Randomized Phase II Study of First-Line Cladribine With Concurrent or Delayed Rituximab in Patients With Hairy Cell Leukemia

Dai Chihara, MD, PhD; Evgeny Arons, PhD; Maryalice Stetler-Stevenson, MD, PhD; Constance M. Yuan, MD, PhD; Hao-Wei Wang, MD, PhD; Hong Zhou, BS; Mark Raffeld, MD; Liqiang Xi, MD; Seth M. Steinberg, PhD; Julie Feurtado, RN; Lacey James, CRNP; Wyndham Wilson, MD, PhD; Raul C. Braylan, MD; Katherine R. Calvo, MD, PhD; Irina Maric, MD; Alina Dulau-Florea, MD; Robert J. Kreitman, MD


J Clin Oncol. 2020;38(14):1527-1538. 

In This Article

Abstract and Introduction


Purpose: Single-agent purine analog, usually cladribine, has been the standard first-line therapy of hairy cell leukemia (HCL) for 30 years. High complete remission (CR) rates often include minimal residual disease (MRD), leading to relapse and repeated treatments. Rituximab can clear MRD, but long-term results are unknown and optimal timing of rituximab undefined.

Patients and Methods: Patients were randomly assigned to first-line cladribine 0.15 mg/kg intravenously days 1–5 with 8 weekly doses of rituximab 375 mg/m2 begun either day 1 (concurrent, CDAR) or ≥ 6 months later (delayed) after detection of MRD in blood. MRD tests included blood and bone marrow (BM) flow cytometry, and BM immunohistochemistry.

Results: Sixty-eight patients with purine analog-naïve classic HCL were randomly assigned 1:1 to concurrent versus delayed arms. At 6 months after CDAR versus cladribine monotherapy, CR rates were 100% versus 88% (P = .11), MRD-free CR rates 97% versus 24% (P<.0001, primary end point), and blood MRD-free rates 100% versus 50% (P < .0001), respectively. At 96 months median follow-up, 94% versus 12% remained MRD free. Compared with CDAR, delayed rituximab after cladribine achieved lower rate (67% of 21 evaluable patients; P = .0034) and durability (P = .0081, hazard radio favoring CDAR, 0.094) of MRD-free CR. Nevertheless, 12 patients in the delayed arm remained MRD free when restaged 6–104 (median, 78) months after last delayed rituximab treatment. Compared with cladribine monotherapy, CDAR led to brief grade 3/4 thrombocytopenia (59% v 9%; P < .0001) and platelet transfusions without bleeding (35% v 0%; P = .0002), but higher neutrophil (P = .017) and platelet (P = .0015) counts at 4 weeks.

Conclusion: Achieving MRD-free CR of HCL after first-line cladribine is greatly enhanced by concurrent rituximab and less so by delayed rituximab. Longer follow-up will determine if MRD-free survival leads to less need for additional therapy or cure of HCL.


Hairy cell leukemia (HCL) is an indolent B-cell neoplasm comprising 2% of leukemias, estimated at 1,100–1,240 new cases per year in the United States.[1,2] Standard first-line purine analogs cladribine or pentostatin achieve 75%-90% complete remission (CR) rates.[3–5] Relapse occurs at a median 4.5–16 years, depending on the population and whether follow-up includes bone marrow (BM) tests[6] or just blood counts.[3] Repeated courses of purine analogs achieve high but usually declining rates and durations of response, toxicity accumulates with retreat-ment, and evidence of cure is lacking.[3,4,7–9] Because median age at diagnosis is approximately 58 years,[10] most can expect to relapse, in many cases repeatedly, after first-line therapy, although follow-up is often too short to document this.

Rituximab has modest single-agent activity, with 13% CRs in relapsed HCL with cytopenias requiring treat-ment,[11] but when combined with purine analog it can increase CR rate and eliminate minimal residual disease (MRD).[12] Retrospective data showed second- to seventh-line purine analog-rituximab either concurrently in 20 or sequentially in 6 patients achieved 88% CR.[13] In a phase II study from MD Anderson Cancer Center, 8 weekly doses of rituximab 1 month after cladribine in 59 untreated patients achieved 100% CR and 95% 5-year failure-free survival.[14,15] MRD, assessed by BM aspirate (BMA) flow cytometry until 3 months after cladribine, just after completion of rituximab, was negative in 22 (76%) of 28 evaluable patients.[15]

In vitro, cladribine-rituximab synergy involved rituximab increasing the sensitivity of lymphoma/leukemia cells to cladribine.[16] However, cladribine is rapidly excreted,[17] the active intracellular 2-chlorodeoxyadenosine triphopsphate (CdATP) undetectable 48 hours after the last dose, and thus synergy cannot occur with rituximab begun more than several days after cladribine. We therefore tested concurrent cladribine-rituximab and compared with cladribine followed at least 6 months later by delayed rituximab if/when MRD was detected in blood. To determine whether eradication of MRD might require > 8 weekly doses of rituximab, both concurrent and delayed arms could receive a second rituximab course if MRD was detected in blood at least 6 months after the first.