Cladribine (2‐CDA) given as subcutaneous bolus injections is active in pretreated Waldenström's macroglobulinaemia

Abstract

Summary. Clinical trials with intravenous cladribine infusions in pretreated patients with Waldenström's macroglobulinaemia have shown a response rate of 40%. Our pharmacokinetic studies revealed that the bioavailability of subcutaneous cladribine is complete but that the concentration-time profile is very different from intravenous administration. We designed this phase II multi-institutional trial to study the activity and toxicity of cladribine given as s.c. bolus injections in patients with symptomatic Waldenström's macroglobulinaemia.Between May 1993 and October 1995, 25 patients were accrued: male/female 18/7, median age 65 years (range 44-85). All except one patient had been pretreated with more than one regimen (median 2, range 0-10). 18 patients had progressed under previous therapy and six were in relapse. All patients received cladribine for a total dose of 0 . 5 mg/kg per cycle as s.c. bolus injections divided over 5 d at у 4 week intervals, for a maximum of six cycles.All 25 patients were evaluable for toxicity and response. A total of 67 cycles were administered (median 3 cycles, range 1-6). Overall response rate including disease stabilization which had been progressive under previous therapy was 68%. 10 patients (40%, 95% CI 21-61%) achieved a partial remission. Seven responders had been progressive under previous therapy. Maximum responses were reached no later than the third cycle. Median time to treatment failure and remission duration were 4 . 4 (range 0 . 5-33) and 8 months (5-29), respectively. Four patients (16%) suffered from infections W.H.O. grade у 2 (pneumonia grade 2, Staphylococcus septicaemia grade 3, viral encephalitis and pneumonia, both grade 4 with complete resolution). No other severe adverse events were observed. Cladribine given as s.c. 5 d bolus injections was found to be active in pretreated Waldenström's macroglobulinaemia and resulted in durable remissions.

Long-term outcomes to fludarabine and rituximab in Waldenström macroglobulinemia

“…Response rates of 30% to 70% and durations of response of 20 to 24 months have been reported with the use of nucleoside analogs in WM patients. [4][5][6][7][8][9][10][11][12][13] Importantly, similar response rates were reported in these studies whether nucleoside analogs were used as first line or salvage therapy. The use of rituximab has also been extensively evaluated in patients with WM.…”

“…Viral encephalitis suspected on the basis of a herpetic infection was previously reported in a WM patient receiving treatment with cladribine. 8 In addition to the aforementioned short-term toxicities, we also observed the development of diffuse large cell lymphoma (n ϭ 3), myelodysplasia and acute myelogenous leukemia (n ϭ 3), and carcinomas (n ϭ 2) among patients treated in this study with a median follow-up period of 40.3 months. Although previous alkylator therapy may have been contributory in some of these cases to the development of secondary malignancies, only half of these patients received such therapy.…”

Waldenström macroglobulinemia: A review of therapy

“…One treatment-related death was recorded [39]. These results have been confirmed using cladribine by continuous infusion, 2-hr daily infusion, or subcutaneous injection, with response rates of 38-54% [40][41][42][43][44].…”

Activity of a Nitroxylated Analog of Daunorubicin, Ruboxyl, in B-Lymphoproliferative Disorders

“…Such problems are also encountered in the treatment of hematologic malignancies with other drugs such as pentostatine, fludarabine and cladribine [15, 16, 17]. Further studies with RBX are needed to ascertain which schedules and doses might be clinically useful and relatively free of toxicity.…”