Fludarabine and Rituximab (FR) Is a Safe

and Effective Treatment Alternative for

Relapsed or Refractory Hairy Cell
Leukemia (HCL)
Alina S. Gerrie, Leslie N. Zypchen and Joseph M. Connors
Blood 2010 116:2454;

Abstract
Abstract 2454
Background: Purine nucleoside analogs have been shown to produce high remission rates of
7590% 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 15 [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 20042009 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, 4682 years); 85% of patients were male. Patients
were heavily pre-treated with a median of 2 prior systemic treatments (range, 15). 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, 2155). Prior to FR therapy, the average interval
between therapies was 46 months (range, 15165). Median counts at time of FR were (data
missing on 2 patients): hemoglobin 115 g/L (range, 79145), white blood cell count 2.2
109/L (range, 0.98.6), lymphocyte count 1.0 109/L (range, 0.47.14), neutrophil count 1.09
109/L (range, 0.31.6), and platelets 98 109/L (range, 29203). Patients underwent a
median of 4 cycles of FR (range, 24) 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, 572), 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.

2010 by The American Society of Hematology