Ofatumumab is active in patients with fludarabine-refractory CLL irrespective of prior rituximab: results from the phase 2 international study

Incorporation of CD20 monoclonal antibody (mAb) has significantly advanced treatment for patients with chronic lymphocytic leukemia (CLL). Improved outcomes were demonstrated with the addition of the CD20 mAb rituximab to fludarabine-based therapy, both in frontline and relapsed settings,^1-5  including improved overall survival (OS) in the frontline setting with combined fludarabine, cyclophosphamide, and rituximab (FCR).⁵  Monotherapy with standard dose and schedule of rituximab has limited efficacy, especially in relapsed/refractory CLL.^6,7  A large number of patients in the United States receive rituximab either as monotherapy or in combination with fludarabine-based chemotherapy in both frontline and relapsed/refractory settings⁸ ; refractoriness to CD20 mAb in CLL is poorly defined. Moreover, no data are currently available regarding treatment outcomes with other CD20 mAbs in CLL patients previously treated with rituximab or refractory to their last rituximab-containing regimen.

Refractoriness to fludarabine or alemtuzumab was defined as failure to achieve at least partial remission to the last regimen or relapse within 6 months of treatment, including combinations. The prognosis for patients with fludarabine-refractory CLL was poor, with low response rates and short progression-free survival (PFS) and OS.^9,10  Outcomes were worse for patients also refractory to alemtuzumab, the CD52 mAb approved for fludarabine-refractory CLL.^9,10 

Ofatumumab is a human CD20 mAb with single-agent activity in refractory CLL. In the interim analysis of the pivotal international trial in patients with fludarabine- and alemtuzumab-refractory (FA-ref; n = 59) CLL or fludarabine-refractory CLL with bulky (> 5 cm lymph nodes) lymphadenopathy (BF-ref; n = 79), the overall response rate (ORR) with ofatumumab was 58% and 47% in the FA-ref and BF-ref groups, respectively.¹¹  Median PFS and OS were 5.7 months and 13.7 months for the FA-ref group, and 5.9 months and 15.4 months for the BF-ref group, respectively.¹¹  Based on these results, ofatumumab was approved by the United States Food and Drug Administration and European Medicines Agency for FA-ref CLL.^12,13  Ofatumumab binds to a distinct epitope composed of the small and large loop domains of CD20, with more effective in vitro complement-dependent cytotoxicity^14-16  in cell lines and primary CLL cells with low CD20 expression. Therefore, resistance to rituximab may not translate into resistance to ofatumumab in CLL. A posthoc analysis of the pivotal study was performed to potentially gain perspective into whether prior exposure and refractoriness to rituximab correlated with ofatumumab treatment outcomes.

All patients provided signed consent at enrollment. Protocol, amendments, consent forms, and patient information were approved by health authorities and local independent ethics committees or institutional review boards. The study was conducted in accordance with Guidelines for Good Clinical Practice and ethical principles of the Declaration of Helsinki and was registered at Clinical Trials.gov (NCT00349349). Inclusion and exclusion criteria were previously reported; all cases were confirmed CD20⁺ at enrollment.¹¹  All patients were to receive 8 weekly, then 4 monthly, intravenous infusions of ofatumumab (dose 1, 300 mg; doses 2-12, 2000 mg). The primary end point was ORR assessed by an Independent Endpoint Review Committee (1996 National Cancer Institute Working Group criteria).¹⁷  Secondary endpoints included PFS, OS, and safety (based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0).¹¹  Final enrollment (n = 206) for this analysis included all patients from the interim analysis (n = 138) and an additional 68 patients (36 FA-ref; 32 BF-ref).¹⁸  Median follow-up was 25.8 months. Patients were categorized into subgroups according to prior rituximab exposure: rituximab-naive; refractory to last rituximab therapy (defined as no response or response duration ≤ 6 months from last rituximab-containing regimen); number of prior rituximab-containing regimens; type of prior rituximab regimen (monotherapy vs combination therapy); duration from last rituximab regimen and start of ofatumumab treatment (categorized by median of 10 months); and time to progression after last rituximab-containing regimen (categorized by median of 3 months). The ORR with 95% confidence interval (CI) was determined for each subgroup; proportion of responders was compared by Fisher exact test. Median PFS and OS by subgroup were evaluated using Kaplan-Meier estimates; survival plot comparisons were made by a 2-sided log-rank test. Descriptive statistics were used for pretreatment characteristics and adverse events.

Among 206 patients (FA-ref, n = 95; BF-ref, n = 111), 117 received prior rituximab monotherapy or rituximab-containing therapy and 89 were rituximab-naive. There were no statistically significant differences in the proportion of patients with Rai high-risk (III or IV) disease, bulky lymph nodes (> 5 cm), 17p del, 11q del, or alemtuzumab refractoriness between patients previously treated with rituximab versus rituximab-naive patients (Table 1). The prior rituximab subgroup had a higher proportion of patients with poorer Eastern Cooperative Oncology Group Performance Status (1 or 2 vs 0; P = .027) and was more heavily pretreated (median prior treatments 5 vs 4; P < .001) compared with the rituximab-naive subgroup.

The ORR with ofatumumab for all patients (n = 206) was 47% (95% CI, 40%-54%) and 43% (95% CI, 34%-52%) for the prior rituximab subgroup (n = 117) versus 53% (95% CI, 42%-63%) for the rituximab-naive subgroup (n = 89; Table 2). There was slightly longer median progression-free survival (mPFS) after ofatumumab for rituximab-naive patients compared with patients previously treated with rituximab (5.6 vs 5.3 months, respectively, P = .04), and no difference in ORR or median overall survival (OS). Of patients with prior rituximab exposure, type of last rituximab-containing therapy (eg, monotherapy or combination regimen), refractoriness to last rituximab regimen, and time to progression from the last rituximab regimen did not appear to impact ORR, mPFS, or mOS with ofatumumab treatment (Table 2). Longer duration between last rituximab regimen and initiation of ofatumumab was associated with longer mOS (P = .024), although it was not associated with a significant difference in ORR or mPFS (Table 2). This probably reflects greater proliferative activity and disease refractoriness for patients with the shorter treatment-free interval. Furthermore, among patients with prior rituximab, those previously treated with FCR (n = 54) had shorter mPFS compared with patients who had not received prior FCR (n = 63; 4.6 vs 5.5 months, respectively; P = .23), potentially reflecting the proliferative nature and aggressiveness of disease relapsing after a more intensive chemoimmunotherapy regimen. There were no significant differences between ORR or mOS in these comparisons (data not shown).

Rituximab can be detected in plasma up to 6 months after treatment in indolent non-Hodgkin lymphoma.¹⁹  In addition, loss of CD20 expression and depletion of complement after rituximab treatment have been reported in CLL patients.²⁰  In this study, all patients must have had documented CD20 expression to be eligible for treatment.²⁰  Importantly, ORR, PFS, and OS for patients considered refractory to last rituximab regimen were similar to outcomes for patients previously treated with, but not refractory to, rituximab, and similar to outcomes for rituximab-naive patients (Table 2), suggesting that killing of CLL cells via anti-CD20 mAb activity was maintained with ofatumumab in patients with rituximab-refractory disease.

Safety outcomes by prior rituximab are shown in Table 1. Interestingly, the proportion of grade 1 or 2 ofatumumab-related infusion reactions was higher for patients previously treated with rituximab than for rituximab-naive patients. However, the incidence of worst-grade infusion reactions and grade ≥ 3 hematologic toxicities were similar between subgroups. Infectious events were the most common nonhematologic ≥ grade 3 adverse events, which was expected for this heavily pretreated, treatment-refractory population. The proportion of patients who experienced ≥ grade 3 infections did not differ between subgroups. The safety profile of the prior rituximab subgroup was consistent with that reported in the overall study.¹⁸  Thus, prior exposure to rituximab did not seem to correlate with the toxicity profile of ofatumumab in this patient population.

In conclusion, ofatumumab monotherapy is effective and well tolerated in patients with fludarabine-refractory CLL, irrespective of previous exposure to rituximab-containing therapy. Because this analysis was done post hoc and the pivotal trial was not designed or powered to address comparisons of outcomes for patients previously treated with rituximab versus rituximab-naive patients, these observations merit confirmation in a prospective phase 3 clinical trial.

The authors thank the patients and the investigators in the Hx-CD20-406 Study Group for their participation. The authors also thank the Independent Endpoint Review Committee: T. Lin, Columbus, OH; M. Keating, Houston, TX; N. Kay, Rochester, MN; A. M. Dalseg, Herlev, Denmark; and L. M. Pedersen, Odense, Denmark.

Ofatumumab is codeveloped by Genmab A/S and GlaxoSmithKline. The study was cosponsored by Genmab A/S and GlaxoSmithKline. Editorial support in the form of data listing review and data compilation, development and revision of outline, development of initial manuscript draft under the direction of first author, referencing, and development of tables was provided by Nancy Goldstein (GlaxoSmithKline, Research Triangle Park, NC) and Jennifer Phillips (GlaxoSmithKline, Collegeville, PA). Editorial support in the form of development of outline, collation of author comments, copyediting, and referencing was provided by Samantha Taylor, PhD, Scientific Director, Medicus International New York, and funded by GlaxoSmithKline.

Contribution: G.W.C., S.L., A.Ö., and W.G.W. conceived and designed the study; A.Ö., S.P., and W.G.W. provided study materials or patients; G.W.C., I.V.G., and W.G.W. collected and assembled data; G.W.C., I.V.G., A.Ö., S.P., and W.G.W. analyzed and interpreted data; G.W.C., I.V.G., S.L., A.Ö., and W.G.W. prepared the manuscript; and all authors approved the final manuscript.

Conflict-of-interest disclosure: G.W.C. and I.V.G. are employees of, and hold stock in, GlaxoSmithKline. S.L. is an employee of, and has consulted or advised for, Genmab A/S. A.Ö. has advised for, and has received research funding and honoraria from, GlaxoSmithKline. S.P. has consulted or advised for, and has received honoraria from, GlaxoSmithKline. W.G.W. has received research funding from GlaxoSmithKline.

A complete list of the Hx-CD20-406 Study Investigators appears in the supplemental Appendix (available on the Blood Web site; see the Supplemental Materials link at the top of the online article).

Correspondence: William G. Wierda, The University of Texas, M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 428, Houston, TX 77030; e-mail: wwierda@mdanderson.org.