Journal of Clinical Oncology, Vol 18, Issue 5
(March), 2000: 956
© 2000 American Society for Clinical Oncology
Low-Dose 5-Aza-2'-Deoxycytidine, a DNA Hypomethylating Agent, for the Treatment of High-Risk Myelodysplastic Syndrome: A Multicenter Phase II Study in Elderly Patients
By P. Wijermans,
M. Lübbert,
G. Verhoef,
A. Bosly,
C. Ravoet,
M. Andre,
A. Ferrant
From the Department of Haematology, Leyenburg Hospital, The Hague, the Netherlands; University Hospital, Albert-Ludwigs University, Freiburg, Germany; University Hospital Gasthuisberg, Leuven; Mont-Godinne UCL University Hospital, Yvoir; Hospital de Jolimont, Haine Saint Paul; and Hospital Notre-Dame Charleroi and Cliniques Universitaires Saint-Luc, Brussels, Belgium.
Address reprint requests to P.W. Wijermans, MD, Department of Haematology, Leyenburg Hospital, Leyweg 275, 2545 CH The Hague, the Netherlands; email hematley{at}worldonline.nl
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ABSTRACT
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PURPOSE: 5-Aza-2'-deoxycytidine (decitabine; DAC) is a DNA hypomethylating agent that has shown a 50% response rate in a small phase II study in elderly patients with high-risk myelodysplastic syndrome. We performed a second, multicenter phase II study in a larger group of patients to confirm our findings and to study the toxicity of DAC.
PATIENTS AND METHODS: Between June 1996 and September 1997, 66 patients (median age, 68 years) from seven centers received DAC 45 mg/m2/d for 3 days every 6 weeks. For patients in whom a complete response (CR) was reached after two courses, two further cycles were administered as consolidation therapy. In case of a stable disease situation, improvement, or a partial response (PR), a maximum of six cycles was administered. The primary end points were response rate and toxicity. The secondary end points were response duration, survival from the start of therapy, and overall survival.
RESULTS: The observed overall response rate was 49%, with a 64% response rate in the patients with an International Prognostic Scoring System (IPSS) high-risk score. The actuarial median response duration was 31 weeks, with a response duration of 39 weeks and 36 weeks for patients who reached a PR or CR, respectively. The actuarial median survival time from the time of diagnosis was 22 months and from the start of therapy was 15 months. For the IPSS high-risk group, the median survival time was 14 months. The median progression-free survival time was 25 weeks. Myelosuppression was rather common, and the treatment-related mortality rate was 7% and was primarily associated with pancytopenia and infection. Significant responses were observed with regard to megakaryopoiesis, with increases in platelet counts having already occurred after one cycle of DAC therapy in the majority of the responding patients.
CONCLUSION: We were able to confirm our previous observation that DAC therapy was effective in half of the studied patients with high-risk myelodysplastic syndrome and is especially active in the patients with the worst prognoses. Myelosuppression was the only major adverse effect observed.
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INTRODUCTION
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THE MYELODYSPLASTIC syndromes (MDSs) consist of a heterogeneous group of clonal hemopathies characterized by maturation defects that result in ineffective hematopoiesis and a variable risk of progression to acute leukemia. The majority of MDS patients are elderly, and their prognosis, especially when they have high-risk features, is rather poor.1 For this particular group of patients, who cannot tolerate intensive chemotherapy, there is really no effective therapy available. Eradication of the malignant clone by mild cytoreductive therapy or agents that induce cellular differentiation could provide the best therapeutic option to date in these patients.
DNA hypermethylation of densely clustered cytosines (so-called CpG islands) within the promoter region of tumor suppressor genes involved in cell proliferation and differentiation is a common phenomenon in numerous solid tumors.2,3 In addition, in several hematopoietic neoplasms, such as acute myelogenous leukemia and MDS, hypermethylation that resulted in gene silencing has recently been described.4 5-Aza-2'-deoxycytidine (decitabine; DAC) is a pyrimidine nucleoside analog that strongly inhibits DNA methyltransferase activity and as such is one of the strongest inhibitors of DNA methylation.5 Several lines of evidence have indicated that demethylation of specific sequences of genes is associated with cell differentiation.6,7
At low concentrations, DAC has shown cellular differentiating activity in vitro, and in vivo it stimulates gamma globin chain synthesis, leading to an increase in fetal hemoglobin (Hb) in patients with a hemoglobinopathy.8,9 Pharmacologic reversion of aberrant methylation could be an approach to influence the abnormal growth and differentiation seen in leukemia and myelodysplasia. On the other hand, DAC has shown antitumor activity, which is probably mediated by cytotoxicity, when used at high doses in acute leukemia10,11 and in chronic myelogenous leukemia blast crisis.12
With both 5-azacytidine and DAC at low doses, trilineage responses were observed in MDS, with myelotoxicity as the single adverse effect.13-15 In an earlier study, we observed favorable effects of low-dose DAC in 54% of patients with high-risk MDS.15 To confirm our findings, we performed a second multicenter phase II study.
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PATIENTS AND METHODS
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Patient Characteristics
The protocol was approved by all local medical ethical committees, and the patients were required to provide their written informed consent before enrolling onto the study. Patients who had not been previously treated with chemotherapy and who had a primary MDS of the following subtype, according to the French-American-British (FAB) criteria, were eligible: refractory anemia with excess blasts (RAEB); RAEB in transformation (RAEB-T); chronic myelomonocytic leukemia (CMML); and refractory anemia (RA) or refractory anemia with ringed sideroblasts (RARS) with a transfusion requirement that exceeded 3 units of RBCs or 6 units of platelets per 6 weeks. Normal renal and liver function test results were required. Only a moderate elevation of liver enzyme levels (maximum, two times normal) was allowed when, according to the physician responsible, it was deemed a result of the underlying disorder. Cardiac function was expected to be normal. Only patients with an Eastern Cooperative Oncology Group performance status of 0, 1, or 2 were allowed to enter onto the study.
A total of 66 patients (46 males and 20 females) were entered onto the study. The patients’ median age was 68 years (range, 38 to 84 years). Eight patients had RA/RARS (seven patients with RA, one patients with RARS), 29 had RAEB, 20 had RAEB-T, and nine had CMML. Table 1 lists the distribution of the patients according to FAB subtype and IPSS risk score.1 The FAB subtypes and risk scores were determined on the basis of the parameters at the start of therapy and were not based on the values measured at the time of MDS diagnosis. No cytogenetic data were available for six patients (9%). No metaphases could be obtained from the marrow of three patients. The IPSS risk scores of these nine patients were based on the other available data, so the risk could be underscored in these patients. No IPSS low-risk patients were entered onto this study. Normal cytogenetic and low-risk cytogenetic abnormalities were found in 28 and four patients, respectively, whereas intermediate-risk cytogenetic abnormalities were seen in 12 patients and high-risk cytogenetic abnormalities in 13. Thus chromosomal abnormalities were seen in 48% of the patients tested.
Therapy
The DAC was a gift of Pharmachemie B.V., Haarlem, the Netherlands. The drug was administered at a dose of 15 mg/m2 infused over a 4-hour period every 8 hours (45 mg/m2 per day) for 3 consecutive days. Courses were repeated every 6 weeks, provided that hematologic recovery had taken place before patients started a new cycle of therapy or, in case of a low blood cell count before treatment, that the hematologic parameters (WBC, platelets, and Hb) had at least reached pretreatment values. No dose reduction was allowed. The effect of DAC therapy was first evaluated by bone marrow aspirate after the second cycle. In case of a complete response (CR), two more courses were administered, and if the CR persisted, therapy was stopped. When an improvement, partial response (PR), or stable disease was found, two more courses were administered, with a maximum of six courses. Whenever disease progression occurred, the therapy was stopped.
Response Criteria
Because the bone marrow aspirate was repeated after every other course, patients were assessable after at least two courses of therapy. A complete response was defined as a normocellular or slightly hypocellular marrow with less than 5% blasts and a normal hemogram (Hb, > 11g/dL; granulocytes, 1.0 x 109/L; platelets, > 100 x 109/L). A PR was defined as a more than 50% decrease in the number of bone marrow myeloblasts and a trilineage response of at least an increase in Hb by more than 2 g/dL, in platelet count by more than 50 x 109/L, and in granulocyte count by more than 1.0 x 109/L. An improvement was defined as a decrease of at least 50% in transfusion requirements, together with at least an improvement of one or two cell lineages of the peripheral cell counts but not enough to qualify for a PR. Stable disease was defined by the absence of CR, PR, or improvement but without clear disease progression. The response duration was measured from the time of CR or of achievement of the best response. Relapse was diagnosed when patients in CR developed more than 5% myeloblasts and/or deterioration of blood counts leading to transfusion or, in cases of a low blast count (RA and RARS), a drop in the cell count toward pretreatment levels. Progression was defined as a deterioration of blood counts leading to increased transfusion requirements or an increase in the number of myeloblasts by more than 10%.
Statistical Methods
This report contains all the data as they were available on March 1, 1999. Response data are presented on the basis of "intention to treat" (n = 66). All the survival analyses were performed using Kaplan-Meier plots and log-rank tests. Median survival estimates are provided with 95% confidence intervals. Response rates were compared with the  2 tests, and trends were analyzed by linear-by-linear association analysis. The number of patients needed for this phase II study was calculated on the basis of the Gehan two-step procedure.16 Some extra patients were included to substitute for those patients who progressed or who were removed from the study before two cycles of therapy could be provided, as stated as part of the study protocol. In this analysis, however, all patients were taken into account.
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RESULTS
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Patient Eligibility and Assessability
Sixty-six patients were entered onto the study between June 1996 and September 1997. Fourteen patients received only one course of treatment each: 10 because of progressive disease or toxic death, three because of persistent cytopenia after one cycle of DAC, and one because he refused further treatment after he initially obtained a good response. All results are presented on the basis of intention to treat (ie, n = 66).
Response Rate
Five patients died during or shortly after the treatment, three of them because of drug-induced myelotoxicity and two because of causes that were probably not related to the DAC treatment. One patient died of a myocardial infarction while in CR after recovery of the third course, and another patient probably died of a pulmonary embolism while in a stable disease condition after two courses of DAC therapy.
Table 2 lists the types of response and the response rates divided for the different IPSS risk groups observed. The response rate was 49% (32 of 66 patients; 95% confidence interval [CI], 38% to 63%) when the patient who showed a response after one cycle and then refused further therapy was taken into account. Thirty-four (51%) of the patients showed an improvement in one or more cell lineages: 11 showed a two-lineage response, and nine, a trilineage response. Table 3 lists the distribution of the responding patients according the FAB classification. The three patients who received only one cycle of DAC because of persistent cytopenia were scored as having disease progression.
By FAB subtype, the response rates were as follows: RA, two of eight patients (25%); CMML, four of nine patients (44%); RAEB, 12 of 29 patients (41%); and RAEB-T, 14 of 20 patients (70%). By IPSS risk score, the response rates were as follows: intermediate I, four of 16 patients (25%); intermediate II, 12 of 25 patients (48%); and high risk, 16 of 25 patients (64%). Using both the IPSS risk score and the FAB classification, there was a statistically significant trend to a higher response with increasing risk (P = .014, 2 test) The high-risk group had a significant higher response rate on DAC therapy than did the intermediate-risk patients (P = .025, 2 test). The majority of the patients already showed a response after the first three courses of DAC. The mean number of treatment cycles of DAC necessary to reach the best observed response was 3.2. Sixteen percent of the responses were observed after four to six cycles of DAC therapy.
The cytogenetic risks among the responders were as follows: low risk, 16 of 33 patients (48%); intermediate risk, five of 12 patients (42%); and high risk, nine of 12 patients (75%). Thus, although the numbers for each group are small, the observed response rates increase with the observed risk category of the patients. PRs and even CRs were seen among patients with high-risk cytogenetic abnormalities such as chromosome 7 anomalies and/or complex abnormalities. Normalization of abnormal karyotypes, even with the more sensitive fluorescent in situ hybridization technique, were seen. The results of these studies are reported in greater detail elsewhere.17
One of the most remarkable findings was the observed increase in the platelet counts. Of 53 patients who received at least one course of DAC, sufficient follow-up data were available. Thirty-five (66%) of them experienced an increase in platelet count. Nineteen (36%) showed a increase in platelet count to values greater than 100 x 109/L, and 16 (30%) showed an increase of at least 50% and above 30 x 109/L. This phenomenon was frequently observed already after the first course of therapy.
Response Duration
The actuarial median response duration was 31 weeks (95% CI, 22.6 to 37.4 weeks). The actuarial response duration was 26 weeks (95% CI, 16 to 36 weeks) for those patients who showed an improvement, 39 weeks (95% CI, 25 to 47 weeks) for the patients with a PR, and 36 weeks (95% CI, 25 to 47 weeks) for the CR patients. These differences in response duration for the different risk groups were not statistically different.
Survival
The actuarial median survival time from the start of therapy was 15 months (95% CI, 13.3 to 16.7 months; n = 66) (Fig 1). No differences were found between male and female patients. The median survival time of those patients who showed improvement was equal to the survival time of patients who experienced a PR (both median survival times, 15 months; 95% CIs, 10.6 to 19.4 months and 7.5 to 22.5 months, respectively). Patients who reached a CR had a median survival time of 19 months (95% CI, 16.4 to 21.6 months). The overall survival time from the time of diagnosis was 22 months (95% CI, 14.2 to 29.8 months).
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Fig 1. Graph showing the survival rates (by Kaplan-Meier test) from the start of therapy (x, patients censored as being alive at last contact).
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Because of the lack of cytogenetic data at the time of diagnosis, we calculated survival times on the basis of the risk score from the start of treatment. This analysis showed a median survival time from the start of therapy of 25 months (95% CI, 14.2 to 35.9 months) for the intermediate I risk group, 13 months for the intermediate II group (95% CI, 9.3 to 16.8 months), and 14 months for the high-risk group (95% CI, 12.1 to 15.9) (Fig 2). Analysis on the basis of FAB classification resulted in the following survival times from the start of therapy: RA/RARS, not yet reached; RAEB, 13 months (95% CI, 7.8 to 18.3); and RAEB-T, 13 months (95% CI, 11.0 to 15.0 months). The actuarial median progression-free survival time was 25 weeks (95% CI, 4 to 84 weeks; n = 66).
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Fig 2. Graph showing the Kaplan-Meier plot of the survival rates from the start of DAC therapy, according to IPSS risk score. – – – –, IPSS intermediate I risk score; ···, IPSS intermediate II risk score; ——, IPSS high-risk score.
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Toxicity
Results of an earlier study15 suggested that myelotoxicity was the most important adverse effect observed in patients who received DAC therapy, with rather delayed nadirs for both neutrophilic granulocytes and platelets. In the study presented here, myelotoxicity also led to a substantial number of episodes with fever and/or proven infections. Table 4 summarizes the World Health Organization grade III and IV toxicities experienced by patients in this study, as well as those grade II toxicities that made admission into the hospital necessary. Only nine patients experienced grade III and IV toxicities that did not result from myelosuppression. Three patients died of infection during episodes of granulocytopenia. Two other patients died of cardiac problems that were not experienced during pancytopenia or platelet-recovery episodes. According to the patients’ physicians, these adverse effects were probably not related to the treatment with the experimental drug. Two patients experienced atrial fibrillation during an episode of fever (together with a very low Hb level in one patient). According to the patients’ physicians, this event was a result of the patients’ clinical conditions and any relationship to the DAC therapy was, in their opinion, unlikely.
One patient had an attack of seizures. Extensive investigation by computed tomographic scan, magnetic resonance imaging, and EEG and CSF examinations revealed no abnormalities. This reaction was recorded as possibly having occurred because of the DAC treatment. A transient increase in creatinine level that was possibly related to DAC was observed in one patient. Four patients experienced gastrointestinal toxicity, including two patients with diarrhea, one patient with cholecystitis, and one patient with spasmodic pain. Of the 44 episodes of fever, infection, and septicemia, eight were unrelated to DAC treatment. Patients’ physicians scored 19 of them as possibly being related; however, the underlying disease with pancytopenia could also have been the reason for the event. For 17 episodes of fever and/or infection, the relationship to DAC was scored as probable or definitive.
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DISCUSSION
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In the study presented here, we were able to confirm our earlier findings from a study of with low-dose DAC in elderly patients with high-risk MDS.15 The observed response rate of 49% in the study presented here is comparable with the 54% response rate in our earlier study and with the 49% response rate that was seen with 5-azacytidine in a comparable group of patients.13 The highest response rate was seen in the patients with a high-risk IPSS score and thus probably in those with the highest blast count. Trilineage responses were seen even in patients with IPSS-scored high risk MDS with severe cytogenetic abnormalities, often with a remarkable response of the platelet count.
Although cytogenetically proven CRs are the ultimate goal of this therapy, we have also presented data regarding the PRs and improvements, not only to be able to compare our results but also because responses other than CRs may be of value to patients. For this reason, an international committee is currently working on a definition of the response criteria for the treatment of MDS (B.D. Cheson, personal communication, 1999). We have presented our data accordingly and have adhered to strict criteria for PR (trilineage response) and improvement.
To date, it is unclear whether the observed responses were induced by the cytotoxic effect of DAC or by its differentiating effect, possibly via gene demethylation. The observed myelosuppression suggests a cytotoxic mode of action. We were able to show demethylation of initially hypermethylated p15INK4B, an inhibitor of cyclin-dependent kinases frequently hypermethylated in MDS patients, in the majority of the responding patients.18 This and the slow response over time as was seen in many patients may, however, indicate that the activity of DAC is not limited to cytotoxicity but that its demethylating effect plays a role in the treatment of MDS. This idea is supported by the fact that DAC and 5-azacytidine are capable of increasing fetal Hb in patients treated for sickle cell disease.9 Further studies are presently being performed to determine whether p15-promoter demethylation reflects the actual introduction of demethylated cytosine molecules or if it is merely the consequence of the removal of transformed cells.
It thus seems that demethylating agents can induce responses in this type of MDS patients either by cytotoxicity, by cell differentiation, or both. This type of treatment is well tolerated in this group of patients, and only myelotoxicity was seen as a common therapy-related adverse effect. Compared with other treatments, the myelotoxicity and drug-related mortality is this study was modest. Cheson et al19 reported myelotoxicity in 88% of the patients treated with low-dose cytarabine, with a 15% death rate among those patients. In the randomized study of Miller et al,20 only two lethal infections were seen among 70 patients; the infection rate (22.5%), however, was comparable. It is worth noting that among patients who received supportive care only in this study, a substantial number of infections were seen as a consequence of the underlying disorder. In the European Organization for Research and Treatment of Cancer study with low-dose cytarabine plus granulocyte-macrophage colony-stimulating factor (GM-CSF), the toxic death rate was 15% and a high incidence of infections and hemorrhages were observed (>50%).21
With the exception of intensive chemotherapy including allogeneic stem-cell transplantation, there are no curative therapeutic options for patients with an MDS,22 that form of treatment is only available for a minority of younger patients, perhaps with the exception of the recently introduced so-called "mini-transplants."23 Intensive chemotherapy with autologous stem-cell support is also only available for patients under the age of 65, and its value remains to be proven.24 The response duration is often short and the relapse rate high. The majority of patients with MDS, however, are elderly and often have serious comorbidity. For these patients, the therapeutic approach can be aimed at eradication or suppression of the abnormal clone only by mild chemotherapy or by differentiation of the malignant clone.
In a review published in 1987, Cheson et al19 calculated that the response rate with low-dose cytarabine was only 17%. No survival benefit was seen in a randomized trial that compared low-dose cytarabine with supportive care.20 In a study in which GM-CSF was added to low-dose cytarabine, the response rate was 39%.21 Topoisomerase I inhibitors have gained interest because good response rates were reported, but they were reported with substantial toxicity.25 Phase II trials combining topotecan with high-dose cytarabine are currently being performed, with promising results.26
Cell-differentiation therapy with either retinoids or vitamin D3 analogs yielded only disappointing results.27 Newer drugs such as amifostine, which can stimulate hematopoiesis in vitro, still have to prove their potential, because the first optimistic reports were followed by more negative findings.28,29
Another approach is growth stimulation of those cell lines that are deficient by the use of and combinations of lineage-specific growth factors such as erythropoietin, G-CSF, or GM-CSF to increase cell counts and thus to improve the quality of life of the patients. Recombinant human erythropoietin has only a limited effect in MDS patients, especially in those who are transfusion-dependent.30 Combinations with G-CSF resulted in a higher response rate of the erythroid cell lineage.31 However, subgroup analysis revealed a response rate ranging from 74% in patients with a low transfusion requirement and low erythropoietin level to 7% in patients with a high level of erythropoietin and a high transfusion rate.32 The addition of interleukin-3 to erythropoietin only leads to an increase in toxicity.33 There are no data to suggest a survival benefit in patients treated with growth factors, although such patients’ quality of life may increase.
As long as an effective therapy with low toxicity is not available for the majority of patients with MDS—ie, the elderly—we must study those drugs that can influence the natural course of the disease with a low toxicity. DAC seems to be such a drug, and it seems to be especially active in patients with a high-risk IPSS score. Whether it leads to an improvement of overall survival with an increase in quality of life remains to be established in a phase III study, as does whether patients with a high-risk IPSS score indeed will benefit more from this therapy as patients with a low-risk score do. However, phase II studies with this drug administered in lower doses or in combination with, for instance, growth factors can perhaps lead us to more useful therapeutic options.
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Submitted May 13, 1999;
accepted November 12, 1999.
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TOP
ABSTRACT
INTRODUCTION
