In chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) partial response (PR) category is heterogeneous and complex to evaluate and includes patients with varying outcomes.1 Changes in clinical staging (Binet, Rai) have been proposed as a method to evaluate response in CLL.2,3 Ibrutinib (ibr), a first-in-class, once-daily inhibitor of Bruton’s tyrosine kinase, is indicated by the FDA for the treatment of patients with CLL/SLL and allows for treatment without chemotherapy. Robust improvements in progression-free survival (PFS) and overall survival (OS) among ibr-treated patients in the phase 3 RESONATE trial demonstrated superiority of ibr over ofatumumab (ofa) in heavily pretreated CLL, regardless of prognostic features.4 Since the majority of ibr patients achieved iwCLL PR or PR with lymphocytosis (PR-L) manifested by improved hematologic function and/or disease burden, both of which are factors that define clinical stage, Moreno and colleagues analyzed RESONATE patients to determine if changes in Binet stage distinguish clinically meaningful outcomes in CLL patients treated with ibr who attained iwCLL PR/PR-L.
Among 391 previously treated CLL patients randomized to receive oral ibr (n = 195) or intravenous ofa (n = 196), those who achieved a best overall response of PR or PR-L on ibr (n = 162) were assessed for Binet stage at time of first response. Stage A was defined as no anemia or thrombocytopenia and <3/5 sites of involvement (unilateral or bilateral cervical, axillary, and inguinal lymph nodes, liver, spleen); stage B as no anemia or thrombocytopenia and ≥3/5 involved sites; and stage C as anemia (hemoglobin <10 g/dL) and/or thrombocytopenia (platelets <100,000/µL) regardless of lymph node/organ-site involvement.
A total of 162 (83%) ibr patients and 45 (23%) ofa patients achieved PR/PR-L as best overall response as assessed by the investigator; 53% of ibr responders were PR and 46% were PR-L at first response. A majority of PR/PR-L ibr patients were downstaged to stage A reflecting improvement in lymphadenopathy/organomegaly and/or cytopenias with treatment. At time of first PR/PR-L, the proportion of stage C patients decreased from 44% (n = 72) at baseline to 27% (n = 44) for the ibr arm and from 42% (n = 19) to 33% (n = 15) for the ofa arm. While maintaining PR/PR-L, 48% of ibr-treated and 40% of ofa-treated patients shifted from stage C to A (or to B/A). The efficacy of ibr over ofa in PR/PR-L patients was similar to that observed in the intent-to-treat population for median PFS (not reached [NR] for ibr vs 8.48 months for ofa; P<0.0001). A treatment effect between ibr versus ofa was also observed for duration of response (DOR) in PR/PR-L patients (NR for ibr vs 5.52 months for ofa; P<0.0001). Responders with PR/stage A showed a longer PFS outcome than responders with PR/stage C at time of first response to ibr (P=0.0314). Within the ofa arm, no difference in PFS between PR/stage A versus PR/stage C was observed, although a limited sample size of responders prohibits robust analysis of this arm. For the ibr arm, both OS (P=0.0281) and DOR (P=0.0431) suggest a trend for improved outcome for PR/stage A versus PR/stage C.
These results suggest that Binet staging (A vs C) may distinguish survival outcomes with the iwCLL PR response category, and that changes in clinical stage can break down the PR/PR-L (iwCLL) category into different, clinically meaningful subgroups, and reinforces the notion that improving cytopenias is a desirable goal of CLL therapy with ibr. Altogether, this study demonstrates that changes in clinical stage largely reflected by the presence or absence of cytopenias could be a useful and cost-effective method to evaluate treatment response at different time points over the course of the disease.
Moreno C, et al. ASH 2016. Abstract 4384.
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