Ofatumumab Plus Ifosfamide/Etoposide (OIE) Followed By Autologous Stem Cell Transplantation (ASCT) in Patients with b-Cell Non-Hodgkin's Lymphomas (NHL)

Background: High-dose therapy and ASCT is the standard treatment for high-risk or relapsed NHL. Prior exposure to rituximab (Gisselbrecht C et al. J Clin Oncol 2010) and a 15-25% risk of inadequate stem cell collection using rituximab + ifosfamide/etoposide (RIE) (Khouri et al. J Clin Oncol 2005) are major reasons for failure. Ofatumumab, a type I human antibody which binds to a different epitope of CD20 than rituximab, has been studied to circumvent resistance to the latter. We studied the feasibility of substituting rituximab with ofatumumab in combination with our institutional standard chemotherapy of IE (OIE) for priming of stem cell collection. We also analyzed patients' outcomes after ASCT.

Patients and Methods: Eligibility criteria included patients with chemosensitive NHL with <5% marrow involvement at study entry, a platelet count of > 100,000/mm³ and an ANC > 1500/mm³. Ofatumumab was then given at 1000 mg on day 1 and 2000 mg on day 8. IE was given on days 2, 3, and 4, followed by filgrastim for stem cell collection (Khouri et al. J Clin Oncol 2005). This was followed by ASCT with carmustine/etoposide/cytarabine/melphalan/rituximab (BEAM/R).

Results: Fifty patients were studied. The median age at ASCT was 55 years (range, 25-70).Histologies included: Diffuse large cell (DLCL) (n=24; 48%), double-hit (DHL) (n=9; 18%), mantle cell (MCL) (n= 12, 24%), and indolent (n=5, 10%). The median number of prior chemotherapies received was 2 (range, 1-5). Eighteen (36%) (10 MCL, 6 DHL and 2 DLCL) patients were in first complete remission (CR1), 22 (44%) were in CR > 1, 3 (6%) were in partial response (PR), and 7 (14%) in primary induction failure, sensitive. At study entry (SE), 9/48 (19%) patients were FDG PET+. Forty-seven (94%) patients mobilized autologous stem cells of at least 2 x 10⁶ CD34/cells after a median of 2 (range, 1-7) apheresis. Median WBC count at day one of collection was 17.7 (range, 3.6 - 52.3) k/μL. Three (6%) patients failed collection but then mobilized successfully after receiving plerixafor. Four (8%) patients experienced grade 2 toxicity with ofatumumab (hypertension, rash, rigor and bone pain). None had > grade 2. All 50 patients were able to receive an ASCT with BEAM/R as per our practice. The median number of CD34 infused was 6.3x10⁶/kg (range, 3.2-16.9). Following ASCT, the median times to recovery of ANC > 500/mm³ and a platelet count of >20,000/mm³ were 10 days (range, 9-12) and 12 days (range, 0-25), respectively. With a median follow-up time of 14.4 months (range, 1.2-50 months) post-transplant, the overall survival (OS) and progression-free survival (PFS) rates were 85% and 75%, respectively. There was no significant difference in OS and PFS by histology, PET status, or number of prior therapies at SE. However, the difference in OS by disease status approached significance (P= 0.053) where 100% CR1 patients survived compared to 74% in CR > 1 and 56% in all others.

Conclusions: The OIE combination resulted in a 94% success rate of autologous stem cell collection with minimal toxicity and promising OS and PFS rates after ASCT. Additional prospective studies comparing outcomes of rituximab vs. ofatumumab with IE and BEAM in this setting are warranted.