Anti-CD20 monoclonal antibodies (mAb) are an essential component of CLL therapy. Addition of anti-CD20 mAb to induction chemotherapy improves progression-free survival (PFS) and overall survival (OS) in treatment-naïve CLL. Patients who achieve minimal residual disease negativity (MRD-) after induction chemoimmunotherapy (CIT) have prolonged PFS and OS. It is unclear, whether an extended therapy with an anti-CD20 mAb after induction CIT can improve the depth of response and long-term outcomes in patients with detectable residual disease (MRD+). Here we report results from a phase II study using risk-adapted, ofatumumab-based CIT induction followed by ofatumumab maintenance in treatment-naïve CLL patients. (NCT01145209)
Treatment-naïve CLL patients were stratified twice: first, based on pre-treatment FISH, and second, based on post-induction peripheral blood (PB) MRD status. Patients with high-risk FISH (17p or 11q deletion) received up to 6 cycles of fludarabine, cyclophosphamide and ofatumumab (FCO). Patients without high-risk FISH received fludarabine, and ofatumumab (FO). Ofatumumab was dosed at 300mg for the first cycle, and 1000mg for subsequent cycles. After induction, patients were re-stratified based on PB MRD status using flow cytometry. MRD- was defined <10-4 CLL cells. MRD+ patients after CIT received 4 doses of ofatumumab as maintenance therapy while those with MRD- were observed without intervention. The primary endpoint was PFS at 2 years since starting the induction. We quantified the surface expression of CD20 and CD22 by using antibody binding capacity (ABC) of PB CLL cells in flow cytometry (QuantiBRITETM, BD Biosciences, San Jose, CA) and CD20 and CD79 expression in bone marrow (BM) CLL cells by using immunohistochemistry. We measured ofatumumab concentrations at pre-treatment; 2, 6, and 24 hours after the first dose of ofatumumab; after each ofatumumab dose during cycle 2 to 4; and after completion of induction CIT.
We enrolled 32 patients. Twenty-eight patients received 3 or more cycles of induction CIT and were evaluable for outcomes. The overall response rate was 100%, including 8 (28.6%) patients achieving a complete response. The median PFS was 42.8 months and was significantly longer for patients who achieved MRD- after induction CIT compared to those with MRD+ (Not reached vs 36.2 months, p<0.009). There was no statistically significant difference in PFS between the group with high-risk FISH treated with FCO vs. the non-high-risk group treated with FO (57.8 vs 39.2months, p=0.4). Additional doses of ofatumumab did not improve the depth of response as none of the MRD+ patients became MRD- after ofatumumab maintenance. However, ofatumumab kept CLL in control and none of the patients progressed during maintenance. After completion of maintenance ofatumumab, PB MRD levels increased with a mean doubling time of 5.37 months. At a median follow up of 43 months, 11 (61%) patients in the MRD+ group progressed.
Antigen loss through Fc-gamma receptor-mediated uptake of antibody-antigen complexes into effector cells, referred to as trogocytosis, allows tumor cells to escape antibody-dependent cytotoxicity. At the same time, trogocytosis contributes to rapid clearance of circulating mAb. Investigating whether residual cells still expressed CD20, we measured expression of CD20 on CLL cells at the end of CIT. Most residual CLL in PB showed virtually complete loss of CD20 expression. We also stained BM biopsies obtained after 3 and 6 cycles of CIT for CD20 confirming absent or markedly reduced CD20 expressions on residual CD79+ CLL cells. In addition, the median trough level of ofatumumab on day 28 of each cycle increased with each advancing cycle (0, 13, and 51 mcg/mL after cycle 1, 2, and 3, respectively). Similarly, clearance of ofatumumab below the limit of detection (< 0.5mcg/mL) was observed in 60% of patients after the initial dose, and only 20% after cycle 3.
Scaling intensity of CIT to genetic risk profiles achieved comparable outcomes for high-risk and standard-risk patients. MRD- remissions were associated with superior PFS, irrespective of the induction CIT regimen used. Maintenance therapy with ofatumumab did not improve the depth of response in MRD+ patients. Antibody induced antigen loss on tumor cells limits the efficacy of anti-CD20 mAbs even in settings with low tumor burden.
Farooqui:Merck: Employment. Lindorfer:Genmab: Research Funding. Wiestner:Pharmayclics: Research Funding; Acerta: Research Funding; Merck: Research Funding; Nurix: Research Funding.
Asterisk with author names denotes non-ASH members.