Fludarabine and Rituximab (FR) Is a Safe and Effective Treatment Alternative for Relapsed or Refractory Hairy Cell Leukemia (HCL)
Authors: Gerrie Alina S. , Zypchen Leslie N. , Connors Joseph M. 
Published: October 2019

Abstract 2454

Background:
Purine nucleoside analogs have been shown to produce high remission rates of 75–90% when used as first-line monotherapy for HCL. Long-term studies have shown that remissions may be lasting but are not durable. Median progression-free survival is approximately 8 years. Fludarabine (F) is an attractive option for treatment of relapsed HCL due to its similar mechanism of action, the ability to administer multiple courses for repeated exposure and its oral bioavailability. Rituximab (R) has shown single-agent activity in HCL as well as synergy with fludarabine in vivo. In addition, clinical trials have demonstrated that FR is effective in other indolent B-cell lymphoproliferative disorders. We assessed the tolerability and efficacy of FR for relapsed or refractory HCL.

Patients and Methods:
The British Columbia Cancer Agency (BCCA) Lymphoid Cancer Database was searched to identify patients treated with FR for relapsed or refractory HCL (F 40 mg/m2/d orally d 1–5 [adjusted for renal function] and R 375 mg/m2 IV d 1, every 28 days for 4 cycles). All cases were centrally reviewed to exclude variant HCL and splenic marginal zone lymphoma.

Results:
252 patients with HCL were identified, of whom 90 developed progressive disease after initial therapy (36%). 13 patients were treated with FR between 2004–2009 for relapsed or refractory disease after first-line cladribine (n=2) or after multiple lines of therapy (n=11). Median age at FR was 59 years (range, 46–82 years); 85% of patients were male. Patients were heavily pre-treated with a median of 2 prior systemic treatments (range, 1–5). All patients had received at least 1 course of cladribine; 5 had received 2 courses (38%). Additional systemic treatments included interferon (n= 5, 38%) and deoxycoformycin (n= 4, 31%). A purine analogue was the therapy immediately prior to FR in all patients with cladribine in 11 (85%) and fludarabine alone in 2 (15%). 11 patients had a response to their last course of purine analog therapy, while 2 patients had refractory disease. FR therapy was administered at a median of 12.9 years from diagnosis (range, 3.4 –27.5) and at a median of 58 months from the last therapy (range, 2–155). Prior to FR therapy, the average interval between therapies was 46 months (range, 15–165). Median counts at time of FR were (data missing on 2 patients): hemoglobin 115 g/L (range, 79–145), white blood cell count 2.2 × 109/L (range, 0.9–8.6), lymphocyte count 1.0 × 109/L (range, 0.4–7.14), neutrophil count 1.09 × 109/L (range, 0.3–1.6), and platelets 98 × 109/L (range, 29–203). Patients underwent a median of 4 cycles of FR (range, 2–4) with oral fludarabine well tolerated in all cycles. Treatment was discontinued in 1 patient after 2 cycles due to a hypersensitivity reaction to rituximab and fludarabine was discontinued in 1 patient after 3 cycles due to the development of interstitial lung disease. The latter patient went on to receive a total of 6 rituximab infusions. Herpes zoster occurred in 2 patients, during and 6 months after completion of FR therapy, respectively. No patients required hospitalization during therapy. Information regarding response was available in 10 patients. All 10 patients had complete normalization of peripheral blood counts, absence of abnormal circulating lymphocytes and resolution of splenomegaly if present at initiation of FR. 3 patients had bone marrow biopsies at completion of therapy and all showed an absence of minimal residual disease by immunophenotyping. Currently, 12 patients (92%) remain in remission without further therapy while 1 patient has developed recurrent disease, 31 months after FR. With a median follow-up of 26 months from FR (range, 5–72), progression-free survival is 80% and overall survival 100%.

Conclusion:
In this multiply relapsed and heavily pre-treated group of patients with HCL, including patients previously exposed to purine analog therapy, the combination of oral fludarabine and rituximab was well tolerated, safe and effective. FR is a reasonable treatment option for patients with relapsed or refractory HCL.

Disclosures:
Off Label Use: Rituximab is being included because of previously documented phase II clinical trial activity against hairy cell leukemia.