Analysis of Toxicity and Efficacy of Subcutaneous Cladribine at Reduced or Standard Doses (Five Versus Seven Consecutive Days) In Patients with Hairy Cell Leukemia (HCL) In the ICGHCL2004 Protocol by the Italian Cooperative Group on Hcl

Hairy cell leukemia (HCL) is generally responsive to intravenous Cladribine (iv2CdA). Subcutaneous Cladribine (sc2CdA) is an alternative route with 100% bioavailability. In indolent non-Hodgkin lymphomas other than HCL, at the dose of 0.7 mg/kg/cycle, efficacy of sc2CdA is similar to iv2CdA and reduction to 0.5 mg/kg/cycle determines equivalent efficacy and lower toxicity.

In a national multicentre clinical trial (protocol EudraCT code: ICGHCL 2004), we prospectively evaluated toxicity and efficacy of sc2CdA given 0.1mg/kg/die for 5 (total dose 0.5 mg/kg, arm A) or for 7 consecutive days (total dose 0.7 mg/kg, arm B) as a single course in classic HCL requiring first treatment.

Clinical data and diagnostic samples were collected from all patients for central revision of classical HCL diagnosis (WHO criteria) and for molecular analyses at the University of Siena, prior to study entry. Early grade 3–4 toxicity was assessed on days 7 to 30 after treatment, according to the 2003 NCI/CTCAE v3 criteria and occurrence of second tumors was assessed at every subsequent follow-up. Enpoints of sc2CdA efficacy were response to treatment, treatment free interval (TFI), relapse free survival (RFS), time to second tumor (TTST) and overall survival (OS). Responses to treatment were assessed on days 60 and 180 after treatment and defined according to the 1987 Consensus criteria. Complete Remissions (CR) and Partial Remissions (PR) were rated as beneficial responses (CR/PR), while minor Responses (mR) and No Responses (NR) were rated as treatment failures (mR/NR). TFI was measured as the time elapsed from sc2CdA initiation to second treatment because of new progression or failure to sc2CdA. RFS was measured in patients with a CR/PR from treatment inititation to relapse. OS was measured from sc2CdA initiation to death for any cause.

of 156 patients screened centrally, 148 scored as classical HCL and entered the study. Gender (male total 116/148, 78,4%; arm A: 62/77, 80,5% vs arm B: 54/71, 76,1%), age (total: median age 52 years, range 30–83; arm A: median 56, range 30–83; arm B: median 51, range 33–82), clinical and laboratory parameters prior to treatment (including spleen, hemoglobin, platelet, leucocyte and hairy cell counts) were equally balanced in the two arms. Dose reduction was required in no patients from arm A and in 2 patients from arm B due to concurrent infection. Overall hematological toxicity was no different among the two treatment arms. Requirement of platelet transfusions (total 7/148, 4,7%; arm A: 2/77, 2,6% vs arm B: 5/71, 7%), red blood cell transfusion (total 32/148; 21,6%, arm A: 15/77, 19,5% vs arm B: 17/71, 23,9%), or G-CSF (total 102/148; 68,9%, arm A: 55/77, 71,4% vs arm B: 47/71, 66,2%) was no different among the two arms. However, a significantly higher non hematological toxicity (total 28/148; 18,9%, arm A: 9/77, 11,7% vs arm B: 19/71, 26,8%) was observed in arm B (p=.019). Non haematological toxicity was mainly represented by infections or FUO (total 25/148; 16,9%) that were significantly more frequent in arm B (arm A: 8/77, 10,4% vs arm B: 17/71, 23,9%, p=.028). Higher prevalence of toxicity resulted in a higher hospitalization rate in arm B than in arm A (total 29/148; 19,6%, arm A: 9/77, 11,7% vs arm B: 20/71, 28,2%, p=.012) and one early death was experienced because of lung aspergillosis in arm B. Onehundred-forty patients (94,6%) had a beneficial response (101 CR, 68,2%; 39 PR, 26,4%) and 8 (5,4%) failed treatment (5 mR, 3,4%; 3 NR, 2%). Responses were equivalent in the two arms, with 72/77 (93,5%) beneficial responses (49/77 CR, 63,6%; 23/77 PR, 29,9%; 4/77 mR, 5,2% and 1/77 NR, 1,3%) in arm A versus 68/71 (95,8%) beneficial responses in arm B (52/71 CR, 73,2%; 16/71 PR, 22,5%; 1/71 mR, 1,4%; 2/71 NR, 2,8%). After a median follow-up of 36 months (range 12–66), 5 year TFI, RFS, TTST and OS were 67%, 71% 87% and 94%, respectively. Causes of late death were 2 cardiac events and 3 second tumors. No differences of TFI, RFS, TTST and OS were observed in the 2 arms of treatment.

The present data indicate that overall activity of sc2CdA is similar to iv2CdA (Cheson, 1998). Furthermore, this study indicates that sc2CdA given at 25% reduced doses (0.5 mg/kg) has equivalent activity and significantly lower toxicity than sc2CdA at standard doses (0.7 mg/kg). The reduced infection rates and hospitalization rates of sc2CdA have important pharmaco-economic implications.

No relevant conflicts of interest to declare.