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F. Lauria et al.
infectious complications [16]. At the Scripps Clinic, of 349 patients with HCL treated with the continuous weekly infusion regimen, 42% experienced a febrile episode, and 87% developed grade 3–4 neutropenia [13]. Thrombocytopenia and anemia are generally less frequent and less severe [13]. High rates of in- fectious complications were also documented in our study in patients with relapsed HCL, with a similar regimen [8], and it was noted that this problem was particularly crucial in those patients showing severe pancytopenia at the onset of treatment [8]. In order to probe a regimen less toxic than the daily
infusion, the efficacy and toxicity of cladribine at a dose of 0.15 mg/kg once a week for six courses given to severely neutropenic patients was also investigated in a pilot analysis by our group [17]. Of 25 patients evaluable, 100% OR (73% CR) rates were documen- ted, similar to the daily infusion regimens. However, only 16% severe neutropenias and 8% infections were observed [17]. Robak et al. subsequently explored the efficacy and toxicity of cladribine in 132 patients with untreated HCL randomized to receive cladribine in a weekly versus daily schedule; analysis of the treatment response confirmed similar efficacy. However, the expectedly lower toxicity rate of the weekly schedule from our study was not confirmed, to document that weekly and daily regimens show overall similar efficacy and toxicity [18].
Subcutaneous administration
Subcutaneous administration is an alternative route with 100% bioavailability. The clinical efficacy and safety of subcutaneous cladribine were first evaluated in HCL Liliemark and colleagues in 1992 [9]. Seventy-three patients with symptomatic HCL were given cladribine as a subcutaneous injection once daily for 7 consecutive days. Plasma levels of cladribine were similar to those achieved after intravenous administration, confirming full bioavail- ability of the compound if administered subcuta- neously. Fifty-nine patients (81%) achieved a
durable CR after one (n¼55) or two courses, 10 had a PR, with an OR of 94%, and none of the patients had relapsed after 20 months of follow-up. Febrile neutropenias requiring antibiotics were re- ported in 38% of patients. Since in indolent non-Hodgkin lymphoma (NHL)
other than HCL a 25% reduction of cladribine, given either intravenously or subcutaneously, determined equivalent efficacy and lower toxicity than the standard dose [19,20], our unit has investigated the efficacy and toxicity of subcutaneous cladribine given 0.1 mg/kg/day for 5 (total dose 0.5 mg/kg, arm A, reduced dose) or for 7 days (total dose 0.7 mg/kg, arm B, standard dose) as a single course in newly
diagnosed HCL requiring treatment, in a national multicenter clinical trial (protocol EudraCT code: ICGHCL2004). In an interimanalysis on 92 patients presented at the American Society of Hematology in 2008, we found that responses were equivalent in the
two arms (p¼0.7), with 91% OR rates in arm A versus 94% OR rates in arm B. However, grade 3–4 overall toxicity appeared less frequently in arm A
(9%) than in arm B (25%) (p¼0.03). Toxicity was largely represented by neutropenic fevers and infec- tions that were less frequent in arm A (4%) than in
arm B (22%) (p¼0.02). The final results of the trial on 150 patients were due to be presented at the 2010 Meeting of the American Society of Hematology in Orlando.
Conclusions
Cladribine is a very effective compound in HCL and induces high CR rates. From the current data we can conclude that the activity of subcutaneous cladribine is similar to that with the intravenous formulation [7,11]. Choice of regimen and route of administra- tion may be decided based on circumstantial convenience for patients and physicians at different institutions worldwide. The subcutaneous route may be deemed a very convenient route since it does not require hospitalization. A reduced dosage of cladri- bine may also be advantageous as it may be associated with reduced toxicity and may set the dose needed for combinations with antibody treat- ments.
Acknowledgements
The work was supported by: Istituto Toscano Tumori, Italy; Siena-AIL (Associazione Italiana contro le Leucemie, Linfomi e Mielomi, Siena Section); Hairy Cell Leukemia Research Foundation (Illinois, USA); Associazione Italiana per la Ricerca contro il Cancro (AIRC), Milan, Italy; and Fonda- zione MPS 2009 (Siena, Italy).
Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at
www.informahealthcare.com/lal.
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1. Bouroncle BA, Wiseman BK, Doan CA. Leukemic reticu- loendotheliosis. Blood 1958;13:609–630.
2. Zakarija A, Peterson LC, Tallman MS. Splenectomy and treatments of historical interest. Best Pract Res Clin Haematol 2003;16:57–68.
3. Quesada JR, Reuben J, Manning JT, Hersh EM, Gutterman JU. Alpha interferon for induction of remission in hairy-cell leukemia. N Engl J Med 1984;310:15–18.
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