A Phase I Trial of SYK Inhibition with Fostamatinib in the Prevention and Treatment of Chronic Graft-Versus-Host Disease

Abstract

Despite the exciting advancement of novel therapies, chronic graft-versus-host disease (cGVHD) remains the most common cause of non-relapse mortality after allogeneic hematopoietic stem cell transplantation (HCT). Frontline treatment of cGVHD involves systemic steroids, which are associated with significant morbidities. We previously found that inhibition of spleen tyrosine kinase (SYK) with fostamatinib preferentially eradicated aberrantly activated B cells in both ex vivo studies of cGVHD patient B cells, as well as in vivo mouse studies. These and other preclinical studies implicated hyper-reactive B-cell receptor signaling and increased SYK expression in the pathogenesis of cGVHD and compelled this first in-human allogeneic HCT clinical trial. We investigated the safety and efficacy of the oral SYK inhibitor, fostamatinib, for both the prevention and treatment of cGVHD. The primary objective was to evaluate the safety of fostamatinib and determine its maximum tolerated dose in the post-HCT setting. Secondary objectives included assessing the efficacy of fostamatinib in preventing and treating cGVHD, as well as examining alterations in B-cell compartments with treatment. This was a single-institution phase I clinical trial that evaluated the use of fostamatinib in allogeneic HCT patients before the development of cGVHD or at the time of steroid-refractory cGVHD (SR-cGVHD). Patients received fostamatinib at one of three dose levels using a continual reassessment algorithm to determine the maximum tolerated dose. Multiparameter flow cytometry was used to evaluate changes in B cell subpopulations over the first year of treatment with fostamatinib. Nineteen patients were enrolled in this phase I trial, with 5 in the prophylaxis arm and 14 in the therapeutic arm. One patient (5%) required discontinuation of therapy for a dose-limiting toxicity. At a median follow-up of over 3 years, no patients had cancer relapse while on fostamatinib treatment, and recurrent malignancy was observed in 1 patient 2 years after the end of therapy. In the prophylaxis arm, 1 of 5 patients (20%) developed cGVHD while on fostamatinib. In the therapeutic arm, the overall response rate was 77%, with a complete response rate of 31%. The median duration of response was 19.3 months and the 12-month failure-free survival was 69% (95% confidence interval, 48-100). Patients were able to reduce their steroid dose by a median of 80%, with 73% remaining on a lower dose at 1 year compared to baseline. There was an early reduction in the proportion of IgD^-CD38^hi plasmablast-like cells with fostamatinib treatment, particularly in those SR-cGVHD patients who had an eventual response. B-cell reconstitution was not significantly impacted by fostamatinib therapy after allogeneic HCT. Fostamatinib featured a favorable safety profile in the post-HCT setting. Our data suggests an early efficacy signal that was associated with effects on expected cell targets in both the prophylaxis and treatment of cGVHD, providing rationale for a phase II investigation.

Keywords: B cells; Graft versus host disease; clinical trial; fostamatinib; spleen tyrosine kinase; stem cell transplantation.

Figure 1.

Patients enrolled and treated with fostamatinib after allogeneic hematopoietic stem cell transplantation. A. Consolidated Standards of Reporting Trials (CONSORT) diagram depicting enrollment onto trial. The dose level for each patient was determined by the continual reassessment method. B. Distribution of cGVHD severity scores by organ system in the therapeutic arm at the time of enrollment. Percentages indicate the overall proportion of patients with involvement of the respective organ system by cGVHD. cGVHD: chronic graft-versus-host disease, GI: gastrointestinal.

Figure 2.

Clinical outcomes of patients treated with fostamatinib in both the prophylaxis and therapeutic arms. A. Swimmer’s plot of treatment responses and progression events for patients in the prophylaxis (P) and therapeutic arms (SR). For the therapeutic arm, the protocol-defined one year of treatment is indicated in blue. Due to progression events observed soon after discontinuation of fostamatinib, the study protocol was amended to allow continued off-label treatment with fostamatinib after the end of the 1 year (indicated in green). B. Bar graph depicting response rates by organ system. Responses were generally consistent across organ types. There was no baseline liver involvement by chronic GVHD in this cohort. C. Mean prednisone dose in mg/kg during treatment with fostamatinib, demonstrating an overall downward trend in steroid requirement. Error bars indicate 95% confidence intervals. Of note, Patient SR02 was unevaluable for response and thus excluded from figures 3B and 3C. CR: complete response, PR: partial response, GI: gastrointestinal, cGVHD: chronic graft-versus-host disease.

Figure 3.

Changes in SYK-expressing immune cells with fostamatinib therapy. A. Paired t-test analysis comparing the fold change of plasmablast (PB)-like cells relative to baseline in the prophylaxis arm patients, demonstrating a decrease in PB-like cell frequencies with fostamatinib treatment. The median day post-transplant at which these patients began fostamatinib was post-transplant day 117 (range, 97–134 days). B. Paired t-test analysis comparing the fold change of PB-like cells relative to baseline in the therapeutic arm patients. Patient SR16 was excluded from these analyses due to severe infection and poor drug absorption during this period, while patient SR10 was excluded due to lack of a baseline sample. C. Violin plot of fold change in PB-like cell frequencies among patients in the therapeutic arm, comparing responders to fostamatinib with non-responders. D, E. Paired t-tests demonstrating an early reduction in monocyte counts with fostamatinib treatment in the prophylaxis arm and therapeutic arm, respectively. F. Among patients in the prophylaxis arm, the monocyte counts had an initial decrease but recovered by 6 and 12 months after the end of therapy. Freq: frequency, EOT: end of therapy. P1-P5 refer to the patients enrolled in the prophylaxis arm, while SR1-SR14 refer to patients in the therapeutic arm. * indicates a statistically significant change from baseline, while ns refers to a non-significant change.

Figure 4.

Non-pathogenic lymphocyte subsets are not significantly impacted by fostamatinib treatment. A, B. Paired t-test of changes in IgD⁺CD38^lo mature naïve B cell subsets in the early treatment period demonstrated no significant change in this subset after starting fostamatinib. C, D. Longitudinal plots of total B cells and total non-B cells (T and NK cells) in the prophylaxis arm. Total B cell counts in the prophylaxis arm were not reduced with fostamatinib therapy, suggesting preserved B cell reconstitution. The median days of study collection for each time point were as follows: 3 (range, 3–3), 8 (range, 8–15), 24 (range, 22–29), 38 (range, 36–43), 59 (range, 57–64), 92 (range, 85–94), 113 (range, 101–121), 141 (range, 141–142), 183 (range, 183–183), 225 (range, 225–232), and 253 for EOT (range, 155–281). Post-HCT: median day after allogeneic stem cell transplantation, Freq: frequency, GC: germinal center, Tx: treatment.