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Further Analysis of Trials With Azacitidine in Patients With Myelodysplastic Syndrome: Studies 8421, 8921, and 9221 by the Cancer and Leukemia Group B

Lewis R. Silverman, David R. McKenzie, Bercedis L. Peterson, James F. Holland, Jay T. Backstrom, C.L. Beach, Richard A. Larson

From the Mount Sinai School of Medicine, New York, NY; Pharmion Corporation, Overland Park, KS; Cancer and Leukemia Group B Statistical Center and Duke University, Durham, NC; and the University of Chicago, Chicago, IL

Address reprint requests to Lewis R. Silverman, MD, Division of Hematology/Oncology, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1129, New York, NY 10029; e-mail: lewis.silverman{at}mssm.edu

	ABSTRACT

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PURPOSE: Within the last two decades, a new understanding of the biology of myelodysplastic syndrome (MDS) has developed. With this understanding, new classification systems, such as the WHO diagnostic criteria, and the International Prognostic Scoring System and response criteria guidelines reported by the International Working Group (IWG) have been developed. We report the combined results of three previously reported clinical trials (n = 309) with azacitidine using the WHO classification system for MDS and acute myeloid leukemia (AML) and IWG criteria for response.

PATIENTS AND METHODS: Data from three sequential Cancer and Leukemia Group B trials with azacitidine were recollected and reanalyzed as part of the New Drug Application process. The trials were conducted with either intravenous or subcutaneous azacitidine (75 mg/m²/d for 7 days every 28 days).

RESULTS: Complete remissions were seen in 10% to 17% of azacitidine-treated patients; partial remissions were rare; 23% to 36% of patients had hematologic improvement (HI). The median number of cycles to first response was three, and 90% of responses were seen by cycle 6. Using current WHO criteria, 103 patients had AML at baseline; 35% to 48% had HI or better responses. The median survival time for the 27 AML patients randomly assigned to azacitidine was 19.3 months compared with 12.9 months for the 25 patients assigned to observation. Furthermore, azacitidine did not increase the rate of infection or bleeding above the rate caused by underlying disease.

CONCLUSION: Azacitidine provides important clinical benefits for patients with high-risk MDS.

	INTRODUCTION

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In 1984, the Cancer and Leukemia Group B (CALGB) began a series of clinical trials with azacitidine (Vidaza; Pharmion Corporation, Overland Park, KS) in patients with myelodysplastic syndrome (MDS).^1-4 These studies and other supportive data culminated in the 2004 US Food and Drug Administration approval of azacitidine for treatment of symptomatic patients with MDS. During the intervening two decades, a greater understanding of the biology of myelodysplasia has evolved, along with a new classification system developed by WHO that more clearly distinguishes MDS from acute myeloid leukemia (AML) and from chronic myeloproliferative disorders.^5,6 In addition, an International Working Group (IWG) sponsored by the National Cancer Institute (NCI) has published new response criteria for evaluation of new treatments for MDS.^7,8 As part of the New Drug Application process, Pharmion recollected and reanalyzed the CALGB data, including expert pathology review of blood and bone marrow slides. Some of the CALGB data from these three trials was previously published using the protocol-specified diagnostic and response criteria. Here, we report the combined results of a reanalysis using the WHO classification for MDS and AML and the IWG criteria for response in MDS.

	PATIENTS AND METHODS

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Data Collection
For the reanalysis, data were recollected from patients enrolled onto CALGB Protocols 8421, 8921, and 9221.^1-3 A comprehensive retrospective collection and reverification of all clinical data in the original protocols were conducted. A complete safety database was collected, including additional data for azacitidine and data for the best supportive care (observation) arm of Protocol 9221; in the initial report by Silverman et al,³ safety data were only collected and reported for azacitidine-treated patients. To validate the reliability of bone marrow slides and peripheral-blood films used for diagnosis and response, an independent blinded review was performed retrospectively (John M. Bennett) in addition to the previously conducted prospective local and central pathology reviews (Frederick R. Davey and Rose Ruth Ellison). All recollected data were entered into a new database held by Pharmion; our analyses were conducted separately from those reported in Silverman et al.^1-3

Patient Selection
All patients enrolled onto CALGB Protocols 8421, 8921, and 9221 were included in our analyses. Consent forms were approved annually by local institutional review boards; each patient provided written consent. Detailed descriptions of the study designs of these three studies have been previously published.^1-3 Because Protocol 9221 included a comparative arm of best supportive care (observation), further analyses (eg, time to response, transfusion independence, and safety comparisons) were conducted.

Treatment Regimen
Although the route of administration was either continuous intravenous infusion (Protocol 8421) or subcutaneous (Protocols 8921 and 9221), the azacitidine dose investigated was 75 mg/m²/d for 7 days, repeated in a 28-day cycle, in all three studies. No dose adjustments at inception of treatment were made for pre-existing cytopenias despite severity. Therapy was continued for three cycles after complete remission (CR) or until progressive disease or toxicity in patients with partial remission (PR) or hematologic improvement (HI). After 4 months, patients in the observation group could cross over to azacitidine after evidence of disease progression.³

Definitions
Treatment groups. In Protocol 9221, patients randomly assigned to azacitidine plus best supportive care were referred to as the azacitidine arm (n = 99); patients randomly assigned to best supportive care alone were referred to as the observation arm (n = 92). Patients randomly assigned to best supportive care alone but who did not cross over to azacitidine were referred to as the observation-only arm (n = 41); patients randomly assigned to best supportive care and who received azacitidine after cross over from the observation group were referred to as the azacitidine after observation arm (n = 51).

Response criteria. General differences between CALGB and IWG response criteria for MDS included duration of response (CALGB: 4 weeks; IWG: 8 weeks), normal target peripheral-blood values (CALGB: different criteria for hemoglobin targets for males and females; IWG: same criteria for males and females), and generally more stringent criteria for lineage response with the CALGB criteria. The IWG criteria for improvement differentiate major and minor responses by peripheral-blood values⁷ but were combined in our analyses to give one overall calculation of improvement for patients.

WHO AML response rates. To evaluate responses in patients with MDS who were determined after expert pathology review to have AML at study entry, we applied the WHO classification for AML and removed refractory anemia with excess blasts (RAEB) in transformation (RAEB-T) from the MDS classification.^5,6 Therefore, our use of the WHO definition of AML includes patients previously defined as RAEB-T and AML by French-American-British criteria.

Transfusion independence. On the basis of IWG criteria, transfusion independence was defined as a transfusion-free period of 56 days (8 weeks) occurring anytime after random assignment. Transfusion dependence at baseline was defined as one transfusion within 90 days before random assignment.⁸

Adverse events. Any event occurring during the study not present at baseline or that worsened from baseline was documented as an adverse event (AE). All patients who received one dose of azacitidine were included in the azacitidine group as part of the safety analyses. For observation patients who crossed over, AEs that occurred during the period of observation were included in the observation safety analyses; any event that occurred after exposure to azacitidine was considered an azacitidine event and included in the azacitidine safety analyses.

Statistical Methods
For response rate analysis, the azacitidine group was compared with the observation-only group. For the survival analysis of patients with WHO AML, patients were analyzed as randomly assigned. If a patient was randomly assigned to the observation group, then all time to event data for that patient were analyzed in the observation group even if the patient later crossed over to azacitidine treatment. Safety analyses were performed on an as-treated basis.

Because the studies were conducted before availability of the IWG standardized response criteria for MDS, we retrospectively applied the IWG response criteria⁷ for CR, PR, and HI. Time to response was measured from the date of random assignment (Protocol 9221) or entry onto the phase II studies (Protocols 8421 and 8921) to the date of the event.

The original 9221 study was not powered for overall survival in the subgroup of WHO AML patients. However, overall survival times were compared using the exact log-rank test. Statistical comparisons of groups in the proportion of patients achieving transfusion independence were performed using Fisher's exact test.

Numeric laboratory values were defined by a specific NCI Common Toxicity Criteria (CTC) grade, ranging from 0 to 4. The maximum NCI CTC grade within a cycle was used to represent that cycle. Baseline was determined as the maximum grade before the date of random assignment or, if no value was available before random assignment, as the earliest value after random assignment up to and including the day of the first dose of azacitidine for azacitidine patients, and baseline was determined as the maximum grade on the day of random assignment for observation patients.

To determine whether azacitidine was associated with an increase in either infection or bleeding, we examined the rates (in patient-years) of infection or bleeding AEs associated with azacitidine therapy compared with the rates seen with the underlying disease (on the observation arm). Summaries are inclusive of nonserious and serious AEs.

	RESULTS

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Patient Characteristics in Protocols 8421, 8921, and 9221
Among the three studies, 268 patients were treated with azacitidine, of whom 220 patients were treated with subcutaneous azacitidine and 48 were treated with intravenous azacitidine; 41 patients received best supportive care on the observation arm of Protocol 9221 (Table 1). The majority of all 309 patients registered or randomly assigned to azacitidine or observation were male (68%, 210 of 309 patients), white (94%, 292 of 309 patients), and 65 years of age (61%, 188 of 309 patients). The distribution of MDS subtypes at baseline diagnosis was similar among the azacitidine and observation groups in Protocol 9221. The percentage of patients with AML using WHO criteria was 52% in Protocol 8421, 37% in Protocol 8921, and 27% in the azacitidine arm and 27% (25 of 92 patients) in the observation arm of Protocol 9221.

Time to Response and Duration of Response Based on IWG Response Criteria in Protocols 8421, 8921, and 9221
In all three studies, the median number of cycles from the first treatment with azacitidine to any response (CR, PR, or HI) was three cycles (range, one to 17 cycles). Although 75% of the responders achieved a response by cycle 4, the other 25% achieved a response as late as cycle 17. The majority of responders (90%) achieved a response by cycle 6. Best response was observed, on average, two cycles after initial response and lasted for a median of five cycles.

Transfusion Independence in Protocol 9221
Of the 191 patients enrolled onto Protocol 9221, 121 (63%) were RBC transfusion dependent at baseline. Of these RBC transfusion–dependent patients, 45 showed a response (CR, PR, or HI). A total of 36 of the responders became transfusion independent, of whom 35 had received azacitidine (Table 4). Among all RBC transfusion–dependent patients treated initially with azacitidine, 45% (29 of 65 patients) achieved RBC transfusion independence. A similar trend was noted for the 27 patients who were platelet transfusion dependent at baseline. Furthermore, among all 72 overall responders, platelet transfusion independence was achieved in all eight patients randomly assigned to azacitidine and in both patients who received azacitidine after cross over.

Safety Results in Protocol 9221
Hematology. Mean times to nadir values (across all cycles) for RBC, hemoglobin, WBC, absolute neutrophils, and platelets were between 15 and 16 days. On the basis of the overall frequency of time to nadir within the cycle (days 1 to 7, 8 to 14, 15 to 21, or > 21), hematology values tended to reach nadir values during the second or third week of the cycle (Table 5).

	DISCUSSION

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When the IWG response criteria were applied to all three studies, overall response rates were generally consistent among the studies and with the original CALGB response rates. However, the IWG criteria had lower sensitivity in determining PR rates when compared with the CALGB criteria. IWG criteria had lower sensitivity to discriminate responses, as demonstrated by 17% of patients in the observation-only group who qualified for an IWG response of HI (10% minor hematologic response) compared with only 5% of patients using the original CALGB criteria.

The overall IWG response rates for patients with a retrospective diagnosis of WHO AML were encouraging. Although the CR rate of 9% using IWG MDS response criteria is not outstanding relative to standard AML remission induction chemotherapy, the prolongation in survival time to 19.3 months exceeds that typically seen with standard induction chemotherapy, suggesting that azacitidine may alter the natural history of the disease independent of CR response criteria.¹⁰ Furthermore, treatment with azacitidine is associated with significant reduction in risk of transformation to AML and a significant prolongation of survival in patients with high-risk MDS, including RAEB patients, RAEB-T patients 65 years of age, and patients with equivalent intermediate-2 and high-risk disease.^11,12 This finding and the data presented in this article suggest a paradigm shift, with azacitidine altering the natural history of MDS by modulating the behavior of the MDS clone without necessarily eradicating it. In addition, treatment with azacitidine significantly delays the onset of RBC and platelet transfusions in patients who are transfusion independent at study entry. These findings warrant further studies of azacitidine in patients with smoldering AML with multilineage dysplasia (ie, patients who were previously diagnosed as having RAEB-T).

The time to response data indicate that azacitidine can have an effect at the bone marrow level as early as the first treatment cycle. However, for this effect to translate into an improvement in bone marrow function leading to clinically significant increases in peripheral cell counts, the majority of responders can require up to six cycles of azacitidine. To ensure adequate exposure for patients to demonstrate a clinical response, azacitidine should be administered for a minimum of four cycles. Furthermore, patients will most likely continue to require transfusion support during the first several cycles of treatment with azacitidine. In patients who were transfusion dependent at baseline with a response, azacitidine was associated with a median of 9 months of transfusion independence.

Given the underlying disease process and the myelotoxicity of compounds such as azacitidine and decitabine, an increase in rates of infection and bleeding would be expected during treatment. Despite the potential to exacerbate pre-existing cytopenias early in therapy, azacitidine did not increase the rate of infection or bleeding above the rate caused by underlying disease.

This reanalysis demonstrates that azacitidine is effective therapy that directly impacts the disease of MDS rather than just managing the symptoms. It reconfirms the findings discussed in Silverman et al³ and adds additional data pertaining to safety and more current classification and response criteria. Furthermore, azacitidine warrants additional studies in patients with AML with dysplasia.

	Appendix

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The following investigators and institutions participated in this study: Cancer and Leukemia Group B Statistical Center, Durham, NC–Stephen George, PhD, supported by CA33601; Columbia University, New York, NY; Dana-Farber Cancer Institute, Boston, MA–George P. Canellos, MD, supported by CA32291; Dartmouth Medical School–Norris Cotton Cancer Center, Lebanon, NH–Marc S. Ernstoff, MD, supported by CA04326; Duke University Medical Center, Durham, NC–Jeffrey Crawford, MD, supported by CA47577; Massachusetts General Hospital, Boston, MA–Michael L. Grossbard, MD, supported by CA12449; McGill University, Montreal, Quebec, Canada–Gerald Batist, MD; Medical University of South Carolina, Charleston, SC–Mark Green, MD, supported by CA03927; Mount Sinai School of Medicine, New York, NY–Lewis R. Silverman, MD, supported by CA04457; North Shore–Long Island Jewish Medical Center, Manhasset, NY–Daniel R. Budman, MD, supported by CA35279; Rhode Island Hospital, Providence, RI–William Sikov, MD, supported by CA08025; Roswell Park Cancer Institute, Buffalo, NY–Ellis Levine, MD, supported by CA02599; State University of New York Upstate Medical University, Syracuse, NY–Stephen L. Graziano, MD, supported by CA21060; University of Alabama Birmingham, Birmingham, AL–Robert Diasio, MD, supported by CA47545; University of California at San Diego, San Diego, CA–Stephen L. Seagren, MD, supported by CA11789; University of California at San Francisco, San Francisco, CA–Alan P. Venook, MD, supported by CA60138; University of Chicago Medical Center, Chicago, IL –Gini Fleming, MD, supported by CA41287; University of Cincinnati Medical Center, Cincinnati, OH; University of Iowa, Iowa City, IA–Gerald Clamon, MD, supported by CA47642; University of Maryland Greenebaum Cancer Center, Baltimore, MD–Martin Edelman, MD, supported by CA31983; University of Massachusetts Medical Center, Worcester, MA–William V. Walsh, MD, supported by CA37135; University of Minnesota, Minneapolis, MN–Bruce A. Peterson, MD, supported by CA16450; University of Missouri/Ellis Fischel Cancer Center, Columbia, MO–Michael C. Perry, MD, supported by CA12046; University of North Carolina at Chapel Hill, Chapel Hill, NC–Thomas C. Shea, MD, supported by CA47559; University of Tennessee Memphis, Memphis, TN–Harvey B. Niell, MD, supported by CA47555; Vermont Cancer Center, Burlington, VT–Hyman B. Muss, MD, supported by CA77406; Virginia Commonwealth University Massey Cancer Center Community Clinical Oncology Program, Richmond, VA–John D. Roberts, MD, supported by CA52784; Wake Forest University School of Medicine, Winston-Salem, NC–David D. Hurd, MD, supported by CA03927; Walter Reed Army Medical Center, Washington, DC–Thomas Reid, MD, supported by CA26806; Washington University School of Medicine, St Louis, MO–Nancy Bartlett, MD, supported by CA77440; and Weill Medical College of Cornell University, New York, NY–Scott Wadler, MD, supported by CA07968.

	Authors' Disclosures of Potential Conflicts of Interest

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Although all authors completed the disclosure declaration, the following author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other David R. McKenzie Pharmion Corporation (N/R) EMB Statistical Solutions (A) Pharmion Corporation (N/R) Jay T. Backstrom Pharmion Corporation (N/R) C.L. Beach Pharmion Corporation (N/R)

Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required

	Author Contributions

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Conception and design: Lewis R. Silverman, James F. Holland, Richard A. Larson Provision of study materials or patients: Lewis R. Silverman, James F. Holland, Richard A. Larson Collection and assembly of data: Lewis R. Silverman, Richard A. Larson Data analysis and interpretation: Lewis R. Silverman, David R. McKenzie, Bercedis L. Peterson, James F. Holland, Jay T. Backstrom, C.L. Beach, Richard A. Larson Manuscript writing: Lewis R. Silverman, James F. Holland, Jay T. Backstrom, C.L. Beach, Richard A. Larson Final approval of manuscript: Lewis R. Silverman, James F. Holland, Jay T. Backstrom, C.L. Beach, Richard A. Larson

 

	ACKNOWLEDGMENTS

 
We acknowledge the contribution made by John Bennett, Frederick R. Davey, and Rose Ruth Ellison in review of the pathology data; Richard M. Stone for his involvement in the study; and the assistance of Christy Mayo in the development of this article.

	NOTES

 
Supported by federal grants from the US Food and Drug Administration, by National Cancer Institute (NCI) Grant No. CA31946 to the Cancer and Leukemia Group B, and by NCI Grants No. CA04457, CA33601, and CA41287. The subsequent recollection and further analyses were sponsored by Pharmion Corporation.

The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
1. Silverman LR, Holland JF, Weinberg RS, et al: Effects of treatment with 5-azacytidine on the in vivo and in vitro hematopoiesis in patients with myelodysplastic syndromes. Leukemia 7: 21-29, 1993[Medline]

2. Silverman LR, Holland JF, Demakos EP, et al: Azacitidine (Aza C) in myelodysplastic syndromes (MDS), CALGB studies 8421 and 8921. Ann Hematol 68:A12, 1994 (abstr 46)

3. Silverman LR, Demakos EP, Peterson BL, et al: Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: A study of the cancer and leukemia group B. J Clin Oncol 20: 2429-2440, 2002[Abstract/Free Full Text]

4. Kornblith AB, Herndon JE II, Silverman LR, et al: Impact of azacytidine on the quality of life of patients with myelodysplastic syndrome treated in a randomized phase III Trial: A Cancer and Leukemia Group B Study. J Clin Oncol 20: 2441-2452, 2002[Abstract/Free Full Text]

5. Harris NL, Jaffe ES, Diebold J, et al: World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: Report of the Clinical Advisory Committee Meeting–Airlie House, Virginia, November 1997. J Clin Oncol 17: 3835-3849, 1999[Abstract/Free Full Text]

6. Germing U, Gattermann N, Strupp C, et al: Validation of the WHO proposals for a new classification of primary myelodysplastic syndromes: A retrospective analysis of 1600 patients. Leuk Res 24: 983-992, 2000[CrossRef][Medline]

7. Cheson BD, Bennett JM, Kantarjian H, et al: Report of an international working group to standardize response criteria for myelodysplastic syndromes. Blood 96: 3671-3674, 2000[Abstract/Free Full Text]

8. Bennett JM, Catovsky D, Daniel MT, et al: Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 51: 189-199, 1982[Medline]

9. Pomeroy C, Oken MM, Rydell RE, et al: Infection in the myelodysplastic syndromes. Am J Med 90: 338-344, 1991[Medline]

10. de Witte T, Oosterveld M: Hematopoietic stem cell transplant strategies in patients with myelodysplastic syndrome and secondary acute myeloid leukemia: The role of reduced intensity conditioning regimens, in List AF, Vardiman J, Issa JPJ, et al (eds): Myelodysplastic Syndromes, Hematology: The American Society of Hematology Education Program Book. Washington, DC, American Society of Hematology, 2004, pp 308-313

11. Silverman LR, McKenzie DR, Peterson BL: Azacitidine prolongs survival and time to AML transformation in high risk myelodysplastic syndrome patients 65 years of age. Blood 106: 709a, 2005 (abstr 2524)

12. Silverman LR, McKenzie DR, Peterson BL: Analysis of survival, AML transformation and transfusion independence in patients with high risk myelodysplastic syndromes receiving azacitidine determined using a prognostic model. Blood 106: 708a, 2005 (abstr 2523)

Submitted February 2, 2006; accepted June 15, 2006.

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