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; minimal residual disease; ofatumumab; trogocytosis.

Figures

Fig 1.

Consort diagram Patients were risk stratified twice: first, to different induction regimens based on hierarchical FISH cytogenetics at baseline and, second, to consolidation ofatumumab based on MRD status after induction therapy. Deletion 17p and deletion 11q were considered as high-risk FISH categories. Abbreviations: FCO, fludarabine, cyclophosphamide, and ofatumumab; FO, fludarabine and ofatumumab; MRD, minimal residual disease; N, number of patients; Ofa, ofatumumab.

Fig 2.

Kaplan-Meier estimates of progression-free survival (PFS) (A) PFS of the high-risk group treated with FCO for induction and the standard-risk group treated with FO. (B) PFS by peripheral blood MRD status after completion of induction therapy. The x axis is time from the MRD assessment. (C) PFS stratified by IGHV mutational status. Abbreviations: FCO, fludarabine, cyclophosphamide, ofatumumab; FO, fludarabine, ofatumumab; M, mutated immunoglobulin heavy chain variable region gene (IGHV); U, unmutated IGHV; MRD, minimal residual disease;

Fig 3.

Peripheral blood minimal residual disease (MRD) (A) MRD at pre-treatment (Pre), after 3 cycles of induction (p3C), after completion of induction (p6C), and at 2 years since treatment initiation (2Y). (B) MRD dynamics in patients who were MRD positive (MRD+) after induction. (C) MRD dynamics in patients who achieved MRD negativity (MRD−) after induction. Abbreviation: pre ofa1, before dose #1 of consolidation ofatumumab; pre ofa 2, before dose #2 of consolidation ofatumumab; pre ofa 3, before dose #3 of consolidation ofatumumab; pre ofa 4, before dose #4 of consolidation ofatumumab; Y, years since treatment initiation.

Fig 4.

CD20 antigen loss and ofatumumab clearance (A) Bone marrow biopsy of a patient who was minimal residual disease positive (MRD+) after induction. H&E and immunohistochemistry stains for CD79a and CD20 are shown in bone marrow specimens collected at pre-treatment (Pre CIT), after 3 cycles of induction (p3C) and after completion of induction (Post CIT). Magnification of the left panel is 10x, and the right panel, 20x. (B) Baseline CD20 antibody binding capacity (ABC) measured by flow cytometry. Patients subdivided by the post-induction MRD status. Black solid lines indicate median. Dashed lines indicate quartiles. P, Wilcoxon rank-sum test. (C) Sequential changes of CD20 ABC in 18 patients in the MRD + group. A grey dashed line indicates limit of detection for CD20 ABC, set at 100. Values for CD20 negative samples are set at 80 for graphing. The number of patients with detectable CD20 (positive) or undetectable CD20 (negative) at each time point are shown. Results of Wilcoxon matched-pairs signed-rank tests between baseline and on-treatment time points are indicated. Comparison of CD20 ABC at baseline vs. C2–C4 and post C4 was significant and not shown (P