Long term follow-up of a phase II study of cladribine with concurrent rituximab with hairy cell leukemia variant

Abstract

Hairy cell leukemia variant (HCLv) responds poorly to purine analogue monotherapy. Rituximab concurrent with cladribine (CDAR) improves response rates, but long-term outcomes are unknown. We report final results of a phase 2 study of CDAR for patients with HCLv. Twenty patients with 0 to 1 prior courses of cladribine and/or rituximab, including 8 who were previously untreated, received cladribine 0.15 mg/kg on days 1 to 5 with 8 weekly rituximab doses of 375 mg/m2 beginning day 1. Patients received a second rituximab course ≥6 months after cladribine, if and when minimal residual disease (MRD) was detected in blood. The complete remission (CR) rate from CDAR was 95% (95% confidence interval, 75-100). Sixteen (80%) of 20 patients (95% confidence interval, 56-94) became MRD negative according to bone marrow at 6 months. The median duration of MRD-negative CR was 70.1 months, and 7 of 16 are still MRD negative up to 120 months. With a median follow-up of 69.7 months, 11 patients received delayed rituximab, and the 5-year progression-free survival (PFS) and overall survival (OS) were 63.3% and 73.9%, respectively. Five patients with TP53 mutations had shorter PFS (median, 36.4 months vs unreached; P = .0024) and OS (median, 52.4 months vs unreached; P = .032). MRD-negative CR at 6 months was significantly associated with longer PFS (unreached vs 17.4 months; P < .0001) and OS (unreached vs 38.2 months; P < .0001). Lack of MRD in blood at 6 months was also predictive of longer PFS and OS (P < .0001). After progression following CDAR, median OS was 29.7 months. CDAR is effective in HCLv, with better outcomes in patients who achieve MRD-negative CR. This trial is registered at www.clinicaltrials.gov as #NCT00923013.

Graphical abstract

Figure 1.

Survival outcomes and duration of response. MRD-negative CR duration is shown for 16 patients achieving MRD-negative CR with CDAR (A), and blood MRD-negative duration is shown for 17 patients becoming blood MRD-negative (B). OS and PFS are shown for all 20 patients (C), and OS after progression is shown for 8 patients who progressed (D). PFS (E) and OS (F) are shown for 5 patients with a TP53 mutation vs 14 patients without a TP53 mutation.

Figure 2.

Swimmer’s plot showing MRD status until last assessment and timing of delayed rituximab (◇), next treatment (▴), or death (×). Letters to the left of the swimmer’s plot indicate which patients had mutations in MAP2K (M), TP53 (T), or expressed unmutated IGHV4-34 immunoglobulin rearrangements (V). TP53 and MAP2K mutations are listed in Table 2. Patient #2 was not characterized molecularly. Patient #19 became MRD-negative in blood (blue) after delayed rituximab, just before date cutoff. BM, bone marrow.

Figure 3.

Survival outcomes by MRD status. Patients with HCLv achieving (n = 16, red) or not achieving (n = 4, blue) MRD-negative CR at 6 months are compared with respect to PFS (A) and OS (B). Similarly, PFS (C, E) and OS (D, F) are shown for patients who were blood MRD-negative (n = 14, red) vs positive (n = 5, blue) at 1 month (C, D), and blood MRD-negative (n = 17, red) vs positive (n = 3, blue) at 6 months (E, F). Patient #11 experienced progression at 4.1 months and is included in the analyses of PFS and OS curves based on results at 6 months because the patient was blood MRD positive at both 1 and 6 months. These 2 sets of analyses could have been done starting at 6 months after beginning treatment to ensure that the trait was considered at the start of the curves but doing so would have eliminated this patient from the PFS curves in panels A and E, and it was judged to be more important to show these full results.