Phase 2 trial of cladribine plus immediate rituximab for 1st-line treatment of hairy cell leukemia – long term follow-up of original and additional patient cohorts

Abstract Background: Hairy cell leukemia is a B-cell malignancy presenting with cytopenias and splenomegaly. It responds well to purine analogs cladribine (CDA) and pentostatin, but minimal residual disease (MRD) and relapses are common. Randomized 1st line data showed higher MRD-free CR rate using cladribine with (CDAR) vs without (CDA) concurrent rituximab (97% vs 24% at 6 months, 94% vs 32% long term, both p<0.0001). Published results from rituximab started 4 weeks after cladribine (CDA+R) include MRD-free CR rate 83/107 (78%) at 3-4 months. To validate the 94% MRD-free CR rate after CDAR, 25 additional patients received CDAR, and follow-up from the 34 randomized patients after CDAR updated. Reportedly, rituximab increases cell sensitivity to cladribine, resulting in ex vivo synergy; this would be possible after CDAR but not after CDA+R due to cladribine's short half-life. Patients and Methods Patients (N=25) with untreated HCL received CDAR, cladribine 0.15 mg/kg IV days 1-5 with 8 weekly doses of rituximab 375 mg/m2 begun day 1. Rituximab was given before cladribine on day 1 to compare to the 34 randomized CDAR patients who received cladribine before rituximab on day 1. MRD was assessed by blood and bone marrow aspirate (BMA) flow cytometry (FC, sensitivity 0.002% of cells) and bone marrow biopsy immunohistochemistry (IHC). As in the published CDAR trial, patients received one 8-week course of delayed rituximab if blood MRD was detected by FC >6 months after day 1. After beginning CDAR, blood was evaluated every 3 months for 1 year, semiannually until 2.5 years, then annually. Bone marrow was evaluated at 1, 6, 18 and 30 months, then every 2 years indefinitely. Patients treated with CDAR on the earlier randomized trial (N=34) were followed similarly. Results: Of 25 non-randomized patients after CDAR, 25/25 (100%) achieved CR, and 21/25 (86%) achieved MRD-free CR by 6 months. One patient achieved MRD-free CR by 1.5-years and another by 4.5-years, both repeatedly redemonstrating MRD-free CR thereafter. At 7.3-11.1 (median 9.0) years of follow-up, 23/25 (92%) patients achieved and remained in MRD-free CR, with median MRD-free survival of 9.0 years. One of 2 patients with MRD received delayed rituximab for blood MRD, which resolved blood but not BMA MRD for 3.5 years. No new safety signals were seen; 4/25 (16%) patients received prophylactic platelet transfusion on day 1-2 due to grade 4 thrombocytopenia. This was due to rituximab unrelated to cladribine, and no significant bleeding occurred. The order of rituximab and cladribine on day 1 had no impact on efficacy or toxicity. Regarding the 34-patient CDAR randomized cohort, 5.0-15.9 (median 13.4) year follow-up is now available. Three of 34 patients died of causes unrelated to HCL or CDAR, and 3 patients were lost to follow-up. The remaining 28 patients continue to be followed, including bone marrow studies for MRD. As previously reported, the 6-month MRD-free CR rate was 97%, and the 1 patient who relapsed at 1.5 years had >20 years of interferon treatment but was eligible since purine analog naïve. However, no other patients have relapsed from MRD-free CR, and all remaining 32 (94%) patients had MRD-free CR reconfirmed by the last bone marrow assessment. Interestingly, 3 patients had transient MRD; 1 patient became MRD+ at 10.5 years but negative at 12.5 and 14.5 years; 1 became MRD+ at 4.5 years but negative at 6.5, 8.5, 10.5, and 12.5 years; 1 became MRD+ at 2.5 years but negative at 4.5, 6.5, 8.5, and 12.5 years. Of the 59 total patients after CDAR, with 5.0-15.9 (median 11.5) years of follow-up, 55/59 (93%) patients remain MRD-free at the most recent assessment. Conclusion: First-line CDAR is highly effective for HCL, achieving MRD-free CR in 54/59 (92%) total patients at 6 months and 55/59 (93%) long term. The high MRD-free CR rate may be due to synergy of cladribine and rituximab starting the same day. Transient appearance of MRD which later resolved may be related to immune destruction. Thrombocytopenia on day 1-2 was a minor issue, and the randomized trial reported higher platelet (and neutrophil) counts after CDAR vs CDA probably due to more rapid bone marrow clearing. To evaluate the clinical importance of remaining MRD-free, patients after CDAR are being compared to patients in MRD+ CR after 1st line CDA or CDA+R to determine if there is a difference in progression free survival or time to next treatment.