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

Abstract

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.

Trial registration: ClinicalTrials.gov NCT00923013.

FIG 1.

Consort diagram. Sixty-eight patients were randomly assigned 1:1 to concurrent or delayed rituximab with cladribine. One and 22 patients in concurrent and delayed arms received a first course of delayed rituximab, respectively. Six patients received a second course of delayed rituximab in the delayed arm. Patients labeled as MRD-negative were minimal residual disease (MRD) free by all tests, blood and bone marrow aspirate (BMA) flow cytometry, and bone marrow biopsy immunohistochemistry. Patients labeled as blood MRD-negative were MRD-positive by BMA flow cytometry but negative by blood flow cytometry.

FIG 2.

Swimmer plot. Times after enrollment are shown when minimal residual disease (MRD) by flow cytometry was positive in both marrow and blood (red), positive in marrow but negative in blood (green), and negative in both (blue). Delayed rituximab courses are shown by diamonds. (A) Patients 24, 26, and 30 were MRD negative before the 6-month time point, and patients 7, 9, 10, 17, and 21 became MRD negative at the 6-month time point, making 8 patients in the delayed arm MRD negative by 6 months, as indicated in Table 2. (B) Patient 33 at 6 months was bone marrow biopsy negative, but bone marrow aspirate flow was unevaluable; the repeat at 8.7 months was negative, so it was included in the 6-month results.

FIG 3.

Kaplan-Meier curves showing minimal residual disease (MRD)-free survival. (A) After concurrent cladribine-rituximab (CDAR, blue) versus cladribine (CDA, red) monotherapy. (B) Thirty-four patients receiving concurrent CDAR (blue) versus 20 receiving CDA (red) becoming MRD free in blood by 6 months are compared for blood MRD-free survival. (C) MRD-free survival is shown for the 14 patients in the delayed arm achieving MRD-free complete remission after the first course of delayed rituximab (red), compared with the same group as in A receiving concurrent rituximab (blue). Two patients in the delayed arm became positive at similar times, 22.6 and 22.8 months after delayed rituximab. (D and E) Median neutrophil and platelet counts are shown for concurrent CDAR (blue) and delayed CDA (red) groups, with the first day of cladribine given on day 1. At each time point for D and E, 68 patients were evaluable, except 1 in the concurrent arm and 2 in the delayed arm on day 2, and 1 in the concurrent arm and 1 in the delayed arm each on days 3 and 15. Day 15 was ± 4 days. Median neutrophil and platelet counts for CDAR versus CDA arms were 0.96 versus 0.8 (P = .60) and 29 versus 70 (P < .0001) for day 2, 0.705 versus 0.842 (P = .67) and 47 versus 69 (P = .0028) for day 5, 0.634 versus 0.616 (P = .98) and 143 versus 113 (P = .062) for 2 weeks, and 1.339 versus 1.025 (P = .017) and 178 versus 130 (P = .0015) for 4 weeks.