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Concurrent rituximab with cladribine enhances complete responses in untreated hairy cell leukemia
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CHICAGO — Rituximab administered concurrently with cladribine as first-line treatment of hairy cell leukemia appeared to induce more durable complete responses with no minimal residual disease compared with delayed rituximab administration, according to results of a phase 2 randomized study presented at ASCO Annual Meeting.
“Delayed rituximab achieved minimal residual disease-free complete responses but not as frequently or as durable as concurrent rituximab,” Dai Chihara, MD, PhD, fellow at NCI, said during the presentation. “Thrombocytopenia was common but [did not cause] significant bleeding. Platelets and neutrophils recovered more quickly [with concurrent therapy].”
Purine analog therapy with a single agent, typically cladribine, has been the standard first-line therapy for hairy cell leukemia for 30 years, according to researchers. Relapse is usually due to minimal residual disease (MRD), despite complete response.
Rituximab (Rituxan; Genentech, Biogen) has demonstrated the ability to clear MRD, but there is a lack of long-term data on how frequently or how long this occurs, or how often MRD remains after treatment with cladribine.
Chihara and colleagues randomly assigned 68 patients with untreated hairy cell leukemia to concurrent (n = 34) or delayed (n = 34) rituximab with cladribine.
Patients in the concurrent group received eight weekly IV doses of 375 mg/m2 rituximab with five daily IV doses of 0.15 mg/kg cladribine. Patients in the delayed group received the rituximab doses if or when MRD appeared in the blood or if disease-related cytopenias persisted 6 months or more after cladribine.
Determining whether the concurrent combination reduced MRD after 6 months compared with cladribine alone served as the study’s primary endpoint. Evaluating delayed rituximab administration served as a secondary endpoint.
Researchers assessed MRD in blood and bone marrow using flow cytometry, consensus polymerase chain reaction and immunohistochemistry.
Results showed that 6 months after initiating cladribine, 97% of patients in the concurrent group and 24% of patients in the delayed group had no MRD according to all tests (P < .0001).
Researchers noted that the one patient with MRD in the concurrent rituximab group was “unusual” in that they had a mixture of hairy cell leukemia and hairy cell leukemia variant cells at 6 months that were not in their pretreatment samples.
One patient in the concurrent group required a second course of rituximab for MRD after median follow-up of 87.3 months. Twenty-one patients in the delayed group required 27 courses of rituximab for MRD.
MRD-free complete remission was “more frequent and more durable with than without rituximab,” Chihara said, occurring in 33 patients after concurrent cladribine-rituximab vs. 11 after cladribine alone (HR = 0.035; P < .0001). After those in the delayed group received rituximab, rates MRD-free complete remission remained higher in the concurrent group (33 vs. 13; HR = 0.12; P =.0011).
“Delayed rituximab was effective, but both MRD-free rate and durability were higher with concurrent than with delayed rituximab”, Chihara said.
Median MRD-free survival after initial rituximab was not reached in the concurrent group, with 94% of patients demonstrating no MRD after a median of 72 months. Median MRD-free survival in the delayed group was 60.1 months with 10 patients (48%) still MRD-free (P < .0001).
In terms of safety, researchers noted that thrombocytopenia occurred more frequently among patients in the concurrent arm, both for all grades (68% vs. 9%) and grade 3 to grade 4 occurrences (59% vs. 9%; P < .0001). However, this occurred without significant bleeding, Chihara noted.
“Additional follow-up will determine if durable MRD-free complete response after cladribine and concurrent rituximab will lead to increased complete response duration, less need for additional therapy and cure of hairy cell leukemia,” Chihara said. – by John DeRosier
Reference:
Chihara D, et al. Abstract 7003. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.
Disclosures: Chihara reports no relevant financial disclosures. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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Andre Goy, MD, MS
Nucleoside analogs — particularly 2-chlorodeoxyadenosine or cladribine — have changed the outcomes for hairy cell leukemia. As single agents, they typically lead to high response rate, although relapses are not uncommon and attributed to MRD after chemotherapy induction. Rituximab has been known to have activity in hairy cell leukemia, although it remains unclear if it would be preferable to use rituximab with chemotherapy or post-chemotherapy as consolidation (in the stage of “already lesser disease” post-chemotherapy). A randomized phase 2 study presented at ASCO aimed at answering exactly this question.
This study, led by Dr. Chihara, enrolled 68 patients with untreated hairy cell leukemia, comparing the efficacy — including MRD monitoring — of cladribine with simultaneous rituximab starting the same day as five daily doses of cladribine or delayed rituximab, beginning if/when MRD was detected in peripheral blood lymphocytes (or if hairy cell leukemia-related cytopenias persisted preventing consideration of complete response 6 or more months after cladribine).
The results showed that concomitant rituximab led to a much higher MRD-negative status at 6 months (97% concurrent vs. 24% delayed; P < .0001). At a median follow-up of over 7 years, the MRD-free survival was 94% in the concomitant arm vs. 48% in delayed rituximab (P < .0001).
Although longer follow-up is needed to look at impact on survival, these suggest strongly that concomitant rituximab with cladribine allows for an earlier, deeper and likely more durable response, setting — I would argue — a new standard.
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