Other chemotherapeutic agents

Not much is known about the effectiveness of other cytoreductive agents in managing CMML as assessed in phase I/II trials. For example, three separate studies with the anthracycline idarubicin suggested that it has limited activity, with no significant responses observed in CMML patients who were treated daily with intermediate dosages.1112

In the first trial of oral etoposide (VP-16), 10 consecutive patients with CMML were treated with 100 mg of etoposide orally, daily for 3 days (50 mg in "nonproliferative" disease), followed by a "maintenance" dose of 50 mg twice weekly. Clinical benefit, observed in seven patients, included improvement of anemia, thrombo-cytopenia, and extramedullary disease. Diminished benefit was noted in patients with increased blasts in the blood and bone marrow.13 A second etoposide trial used 50 mg orally, daily for 21 days every 4 weeks.14 Twelve of 17 patients with CMML experienced hema-tologic responses, three after failing treatment with hydroxyurea. The median duration of hematologic responses was 9+ months (range 4-49+ months). Responses consisted of control of leukocytosis in 12 patients, normalization of platelet counts in 2 throm-bocytopenic patients, and resolution of anemia in 1 case. Two of six patients with splenomegaly had >50% reduction in spleen size.15

The use of cladribine (2-chlorodeoxyadenosine-2 CdA, or 2-CdA) to manage CMML was prompted by the drug's proven efficacy in indolent lymphoproliferative disorders and by the observation of decrease in mono-cyte counts in patients with lymphoproliferative disorders treated with cladribine. An initial trial of cladribine at 0.1 mg/kg/day for 5-7 days in four patients15 resulted in a rapid decrease in monocyte counts. These results were subsequently confirmed in seven patients given cladribine in a dosing schedule of 0.2 mg/m2 daily for 5 days every 3 weeks for a total of three cycles.16 With this regimen, one patient attained a CR lasting 4 months and three patients exhibited partial responses (PRs) lasting 3-6 month. Although the overall response of 55% was encouraging, no further trials were conducted.

Cytarabine (cytosine arabinoside, or ara-C), administered subcutaneously at low dosages of 10-20 mg daily for 10-21 days, was studied extensively in the management of MDS and to a lesser degree of CMML during the 1980s and early 1990s. The initial enthusiasm was sparked by speculation on the ability of cytara-bine to induce terminal differentiation of malignant hematopoietic cells. Although the contribution of differentiation to the treatment outcome was never proven and the effect was attributed to the cytotoxic action of the drug, the effectiveness of the regimen was well documented. In small studies using cytarabine to manage CMML, the CR rates varied from 0 to 25%, and a review of data from 80 patients noted 9 CRs and a calculated CR rate of 14%.17 Thus, the efficacy of cytarabine was modest and, ultimately, the treatment outcomes were viewed skeptically. Because of the small numbers of patients in the reported trials, the associated myelosuppression, and the lack of information on response durations, the value of cytarabine in the management of CMML is poorly documented. However, the activity of low-dose cytarabine is probably comparable to that of other single agents, such as 5-azacytidine, decitabine, and topotecan, in terms of effect on the bone marrow and CR rates. Its future use may more likely lie in combination with other agents, as documented for high-dose cytarabine plus topotecan.18

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