Hairy cell leukemia (HCL) is a rare lymphoproliferative disease with specific morphologic and molecular features and excellent prognosis. Although high rate of complete response (CR) has been reported after treatment with purine analogs, expecially cladribine (2CDA), relapse may occur during follow-up. The aim of the study is to review the efficacy, safety, long term remission rate and overall survival (OS) in those patients (pts) that received 2CDA as first line treatment.
We retrospectively reviewed data of all HCL pts treated with 2CDA between March 1991 and May 2019 at 18 Italian Hematological centers. Among 553 pts reported, only 513 were evaluable because treated with 2CDA alone. Considering the clinical carachteristics, M/F ratio was 4.5 with a median age of 54 years (range 24-88) and ECOG 0 in 85% of cases. Splenomegaly and presence of circulating hairy cells recorded by morphology were reported in 241 (47%) and 138 (27%) pts, respectively. Thirty-seven (7%) pts presented with an infection. Other comorbidities were cardiovascular in 29 (6%) pts, a previous cancer or diabetes in 27 (5%) each, chronic hepatic disorders in 18 (3%), obstructive pulmonary disease in 16 (3%), chronic kidney disease in 3 (1%). Three hundred-thirty (64%) pts received 2CDA intravenously (253 as daily continuous infusion for 5-7 consecutive days and 77 as weekly infusion for 5-7 consecutive weeks) and 183 (36%) subcutaneously. Response criteria were defined as per recent consensus guidelines (Grever MR et al. Blood 2017). The overall response rate (ORR) was 83%: CR in 335 pts (65%) and partial response (PR) in 96 (19%); 40 (8%) pts obtained hematological improvement (HI) and in 42 (8%) no response was observed. Nine of 11 (82%) pts with HI and 18/25 (72%) non responders who received salvage therapy obtained a major response (fig. 1). A slightly higher hemoglobin value (12.4 vs 11.4 g/dl, p=0.044), a reduced frequency of circulating hairy cells (28.7% vs 31.8%, p=0.039), absence of palpable splenomegaly (p=<0.001) and a faster recovery of ANC (28 days vs 41 days, p= 0.006) were associated with CR compared to PR in univariable analysis. No differences in terms of quality and duration of response, infection rate and time to blood counts recovery were reported according to the 2 routes of administration. Among pts receiving intravenous 2CDA, ORR was 85% for continuous infusion and 78% for weekly infusion: no statistically significant difference could be observed. Median duration of response was 12.2 years: 75.1%, 53.6% and 45.5% of responding pts are expected to be free from relapse at 5, 10 and 15 years, respectively. A statistically significant difference in duration of response was identified between pts that obtained a CR compared to pts in PR (19.4 years versus 4.7 years, p<0.0001) (fig. 2). No other differences in relapse free survival (RFS) were identified. Non-hematological grade-3 or higher early toxicity was reported in 108 (21%) pts, due to infections in 102 cases (20%), mainly fever of unknown origin and pneumonia. In 6 cases infection due to invasive aspergillosis, bacteric pneumonia and bacteric sepsis caused the death of pts. Other non-hematological adverse events were almost all grade-1 allergy (47 pts, 9%). No late toxicity was reported, but 19 (4%) second cancers were observed. Among 118 pts relapsed after a median of 4.4 years (fig. 1), 85 (72%) were retreated with 2CDA, alone (65 cases) or associated with rituximab (20 cases); 11 (9%) with pentostatin, alone (7 cases) or associated with rituximab (4 cases), 8 (7%) with interferon α, 8 (7%) with rituximab alone, 1 (1%) with vemurafenib and zanubrutinib each; 2 were lost at follow-up and 2 died before retreatment. Overall, 58 (51%) retreated pts obtained a CR (42 after 2CDA), 37 (32%) a PR (32 after 2CDA), 7 (6%) a HI (4 after 2CDA) and 12 (11%) did not show any response (6 after 2CDA). Median OS was not reached; 95.7%, 92.8% and 82.3% of pts are expected to be alive at 5, 10 and 15 years, respectively (fig. 2). Overall 51 pts died (10%), during the induction phase in 6 cases and during follow-up in 45: overall, mortality was HCL-related in 14 patients (2 progression of disease and 12 infections) and HCL-unrelated in 37 patients (cardiovascular events in 16, natural causes in 15, a second cancer in 6).
2CDA is greatly effective in treating HCL, with an ORR of 83%. Early and long term adverse events were rare and easily managed: although HCL-related mortality is still possible, OS at 15 years is higher than 80%
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