Risk-adapted, ofatumumab-based chemoimmunotherapy and consolidation in treatment-naïve chronic lymphocytic leukemia: a phase 2 study

Abstract

High-risk cytogenetics and minimal residual disease (MRD) after chemoimmunotherapy (CIT) predict unfavorable outcome in chronic lymphocytic leukemia (CLL). This phase 2 study investigated risk-adapted CIT in treatment-naïve CLL (NCT01145209). Patients with high-risk cytogenetics received induction with fludarabine, cyclophosphamide, and ofatumumab. Those without high-risk cytogenetics received fludarabine and ofatumumab. After induction, MRD positive (MRD+) patients received 4 doses of ofatumumab consolidation. MRD negative (MRD-) patients had no intervention. Of 28 evaluable for response, all responded to induction and 10 (36%) achieved MRD-. Two-year progression-free survival (PFS) was 71.4% (CI₉₅, 56.5–90.3%). There was no significant difference in median PFS between the high-risk and the standard-risk groups. Ofatumumab consolidation didn’t convert MRD + to MRD-. In the MRD + group, we saw selective loss of CD20 antigens during therapy. In conclusion, risk-adapted CIT is feasible in treatment-naïve CLL. Ofatumumab consolidation didn’t improve depth of response in MRD + patients. Loss of targetable CD20 likely reduces efficacy of consolidation therapy.

Keywords:

• Chronic lymphocytic leukemia
• chemoimmunotherapy
• trogocytosis
• minimal residual disease
• ofatumumab

Acknowledgements

We thank patients who participated in this trial and their families. We thank Adriana Byrnes, Stephanie Housel and Ovsanna Melikyan for protocol support. The current affiliation of MZF is Merck & Co., Inc., Kenilworth, NJ, USA. MZF was an employee of the National Institutes of Health, Bethesda, MD while contributing to this study. IEA received research support from the American Society of Hematology Scholar Award. There are no other conflicts of interest. Novartis provided the study drug for the trials included in this study. MZF is employed by Merck, owns stocks and has received travel support from Merck. AW received research support from Pharmacyclics LLC, an AbbVie Company, and Acerta LLC, a member of the AstraZeneca Group.

Author contributions

CM, RPT, and AW designed the trial. CM, AW, MZF, and IEA conducted the clinical trial. JV, JL, CP, CS, JS and GEM evaluated patients and collected data. SS and PN provided research nurse support. EMG, MAL, RPT performed measurements and analyzed data. CM, SD, AW, MZF, IEA and CN collected data. EMG and SEMH coordinated laboratory analysis. DCD, SD, CM, IEA and AW analyzed data and drafted the report. MS and CMY analyzed flow cytometry. IM and LW evaluated bone marrow biopsies. TEH provided pharmacy support. XT performed statistical analysis. All authors reviewed and approved the manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

The study was funded by the Intramural Research Program of the National Heart, Lung, and Blood Institute at the National Institutes of Health.