A Randomized Phase 2 Trial of 2nd-Line Cladribine with Concurrent or Delayed Rituximab in Patients with Classic Hairy Cell Leukemia

Background: Hairy cell leukemia is a B-cell malignancy characterized by pancytopenia, splenomegaly, and long-term remissions to purine analogs cladribine (CDA) and pentostatin, but late relapses occur, presumably from minimal residual disease (MRD). For nearly 35 years, CDA monotherapy has been standard 1st and 2nd line therapy. Other agents are increasingly being used in 2nd line, including concurrent or delayed rituximab. Randomized 1st line data indicate a trend for higher CR rate (100% vs 88%) and much higher MRD-free CR rate (97% vs 24%, p<0.0001) using cladribine with (CDAR) vs without (CDA) concurrent rituximab. Randomized 2nd line data are not reported, but prospective 2nd-line data showed high CR and MRD-free CR rates (100% and 64%, n=14) when rituximab was begun 4 weeks after 2nd-line cladribine. We completed a randomized trial of 2nd line CDAR vs CDA in 62 patients with once-relapsed HCL. Similar to the 1st line randomized trial, all patients could receive up to 2 courses of rituximab to eliminate MRD detected in blood, with delayed rituximab begun at least 6 months after beginning the previous course of CDA or rituximab.

Patients and Methods: Patients with relapsed HCL after initial purine analog were randomized to CDAR (2nd line cladribine 0.15 mg/kg intravenously days 1-5 with 8 weekly doses of rituximab 375 mg/m² begun on day 1) or CDA alone. MRD was assessed by blood and bone marrow aspirate (BMA) flow cytometry (FC, sensitivity 0.002% of cells) and bone marrow biopsy immunohistochemistry (IHC). If blood MRD was detected by FC after 6 months, patients could receive delayed rituximab, one 8-dose course for those after CDAR, and up to 2 courses for those after CDA. After beginning each course of CDAR, CDA or delayed rituximab, blood was evaluated every 3 months for a year, then every 6 months until 2.5 years, then annually. Bone marrow was evaluated at 1, 6, 18 and 30 months, and then every 2 years. CR required resolution of enlarged spleen and lymph nodes, morphologic resolution of blood and bone marrow disease, and resolution of cytopenias to neutrophils >1.5/nL, hemoglobin >11 g/dL, and platelets >100/nL, unless patients were MRD-free by all tests.

Results: Sixty-two patients, each with 1 prior course of CDA (n=60) or pentostatin (n=2), were randomized to either CDAR (n=32) or CDA (n=30). At 4 weeks posttreatment, CR rates were 50% vs 20% (p=0.018), and MRD-free CR rates were 38% vs 0% (p=0.0001). By 6 months (prior to delayed rituximab), CR rates were 91% vs 73% (p=0.10) and MRD-free rates were 63% vs 3% (p<0.0001). With subsequent resolution of MRD without delayed rituximab, MRD-free CR rates after CDAR vs CDA improved to 72% vs 10% (p<0.0001). Before delayed rituximab, relapse-free survival (RSF) was not different for CDAR vs CDA, with relapses in 3 of 29 vs 5 of 22 from CR (median not reached vs 157 months, p=0.29), and 5 of 23 vs 1 of 3 from MRD-free CR (medians both not reached, p=0.86). A first course of delayed rituximab was given 6.5-104 (median 16.3) months after CDAR (n=9) and 6.2-44 (median 7.9 months) after CDA (n=23). After 1 course of delayed rituximab, CR was observed in 8 (89%) of 9 CDAR vs 21 (91%) of 23 CDA patients, and MRD-free CR in 2 (22%) of 9 vs 8 (35%) of 23. Ten patients received a 2nd course of delayed rituximab after CDA and 6-91 (median 56) months after the 1st delayed rituximab course, with CRs in 8 of 10 and MRD-free CR in 1 of 10. At 7.0-182 (median 113) months of follow-up after CDAR vs CDA including delayed rituximab, 100% vs 90% (p=0.11) achieved CR and 75% vs 60% (p=0.28) MRD-free CR, without significant differences in RFS for these CRs. Two after CDAR vs 4 after CDA (p=0.42) progressed and required alternative therapy, several of whom remain MRD-free after moxetumomab pasudotox with rituximab.

Conclusion: In once-relapsed HCL, like untreated HCL, CDAR compared to CDA trended towards a higher CR rate and achieved a much higher MRD-free CR rate. However, delayed rituximab after CDAR and CDA improved rates and durations of response to similar levels. This differs from untreated HCL, where MRD-free CR remained higher after CDAR than after CDA even after delayed rituximab. It is possible that CDA has less synergy with rituximab once CDA is already used. Thus, CDA with delayed rituximab at >6 months if/when blood becomes MRD-positive is still reasonable 2nd line treatment of HCL. Delayed rituximab is now being tested to eliminate MRD in patients who achieve MRD-positive CR to MEK +/- BRAF inhibition.