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© 2002 American Society for Clinical Oncology Randomized Controlled Trial of Azacitidine in Patients With the Myelodysplastic Syndrome: A Study of the Cancer and Leukemia Group BByFrom the Mount Sinai School of Medicine and Memorial Sloan-Kettering Cancer Center, New York, and State University of New York School of Medicine at Syracuse, Syracuse, NY; Cancer and Leukemia Group B, Statistical Center, Duke University Medical Center, Durham, and Wake Forest University Bowman Gray School of Medicine, Winston-Salem, NC; Dana-Farber Cancer Institute, Boston, MA; University Medical Center–S. Nevada Community Clinical Oncology Program, Las Vegas, NV; University of Chicago, Chicago, IL; and Wayne State University, Detroit, MI. Address reprint requests to Lewis R. Silverman, MD, Mount Sinai Medical Center, Division of Medical Oncology, Box 1129, One Gustave L. Levy Place, New York, NY 10029; email: lewis.silverman{at}mssm.edu
PURPOSE: Patients with high-risk myelodysplastic syndrome (MDS) have high mortality from bone marrow failure or transformation to acute leukemia. Supportive care is standard therapy. We previously reported that azacitidine (Aza C) was active in patients with high-risk MDS. PATIENTS AND METHODS: A randomized controlled trial was undertaken in 191 patients with MDS to compare Aza C (75 mg/m2/d subcutaneously for 7 days every 28 days) with supportive care. MDS was defined by French-American-British criteria. New rigorous response criteria were applied. Both arms received transfusions and antibiotics as required. Patients in the supportive care arm whose disease worsened were permitted to cross over to Aza C. RESULTS: Responses occurred in 60% of patients on the Aza C arm (7% complete response, 16% partial response, 37% improved) compared with 5% (improved) receiving supportive care (P < .001). Median time to leukemic transformation or death was 21 months for Aza C versus 13 months for supportive care (P = .007). Transformation to acute myelogenous leukemia occurred as the first event in 15% of patients on the Aza C arm and in 38% receiving supportive care (P = .001). Eliminating the confounding effect of early cross-over to Aza C, a landmark analysis after 6 months showed median survival of an additional 18 months for Aza C and 11 months for supportive care (P = .03). Quality-of-life assessment found significant major advantages in physical function, symptoms, and psychological state for patients initially randomized to Aza C. CONCLUSION: Aza C treatment results in significantly higher response rates, improved quality of life, reduced risk of leukemic transformation, and improved survival compared with supportive care. Aza C provides a new treatment option that is superior to supportive care for patients with the MDS subtypes and specific entry criteria treated in this study.
MYELODYSPLASTIC syndrome (MDS) represents a heterogeneous hematopoietic disorder in which mature blood cells are derived from an abnormal multipotent progenitor cell. The disease is characterized by morphologic features of dyspoiesis, a hyperproliferative bone marrow, and peripheral-blood cytopenias involving one or more lineages.1 Refractory anemia (RA) with or without ringed sideroblasts can persist for years, but RA with excess blasts (RAEBs) or RAEBs in transformation to leukemia (RAEB-T) exhibit an accelerated course.2-5 Most patients with high-risk MDS (ie, French-American-British [FAB] subtypes with excess blasts) die within 1 year from progressive bone marrow failure attributable to hemorrhage or infection. In 35% to 40% of patients, transformation to acute leukemia occurs, which is often refractory to present therapy.1 Therapies tried for MDS include granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), erythropoietin, and chemotherapy.6-22 None has altered the natural history of the disease. Supportive care with antibiotics and transfusions is considered the standard of care. Allogeneic bone marrow transplantation, a potentially curative approach, is a realistic option for only approximately 5% of patients.23-28 Azacitidine (Aza C), a pyrimidine nucleoside analog, was developed as an antitumor agent.29-31 In addition to cytotoxic effects, it induces differentiation of malignant cells in vitro.32-35 Aza C inhibits DNA methyltransferase, the enzyme in mammalian cells responsible for methylating newly synthesized DNA, resulting in synthesis of hypomethylated DNA and changes in gene transcription and expression.32-34 In patients with beta-thalassemia or sickle-cell anemia, Aza C caused hypomethylation of the gamma globin chain gene with increased production of fetal hemoglobin.36-38 The Cancer and Leukemia Group B (CALGB) conducted a phase II study of Aza C administered to 43 hospitalized patients as a continuous intravenous infusion for 7 days every 28 days for 4 months.39 Responses (complete response [CR], partial response [PR], or improved) occurred in 49% of patients with high-risk MDS (RAEB and RAEB-T). A second phase II study of 67 patients with high-risk MDS showed that Aza C as a subcutaneous daily bolus injection at the same dose and schedule on an ambulatory basis produced comparable results in response rate, response duration, and survival.40 The present phase III randomized trial compares subcutaneous Aza C treatment with supportive care.
Patient Selection All patients fulfilled the FAB classification criteria for MDS.41-43 Patients with RA or RA with ringed sideroblasts (RARS) met additional criteria of significant marrow dysfunction (Table 1). Bone marrow aspiration and biopsy were required within the 2 weeks before registration. Peripheral-blood films and marrow specimens were independently evaluated through centralized pathology review (D.N.).
Patients with therapy-related MDS were eligible if they were cancer-free for at least 3 years and had not received radiation or chemotherapy for 6 months. Additional eligibility requirements are listed in Table 2. The protocol was approved by the institutional review boards of all participating institutions. Each patient provided written informed consent.
Treatment Regimen Patients were stratified by FAB subtype and randomly assigned to supportive care or Aza C. The use of all hematopoietic growth factors was prohibited. Transfusions and antibiotics were administered as required. Marrow samples were obtained before study entry, at day 57, and at day 113. Aza C arm. Aza C (75 mg/m2/d) was injected subcutaneously in 7-day cycles beginning on days 1, 29, 57, and 85. Aza C, supplied by the National Cancer Institute (Bethesda, MD) in vials of 100 mg of powder plus 100 mg of mannitol, was suspended in 4 mL of sterile water and injected as a slurry with a maximum volume of 4 mL per injection site. If a beneficial effect was not demonstrated by day 57 and no significant toxicity other than nausea or vomiting had occurred, the dose of Aza C was increased by 33%. Once benefit occurred on a particular dosage, Aza C was continued unless toxicity developed. Patients were assessed after the fourth cycle. Those who achieved CR continued on Aza C for three more cycles; those with PR or improvement continued on Aza C until either CR or relapse occurred. Responses were initially evaluated by the treating physician but subsequently were scored independently by two experienced investigators (L.R.S. and R.M.S.) to validate responses. Patients who progressed (see Definitions, below) during the induction phase and those with stable disease at day 113 were classified treatment failures and removed from treatment. Supportive care arm. After a minimum interval of 4 months of supportive care, patients whose disease was worsening (see Definitions, below) were permitted to cross over to Aza C treatment. Patients could exit supportive care before 4 months but only because of death, withdrawal of consent, transformation to acute leukemia, or a platelet count persistently less than 20 x 109/L after week 8. Patients transforming to acute myelogenous leukemia (AML) exited at any time; those with less than or equal to 40% blasts in the marrow crossed over to Aza C, whereas those with greater than 40% blasts received other treatments. Cross-over. All data necessary to establish eligibility for cross-over from supportive care to Aza C were independently reviewed by the study chair, whose prior approval was required before cross-over (n = 46 of 49). Cross-over patients were studied and treated identically to patients initially randomized to Aza C. Quality-of-life assessment. Quality of life (QOL), an integral component of the study, was systematically assessed during standard telephone interviews by one of two trained nurses (E.P.D. or R.O.R.) before randomization and on days 50, 106, and 182. The QOL battery included measures of four dimensions: physical symptoms and functioning, psychological state, social functioning, and sociodemographic characteristics. The questionnaire consisted of two validated scales, the European Organization for Research and Treatment of Cancer (EORTC) QOL and the Mental Health Inventory (MHI). Questionnaires were given or mailed to patients before the telephone interviews; the interview methodologies have been validated in prior CALGB studies.44
Definitions
Relapse of responders. Relapse from CR was defined as greater than 5% myeloblasts in the bone marrow. Relapse from a PR was defined as  30% myeloblasts in the bone marrow (except for patients with RA and RARS, where peripheral-blood criteria alone or in conjunction with the bone marrow were used). Relapse for improved patients was defined as a decline to pretreatment levels in the blood counts, which were the criteria for response, or the recurrence of a transfusion requirement secondary to disease progression. Reversible changes in blood counts secondary to drug-induced myelosuppression did not constitute criteria for relapse.
Treatment failure in nonresponders.
Treatment was considered to have failed in nonresponders receiving supportive care if they advanced to a higher FAB subtype (ie, to RAEB or RAEB-T) or to AML, remained RBC transfusion–dependent before and during study, or developed progressive bone marrow failure, defined as the following: (1) confirmed fall from baseline of greater than 25% in all three peripheral-blood cell lines or greater than 50% fall in two cell lines or a greater than 75% fall in one cell lineage or (2) development of a RBC transfusion requirement (ie, in patients not receiving RBC transfusions before study entry, if the hemoglobin fell to < 9 g/L in patients > 65 years of age or to
Statistical Methods
Analyses were performed on an intention-to-treat basis. Patients (n = 20) determined by central pathology review to have acute leukemia at entry were noninformative for AML transformation and the time-to-treatment failure analyses. Response rates of the randomized arms were compared with the Prestudy RBC transfusion requirements (present/absent) were calculated. RBC transfusion data were standardized to the number of units per month and the means across time. Differences in transfusion requirements could have been influenced by the loss of patients because of death, cross-over, and dropout (attrition bias) and by physician discretion in the administration of transfusions. Times to initial response and to best response were measured from study entry to the date that initial and best response criteria were met, respectively. Duration of response was measured from initial response to relapse. Time to treatment failure was measured from study entry to the point of relapse (for responders) or failure (for nonresponders). The time from study entry to transformation to AML or death was chosen as the most meaningful clinical end point, because survival and QOL decline rapidly for patients with MDS after AML develops.
QOL Analysis
Patient Characteristics One hundred ninety-one patients with MDS deemed eligible by treating investigators were entered on CALGB 9221 between February 1994 and May 1996 from 26 main member institutions and their 30 affiliated hospitals. Response and toxicity were analyzed on data available through February 1999. After central pathology review, 20 patients were determined to have AML at study entry. These patients are excluded only from the AML transformation and time to progression analyses. The conclusions were unchanged if these patients were excluded from all analyses (data not shown). The two arms were evenly balanced at study entry (Table 4). There were no differences by FAB subtype, cytogenetic analysis (n = 81), International Prognostic Scoring System score,52 or time from diagnosis to study entry. Hematologic parameters at study registration are described in Table 5.
Analysis of Response Among patients randomized to supportive care, 5% (n = 5) met the criteria for improvement. No patient achieved a CR or PR (Table 6). All five patients categorized as improved either had a rising WBC count or absolute neutrophil count (n = 4) or platelets (n = 1) in the process of transforming from MDS to AML. On the Aza C arm, 60% (n = 60) responded (P < .0001), with 7% (n = 7) achieving CR, 16% (n = 16) having PR, and 37% (n = 37) improving. In no case was improvement of cytopenia a component of transformation to AML. The trilineage response was 23% for Aza C and 0% for supportive care. Among the 37 Aza C patients categorized as improved, 35% had increases in all three cell lines (but insufficient to meet criteria for PR), 30% had increases in two cell lines, and 35% had an increase in only a single cell line (Fig 1). Response to Aza C was independent of MDS classification. Responses for patients with RA and RARS (9% CR [n = 2]; 18% PR [n = 4]; 32% improved [n = 7]) were comparable with patients with RAEB, RAEB-T, and chronic myelomonocytic leukemia (CMMoL) (8% CR [n = 5], 15% PR [n = 10], 38% improved [n = 25]) among patients classified according to central pathology review (Table 4). Median times to initial response and best response were 64 and 93 days, respectively. The median duration of response among patients who achieved CR, PR, or improvement was 15 months (95% confidence interval [CI], 11 to 20 months) (Fig 2).
Of 49 patients who crossed over from supportive care to Aza C, 47% (n = 23) then responded, with 10% (five patients) achieving CR, 4% (two patients) having PR, and 33% (16 patients) improving. The trilineage response was 14%. Neither age nor sex influenced response rates.
Time to Treatment Failure
Analysis of Time-to-AML Transformation or Death
Transformation to AML occurred as the first event in 15% of the patients randomized to Aza C compared with 38% of patients randomized to supportive care (P = .001). Indeed, during the first 6 months after study entry, 3% of patients taking Aza C transformed to AML while 24% of patients on supportive care transformed (P < .0001). Of the patients who transformed to AML in the supportive care group, 77% were diagnosed at study entry as having RA/RARS or RAEB but not RAEB-T. Figure 4 represents the percent bone marrow myeloblasts at study entry compared with the percentage of blasts in the marrow or peripheral blood (National Cancer Institute criteria) at the time of transformation. To demonstrate the biologic impact on survival of the transformation to leukemia, we performed a landmark analysis after a 12-month date of the association of transformation to AML with survival. The two subgroups included 13 patients who had already transformed to AML by the landmark date and 93 patients who had not yet transformed, both groups independent of therapy. Patients who died before 12 months were excluded. The median additional survival (after the 12-month landmark) was 3 months (95% CI, 1 to 11 months) for patients who had already transformed and 18 months (95% CI, 14 to 26 months) for patients who had not yet transformed to AML (P < .001).
Effects on RBC and Platelets The mean number of RBC transfusions increased for the patients taking Aza C in the first month of treatment but thereafter declined, whereas the mean number of transfusions remained stable or increased for patients on supportive care. By definition (Table 3), patients achieving CR or PR had an elimination of RBC or platelet transfusion requirements. Among the 37 patients improved, 73% had an RBC response, 35% (n = 13) had a 50% or greater restitution in the RBC deficit (lineage response), 22% (n = 8) had an elimination of all RBC transfusion requirements, and 16% (n = 6) had a decrease by 50% or greater in RBC transfusions. Thus, among the 99 patients randomized to Aza C, 51% had an RBC lineage response. Among the 65 patients receiving RBC transfusions at study entry, 29 (45%) had an elimination of all transfusions and another six (9%) had a reduction in transfusions by 50%. In addition, lineage responses for platelets and WBC occurred in 47% and 40%, respectively, among those treated with Aza C.
Effects of Treatment on QOL
Overall Survival
Treatment-Related Toxicity The most common toxicity of Aza C was myelosuppression. In patients with severe cytopenias from their disease,toxicity was difficult to assess, rendering useless the standard criteria used for hematologic toxicity where the pretreatment marrow is normal. On the basis of standard CALGB criteria, grade 3 or 4 leukopenia occurred in 59%, granulocytopenia in 81%, and thrombocytopenia in 70% of patients receiving Aza C. When hematologic toxicity was reassessed centrally using relative changes in peripheral-blood counts compared with those at study entry, a decrease of 50% to 74% was defined as grade 3 and 75% or greater was defined as grade 4. Based on these criteria, grade 3 or 4 leukopenia occurred in 43%, granulocytopenia in 58%, and thrombocytopenia in 52% of patients receiving Aza C. Toxicity was transient, and patients usually recovered in time for the next treatment cycle. Infection was thought to have been related to treatment in 20% of patients. Nausea or vomiting occurred in 4%. There was one (  1%) treatment-related death.
The present results confirm our earlier observations of the beneficial effects of Aza C on bone marrow function in high-risk MDS and extend these findings to symptomatic RA and RARS. The same stringent response criteria used in our original trials of Aza C, developed and defined in the absence of standardized criteria, were used in the present study.39 The 5% response rate in the supportive care arm indicates that the criteria are sufficiently robust to filter out ordinary variation in blood counts. Incremental changes in peripheral-blood counts among patients improved were sizable (Fig 1). Thus, patients were not categorized as improved on the basis of only a marginal increase in counts as a potential byproduct produced by a quirk of the response criteria. The 60% response rate for Aza C shows that the criteria are sensitive and specific enough to detect biologically important changes, because they are associated with prolonged survival and improved QOL. Our patients were treated at 26 academic centers and 30 of their community affiliates. Thus, our results may predict general medical community achievement. The number of deaths in the two arms in the first 4 months of study was comparable. The frequency of transformation to leukemia for patients on supportive care was eight-fold higher than patients treated with Aza C in the first 6 months from study entry. Over the entire course of the study, the rate was 2.5-fold higher, the lesser frequency possibly reflecting the fact that many patients were receiving Aza C after cross-over. Differences between the arms in leukemic transformation could not be explained by FAB subtype, International Prognostic Scoring System scores, or time from diagnosis to study entry. Time to leukemic transformation or death represents the purest and most objective manifestation of disease progression for MDS. The landmark analysis demonstrates that transformation to AML has a significantly adverse effect on survival. Aza C delays and decreases transformation to acute leukemia. This is the first description of a drug with this capacity. The effect of initial treatment with Aza C on overall survival was confounded by the fact that 49 supportive care patients were crossed over to Aza C during their survival follow-up. The landmark analysis diminishes the confounding effect and demonstrates a significant survival advantage in favor of those treated with Aza C initially compared with those not treated or who received treatment only after 6 months of supportive care (Fig 6). A salvage benefit may nonetheless still be important even for patients treated late in the course of their disease. Significant improvements in QOL, particularly for fatigue, physical functioning, dyspnea, and general well-being, were derived from Aza C treatment, even in the supportive care patients after cross-over. The data indicate that Aza C treatment is more effective in improv-ing QOL than simply raising hemoglobin values with RBC transfusions. Aza C appears to be superior to other drugs that have been used for MDS. Agents that can induce hematopoietic differentiation in vitro have been extensively tested, and 13-cis- and all-trans-retinoic acid, 1,25-dihydroxy vitamin D3, butyrate, cytarabine, and hexamethylene bisacetamide have produced feeble clinical responses. Amifostine has produced responses, but its activity has yet to be fully defined.54 None of these drugs have caused significant trilineage responses, sustained remissions, or prolonged survival.55-65 Aggressive antileukemic type therapy and newer agents such as topotecan alone or in combination have produced response rates up to 65% but have not been reported to alter the disease outcome.66-71 Four randomized controlled trials have been previously conducted in patients with MDS. Cis-retinoic acid demonstrated no advantage compared with placebo.55,72 Low-dose cytarabine (10 mg/m2 every12 hours) compared with supportive care led to a 35% hematologic response (using less stringent criteria than the present study) but no differences in time to progression, frequency of transformation to AML, or survival.22,73 Filgrastim (G-CSF) was compared with supportive care. The death rate for patients with RAEB and RAEB-T was significantly accelerated by G-CSF, with a median survival of 10 months compared with 21 months for supportive care, leading to early termination of the study.74 Treatment with sargramostim (GM-CSF) resulted in increases in myelomonocytic and lymphoid lineages, with a decrease in frequency of infections in those treated. There were no effects on platelets or red cells. Impact on outcome has not been reported.11 The mechanism by which Aza C produces its effects is most likely multifactorial. Aza C can produce significant myelosuppression, particularly at higher doses. The doses used in this study and the two prior phase II studies produced marrow hypoplasia in only 10% of patients. Nevertheless, myelosuppression leading to lower peripheral-blood counts and increased RBC transfusion requirements occurred during the first cycle of treatment. Continued treatment without dose reduction led to improved bone marrow function in most patients. Prolonged treatment may have inhibited the MDS clone, permitting residual normal hematopoiesis to emerge. Conversely, Aza C might have exerted a cytotoxic effect on regulatory T cells or other modulatory cells that were inhibiting hematopoiesis. Aza C could also be acting as a biologic response modifier. The response of hematopoietic progenitors to cytokines is impaired in patients with MDS.75 This may be attributable in part to abnormalities of the signal transduction pathway downstream from the cytokine receptors.76-79 In vitro data suggest that Aza C can modulate the cytokine signal transduction pathway, rendering sensitive unresponsive cells to the effects of cytokines, partially restoring normal hematopoietic regulation.80-82 As observed in our prior studies, most responding patients demonstrated response beginning in the third or fourth month. This is consistent both with a low-dose cytotoxic effect and with Aza C acting as a biologic response modifier. Incorporation of Aza C into DNA inhibits DNA methyltransferase and induces DNA hypomethylation.32,83-86 This effect is S-phase dependent, and two or more cycles of DNA synthesis are required to alter gene transcription and expression.32,84-86 Thus, repetitive exposure on the present low-dose intermittent schedule may have affected small numbers of cells during each treatment, requiring three to four cycles before the effects became clinically apparent. Alteration in the methylation of the p15 gene has been implicated in transformation of MDS to AML and could be modulated by Aza C, thus reducing risk of leukemic transformation.87,88 Although Aza C is active in the present regimen, other doses and schedules might improve its efficacy. Additional studies of Aza C should build on these results. Besides optimization of dose and schedule, combinations with cytokines and other agents that modulate signal transduction are logical areas of exploration. The present study demonstrates that Aza C is effective therapy for patients with MDS with the subgroups and profiles treated in this study. Aza C improves their bone marrow function, decreases and delays significantly transformation to AML, and improves QOL and survival compared with supportive care. These data suggest that Aza C should be considered the treatment of choice for patients with MDS who meet the entry criteria stipulated in this study.
APPENDIX
Supported in part by grants from the T.J. Martell Foundation for Leukemia, Cancer, and AIDS Research, Abdullah Shanfari Memorial Fund, Food and Drug Administration (grant no. FD-R-001114), and National Cancer Institute to the Cancer and Leukemia Group B (Cooperative Group grant nos. CA 31946 and CA 33601).
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ABSTRACT
INTRODUCTION
2 test of proportions. Survival, time to response, and response duration were estimated with the Kaplan-Meier method and compared with the log-rank test.
