Ofatumumab, Very Late Antigen 4 (VLA4), and Dendritic Cells in Patients Undergoing Autologous Peripheral Blood Stem Cell (PBSC) Mobilization and Transplantation (ASCT) for Relapsed b-Cell Non-Hodgkin's Lymphomas (NHL)

Background: The in-vivo use of anti-CD20 monoclonal antibodies during PBSC mobilization has the potential to decrease the relapse rates following ASCT in patients with b-cell NHL (Khouri et al. J Clin Oncol 2005). We studied the feasibility of PBSC mobilization with G-CSF following ofatumumab with ifosfamide/etoposide (a standard chemo-regimen at our center). In addition to mobilizing CD34+ PBSCs, G-CSF mobilizes naïve T cells (CD3+ VLA4 ^low) and myeloid dendritic cells (mDC), as well as activates and matures the latter to become efficient antigen presenting cells. 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 given at 1000 mg on day 1 and 2000 mg on day 8. Chemotherapy (days 2-4) and G-CSF were used per standard protocols at our center. Each patient provided a PB sample prior to mobilization and an aliquot of leukapheresis product (LP) after mobilization for detection of leukocyte subsets including T-, B-, - and DC-subsets, and VLA-4 and VLA-6 molecules on CD34⁺ PBSC by multicolor FACS analyses. Differences in values of leukocyte subsets between LP and PB were determined using the Wilcoxon Signed Rank test. Results: Fifty patients were studied; median age was 55 years (range, 25-70). Histologies included: diffuse large cell (n=33; 66%), including 9 double-hit; mantle cell (n=12; 24%) and indolent lymphoma (n=5; 10%). Median number of prior chemotherapies received was 2 (range, 1-5). Forty (80%) patients were in either first complete remission (CR1, n=18; 36%) or >CR1 (n=22; 44%); 9 (18%) in partial remission (5 of 7 were PET+), and 1 (2%) had stable disease. Forty-six (92%) patients mobilized PBSC after a median of 1.5 (range, 1-6) apheresis. Median WBC count at day one of collection was 17.7 k/μL (range, 3.6-52.3). Four (8%) patients failed collection of at least 2x10⁶ CD34+cells/kg but then mobilized successfully after receiving Plerixafor. All patients were able to receive an ASCT. Median number of CD34 infused was 6.3 x10^6/kg (range, 3.2-16.9). 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, following transplantation. With a median follow-up time of 14.4 months (range, 1.2-50) post-transplant, the median overall survival (OS) and progression-free survival (PFS) rates have not been reached. The OS and PFS at the median follow-up time were 85% and 75%, respectively. Correlative studies have shown significantly higher percentages of CD3⁺ cells (82.2% vs. 74 % p<0.0001), CD4⁺ T cells (45.3% vs 34.2%; p<0.0001), and total DC (1.78% vs 0.41%; p<0.0001), in LP than paired PB samples, respectively. Differences in OS and PFS were evaluated for disease characteristics (histology, disease status, PET, number of prior therapies) and apheresis products. Whereas a significantly better OS rate was observed in patients who had apheresis products that contained naïve T cells (CD3+ VLA4 ^low) [p= 0.017 at the optimal cutoff value (figure) and 0.047 at the median], a better PFS was associated with apheresis products containing a higher percentage of mDCs (p=0.049). We were unable to confirm earlier reports of a positive association between the expression of VLA-4 on CD34⁺ CD38^dim cells and time to engraftment.

Conclusions:

PBSC mobilization with ofatumumab is feasible with minimal toxicity, and resulted in a leukopheresis product with an increase in the recruitment of CD3+, CD4+ T cells, and DC, compared with levels in PB. Whereas superior OS is associated with naïve CD3+ VLA4 ^low T cells, better PFS was associated with higher percentage of mDCs. Since these observations were obtained with a small sample size, additional studies are warranted to validate our findings

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