Equivalent Efficacy and Lower Toxicity of Subcutaneous Cladribine at Reduced Doses (Five versus Seven Consecutive days) in Hairy Cell Leukemia: An Interim Analysis of the ICGHCL 2004 Protocol by the Italian Cooperative Group on Hcl
Authors: Forconi Francesco , Zaja Francesco , Intermesoli Tamara , Rigacci Luigi , Stelitano Caterina , Tavera Silvia , Morello Enrico , Pulsoni Alessandro , Gherlinzoni Filippo , Zaccaria Alfonso , Baraldi Anna , Pierri Ivana , Cantaffa Renato , Martinelli Giovanni , Barulli Sara , Morabito Fortunato , Zinzani Pier Luigi , Spriano Mauro , Galieni Piero , Caremani Alessandra , Pietrini Alice , Cencini Emanuele , Tassi Maristella , Raspadori Donatella , Lauria Francesco 
Published: April 2020

Abstract
Hairy cell leukemia (HCL) is a rare B-cell neoplasm generally responsive to Cladribine. Cladribine is generally administered intravenously either as a continuous weekly infusion or as a 2-hour daily or weekly infusion for 7 days. Subcutaneous Cladribine is an alternative route with 100% bioavailability and with efficacy similar to intravenous 2CdA at the dose of 0.7 mg/kg/cycle. In indolent non-Hodgkin lymphomas other than HCL, reduction to 0.5 mg/kg/cycle determined equivalent efficacy and lower toxicity. In a national multicentre clinical trial (protocol EudraCT code: ICGHCL 2004), we have evaluated efficacy and toxicity of subcutaneous Cladribine given 0.1mg/kg/die for 5 (total dose 0.5 mg/kg, arm A) or for 7 days (total dose 0.7 mg/kg, arm B) as a single course in newly diagnosed HCL requiring treatment. Responses to treatment were assessed on day 60 and day 180 after treatment and defined according to the 1987 Consensus criteria. Complete Remissions (CR) and Partial Remissions (PR) were considered as beneficial responses, while minor Responses (mR) and No Responses (NR) were rated as treatment failures. Toxicity was assessed from day 0 to day 60 after treatment, according to the 2003 NCI/CTCAE v3 criteria. In this interim analysis, 92 of the 132 patients currently recruited (45 patients in arm A and 47 in arm B) were evaluated for toxicity and response to treatment. 2CdA was administered at the proposed regimen with no modifications in all patients. Eighty-five of 92 patients (92%) had a beneficial response to treatment (57/92 CR, 62%; 28/92 PR, 30%). The 7/92 treatment failures scored as 3/92 mR (3%) and 4/92 (5%) NR. Responses were equivalent in the two arms (p=0.7), with 41/45 (91%) beneficial responses (27/45 CR, 60%; 14/45 PR, 31%; 2/45 mR, 4% and 2/45 NR, 4%) in arm A versus 44/47 (94%) beneficial responses in arm B (30/47 CR, 64%; 14/47 PR, 30%; 1/47 mR, 2%; 2/47 NR, 4%). Overall grade 3–4 toxicity was recorded in 16/92 (17%) patients (8/92 FUO, 9%; 4/92 documented infections, 6%, 3/92 skin rashes, 3%; 1/92 hepatic toxicity, 1%) and appeared less frequent in arm A (4/45, 9%) than in arm B (12/47, 25%) (p=0.05). Analysis of distribution of toxicities in the two arms (arm A: 2/45 FUO, 4%; 0/45 documented infections; 1/45 skin rash, 1%; 1/45 hepatic toxicity, 1%; arm B: 6/47 FUO, 13%; 4/47 documented infections, 9%; 2/47 skin rashes, 4%) revealed a significantly lower frequency of FUO and infections in arm A (2/45, 4%) than in arm B (10/47, 22%) (p=0.02), to suggest a higher risk of infection in the 7 day regimen. The present data indicate that overall activity of subcutaneous 2CdA is similar to the intravenous formulation (Cheson, 1998). Furthermore, the current interim analysis suggests that subcutaneous 2CdA given at 25% reduced doses (0.5 mg/kg) has equivalent activity and lower toxicity than subcutaneous 2CdA at standard doses (0.7 mg/kg) and is easy to give in an outpatient setting.