For more than 30 years, the standard firstline treatment of hairy cell leukemia (HCL) has been single-agent purine analog therapy, usually cladribine, but a new study suggests that adding rituximab to firstline treatment could improve outcomes.
According to Dai Chihara, MD, PhD, from the National Cancer Institute’s Center for Cancer Research in Bethesda, Maryland, “rituximab can clear measurable residual disease (MRD), but there are no long-term data for how frequently and for how long this happens, or even how frequently MRD remains after cladribine.”
In a randomized phase II trial presented at the 2019 ASCO Annual Meeting, Dr. Chihara and researchers evaluated whether cladribine with concurrent or delayed rituximab could lead to higher rates of MRD negativity in patients with previously untreated HCL.
“Cladribine has a short half-life, so giving delayed rituximab would reduce synergy, so the potential advantage of the concurrent approach is synergy between the two agents,” Dr. Chihara said, outlining the benefits of each approach. On the other hand, “using the delayed approach might allow one to avoid rituximab altogether.”
Investigators randomized a total of 68 patients 1:1 to receive cladribine with either concurrent or delayed rituximab:
- In the concurrent group, patients received cladribine (0.15 mg/kg on days 1-5) and eight weekly infusions of rituximab 375 mg/m2 that were started on the same day as cladribine treatment.
- In the delayed group, patients received cladribine (0.15 mg/kg on days 1-5) for 6 months. If MRD was detected after cladribine treatment (or if HCL-related cytopenias persisted and prevented consideration of complete response [CR]), patients received eight weekly infusions of rituximab 375 mg/m2.
Participants’ median age was 48 years and baseline characteristics were similar between the groups, except for higher baseline hemoglobin in the delayed group.
MRD was assessed in peripheral blood and bone marrow using flow cytometry, polymerase chain reaction testing, and immunohistochemistry. The study’s primary endpoint was reduction in MRD at six months, while secondary endpoints included testing the efficacy of delayed rituximab.
At six months after cladribine initiation, 97% of patients in the concurrent rituximab group were MRD-negative on all tests, compared with 24% of patients in the delayed rituximab group (p<0.0001).
After a median follow-up of 7.7 years (range = 5-10 years), only one patient who received concurrent rituximab eventually required delayed rituximab, while 21 patients in the delayed group received 27 courses of rituximab.
In the concurrent rituximab group, MRD-free survival was not reached, with 32 patients still MRD-free after a median of 72 months of follow-up, for an MRD-free survival rate of 94%.
However, in the delayed group, patients’ median MRD-free survival was 60.1 months, with only 10 patients (48%) still MRD-free (hazard ratio = 0.09 for concurrent rituximab; p<0.0001).
“Patients who received delayed rituximab were able to achieve MRD-free CRs, but [these responses] were not as frequent and durable” as with concurrent rituximab, Dr. Chihara noted.
“As expected, the most common toxicities were hematologic,” Dr. Chihara said. Of note, thrombocytopenia was higher in the concurrent group (n=23; 68%), but this was not associated with any significant bleeding events.
Based on these results, the authors concluded that “achievement of MRD-free CR after firstline cladribine … is greatly enhanced by concurrent rituximab.”
The findings of this study are potentially limited by the small number of enrolled patients, and the authors noted that longer follow-up is needed to determine if achieving longer-term MRD-free survival can reduce the need for additional therapy.
The authors report no relevant conflicts of interest.
Chihara D, Arons E, Stetler-Stevenson M, et al. Randomized phase II study of cladribine with simultaneous or delayed rituximab in patients with untreated hairy cell leukemia. Abstract #7003. Presented at the 2019 ASCO Annual Meeting, June 1, 2019; Chicago, IL.