Intensive chemotherapy using combination regimens

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The first patients with CMML who were treated with combination chemotherapy used to manage acute myel-ogenous leukemia (AML) were probably those whose initial diagnosis was AML that was later reclassified as MDS or CMML. In later trials in patients with AML, patients with CMML were occasionally included, along with RAEB and RAEBt, as all three categories were considered high-risk MDS. More often than not, little information was given on the clinical and hematologic status of CMML patients, and in such prospective studies, selection bias toward treating younger patients with advanced disease was likely. With few exceptions, treatment regimens consisted of cytarabine (given at standard dosages for 5-7 days) plus anthracycline or anthracene-dione antibiotics (daunorubicin, mitoxantrone, or idaru-bicin). A review of six such studies conducted between 1980 and 1995 identified only 35 patients with CMML, 11 (31%; 95% confidence interval 15.9-47.0%) of whom achieved a CR.18 Duration of remission and overall survival, when reported, tended to be short and there was no convincing evidence that addition of anthracyclines to cytarabine improved the outcome.

Unfortunately, in most clinical trials, the responses of the CMML cohort were not evaluated separately, further clouding their interpretation. From the results of studies with at least some data available, it may be concluded that such treatments are feasible and that in a portion of patients with CMML, a CR can be obtained, although at the expense of substantial morbidity and even mortality.

Further information on the role of intensive combination chemotherapy was obtained from a series of clinical trials that used chemotherapy of increasing intensity to manage CMML. One such trial used a combination of two single agents with documented effectiveness in CMML and low cardiotoxicity: topote-can, administered as a continuous intravenous infusion at 1.25 mg/m2 over 24 h, daily for 5 days, and cytarabine, as a 2-h infusion at a dosage of intermediate intensity, 1 g/m2/day, for 5 days.18 Patients who did not experience a CR after the first course of therapy received a second course and a dose adjustment when indicated. Patients who experienced a CR were eligible for postremission chemotherapy. In this prospective phase II study, patients with CMML, RAEB, and RAEBt were registered separately, and treatment outcome was evaluated separately for each disease. Among the 27 patients with CMML who enrolled in the study, 12 (44%; 95% confidence interval 25-65) achieved a CR.11 Analysis by disease stage showed a CR rate of 62% in CMML patients with <5% bone marrow blasts (corresponding to CMML I by WHO criteria) and 29% in those with >5% bone marrow blasts (CMML II by WHO criteria). As was the case for the RAEB and RAEBt patients, the response rates were not affected by the presence of diploid or abnormal karyotypes, or by primary or secondary CMML. In most CMML patients with an abnormal karyotype, conversion to diploid status was observed. Responses did not differ in patients treated immediately on diagnosis and in those with up to 6 months' history of antecedent hemato-logic disorder. At a median follow-up of 7 months, the median duration of CR was 33 weeks and the median survival time was 42 weeks.18 Although the presence of an abnormal karyotype had no significant effect on the response rate, its presence appeared to be associated with a shorter response duration. As with any myelosuppressive treatment, neutropenia-associated fever and infections were the most frequently reported complications during treatment and were observed in 50% of the patients. With supportive care and close surveillance, the mortality rate in the CMML cohort was 10%; all deaths were related to infectious causes.18 Most, if not all, combination chemotherapy regimens used to manage CMML included cytarabine as the most active agent. In an attempt to develop an alternative treatment and explore the reported effectiveness of etoposide in CMML,1314 a group of 17 patients with CMML was treated with a combination of etoposide (100-200 mg/m2 daily for 5 days) and carboplatinum (continuous intravenous infusion, 200 mg daily for 3-5 days). Of the 17 patients enrolled, 14 were classified by WHO criteria as having CMML I and 3 as having CMML II; 14 had platelet counts of <100 X 109/L, all 17 were anemic (10 with hemoglobin concentrations less than 10 g/dL), 13 had "proliferative" CMML, and 10 had an abnormal karyotype. Despite the severe myelosuppres-sion and marrow aplasia characteristically caused by this regimen, five (29%) CMML patients achieved a CR with a median duration of 16 weeks (range 3-22 weeks),44 indicating that although intensive combination chemotherapy without cytarabine resulted in a CR in one-third of patients, the benefit, as measured by CR duration, was not durable. Achieved at the price of high toxicity and risk of death, the results were not better than those obtained in another study by the same institution with the single-agent topotecan.1920 This conclusion led to questioning of the benefit of intensification of chemotherapy in managing CMML.

One comparison of chemotherapy regimens of various intensities used to manage CMML over a 15-year time period44 included 23 CMML patients treated with a combination of various high-intensity regimens containing high-dose cytarabine plus flu-darabine, anthracycline antibiotics (idarubicin and liposomal daunorubicin), or both. Compared with a less intensive topotecan plus cytarabine regimen, no further improvement in the CR rate was achieved, likely because the more intensive regimens induced higher mortality. CR duration remained short, as did overall survival.44 Because of the limited size of the CMML cohorts treated with various regimens, identification of covariates associated with response and response duration was inconclusive so far. A trend for lower CR rates was noted for patients with more than 5% marrow blasts (CMML-II and for patients with abnormal karyotype.18 A recent update of the results from the topotecan plus cytarabine regimen, then including 39 patients with CMML, confirmed the earlier results, as did a review of high-dose cytarabine-based regimens updated to 30 patients.44

Taken together, these results indicate that although complete hematologic and cytogenetic responses can be obtained in up to 40% of CMML patients, response durations are limited. Only occasional patients remain disease free at 3 years. Further intensification of induction chemotherapy appears to increase mortality and morbidity without leading to an improved response rate and response duration. Topotecan plus cytarabine yields the best results in terms of morbidity, mortality, response rates, and response durations. Whether similar results could be obtained with less intensive regimens (e.g., standard- or low-dose cytarabine plus topotecan, or anthracycline antibiotics at presumably lower toxicity) remains to be investigated in controlled clinical trials. The benefit of postremission chemotherapy, in terms of both intensity and duration, remains unanswered. Responding patients enjoy a better quality of life and prolonged survival, but the effect of the treatment on survival may be related to the natural history of the disease. To date, no treatment regimen positively impacts the natural history of the disease or extends expected survival. As is the case with every management approach in CMML, the value of combination chemotherapy on patient survival will be determined only in a randomized trial against best standard of care; e.g., supportive care (plus hydroxyurea in patients with proliferative disease).

Should chemotherapy be considered at all in the management of CMML, and if so, which regimen should be chosen? No consensus is currently available, but several observations may guide such decision making. At present, the regimen of topotecan plus cytara-bine appears to be the best studied, most effective, and least toxic. More than 80% of patients who achieve a CR do so after a single course of this treatment. Although additional complete responses may be achieved with further courses, these responses are obtained with an increased risk for complications, at a higher cost, and tend to be shorter. Thus, one course of this regimen (and possibly other combination regimens) may segregate patients who will likely benefit from additional chemotherapy from those who will not. Supportive care or investigational treatment in the setting of clinical trials may be an alternative option, particularly for high-risk CMML patients. Thus, CMML patients with clinical symptoms or a high-risk prognostic score (e.g., MDAPS)4 may be candidates for such trials. Another candidate group for chemotherapy may be patients with HLA-matched donors who are considered for allogeneic SCT. Because CMML is resistant to chemotherapy, the frequency of relapses in patients with active disease who receive SCT is high.46-48 Cytoreduction, and particularly induction of CR, before the SCT may improve the outcome.

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