2079–2088.

Grövdal M, Khan R, Aggerholm A, et al. Maintenance treatmentwith 5-azacitidine for patients with high risk myelodysplas-tic syndrome (MDS) or acute myeloid leukemia followingMDS (MDS-AML) in compete remission after inductionchemotherapy. ASH Annual Meeting Abstracts. Blood.2008;112:223.

Haase D, Germing U, Schanz J, et al. New insights into the prog-nostic impact of the karyotype in MDS and correlationwith subtypes: evidence from a core dataset of 2124 pa-tients. Blood. 2007;110:4385–4395.

HMDS (Haematologic Malignancy Diagnostic Service). Themyelodysplastic syndromes. «http://www.hmds.org.uk//mds.html». Accessed Oct. 15, 2009.

Issa, J-P, Castoro R, Ravandi-Kashani F, et al. Randomized PhaseII Study of Combined Epigenetic Therapy: Decitabine Vs.Decitabine and Valproic Acid in MDS and AML. ASH An-nual Meeting Abstracts. Blood. 2008;112:228.

Jädersten M, Malcovati L, Dybedal I. et al. Erythropoietin andgranulocyte-colony stimulating factor treatment associatedwith improved survival in myelodysplastic syndrome. J ClinOncol. 2008;26:3607–3613.

Kantarjian H, Issa JP, Rosenfeld CS, et al. Decitabine improvespatient outcomes in myelodysplastic syndromes: results of aphase III randomized study. Cancer. 2006;106:1794–1803.

Kelaidi C, Stamatoullas A, Beyne-Rauzy O, et al. MyelodysplasticSyndrome (MDS) in France: Results of a One-Week Cross-Sectional Survey on Daily Practice Management in 919 Pa-tients by the GFM. ASH Annual Meeting Abstracts. Blood.2008;112:2672.

Lyons RM, Cosgriff TM, Modi SS, et al. Hematologic response tothree alternative dosing schedules of azacitidine in patientswith myelodysplastic syndromes. J Clin Oncol. 2009;27:1850–1856.

Magnusson MK, Meade L, Nakamura R, et al. Activity of STI571in chronic myelomoncytic leukemia with a platelet-derivedgrowth factor beta receptor fusion oncogene. Blood.2002;100:1088–1091.

Malcovati L, Della Porta MG, Cazzola M. Predicting survival andleukemic evolution in patients with myelodysplastic syn-drome. Haematologica. 2006;9:1588–1590.

Malcovati L, Germing U, Juendgen A, et al. Time-dependentprognostic scoring system for predicting survival andleukemic evolution in myelodysplastic syndromes. J ClinOncol. 2007;25:3503–3510.

Mufti GJ, Bennett JM, Goasguen J, et al. Diagnosis and classifica-tion of myelodysplastic syndrome: International WorkingGroup on Morphology of myelodysplastic syndrome(IWGM-MDS) consensus proposals for the definition andenumeration of myeloblasts and ring sideroblasts. Haema-tologica. 2008a;93:1712–1717.

Mufti GJ, Fenaux P, Hellström-Lindberg E, et al. Treatment ofhigh-risk MDS patients (pts) with -7/del(7q) with azaciti-dine (AZA) versus conventional care regimens (CCR): Ef-fects on overall survival. J Clin Oncol. 2008b; ASCO Meet-ing Abstract 7033.OS.

NCCN (National Comprehensive Cancer Network). NCCNClinical Practice Guidelines in Oncology: Myelodysplasticsyndromes. v2.2010. «http://www.nccn.org/professionals/physician_gls/PDF/mds.pdf». Accessed Oct. 15, 2009.

Nevill TJ, Fung HC, Shepherd JD, et al. Cytogenetic abnormali-ties in primary myelodysplastic syndrome are highly pre-


dictive of outcome after allogeneic bone marrow transplan-tation. Blood. 1998;92:1910–1917.

Ogata K, Nakamura K, Yokose N, et al. Clinical significance ofphenotypic features of blasts in patients with myelodysplas-tic syndrome. Blood. 2002;100:3887–3896.

Pomeroy C, Oken MM, Rydell RE, Filice GA. Infection in themyelodysplastic syndromes. Am J Med. 1991;90:338–344.

Rollison DE, Howlader N, Smith MT, et al. Epidemiology ofmyelodysplastic syndromes and chronic myeloproliferativedisorders in the United States, 2001–2004, using data fromthe NAACCR and SEER programs. ASH Annual MeetingAbstracts. Blood. 2008;112:45–52.

Scott BL, Sandmaier BM, Storer B, et al. Myeloablative vs. non-myeloablative allogeneic transplantation for patients withmyelodysplastic syndrome or acute myelogenous leukemiawith multilineage dysplasia: a retrospective analysis.Leukemia. 2006;20:128–135.

Sekeres MA, List AF, Cuthbertson D, et al. Final results from aphase I combination study of lenalidomide and azacitidinein patients with higher-risk myelodysplastic syndromes(MDS). ASH Annual Meeting Abstracts. Blood. 2008;112:221.

Silverman LR. Targeting hypomethylation of DNA to achievecellular differentiation in myelodysplastic syndromes(MDS). Oncologist. 2001;6(suppl 5):8–14.

Silverman LR, Verma A, Odchimar-Reissig R, et al. A Phase ITrial of the Epigenetic Modulators Vorinostat, in Combina-tion with Azacitidine (azaC) in Patients with the Myelodys-plastic Syndrome (MDS) and Acute Myeloid Leukemia(AML): a Study of the New York Cancer Consortium. ASHAnnual Meeting Abstracts. Blood. 2008;112: 3656.

Sonneveld P, van Dongen JJ, Haaemeijer A, et al. High expressionof the multidrug resistance P-glycoprotein in high-riskmyelodysplasia is associated with immature phenotype.Leukemia. 1993;7:963–969.

Stasi, R, Abruzzese E, Lanzetta G, et al. Darbepoetin alfa for thetreatment of anemic patients with low- and intermediate-1-risk myelodysplastic syndromes. Ann Oncol. 2005;16:1921–1927.

Szpurka H, Tiu R, Murugesan G, et al. Refractory anemia withringed sideroblasts associated with marked thrombocytosis(RARS-T), another myeloproliferative condition character-ized by JAK2 V617F mutation. Blood. 2006;108:2173–2181.

Vidaza (Azacitidine). [Prescribing Information]. Celgene Corpo-ration, Summit, N.J. 2008.

Wells DA, Benesch M, Loken MR, et al. Myeloid and monocyticdyspoiesis as determined by flow cytometric scoring inmyelodysplastic syndrome correlates with the IPSS andwith outcome after hematopoietic stem cell transplanta-tion. Blood. 2003;102:394–403.

Wijermans P, Suciu S, Baila L, et al. Low dose decitabine versusbest supportive care in elderly patients with intermediate orhigh risk MDS not eligible for intensive chemotherapy:final results of the randomized phase III study (06011) ofthe EORTC Leukemia and German MDS Study groups.ASH Annual Meeting Abstracts. Blood. 2008;112:226.

Disclosure: Bart L. Scott, MD, states that he is a consultant to Celgene Corp. and is on the speakers bureau of Alexion Pharma-ceuticals.

DISCUSSIONSTEVEN R. PESKIN, MD: Decitabine has a different dos-

ing protocol and schedule compared with azacitidine.Dr. Scott, can you clarify that difference?

BART L. SCOTT, MD: Decitabine is given as a continuousIV infusion over 3 hours repeated every 8 hours for 3days, which requires hospitalization. Azacitidine, at astarting dose of 75 mg/m2 once daily for 7 days and re-peated every 4 weeks, can be given either IV or SC onan outpatient basis, which requires about an hour-long outpatient visit. But with the infusion, a nurse hasto check vital signs, get the IV started, and monitor thepatient, so that takes about 2 to 3 hours. Some practi-tioners give decitabine as 20 mg/m2 in a 1-hour IV in-fusion daily for 5 consecutive days, thereby mitigatingthe need for hospitalization. However, that regimen hasnot been compared with the FDA-approved dose.

PESKIN: Why would you choose IV delivery?SCOTT: Patients who already have a line in place would

probably receive the IV. If they have a very low plateletcount, say <50,000, my preference is to give an IV toavoid bruising and bleeding. Otherwise, SC delivery isgenerally preferred, because it is faster, easier, and lessexpensive. Now if a patient tells me that he or she hasan absolute phobia regarding shots, then I have to givean IV.

PESKIN: What was the rationale for studying long-termmaintenance therapy after maximum response with ahypomethylating agent?

SCOTT: One of the important things that has come outof the hypomethylating agents literature is that if a pa-tient has a response, it’s a good idea to continue themedication. In the Fenaux study [2009], of the 175 pa-tients who received azacitidine, 51 percent had an In-ternational Working Group (IWG) response*, butcontinued dosing led to a higher IWG response in 48percent of the patients. In anecdotal reports, discon-tinuation of azacitidine after patients achieve a re-sponse is often followed by disease progression. A de-sign flaw may have contributed to poor outcomeswith decitabine in the Wijermans study [2008]; pa-tients who had a complete remission were taken off thestudy after an additional two cycles of treatment.

PESKIN: You mentioned that in the Fenaux study [2009]cytopenias worsened with azacitidine. The neutrope-nia rate (Grade 3/4) was 61 percent versus 21 percentwith best supportive care, and greater thrombo -cytopenia, leukopenia, and anemia, as well. Was thisa side effect or did the medication not work?

SCOTT: Those data are correct, but remember that thecytopenias that occur during the first 2 months of

treatment with azacitidine usually resolve over time,and later treatment does not induce hematologic tox-icity. This finding is believed to be due to loss of theMDS clone on which the patient has been dependent,and a delay until normal stem cells start working again.In fact, these MDS malignant clones actually down-regulate the production of normal stem cells, and soare especially insidious. But the risks from these cy-topenias are minor. Hospital admissions for IV an-timicrobials during early azacitidine therapy, for in-stance, do not differ much from those withconventional care, and infection rates may, in fact, belower. There are two ways to approach this early tox-icity: First, forewarn patients — be honest with them.Explain that their hematological counts will get a bitworse during the first two cycles, but after that, thecounts will rise and they will feel better. Second, pro-vide support therapies at the first sign of cytopenia. Ifa patient develops neutropenia, consider a prophy-lactic antibiotic or antiviral agent. Also, although theazacitidine PI recommends delaying treatment in theevent of cytopenias, I use my judgment and try tokeep on schedule.

DAVID FRAME, PHARMD: When these drugs first cameout, it was common to delay cycles, but now that wehave more experience, many people will push throughas long as the cytopenias are not too severe. In fact, youactually get to the endpoint faster if you do. The longeryou delay, the more methylation comes back, so it’s likestarting over again. Therefore, what normally takesfour cycles can actually require six, seven, or even ninecycles of therapy to reach best response.

ALLAN JAY KOGAN, MD: But we need standards that arewritten and consistent. It is very difficult to establishprior authorization criteria if standards are not doc-umented and agreed upon. Using a package of care,i.e., an acknowledged and evidence-based agenda ofapproved potential treatments, including adverse eventresolution therapies, to address potential treatment ad-justments would allow employers, for example, to an-ticipate the bill that’s coming. They need to know if thebilling from a particular therapy might be much higherthan by following the PI.

SCOTT: But we don’t know what led the FDA at the timeof azacitidine approval to require dosing delays in thePI dosing guidelines. The data we now have suggestyou should not delay. If the NCCN would corroboratethis position, I think we can agree that this is the stan-dard of care and inform the FDA accordingly.

PESKIN: What are the key issues addressed by Dr. Scottthat would be of greatest interest to MCOs?

KOGAN: The first is accurate diagnosis. We want to iden-tify the best return on investment on any interventionso we do not treat 100 people to achieve the desired out-come in 30. We would like to ensure targeted medicine,


* In 2000, the IWG proposed standardized criteria for evaluatingclinically significant responses in patients with MDS. See Che-son 2000.

even if it requires treatment at specialty centers, or whatwe in the payer community call “centers of excellence.”We want to ensure that we are treating the right popu-lation and not dosing everybody to improve a few.

JEFFREY D. DUNN, PHARMD: The key trials are impor-tant to decision makers at SelectHealth, but the finalprotocols and formulary choices need to be collabo-rative. A multidisciplinary group including represen-tatives from community oncology and academicgroups, the P&T, and financial people would all con-tribute to a final decision. For instance, altering thedecitabine dose without a published data comparisonwith the approved regimen may cut costs, but is it theright thing to do? We need a diverse and well-roundedteam to agree on those decisions.

PESKIN: Can you think of any analogous situations —e.g., multiple sclerosis, rheumatoid arthritis, or Parkin-son’s — in which novel treatments like injectable bi-ologics have altered the way we should think abouttreatment and reimbursement?

DUNN: If you look at the three big cost categories in theinjectable infusible arena, it’s oncology, MS, and RA.There were financial incentives for rheumatologists toinfuse infliximab (Remicade) in their office versusprescribing a SC. But oncology is more political dueto the life and death impact of decisions. Can cost bethe primary factor in those decisions?

KOGAN: About 80 percent of oncologists’ revenue comesfrom infusions given in their offices. So an oncologistdoesn’t want to put patients in the hospital. This is onearea in which MCO and provider needs meet.

KIRBY ENG, RPh: The market is creating collaborationsamong community-based oncologists, hematologists,and payers. The easiest way to save money is to sim-ply reduce physician drug reimbursement fees, butpayers have to create a delicate balance if they want tomaintain a healthy provider network.

PESKIN: When you look at the decitabine versus azaci-tidine trials, a notable difference is that growth factoruse was not allowed in the azacitidine trial, but thedecitabine trials allowed G-CSF growth factor andEPO. In the Phase 3 decitabine trials, about 45 percentof patients on decitabine ended up receiving growthfactors. What are the implications of this difference?

SCOTT: There have been some discussions about look-ing at G-CSF with hypomethylating agents, because ifyou can increase the replication of the clonal stemcell, then presumably you would have more incorpo-ration of the hypomethylating agent. But you mightalso see more toxicity. So I think that deserves furtherinvestigation. It is hard to know if administeringG-CSF concomitantly with a hypomethylating agentwill lead to improved response rates or worse toxicity.

FRAME: Response to EPO improves during treatmentwith a hypomethylating agent.

SCOTT: EPO is frequently used as first-line therapy foranemia. It works very well, but it doesn’t have a durableresponse. Eventually patients become RBC transfusiondependent. In a few cases, patients who were treatedwith azacitidine and EPO added at a later point, the he-moglobin and hematocrit appeared to increase dra-matically. It is theoretically possible that azacitidineled to a restoration of response to the erythroid-stim-ulating agent (ESA) — azacitidine works by manipu-lating gene production and influences cellular mor-phology, which then restores response to EPO. Thisrelationship would be worth investigating further.

KOGAN: This returns to the package of care issue that Imentioned — considering not only drug therapy butsupportive therapies as well and how those are man-aged. It is not an insignificant cost factor, so we mustconsider the proper utilization and potential costs ofall possible interventions.

FRAME: When we look at the azacitidine data in lower-risk patients from a managed care perspective, in theCALGB trial [Silverman 2008], a fair number of lowand intermediate 1 patients were included, and theyhad extremely good responses. I hope there will bemore research that focuses on the use of hypomethy-lating agents in the lower-risk group. From a biologicstandpoint, it makes sense that if we change the biol-ogy earlier, we might be able to prolong survival evenfurther. On the other hand, that raises the concern thatrather than treating patients with these medications for24 months, treatment might continue for 5 to 7 years.

SCOTT: Based on current data, for the patient who hasisolated anemia with less than 5 percent bone marrowblasts, no sign of genetic abnormalities, and erythro-poietin <500, in my opinion ESAs remain the agent ofchoice. But in the same patient with a proven deletion7q mutation, azacitidine therapy would be appropri-ate for front-line therapy. There’s no prospective ran-domized study showing that ESAs prolong survival. Aretrospective study [Jädersten 2008] showed that pa-tients who received ESA therapy had prolonged sur-vival compared with patients who did not, and, anec-dotally, improved functionality and QoL.

PESKIN: Clofarabine is being used more commonly inMDS and leukemia patients, but since it is FDA-ap-proved only for acute lymphoblastic leukemia, willthere be reimbursement challenges?

SCOTT: Yes, patients are already having difficulty with re-imbursement. An oral formulation is being devel-oped, which will simplify administration, but com-plicate the reimbursement issue further. In addition,a histone deacetylase inhibitor, aurora kinase inhibitor,and Jak2/Flt-3 inhibitor are all in the pipeline. But fornow, azacitidine is the only agent that has been shownin a randomized study to prolong survival in MDS,and it is FDA-approved.



KEY POINTS• Dose schedules that include inpatient and

weekend therapy have an enormous impacton treatment-related costs and should be akey consideration in evaluating MDS treat-ment regimens.

• Alternate dosing schedules for azacitidineand decitabine are being explored to avoidweekend therapy and inpatient hospitaliza-tion.

• Although no clinical trials have yet comparedalternate dosing regimens for azacitidineand decitabine and their efficacy with theFDA-approved regimens, the choice of anagent to treat higher-risk MDS should con-sider survival advantage.

The DNA hypomethylating agents azacitidine (Vi-daza) and decitabine (Dacogen) are proving effective intreating myelodysplastic syndromes (MDS) by success-fully mitigating cytopenias, decreasing transfusion de-pendence, increasing the time until progression to acutemyeloid leukemia (AML), and generally improving qual-ity of life (QoL) in patients with all five French-Ameri-can-British (FAB) subtypes and both lower- and higher-risk International Prognostic Scoring System (IPSS)disease (Fenaux 2009, Kantarjian 2006, Silverman 2002,Wijermans 2008). Yet, complicated or inconvenient ad-ministration requirements may interfere with the ac-ceptance of or adherence to these medications by bothpatients and physicians.

Azacitidine has been shown in a phase 3 randomizedtrial to significantly prolong survival in intermediate 2and higher-risk MDS patients (Fenaux 2009); thereby al-tering the natural history of the disease. The U. S. Foodand Drug Administration-approved schedule for azaci-tidine is a subcutaneous (SC) injection at 75 mg/m2

given once daily for 7 days (every 28-day cycle) (Vidaza2008), which requires administration over a weekend —a service many clinics do not provide. Decitabine is FDA- approved as a 3-hour intravenous (IV) infusion of 15mg/m2 repeated every 8 hours for 3 days (every 6-weekcycle) (Dacogen 2006), which necessitates hospitalization

during each treatment cycle. These demands on patientand medical resources can negatively impact the accept-ability of treatment and adherence to a treatment regi-men. As a result, revised treatment schedules are beingconsidered. It is important to recognize, however, that thedose and schedule approved by the FDA and available forwidespread clinical use cannot simply be altered for con-venience — any revised protocols must show, on thebasis of randomized clinical trials, that the alternativedosing regimen yields equivalent or better efficacy andsafety than the FDA-approved dose and schedule.

Most patients prefer a therapy with greater ease of ad-ministration. However, optimal treatment goals cannotbe sacrificed. Such issues as survival benefit, transfusionindependence, complications of therapy, and need forhospitalization for adverse events (AEs) also weigh intothe selection of a preferred treatment regimen. Thus,administration protocols for azacitidine and decitabineusage to treat MDS should attempt to increase patientconvenience along with preserving or improving effi-cacy and safety within cost-control boundaries.

Clinical trials to evaluate alternative administrationroutes must be compared with the current FDA- approved regimens. In phase 3 trials, only SC azacitidinehas shown an established survival advantage and im-proved time to AML in higher-risk MDS compared withconventional care regimens (Fenaux 2009); therefore,any future trials of either azacitidine or decitabine shouldbe compared with the 7-day regimen of SC azacitidine.It is important to understand that pharmacologically,

Alternative Dosing Schedules for Methylation Inhibitors in MDS TreatmentDAVID FRAME, PHARMDAssistant Professor, Pharmacy and Clinical Hematology/Oncology/BMT Specialist

University of Michigan Comprehensive Cancer Center, Ann Arbor

David Frame, PharmD, is assistant professor of pharmacy andclinical hematology/oncology/BMT specialist at the University ofMichigan Comprehensive Cancer Center, Ann Arbor. Frame re-ceived his PharmD degree from Wayne State University, Detroit,and completed an oncology fellowship at the University of Illinois,Chicago. He has practiced at Rush University Medical Center inChicago as director of clinical hematology/oncology/BMT phar-macy services and research, and also was an assistant professor ofpharmacology at Rush Medical School. Frame has been activelyinvolved in oncology research and has presented nationally andinternationally on many oncology topics. He is affiliated with,among others, the American College of Clinical Pharmacy and theSociety of Health-System Pharmacists.

these drugs are not the same. Azacitidinecontains the ribonucleotide sugar, whichis partially metabolized to the deoxynu-cleotide, allowing azacitidine to be incor-porated into RNA and DNA, whereas,decitabine contains the deoxynucleotidesugar and is incorporated only into DNA.This may suggest some added influence ofRNA hypomethylation on the activity ofazacitidine (Glover 1987).

Alternative dosing schedulesGiven the challenges associated with

the administration of azacitidine anddecitabine, the protocols used in clinicalpractice have begun to vary from that rec-ommended in the FDA-approved pre-scribing information. As a result, otherregimens are being explored. For example,to avoid weekend therapy, azacitidine isbeing studied as either a 5-day schedule ora 5-2-2 schedule — that is, treatment is administered for5 days during the first week, 2 days of the weekend areskipped, and the patient returns for the final two SC in-jections on the first 2 consecutive days of the next week,which is repeated on a 28-day schedule. Similarly, someinvestigators have begun to test once-daily decitabine atan increased dose of 20 mg/m2 by 1-hour IV infusion for5 consecutive days repeated every 4 weeks, delivered onan outpatient basis. Results from clinical trials formallyinvestigating the outcomes and safety associated witheach of these alternative regimens have been recentlypublished and are discussed below.

Azacitidine. Lyons (2009) reported preliminary re-sults from a phase 2 study exploring three alternativeazacitidine (AZA) regimens designed to avoid weekenddosing in the treatment of 151 patients with MDS (Fig-ure 1). Patients were randomly assigned to one of the fol-lowing: AZA 5-2-2 (75 mg/m2/day SC for 5 days, followedby 2 days no treatment, then 75 mg/m2/day for 2 days);AZA 5-2-5 (50 mg/m2/day SC for 5 days, followed by 2days no treatment, then 50 mg/m2/day for 5 days); orAZA 5 (75 mg/m2/day SC for 5 days). All regimens wererepeated every 4 weeks for six cycles during the treatmentphase. After two cycles, dose adjustments were allowedbased on response and/or toxicities. Erythropoiesis-stim-ulating agents (ESAs) could be continued if used priorto enrollment, but not started anew. Primary endpointswere hematologic improvement and red blood cell (RBC)transfusion independence. A total of 139 patients (92 per-cent) received at least two treatment cycles and 79 (52percent) completed all six cycles. Hematologic improve-ment was observed in 44 percent, 45 percent, and 56percent in the AZA 5-2-2, AZA 5-2-5, and AZA 5 arms,respectively. Major erythroid improvement occurred in

44 percent, 44 percent, and 46 percent; major platelet im-provement occurred in 43 percent, 27 percent, and 50percent; and major neutrophil improvement occurred in17 percent, 17 percent, and 38 percent in the AZA 5-2-2, AZA 5-2-5, and AZA 5 arms, respectively.

Among patients who were RBC transfusion depend-ent at baseline, 50 percent, 55 percent, and 64 percent ofpatients treated with AZA 5-2-2, AZA 5-2-5, and AZA 5,respectively, achieved transfusion independence withinsix cycles. A subanalysis (Lyons 2009) showed that the ab-sence of baseline neutropenia or thrombocytopenia, aswell as lower baseline transfusion requirement, was as-sociated with a higher rate of RBC transfusion inde-pendence during treatment. Responding patients tendedto be FAB lower-risk patients, including 9 of 12 (75 per-cent), 6 of 12 (50 percent), and 11 of 16 (69 percent) pa-tients in the AZA 5-2-2, AZA 5-2-5, and AZA 5 dosinggroups, respectively. Grade 3-4 hematologic toxicity wasnearly doubled on the AZA 5-2-2 regimen (66 percent)compared with the 5-day regimen (34 percent), and withthe AZA 5-2-5 regimen falling in the middle (50 percent),suggesting a benefit in terms of toxicity with the AZA 5-day schedule.

The population enrolled in this trial was mostly of FABlower-risk disease status (63 percent) or refractory ane-mia with excess blasts (30 percent); therefore, interpre-tation about efficacy of the altered schedules in patientswith higher-risk disease is not possible. Another limita-tion of the trial is that the FDA-approved course of 7 con-secutive days of treatment was not included as a com-parator, so although the efficacy appears to be consistentwith outcomes achieved with the FDA-approved doseand schedule, equivalence cannot be concluded. Also,the trial was not powered to compare outcomes among

FIGURE 1RBC transfusion independence with alternative azacitidineregimens*

* Phase 2 study with 151 baseline transfusion-dependent MDS patients CI=confidence interval’ FAB=French-American-British subtype, RBC=red blood cell.Source: Lyons 2007

FAB low-risk patientsAll patients

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dependence on therapy. These rates were lower thanthose reported in the azacitidine trials (Lyons 2009, Fe-naux 2009, Silverman 2008). Hematologic toxicity washigh in this study; 31 percent of patients experiencedGrade 3 or higher neutropenia (14 percent febrile neu-tropenia), 18 percent thrombocytopenia, and 12 per-cent anemia. Importantly, 65 percent of patients requiredhospitalization during the study. Thus, although the in-vestigators concluded that a 5-day outpatient schedule ofdecitabine provided meaningful clinical benefit, thehematologic toxicity was more severe than that notedwith the FDA-approved regimen, which requires excesshospitalization, and, in some cases, necessitated con-comitant antimicrobial therapy.

FIGURE 2RBC and platelet transfusion independenceduring treatment with DEC 20 mg/m2, 1-hour IV infusion for 5 days every 4 weeks*

* ADOPT trial, 99 patients with median age 72 years.DEC=decitabine, RBC=red blood cell.Source: Steensma 2009a

33%40%

Conversion to RBC transfusion

independence

Conversion to platelet transfusion

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• Overall survival (median): 19.4 months• Number of cycles (median): 5, range, 1–17

the three alternative dosing regimens, so the data demon-strated only that each alternative dosing regimen ad-ministered improved the endpoints investigated. Clearly,these issues will have to be resolved in a phase 3 trial. Inthe meantime, this trial is being extended into a main-tenance treatment phase, offering continuing patientsAZA 75 mg/m2/day administered SC for 5 days, repeatedevery 28 days or every 42 days, to determine the dura-bility of hematologic responses with long-term AZAmaintenance therapy.

Decitabine. In the ADOPT trial (Steensma 2009a), agroup from the Mayo Clinic examined an alternativedosing schedule for decitabine of 20 mg/m2 delivered asa 1-hour IV infusion daily for 5 consecutive days and re-peated every 4 weeks — a regimen conducive to outpa-tient therapy — in the treatment of MDS patients withan IPSS score > 0.5 (Figure 2). There were 99 patients en-rolled in the study, median age 72 years, who were ex-amined for the primary endpoint of overall responserate (ORR) by International Working Group (Cheson2003) criteria and secondary endpoints of cyto genetic re-sponse, hematologic improvement, response duration,survival, and safety.

At the end of a median of 5 cycles, the ORR was 32 per-cent, comprising 17 percent complete responses (CRs)and 15 percent marrow CRs (mCRs), which included 18percent hematologic improvement (HI). mCR is de-fined by ≥50 percent myeloblast reduction from morethan 5 percent myeloblasts to ≤5 percent, but without re-covery of peripheral counts to a level meeting criteria forCR. Responses occurred by the end of cycle 2 in 82 per-cent of subjects who responded. Similar response rateswere observed in all IPSS risk categories. Median survivalwas 19.4 months. Among patients who entered the studyrequiring RBC or platelet transfusions, 33 percent con-verted to RBC and 40 percent to platelet transfusion in-

TABLEResults from two studies with DEC approved 3-day schedule and two studies with DEC 5-day outpatient alternative schedule

Time to RBCMedian Overall AML or Progression- Overall transfusion

# of Overall improvement death free survival survival independence cycles CR (%)a (%) (months) (months) (months) (%)b

3-day regimenD-0007 (N=89) 3 9 30 10 7.3 12.8 23EORTC-06011 (N=119) 4 13 34 8.8 6.6 10.1 32

5-day regimenDACO-020 (N=99) 5 15 43 12.1 8.1 17.8 33ID03-0180 (N=93) 7 37 65 15.2 9.2 20.3 NA

aAs measured by IWG 2000 criteria; bPatients who became RBC transfusion independent while on-study.AML=acute myeloid leukemia, CR=complete response, DEC=decitabine, RBC=red blood cell.Source: Adapted from Steensma 2009b


MDS_suppl_v15_blueschanges.qxp:MDS 11/11/09 4:07 PM Page 17

Several concerns have been noted about the design ofthis trial. As in the Lyons azacitidine study (2009), thestandard of care was not used as a comparator, which didnot allow conclusions to be drawn about relative efficacyand safety. Furthermore, the FDA-approved dose andschedule of decitabine was not used. The majority ofpatients in this study fell into the intermediate 1 riskcategory; thus, these results also cannot be extrapolatedto a higher-risk MDS population. In addition, a costanalysis will have to be carried out to determine the sav-ings achieved if a regimen is revised from inpatient ad-ministration to outpatient therapy, but the toxicity ne-cessitated hospitalization of 65 percent of patients.

Steensma (2009b) compared results from two ran-domized phase 3 studies in which patients were assignedto the inpatient 3-day dosing schedule of decitabine ver-sus supportive care with results from two phase 2 stud-ies in which patients received the outpatient 5-day dos-ing schedule (Table, page 17). This comparison was nota meta-analysis and did not take into account the differ-ence in design or protocol requirements, but the com-parison revealed some interesting findings. The reviewsuggested comparable overall improvement (CR + par-tial response [PR]+ HI), time to AML or death, and pro-gression-free survival (PFS) across all trials and bothregimens (Table 1, page 17), with one additionaldecitabine treatment cycle accomplished with the 5-daylower dose schedule. The PFS and time to AML or deathwas approximately 2 months longer with the 5-day al-ternative schedule. Overall survival was 10 to 12.8 monthswith the FDA-approved schedule versus 17.8 to >20months with the alternative schedule. Conversion toRBC transfusion independence was similar betweenschedules. These findings suggest some advantage asso-ciated with the 5-day protocol, but this must be weighedagainst the increased risk for hematologic toxicity, higherhospitalization rate, and associated costs observed in theADOPT trial with the abbreviated outpatient schedule(Steensma 2009a).

Decision-making considerationsGiven the data accumulated on the use of azacitidine

or decitabine in the treatment of higher-risk MDS, thereare several factors that should be included in a compar-ative analysis of the two drugs. These considerations in-clude efficacy and safety data, inpatient versus outpatienttreatment demands, and the ease and timing of medica-tion administration.

The efficacy and safety data suggest that azacitidine isconsistently effective and safe, with a proven survivaladvantage in patients with higher-risk MDS, whereas instudies done to date, decitabine has failed to significantlyincrease survival and has induced significant toxicityand substantial hospitalization when given on the ab-breviated outpatient regimen. In comparing the delivery

methods for the two agents, the FDA-approved admin-istration of decitabine infusion requires hospitalization,with the attendant increased resource utilization andcost, whereas the traditional protocol for azacitidine is anoutpatient SC injection or IV infusion. In studies of al-ternative regimens that are intended to improve patientand physician convenience, a 5-day/1-hour/once-dailyinfusion of decitabine was feasible as an outpatient reg-imen, but was associated with significant neutropeniaand substantial risk for febrile neutropenia, leading to ahigh hospitalization rate and associated costs.

Investigation into an alternative 5-day azacitidineschedule suggested good efficacy and safety in lower-risk patients, particularly in terms of transition to trans-fusion independence, which, if confirmed in a phase 3trial with comparison to the FDA-approved 7-day sched-ule, may offer improved convenience and cost savings.

Treatment decisions. Treatment decisions and for-mulary development are based on several factors, in-cluding evidence of efficacy and safety of available med-ications, timing and schedule of medication delivery,convenience and ease of administration, and overall costsand resource utilization involved in different medicationregimens. In the class of methylation inhibitors for in-termediate 2/high-risk MDS, these issues are compli-cated by the risks associated with hematologic impair-ment in a disease such as MDS, including transfusiondependence and risk for infection, as well as the limita-tions associated with the recent addition of medicationsto the existing armamentarium for this disease. The ad-ministration schedule and delivery methods for bothmethylation inhibitors currently being studied in higher-risk MDS, as recommended in the prescribing informa-tion, involve substantial logistic and economic chal-lenges. Both azacitidine and decitabine were approvedwith demanding regimens: azacitidine necessitatingweekend therapy, and decitabine infusion requiring hos-pitalization. Yet, the FDA-approved azacitidine regimenis based on outpatient clinical trial experience and doesnot require hospitalization, whereas decitabine is ap-proved only as a 3-day inpatient regimen, which neces-sitates inpatient (hospitalization) treatment.

Because of the concerns about schedule acceptabilityand cost limitations driven by the delivery methods forboth drugs, two studies have been undertaken to improvethe regimens to avoid weekend therapy or inpatient ad-ministration (Lyons 2009, Steensma 2009a, Steensma2009b). The alternative regimens for both hypomethy-lating agents appear to offer activity in MDS consistentwith that observed in the standard regimen; however, nei-ther clinical trial was designed with the approved regimenas a comparator, and both involved predominantly lower-

Disclosure: David Frame, PharmD, states that he is a consultantfor and on the speakers bureau of Celgene Corporation.


risk patients. These limitations, therefore, do not allowconclusions about the benefit of the alternative dosingschedules in patients with advanced MDS or aboutequivalent efficacy and safety relative to the FDA-ap-proved regimen for each drug. However, the approvedazacitidine regimen has been shown to significantly in-crease overall survival in higher-risk MDS comparedwith conventional care regimens (Lyons 2009), whereasdecitabine treatment has not shown that result, nor haveany of the alternative dosing regimens with azacitidineor decitabine.

ConclusionNo randomized, comparative trials of the two methy-

lation inhibitors azacitidine and decitabine have beenundertaken; therefore, the choice of agent to treat higher-risk MDS should depend on the best outcome desired —survival advantage, which is the most clinically mean-ingful outcome in higher-risk MSD. MCOs are con-cerned about drug and administration costs, safety, hos-pitalizations, and adverse events, and theseconsiderations factor into therapeutic decisions. Al-though the current FDA-approved regimens for azaciti-dine and decitabine may not be practical, it is importantto realize that none of the trials evaluating alternativedosing strategies have yet been compared with the FDA-approved regimens studied in randomized trials, andthat the populations, in general, are different. Phase 3comparative studies of these alternative regimens, if im-plemented, may reveal similar efficacy, safety, and costbenefits. However, based on established trial results todate, azacitidine appears to be the preferred agent fortreating intermediate 2 and higher-risk MDS.

ReferencesCheson BD, Bennett JM, Kopecky KJ, et al. Revised recommen-

dations of the International Working Group for Diagnosis,Standardization of Response Criteria, Treatment Out-comes, and Reporting Standards for Therapeutic Trials inAcute Myeloid Leukemia. J Clin Oncol. 2003;21:4642–4649.

Dacogen (decitabine for injection). [Prescribing Information].MGI Pharm, Inc., Bloomington, MN. 2006.

Fenaux P, Mufti GJ, Hellström-Lindberg E, et al. Efficacy ofazacitidine compared with that of conventional care regi-mens in the treatment of higher-risk myelodysplastic syn-dromes: a randomised, open-label, phase III study. LancetOncol. 2009;10:223–232.

Glover AB, Leyland-Jones B. Biochemistry of azacitidine: a re-view. Cancer Treat Rep. 1987;71:959-964.

Kantarjian H, Issa JP, Rosenfeld CS, et al. Decitabine improvespatient outcomes in myelodysplastic syndromes: results ofa phase III randomized study. Cancer. 2006;106:1794–1803.

Lyons RM, Cosgriff TM, Modi SS, et al. Hematologic response tothree alternative dosing schedules of azacitidine in patientswith myelodysplastic syndromes. J Clin Oncol. 2009;27;1850–1856.

Silverman LR, Demakos EP, Peterson EL, et al. Randomizedcontrolled trial of azacitidine in patients with themyelodysplastic syndrome: a study of the cancer andleukemia group B. J Clin Oncol. 2002;20:2429–2440.

Silverman LR, Verma A, Odchimar-Reissig R, et al. A Phase ITrial of the Epigenetic Modulators Vorinostat, in Combina-tion with Azacitidine (azaC) in Patients with the Myelodys-plastic Syndrome (MDS) and Acute Myeloid Leukemia(AML): a Study of the New York Cancer Consortium. ASHAnnual Meeting Abstracts. Blood. 2008;112:3656.

Steensma DP, Baer MR, Slack JL, et al. Multicenter study ofdecitabine administered daily for 5 days every 4 weeks toadults with myelodysplastic syndromes: the alternative dos-ing for outpatient treatment (ADOPT) trial. J Clin Oncol.2009a;27:38423848.

Steensma DP, Kantarjian A, Wijermans P. Clinical experiencewith different dosing schedules of decitabine in patientswith myelodysplastic syndromes (MDS). ASCO AnnualMeeting Proceedings (Post-Meeting Edition). J Clin Oncol.2009b;27:15 (suppl); abstract 7011.

Vidaza (azacitidine for injection) [Prescribing Information].Celgene Corporation, Summit, N.J. 2008.


DISCUSSIONSTEVEN R. PESKIN, MD: In the ADOPT study, one of the

endpoints was marrow complete response, a term I amnot familiar with. Dr. Scott, can you explain what thiscriterion means clinically?

BART L. SCOTT, MD: Marrow complete response ismarked by a reduction in the percentage of blasts inthe marrow to <5 percent, without necessarily evi-dence of concomitant hematologic improvement.Theoretically, this improvement should correlate witha reduced risk of MDS progression. Although the re-lationship has not been confirmed in a clinical trial,there are anecdotal reports of marrow responses ad-vancing to hematologic improvement with contin-ued exposure to medication.

PESKIN: Is it possible that it indicates an actual changein the biology of the cells, and that addition of agrowth factor, like interferon, might push those pa-tients into hematologic response?

DAVID FRAME, PHARMD: Yes, exactly.PESKIN: Based on Dr. Frame’s presentation, does anyone

want to share thoughts about how site of care, routeof administration, timing, or AEs influence preferredprotocols or reimbursement decisions?

JEFFREY D. DUNN, PHARMD: There are several factorsthat would feed into our decisions at SelectHealth.First, we generally would prefer a SC route of admin-istration over IV. This would enable us to keep peopleout of hospital as much as possible. The biggest con-cern with these alternative-dosing regimens is thatthey remain off-label. We need to garner support to getthose protocols in the guidelines before we can im-plement those schedules.

ALLAN JAY KOGAN, MD: I agree. As payers, we have to


be consistent, objective, and evidence-based, so thatwhen we make a decision, it is based on somethingthat’s transferable. In the payer community, we needto hold true to national standards of care. Our mem-bers all expect the same quality of care at the same cost.But if we can generate a revised algorithm — for ex-ample, develop a standardized off-label policy or gainapproval from the FDA — then we can support the al-ternate protocol nationwide.

PESKIN: How about longitudinally? How do the data in-fluence managed care strategies for the longer term?

DUNN: There are very few issues that we think aboutlongitudinally in the payer community. We revise ouremployer relationships at no more than 6-month in-tervals, and there is little room to think about cost sav-ings or better results 5 or 10 years down the road. ForMDS policy, it is particularly complicated, becauseyou must consider not just the cost of medication, butinpatient versus outpatient treatment, managementof adverse events, and adjunctive therapies like ESAsand stem cell transplantation. It is difficult to assessthe overall benefit of changing paradigms years in ad-vance of reported outcomes, with all of these otherfactors playing a role. So we have to make our deci-sions based on the data available today and the ben-efits we know that exist between one drug and an-other.

KOGAN: If we can anticipate the full range of associatedpieces of the therapy, we may be able to make more

longitudinal decisions. We would need to know rela-tive efficacy, potential AEs and their treatments, the costof each, and how many cycles are required, as well asthe parameters to determine when to start treatment,what defines a nonresponse, and how soon can youidentify that. In other words, a complete package ofcare.

DUNN: It is very attractive to prefer one agent over an-other, but it must be accomplished by collaboration.You must sit down with the physicians who actuallytreat patients and see the outcomes and say, “Here’s thedata on comparative effectiveness and the evidence onsurvival, toxicities, site administration, and subse-quent hospitalization. We think the survival data fa-vors one product, which will potentially cost less dueto outpatient delivery, and it is associated with fewerhospitalizations for AEs.” Then, as a team you canmake the decision to document a preferred regimen.

FRAME: The survival advantage with azacitidine is real,and a similar benefit has not been shown withdecitabine in the same population. The studies beingdone with alternative schedules are confounded bydetails like enrollment of patients predominantly withearlier disease, and the failure to include the approvedregimen as a comparator. So for now, I think the sur-vival advantage and outpatient delivery with the tra-ditional azacitidine schedule in patients with higher-risk disease may be the key factors in selecting apreferred therapy for these patients.


KEY POINTS• Specialty Pharmacy provides unique and

dedicated services to optimally managehigh-cost specialty pharmaceuticals and biologics.

• Medication access, adherence to complexdosing regimens, and patient education arecritical areas where Specialty Pharmacy canprovide supportive services to optimize patient outcomes and satisfaction.

• Specialty Pharmacy can assist with MDStreatment programs to better managethe financial challenges posed to patients,providers, and payers.

Specialty Pharmacy has emerged as a means to man-age the delivery of, improve access to, and address thechallenges posed to patients, physicians, payers, andpharmacies by the newer pharmaceutical andbiologic products. These products often comewith high acquisition costs, challenging regi-mens, and difficult reimbursement patterns.Many of the medications used in the treatmentof myelodysplastic syndromes (MDS) — e.g.,lenalidomide, azacitidine, decitabine, and thesupportive care drugs erythropoietin, darbe-poetin, filgrastim, sargramostin, pegfilgrastim,and deferasirox — fall under the SpecialtyPharmacy umbrella. Thus, Specialty Pharmacycan assist with MDS treatment programs tooptimize patient outcomes and satisfaction and helpmanage the financial challenges for the patient, health-care provider, and payer.

Where the challenges lieA number of factors influence the success of treat-

ments for MDS. Although many of the medications haveproven effective in slowing the progression of or im-proving the hematologic profile of MDS, there are fea-tures of these medications and their regimens that chal-lenge their optimal use. As a result, Specialty Pharmacyhas become a purveyor of unique and dedicated servicesdesigned to help ensure favorable outcomes in the faceof access challenges, complex dosing regimens, the needfor patient education, inpatient versus outpatient treat-ment options, requirements for ancillary or supportivetherapies, and rising medication costs (Hay 2008).

Specialty pharmaceuticals such as those prescribedfor MDS can be quite costly (Goss 2006, Greenberg 2008,Sullivan 2008), and the financial demands associatedwith these agents place a great burden on patients thatpotentially can impede access to effective treatment. Theycan also impose a strain on patients’ families and their

employers and managed care providers. Em-ployers and third-party payers must deal notonly with the direct costs of health care cover-age, but also with the indirect costs incurred ineffectively treating patients with a life-threat-ening disease. Health care providers must ad-dress the demands of complicated and time-consuming regimens and understand themanaged care considerations for those treat-ments. For example, eligibility and benefit ver-ification is a vital step in treatment planning,because easy access to therapy depends on iden-

tifying the unique parameters of each patient’s benefitplan prior to assigning a therapy program.

Cost-plus-benefit is the factor in defining a preferredtreatment regimen. Several trials have established that hy-pomethylating therapies can effectively treat MDS (Fenaux2009, Steensma 2009, Wijermans 2008,Wilson 2007), butfew well-designed economic analyses have evaluated thecost-plus-benefit of patient outcomes versus treatment-associated costs. The few relevant pharmaco economicstudies available (Radaelli 2004) suggest that the keydrivers of cost in the treatment of MDS and its potentialprogression to acute myeloid leukemia (AML) are hos-

As director, oncology management services for CVS Caremark,Kirby Eng, RPh, is responsible for developing and implementingSpecialty Pharmacy Oncology strategies for health plan clients.Prior to joining CVS Caremark, Eng served in diverse roles in theareas of specialty pharmacy, group purchasing, oncology drugdistribution, cancer care providers, and pharmaceuticals manu-facturing with CuraScript, US Oncology, Oncology TherapeuticsNetwork, Sicor, Fujisawa, Pharmaceutical, and Eli Lilly and Co.

KIRBY ENG, RPh

The Role of Specialty Pharmacy in the Treatment of Myelodysplastic Syndromes KIRBY ENG, RPHDirector, Oncology Management Services, CVS Caremark


pitalization, length of stay for initial therapy, and theneed for transfusion. Peripheral blood stem cell trans-plants also contribute to cost, but relatively few patientsare eligible for this treatment. It has been shown, how-ever, that when used in an appropriately targeted popu-lation, the approved pharmacologic agents can improvethe hematologic profile of MDS, reverse transfusion de-pendence, and, in some cases, prolong survival, suggest-ing substantial benefit to offset costs (Fenaux 2009, Sul-livan 2008, Wijermans 2008, Wilson 2007).

With the availability of new effective medicationscomes the likelihood that, like other cancers with remis-sion-inducing therapies, pharmacologic therapy for MDSmay become a chronic rather than an acute event (Cook2008). In advanced MDS, treatment with the hypo -methylating agent azacitidine has prolonged survival to24 months compared to 15 months with conventionalcare regiments (P=.001) (Fenaux 2009). Furthermore,specific data suggest that patients with MDS may bene-fit from long-term maintenance therapy, as response totraditional induction therapies, such as ara-C and an-thracycline, are generally of limited duration, and main-tenance treatment with, for example, hypomethylatingagents has been shown to extend treatment response(Grövdal 2008).

Side effects, too, contribute to the demands of MDStherapies. As a result, a great deal of effort in the form ofpatient education, risk evaluation and mitigation strate-gies, and supportive interventions are required to re-duce the impact of medication toxicities. Complex dos-ing schedules, significant toxicities, and potential druginteractions also interfere with patient adherence to ther-apy.

Meeting the challengesCVS Caremark provides unique services to assist

providers and health care plans in delivering the bestpatient care and in optimally managing specialty phar-maceuticals (Sullivan 2008). These services can be cate-gorized as separate yet interrelated functions: customer

service, utilization management, patient care manage-ment, and cost management.

Customer service. At CVS Caremark, customer serv-ice is primarily a function of benefit and eligibility veri-fication. When a patient gets a prescription for a med-ication, he or she is given a telephone number to call tospeak with a front-end client services agent at the Spe-cialty Pharmacy. This representative, upon determiningthe patient’s carrier and benefits, will ascertain eligibil-ity, verify specific benefits, communicate any patient fi-nancial responsibilities, and collaborate with the pa-tient’s physician and health plan to secure any requiredauthorization for treatment.

Oncology utilization management. To establish stan-dards of care and to help promote global clinical prac-tices, particularly with specialty pharmaceuticals likethose used in the treatment of MDS, CVS Caremark hasa designated clinical team that reviews national guide-lines, recent literature, and reported outcomes associatedwith current standards of care to develop, update, and ad-ministrate standardized practice criteria. The criteriathat CVS Caremark uses for prior authorization are basedon two primary drivers: Whether the drug as prescribedis appropriate for the intended use, and whether there aresafety concerns associated with that drug for the indica-tion prescribed. CVS Caremark also can provide patientassessments to monitor adherence to prescribed regi-mens. In this capacity, the pharmacist is charged withmore frequent interaction with the patient to assess top-line treatment response, determine need for re-educationand encouragement, and promote strategies to improvetreatment success.

Patient care management. At CVS Caremark, after afront-end customer services representative has clarifiedthe patient’s coverage and benefits status, the patient isassigned to a Patient Care Team consisting of trainedpharmacists, nurses, and patient service representativesthat are usually certified pharmacy technicians. The CareTeam reviews with the patient the specific features of hisor her benefit design as it affects the diagnosis, clarifyingwhat treatment measures are covered and whether thereis a coordination of benefits and other unique serviceneeds based on the treatment and condition of the pa-tient. The Care Team strives to build a one-on-one con-tinuing relationship with each patient to ensure patienteducation, effective and safe medication use, prescriptionfulfillment, and financial considerations that can im-pede access to medication (Table). The pharmacist on theCare Team is responsible for confirming dose accuracy,minimizing or eliminating potential drug interactions,and coordinating medication shipments. Because manypatients who are diagnosed with an oncologic condi-

TABLE Specialty pharmacy services for MDS patients

• Customer services (various)• Prescription fulfillment

•• Dose accuracy•• Drug interactions•• Shipment coordination

• Drug education• Adherence to treatment regimen• Financial assistance programs• 24/7 pharmacist availability• Dedicated oncology teams

Disclosure: Kirby Eng, RPh, states that he does not have any fi-nancial arrangements or affiliations that might constitute a con-flict of interest with this article.


tion experience much anxiety, the continuing relation-ship with a patient service representative can offer emo-tional support as well.

For newly diagnosed MDS patients, the Care Team of-fers education about MDS, prescribed medications, andlifestyle issues and also recommends strategies to ensuremedication compliance. The Care Team also performsregular follow-ups, calling patients as often as needed tocheck progress and proactively coordinate medication re-fills and supplies. In the event of financial challenges, adedicated team will help a patient with reimbursements,copayments, benefits clarification, and manufacturer as-sistance programs. Pharmacists are available to patients24/7 to answer questions about treatments and theirside effects.

Cost management. Because there are a limited num-ber of drug agents used to treat MDS, Specialty Phar-macy is currently limited in its ability to negotiate drugdiscounts as with some other therapies. However, Spe-cialty Pharmacy can help manage MDS drug costs by en-suring its appropriate use in accordance with U. S. Foodand Drug Administration-approved indications or na-tionally recognized evidenced-based treatment guide-lines and monitoring the safety of prescribed pharma-ceuticals, e.g., ensuring dosing accuracy and identifyingpotential drug interactions or side effects, which allowsthe patient or prescribing physician to take preventive orcorrective measures as necessary.

Future trendsSpecialty Pharmacy is a growing segment of the

healthcare industry, and its involvement with oncologymedications is on the rise. As a result, the focus of futureefforts must take into account the need to keep pacewith this growth, including maintaining a knowledgebase of the increasing numbers of approved medica-tions and combination regimens, supporting adherenceas medication options and regimens increase, continu-ing to monitor research and modify guidelines accord-ingly to ensure best outcomes, and overseeing cost-ef-fective drug utilization by defining formularies andstep-therapy approaches. Specialty Pharmacy is alsouniquely positioned to effectively manage FDA-man-dated risk evaluation and mitigation (REMS) programs.As the number of oncology drug-required REMS pro-grams increase, we will also see some standardization inthe requirements allowing program objectives to be metcost-effectively.

SummarySpecialty Pharmacy plays an integral role in the de-

livery and management of biologic and chemothera-peutic medications for patients with higher-risk MDS bystreamlining the delivery process, educating patients,monitoring treatment adherence and response, manag-

ing complex storage and delivery requirements, and as-sisting both patients and payers with clinical, opera-tional, and financial issues and challenges. Specialty Phar-macy will continue to develop procedures to assistclinicians and patients, maximizing access to pharmacyand clinical advisors who are able to explain medical di-agnoses to patients, walk them through medication op-tions, and describe the specific details of therapeutic reg-imens. Where the use of specialty pharmaceuticals poseschallenges of inventory, sourcing, complex treatmentregimens, patient adherence, and slow reimbursement,Specialty Pharmacy has designed standardized processesto address these needs and will continue to improve andincreases its services to support vital business and clini-cal functions for patients, health care plans, andproviders.

ReferencesCook R. Economic and clinical impact of multiple myeloma to

managed care. J Manag Care Pharm. 2008;14:S19–S25.Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Efficacy of aza-

citidine compared with that of conventional care regimensin the treatment of higher-risk myelodysplastic syndromes:a randomised, open-label, phase III study. Lancet Oncol.2009;10:223–232.

Goss TF, Szende A, Schaefer C, et al. Cost effectiveness oflenalidomide in the treatment of transfusion-dependentmyelodysplastic syndromes in the United States. CancerControl. 2006;13(suppl):17–25.

Greenberg PL, Cosler LE, Ferro SA, Lyman GH. The costs ofdrugs used to treat myelodysplastic syndromes followingNational Comprehensive Cancer Network Guidelines. J Natl Compr Canc Netw. 2008;6:942–953.

Grövdal M, Khan R, Aggerholm A, et al. Maintenance treatmentwith 5-azacitidine for patients with high risk myelodysplas-tic syndrome (MDS) or acute myeloid leukemia followingMDS (MDS-AML) in compete remission after inductionchemotherapy. ASH Annual Meeting Abstracts. Blood.2008;112:223.

Hay JW. Using pharmacoeconomics to value pharmacotherapy.Clin Pharmacol Ther. 2008;84:197–200.

Redaelli A, Botteman MF, Stephens JM, et al. Economic burdenof acute myeloid leukemia: a literature review. Cancer TreatRev. 2004;30:237247.

Steensma DP, Baer MR, Slack JL, et al. Multicenter study ofdecitabine administered daily for 5 days every 4 weeks toadults with myelodysplastic syndromes: the alternative dos-ing for outpatient treatment (ADOPT) trial. J Clin Oncol.2009a;27:38423848.

Sullivan SD. The promise of specialty pharmaceuticals: are theyworth the price? J Manag Care Pharm. 2008;14(suppl4):S3S6.


Wilson J, Yao GL, Raftery J, et al. A systematic review and eco-nomic evaluation of epoetin alpha, epoetin beta, and darbe-poetin alpha in anaemia associated with cancer, especiallythat attributable to cancer treatment. Health Technol Assess.2007;11:1202.


DISCUSSIONSTEVEN R. PESKIN, MD: Mr. Eng, you mentioned that

CVS Caremark is one of the largest dispensers of oraloncology drugs in the United States. Have you seen anincreasing role for Specialty Pharmacy in the infu-sion/injection drug area?

KIRBY ENG, RPh: Yes. While we have seen a significantnumber of new oral oncology drugs come to market,the majority of oncology drug spend still consists ofinfused/injected drugs, typically administered in aphysician’s office and covered under a medical bene-fit design. Recent national payer surveys have indicatedthat payers are willing to adopt more aggressive oraloncology drug management strategies and will con-tinue to explore infusion/injectable drug manage-ment options, including Specialty Pharmacy.

JEFFREY D. DUNN, PHARMD: As part of a health caresystem, we have most of the patient functions thatKirby described in-house, but we do use a SpecialtyPharmacy for distribution.

ALLAN JAY KOGAN, MD: In certain categories like on-cology, we do not have a large enough market to lever-age the costs of some of these oncology drugs andwould need to have a liaison program with a Spe-cialty Pharmacy. Kirby mentioned the growing role ofCVS Caremark in the oncology space, and we mightuse those patient care and medication oversight serv-ices as well. Our providers would come up with theproper diagnosis and assign a treatment regimen, butthen they might capitate it to the Specialty Pharmacyand allow them to oversee the long-term servicing ofpatient follow-up and medication management.

PESKIN: As we move away from oral medications forMDS to injectable and infusional therapy, does it makesense to work more closely with Specialty Pharmacy?Or are these treatments going to end up in the oncol-ogist’s office?

ENG: For the foreseeable future, infused/injectable on-cology drugs will likely continue to be administeredin an oncologist/hematologist office under the physi-cian buy-and-bill model. Specialty Pharmacy will

come into play if it can transition proven oral oncol-ogy drug management strategies into infused/injectable drug formulations.

KOGAN: And as regimens move into a stacking mode —that is “If A and B work, why don’t we use them to-gether?” — the paradigm gets even more complicated.Cost and regimen safety become even more com-pelling goals. That is why there has become a focus onspecificity in treatment and personalized medicine.We need to know we are treating people with regimensto which they will respond and still aim to minimizetoxicity. As a payer, our business is risk management.We are interested in prolonged survival and improvedquality of life, but also in what are the associated costsof that improvement? Not just the drug treatmentcosts, but the total expenditures, including costs ofmanaging adverse events and use of adjuvant therapiesto reduce risk or prevent complications.

DAVID FRAME, PHARMD: That is what was interestingabout the hypomethylating agent studies of Fenaux[2009] and Steensma [2009a,b], because that’s theonly data I know of that looks at a snapshot of MDSpatients at any given time. Only 13 percent of patientstreated with azacitidine were hospitalized. In the studywith the revised decitabine regimen, 65 percent of pa-tients were admitted to the hospital due to side effects.Those were truly notable findings.

PESKIN: What is the role of academic physicians in sort-ing out guidelines that might influence reimburse-ment, influence access, and simplify payments – thatintersection of clinical practice and economics?

BART L. SCOTT, MD: Historically, physicians have beenreluctant to involve themselves in that discussion be-cause of potential conflict of interest between patientcare and economics. But one of the things that we cando is to design better clinical trials, where we do lookat adverse events and at the overall cost of care, and ofcourse make better use of evidence-based medicine. Itis important to remember that we all want the samething and that is good patient outcomes at reasonablecost.


the off-label use of approved medications has become awidespread strategy for expanding the usefulness of novelmedicines. With the generally high costs of these products,health plans must devise new strategies to ensure thatquality care, positive outcomes, and patient safety remainthe goals of treatment for all patients while continuing tomaintain a rational focus on cost control mechanisms.

Changing treatment paradigmsProgress in therapeutic interventions often is achieved

by changing the treatment paradigm. For example, an ad-vance in treatment delivery may be based on improvingthe mode of administration for increased efficacy, con-venience, and safety. This is evident in the case of two hy-

Myelodysplastic Syndromes: Health Care Management ConsiderationsALLAN JAY KOGAN, MD, MSS, ABFP, FAAFP, CPEMedical Director – West Region, CIGNA/Great-West Healthcare, Dallas

JEFFREY D. DUNN, PHARMD, MBAFormulary and Contract Manager, SelectHealth, Salt Lake City

At CIGNA/Great-West Healthcare, Allan Jay Kogan, MD, MSS,ABFP, FAAFP, CPE, has regional responsibility for medical outreachprograms, including the care management, quality management,pharmacy, disease management, and technical assessment pro-grams. Kogan also supports implementation of the Value OptionsBehavioral Health Program and the Specialty Risk Program. He isa board-certified family physician with experience in private prac-tice in single and multispecialty group practices and hospital-basedemergency medicine. Kogan is a colonel in the active reserves of theArmy Medical Corps and served in the First and Second Iraq Wars.He received a Masters degree in Strategic Studies at the Army WarCollege and is currently assigned to the 228th Combat supportHospital, San Antonio.

Jeffrey D. Dunn, PharmD, MBA, is the formulary and contractmanager for SelectHealth, formerly Intermountain Health Care(IHC) Health Plans, in Salt Lake City. The Intermountain Health-care system comprises 22 hospitals, 68 physician clinics and surgerycenters, and employs more than 450 community-based physicians.SelectHealth provides services to approximately 500,000 members.In addition to clinical research and contracting responsibilities,Dunn manages the P&T Committee process and negotiates/main-tains contracts with pharmaceutical companies. Dunn is an activemember of the Academy of Managed Care Pharmacy, American So-ciety of Health-System Pharmacists, and Utah PharmaceuticalAssociation and sits on the State Diversion Board and the StatePharmacy Technician Committee.

KEY POINTS• New, effective therapies for MDS have led to

earlier initiation of treatment and prolonged survival.

• Health plans must devise strategies that notonly ensure quality patient care and positiveoutcomes but also maintain a rational focuson cost control.

• Active collaboration among health careproviders, patients, and health plans is es-sential to improve the efficient managementof MDS patients and improve the overallhealth care economy.

The use of specialty oncology products poses a num-ber of challenges to all stakeholders involved in managedcare medicine — patient, provider, employer, and healthplan. Issues of cost, delivery method, dosage, length oftreatment, benefits design, and approved versus experi-mental use of medications are among the variables thatcomplicate the health care system and threaten the cost-effective administration of novel oncologic therapies.The increasing availability of effective targeted thera-pies for myelodysplastic syndromes (MDS), which havea relatively low incidence and prevalence compared withother cancers, has led to earlier initiation of treatmentand prolonged survival. This trend means more med-ication delivered over longer periods, inciting a growingconcern about how health plans can efficiently cover thecost of these treatments.

The need for long-term or maintenance therapy inMDS can transform the challenges of cost of care further.Maintenance regimens prolong therapy and may neces-sitate altered dosages or increased dosing frequency, de-manding changes in the standard of care, increasedprovider education, and updated health benefits pro-grams. Once the activity of newer agents is established forone oncologic indication, it has become standard thatthey are investigated for other diagnoses. Furthermore,


pomethylating agents for MDS — decitabine (Dacogen),an intravenous (IV) infusion that has an associated needfor clinic or hospital admission, high resource utilization,and greater risk for complications, and azacitidine (Vi-daza), a subcutaneous (SC) injection or IV infusion thathas a simplified administration protocol and a few inex-pensive add-ons.

Similarly, advances in pharmacologic intervention forcancer are frequently attempted by combining thera-pies. Rather than switching from one medication thatyields only short-term or partial responses to anothermedication in an attempt to achieve a better outcome,which is the basis for the sequenced or step-therapy ap-proach, oncology treatments are more likely to be“stacked,” that is added one on top of the other. Theo-retically, the goal of this approach is to improve out-comes by combining complementary drug mechanismsfrom proven active products to drive up the response. Butthere is a cost involved in this approach, and not just thecost associated with prescribing multiple medications.Personalized medicine is lost, so that many patients whodo not benefit are treated with a predefined combinationregimen that realizes an improved outcome for only a fewindividuals. There is the potential for increased toxicitywith a multidrug regimen and the resultant need forsupportive therapies to minimize or manage adverseevents. In addition, there might be different schedulesand doses for the multiple agents, which can complicatethe delivery of the regimen, necessitating greater clinic orprovider time, less convenient schedules for the patient,and an increased risk of nonadherence. Can a healthplan provide maximum benefit from this approach whilemanaging risk and controlling costs?

High cost of medicationsIt is becoming increasingly expensive to

develop a drug and get it to market, and thecost is invariably passed on to the con-sumer. Drugs are being developed thatcarry higher and higher ticket prices, whichcan be compounded by different features ofthe prescribed regimen. The cost per courseis one way to compare the economics oftreatments, but it is not the bottom line.The course schedule, e.g., every 6 weeks orevery 8 weeks, and the length of therapycontribute to the final financial expendi-ture. Some prescribed treatments are basedon body mass or laboratory markers, whichmakes for variable pricing related to uniquepatient characteristics. In addition, pre-ventive interventions and management ofadverse events must be added to the bot-tom line, and the potential benefits of long-term maintenance therapy can increase

costs exponentially. Waste also must be considered — ifonly a half-vial of medication is used, the lost portion ofthe pre-packaged product must be factored into the finalcost of treatment.

A top-line comparison of treatment costs associatedwith the FDA-approved dosing of decitabine versus azac-itidine for 6 months of therapy administered subcuta-neously, as reported by the drug information databaseMediSpan, is shown in the accompanying Figure. Usingthe U.S. Food and Drug Administration-approved dos-ing regimen for each medication, this analysis suggeststhat the expected expenditures for drug administrationalone is $62,145 for decitabine, based on a 15-mg IV in-fusion given every 8 hours for 3 consecutive days andthen repeated every 6 weeks compared with $48,989 forazacitidine given as a 75mg/m2 SC injection for 7 con-secutive days, repeated every 4 weeks. Clearly, both are ex-pensive treatments, although decitabine costs are about25 percent greater. Yet, these estimates do not take intoaccount the ancillary expenses for hospitalizations, ery-thropoiesis stimulating agents, management of side ef-fects, or physician visits — expenses that could poten-tially double the regimen costs. If, indeed, the use ofmaintenance regimens to prolong response to therapybecomes standard in the treatment of MDS, these num-bers will rise even further. Cost, regimen, tolerability,and schedule are contributing to a challenging environ-ment in which payer organizations must develop bene-fits programs that best assign increasingly limited re-sources to cost-effective and evidence-based protocols.

Economic considerationsThe struggles of the current economy have added new

challenges to the benefits coverage quandary. There hasbeen a rise in unemployment and, thus, a contraction in

FIGURE Cost of azacitidine versus decitabine using FDA-approved dosing schedules based on 6 months of therapy

Drug Dose* AWP $/day/courseAWP $/month

or cycle

decitabine 15 mg/m2 every 8hours x 3 days, then

every 6 weeks

50 mg vial = $1726 x3 vials x 3 days =

$15,535(assumes 1 vial/dose)

$15,536.25 x 4 =$62,145

Difference of$13,155

azacitadine 75 mg/m2 every dayx 7 days, then every

4 weeks

100 mg vial x 2 vials= $1,166 x 7 days =

$8,164.94(assumes 2 vials/ dose)

$8,164.94 x 6 =$48,989

*All doses may require adjustment based on tolerability, lab values, etc.Source: MediSpan


health plan membership. Despite an increase in the num-ber of groups enrolled at SelectHealth, for instance, in-dividual memberships have gone down, thus putting agreater burden on available resources.

Changes in benefit design are at a critical point in bal-ancing payer versus patient expenses for covering healthcare. With co-insurance plans, patients are paying moreof the cost of their treatments. Assigning drugs to for-mulary tiers can reduce costs to the payers, especially withhigher-tier drugs for which patients pay an increasingpart of the cost. But increasing patient share can limit ac-cess to medicines or impede the full and proper use oftherapy, reducing compliance, impairing efficacy, and ul-timately increasing overall costs. In the current economy,patients are unable to meet their financial obligationsunder their health benefits design. On the other hand, at-tempting to revise the design to improve benefits for pa-tients is an expensive endeavor. Re-establishing costs anddefining new best practices involves the work of a team ofmanaged care consultants, including actuaries, marketers,clinicians, and government liaisons among others.

Clinical issuesSeveral clinical factors influence managed care deci-

sions for MDS patients. Research support and docu-mented evidence of efficacy and safety are considered inbest practices guidelines and coverage paradigms. TheNational Comprehensive Cancer Network clinical prac-tice guidelines (NCCN 2009), which provide treatmentalgorithms and are regularly updated to reflect ongoingresearch and changing evidence, should certainly be con-sidered. In a very delicate ethical analysis, details of prog-nosis, survival, palliation, and quality of life (QoL) mustbe balanced against the costs of treatment to determinethe value proposition of a regimen. Anticipated out-comes are part of the equation as well, with questions ofsurvival, toxicity, and QoL also playing a role in treat-ment guidelines and benefits decisions.

Provider relations with payer organizations also in-fluence the overall design of a health care plan. Negoti-ated fee schedules and reimbursement parameters mustsatisfy both parties. Place of therapy and right of ad-ministration, i.e., clinicians’ preference to administermedications themselves, are factors in the decision-mak-ing process. In addition, local network issues such as de-fined fees and comparative incentives from different net-works can determine how providers in the communityinterface with local health plan organizations.

Potential strategies to improve care andcontrol costs

A number of strategies are currently under considera-tion aimed at improving current benefits designs (Table),from cost shifting to altered tiering structures and bettercase management to improved guidelines and treatment

algorithms. The challenge is in finding the best strategyright out of the gate. How do we determine the proper mixof tiering and patient expense? Will the concept of two-tiered medical benefits be accepted? How can case man-agers provide better services in the oncology arena?

To minimize their outlay, employers are shifting coststo place more responsibility on employees for their healthcare. Some businesses are encouraging their employeesto participate in health savings accounts, tax-sheltered ac-counts in which individuals can accumulate pre-tax dol-lars to pay for the deductible portion of their insurancecoverage (Hall 2005, Robinson 2005). They are also morelikely to offer insurance policies with a co-insurance pro-vision, meaning the insured is required to pay a per-centage of expenses after the deductible has been met upto the policy’s stop-loss provision. Only after the in-sured’s payout equals the stop-loss, does the insurer pro-vide 100 percent coverage. But these approaches canoverburden patients. If patients cannot afford their costshare, they may discontinue treatment, leading to loss ofmedication efficacy and treatment failure, which subse-quently drives up the overall cost of patient care.

Increased formulary control with prior authorizationrequirements, dose optimization, step therapy, and net ef-fective pricing are all mechanisms being used by healthplans. Mandatory patient support programs can im-prove outcomes and lay the groundwork for educated de-cision making when the need for treatment adjustment

TABLE Potential strategies

• Benefit design•• Tiers, evaluating out-of-pocket expenses and

distribution•• Biosimilars

• Better case management• Guidelines/algorithms/disease management

•• “More than just NCCN”• More formulary control

•• Data•• Contracts

� Work with pharma – Outcome based� Net effective pricing

•• Mandatory patient support programs•• Prior Authorizations – levels of evidence, quantity

limits• Incentive programs

•• Member•• Physician – differential reimbursement,

Pay For Performance•• Is oncology a “value-based” disease state?

• Specialty Pharmacy• Fee schedules• Coordination/collaboration

•• Electronic records (IT) will be key


arises. A larger role for the specialty pharmacy may alsosmooth the way to better patient management. The safeand effective use of new medications and fee scheduleoptimization to satisfy all stakeholders will help to im-prove the overall economy of the health care field.

It also is important to consider all the factors that in-fluence the usage of medication by a patient. For exam-ple, although an oral medication may be preferred by apatient over an injectable or infusible medication, non-compliance is a major issue, because oral agents are nottaken under a clinician’s supervision. Also, the overallcost of therapy can determine whether a patient followsthrough with treatment. In MDS, for example, the finalcost of treatment with decitabine varies, based on bodymass, and includes 3 days of infusion therapy per course.The total cost has been estimated at $62,145 for the fourrecommended courses, exclusive of hospitalization costs.On the other hand, the cost for four recommendedcourses of azacitidine, a SC injection, is estimated to beabout $49,000. Although both costs are high, the rela-tively lower cost of azacitidine and the lack of hospital-ization requirement may mean that patients are morelikely to maintain the regimen.

Providers also must consider the overall clinical ben-efit of treatment. Because azacitidine has been shown toimprove overall survival in patients with higher-riskMDS, whereas decitabine has not, the choice should fallin favor of the treatment with the more favorable clini-cal outcome. To summarize, the preferred treatmentshould be selected based on potential for adherence, bet-ter cost management, and best clinical outcome.

Most importantly, collaboration and shared data are keyfactors in optimal best care practices. An up-to-date data-base of a patient’s history, diagnosis, laboratory values, andprior treatments should be available to all parties involvedin a patient’s care. Without integrated systems, health caredecision making is impaired. Cooperation on formularydevelopment may be another important step to improv-ing the current paradigm for oncology. If the payers andpharmaceutical companies can agree on formulary pref-erences and make them available at reduced costs, allstakeholders may benefit in the long run. Incentive pro-grams, e.g., higher reimbursements for physicians or lowerpremiums for members who adhere to prescribed proto-cols, has been effective in other therapeutic areas andshould be considered in oncology as well. If oncology is avalue-based disease state, is there value in offering a med-ication like azacitidine at a lower benefit level? Is there areturn on investment by ensuring that patients are treatedwith a preferred medication?

Overall, there needs to be better collaboration among

Disclosures: Allan Jay Kogan, MD, MSS, ABFP, FAAFP, CPE, and Jeffrey D. Dunn, PharmD, MBA, state that they do not have any financial arrangements or affiliations that might constitute a conflict of interest with this article.

the health care provider, the payer or health plan, and thepatient with a focus on optimal response, cost manage-ment, and patient satisfaction to ensure everybody wins.

SummaryCosts associated with treating cancers such as MDS are

increasing as new medicines are developed and combi-nation regimens gain hold. This trend presents an im-portant challenge to MCOs who must respond to chang-ing protocols and rising costs. Whereas the new oncologymedications offer a unique opportunity to improve out-comes in patients with MDS, they also demand high fi-nancial outlay, which in turn necessitates adjustments inbenefits programs. As payers look to manage expenses inways that satisfy all stakeholders, increasing importanceis placed on scientific evidence, survival and QoL bene-fits, tolerability factors, and evidence-based standards ofcare. In the treatment of higher-risk MDS, this meansweighing those differences between the two hypomethy-lating agents approved for this indication — azacitidineand decitabine — in terms of proven effectiveness, safe de-livery, and survival gains validated in clinical trials as wellas potentially reduced costs related to administrationmethod and fewer treatment-related toxicities.

The future of MDS treatment in the managed care set-ting will require complex decision making to determinenew treatment guidelines, benefit design, reimburse-ment plans, ethical considerations, and formulary de-velopment. Economic and clinical strategies must aim tomake optimal use of novel treatment approaches whilemeeting the financial objectives of MCOs. The goal is im-proved patient outcomes at reasonable cost, a challengethat will be addressed only with continued discussion andstudy. The therapies azacitidine and decitabine may offera good model for decision making to drive best treatmentfor MDS while moderating cost.

ReferencesHall MA, Havighurst CC. Reviving managed care with health

savings accounts. Health Aff. 2005;24:1490–1500.MediSpan. «http://www.medispan.com/index.aspx». Accessed

Oct. 15, 2009.NCCN (National Comprehensive Cancer Network). NCCN

Clinical Practice Guidelines in Oncology: Myelodysplasticsyndromes. v2.2010. «http://www.nccn.org/professionals/physician_gls/PDF/mds.pdf». Accessed Oct. 15, 2009.

Robinson JC. Health savings accounts – the ownership society inhealth care. N Engl J Med. 2005;353:1199–1202.

DISCUSSIONSTEVEN R. PESKIN, MD: We have talked about the need

for guidelines to standardize care in the oncology area.Where are we on that now?

BART L. SCOTT, MD: The guidelines we rely on now arethose developed by the National Comprehensive Can-cer Network (NCCN). But those guidelines, although


a useful mechanism to give some structure to an oth-erwise chaotic field, are confusing to some cliniciansand, therefore, have limited utility as a national stan-dard of care. Some organizations have suggested theywill be working on more practical alternatives.

KIRBY ENG, RPh: Organizations, such as the Universityof Pittsburgh Medical Center, US Oncology, and oth-ers, have also created oncology drug treatment guide-lines or pathways. All have purported advantages anddisadvantages, and the question is whether they helpor further confuse identifying treatment options thatproduce optimal clinical and financial outcomes.

ALLAN JAY KOGAN, MD: If, as intended, any new guide-lines are evidence-based, clinically relevant, and re-sponsive to the latest data in real time, they could bevery beneficial, especially if a group like US Oncology,which is very influential in the oncology arena, drivesthe change.

DAVID FRAME, PHARMD: I agree. The goal is to achievea higher evidence base. Although the NCCN is prettygood at updating their guidelines, there is room for im-provement in adapting state-of-the-art data to real-time data.

PESKIN: What have been the most important changesyou have observed in the diagnosis and managementof MDS?

FRAME: From an internal medicine perspective, we’veseen an increase in diagnosis now that there are ther-apies that are effective in treating this disease. Prac-ticing internists in the Detroit suburbs or Kalamazooare actually more aware of MDS and are making thediagnosis more often and earlier. More patients arebeing referred to the community oncologist. But thatmeans patients are showing up at the academic cen-ters with more refractory disease.

KOGAN: The whole oncology space has shifted dramat-ically with the ongoing development of new drugs totreat these stage III and IV cancers. Although the ben-efits can be dramatic, most patients realize only a 2-or 3-month survival prolongation. It is a very expen-sive area, so we must continue to weigh the valueproposition in terms of the cost versus outcomes. Butwith many drugs in the pipeline, this analysis is anever-changing target. The key issue is that we do notwant to pay for anything experimental, so we’re ab-solutely committed to adhering to NCCN guidelines.

SCOTT: The emergence of these new treatments has def-initely changed referral patterns, so we tend to see pa-tients with more advanced diseases that have failedprior therapy. My concern, however, is that frequentlythe duration of therapy is not long enough and manypatients are discontinued from treatment and eitherdo not achieve an adequate response or recur rapidly.

PESKIN: In establishing an accurate diagnosis, do you re-quire evidence that a bone marrow analysis was done?

KOGAN: We have a clinical oversight program in qualityoncology, a formalized review system carried out by ac-tive oncologists, some of whom are on our internalteams but others are specialists from outside organiza-tions. We have a checklist that they address, from bonemarrow analysis to prior authorization, for drug use andapproval of supportive care therapies like ESAs.

JEFFREY D. DUNN, PHARMD: Pharmacy manages thePAs, but we basically rely on the oncologist’s diagno-sis and do not monitor for bone marrow aspirates.

PESKIN: How are issues of access and patient cost bur-den affecting the general health care environment?

ENG: An emerging challenge is the function of drug ben-efit design and the out-of-pocket patient costs for on-cology drugs. Given the high costs of many of thenewer agents, patient access may be affected. A num-ber of states are looking at legislation that will requirethat patient financial obligations for these and otherdrugs be the same regardless of the drug benefit design.

DUNN: The focus of our attention these days is drug uti-lization, i.e., how often is a drug used, what are the in-dications, are there many off-label requests? If wedon’t get a handle on these issues, sooner or later we’regoing to run out of money. Employers are looking forways to shift their costs. So for infusional drugs, withco-insurance, you’re talking about 25 to 50 percent ofthe cost, which can be $2,500 to $5,000. We’re proba-bly 3 or 4 years behind where we should be in figur-ing out how to resolve these issues.

FRAME: From a hospital perspective, our numbers ofuninsured or underinsured have gone up dramatically.In 1 year, it has affected our bottom line more than everbefore, and for the first time, we’ve actually had layoffs.When I arrived at the University of Michigan 4 yearsago, we didn’t do PAs for most cancer agents. Now PAsare in full effect. Many of our decisions on what to givepatients are based on what they can pay.

PESKIN: Given the evidence that we heard regarding sur-vival data, treatment efficacy, delivery methods, andadverse events, how should MDS best be managed?

DUNN: From a cost perspective, it makes sense to startmanaging MDS in its earliest stages, when the diseasestate is less aggressive.

KOGAN: I think we definitely have to work out an algo-rithm for this condition. With data support or not, weneed an approach that is transferable across differentpopulations and across different health systems.

PESKIN: Dr. Dunn, can you summarize the messages inyour presentation?

DUNN: I hope that Dr. Kogan and I were able to effec-tively convey the challenges that health plans face indelivering integrated financing for the health care en-vironment. We need to keep up with the needs of anever-changing health care system to create a medicalenvironment that meets the needs of all Americans.


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