Impact of Peri-Transplant Rituximab and Host/Donor Fc Receptor Polymorphisms for Patients with Relapsed or Refractory CD20+ B-Cell Malignancies (2020)

We previously reported results of allogeneic hematopoietic cell transplantation (HCT) in 93 older or medically unfit patients with non-Hodgkin's lymphoma (NHL) or chronic lymphocytic lymphoma (CLL) after conditioning with fludarabine (FLU) and 2-3 Gy total body irradiation (TBI). Three-year survival ranged from 45% to 52% depending on the underlying histology and disease stage. The major complication in those studies was disease relapse (24% at 1 year).The current prospective study in 63 NHL patients tested the hypothesis that disease relapse could be reduced, and overall survival (OS) improved, by peri-transplant rituximab (RTX). Treatment (Figure 1) consisted of RTX (375 mg/m2/day) on days -3, +10, +24 and +38 in addition to 2-3 Gy TBI ± FLU (30 mg/m2 × 3 days).As pharmacokinetics (PK) and optimal dosing of RTX in allogeneic HCT are undefined, we collected PK data to optimize RTX dosing. RTX levels were assayed with murine anti-idiotype monoclonal antibody (18C9) binding to RTX.Median therapeutic RTX levels of >25 μg/mL were achieved through day 84 after HCT, with peak median level of 200.5 μg/mL at day 64. RTX levels were not correlated with relapse or graft-vs-host disease (GVHD) rates. NHL patients had significantly higher median RTX levels than CLL patients (day 84, p=0.003, Figure 2).We collected data on donor and recipient FCγRIIIa receptor polymorphisms expressed predominantly on natural killer cells, thought to affect responsiveness to RTX. This was done to identify patients or donor/recipient pairs most likely to benefit from peri-transplant RTX. FCγRIIIa polymorphisms were determined by PCR and single-strand confirmation polymorphism (SSCP) from DNA isolated from patient cells. Recipients with F/F and V/F FCγRIIIa polymorphisms experienced higher relapse rates compared to recipients with V/V polymorphism (p=0.15). Overall, almost a third of pre-HCT F/F patients relapsed. Probably due to small numbers, no difference in outcome was found with V/V donor pairing for these patients.Results are shown in Figure 3. Relapse rates at 5 years were similar among RTX-treated patients and historical controls (32% vs, 28%; P=0.94). RTX-treated patients experienced higher 5-year OS and progression-free survival; (47% vs, 38%; P=0.13) (41 vs, 32%; P=0.12), respectively, but none of the differences was statistically significant. Non-relapse mortality was lower among RTX-treated patients versus controls (27% vs, 40; P=0.05), respectively; incidences of grade 2-4 acute GVHD and grade 3-4 acute GVHD were similar (60% vs, 57%, 13% vs. 17%); and 5-year chronic GVHD was higher among RTX-treated patients (62% vs, 47%).These findings suggest that for patients with relapsed or refractory NHL, peri-transplant RTX neither reduced relapse nor improved OS or other post-HCT parameters. The role of donor-recipient pairing by FCγRIIIa polymorphisms in outcome remains to be determined. We previously reported results of allogeneic hematopoietic cell transplantation (HCT) in 93 older or medically unfit patients with non-Hodgkin's lymphoma (NHL) or chronic lymphocytic lymphoma (CLL) after conditioning with fludarabine (FLU) and 2-3 Gy total body irradiation (TBI). Three-year survival ranged from 45% to 52% depending on the underlying histology and disease stage. The major complication in those studies was disease relapse (24% at 1 year). The current prospective study in 63 NHL patients tested the hypothesis that disease relapse could be reduced, and overall survival (OS) improved, by peri-transplant rituximab (RTX). Treatment (Figure 1) consisted of RTX (375 mg/m2/day) on days -3, +10, +24 and +38 in addition to 2-3 Gy TBI ± FLU (30 mg/m2 × 3 days). As pharmacokinetics (PK) and optimal dosing of RTX in allogeneic HCT are undefined, we collected PK data to optimize RTX dosing. RTX levels were assayed with murine anti-idiotype monoclonal antibody (18C9) binding to RTX. Median therapeutic RTX levels of >25 μg/mL were achieved through day 84 after HCT, with peak median level of 200.5 μg/mL at day 64. RTX levels were not correlated with relapse or graft-vs-host disease (GVHD) rates. NHL patients had significantly higher median RTX levels than CLL patients (day 84, p=0.003, Figure 2). We collected data on donor and recipient FCγRIIIa receptor polymorphisms expressed predominantly on natural killer cells, thought to affect responsiveness to RTX. This was done to identify patients or donor/recipient pairs most likely to benefit from peri-transplant RTX. FCγRIIIa polymorphisms were determined by PCR and single-strand confirmation polymorphism (SSCP) from DNA isolated from patient cells. Recipients with F/F and V/F FCγRIIIa polymorphisms experienced higher relapse rates compared to recipients with V/V polymorphism (p=0.15). Overall, almost a third of pre-HCT F/F patients relapsed. Probably due to small numbers, no difference in outcome was found with V/V donor pairing for these patients. Results are shown in Figure 3. Relapse rates at 5 years were similar among RTX-treated patients and historical controls (32% vs, 28%; P=0.94). RTX-treated patients experienced higher 5-year OS and progression-free survival; (47% vs, 38%; P=0.13) (41 vs, 32%; P=0.12), respectively, but none of the differences was statistically significant. Non-relapse mortality was lower among RTX-treated patients versus controls (27% vs, 40; P=0.05), respectively; incidences of grade 2-4 acute GVHD and grade 3-4 acute GVHD were similar (60% vs, 57%, 13% vs. 17%); and 5-year chronic GVHD was higher among RTX-treated patients (62% vs, 47%). These findings suggest that for patients with relapsed or refractory NHL, peri-transplant RTX neither reduced relapse nor improved OS or other post-HCT parameters. The role of donor-recipient pairing by FCγRIIIa polymorphisms in outcome remains to be determined. Figures 1, Figure 2, Figure 3.Figure 2Median rituximab levels by diagnosis group NHL; non-Hodgkin's lymphoma (n=54), CLL, chronic lymphocytic lymphoma (n=9). Day -3, p=0.17; day 10, p=0.005; day 24, p=0.03; day 38, p=0.03; day 64, p=0.0007; day 84, p=0.003.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 3Outcome Kaplan-Meir curves- study patients (n=63) vs. historical controls (n=93).View Large Image Figure ViewerDownload Hi-res image Download (PPT)