Phase I Trial of Brentuximab Vedotin for Steroid-Refractory Chronic Graft-versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation.

We conducted a phase I study of brentuximab vedotin (BV), an antibody-drug conjugate targeting CD30, for the treatment of steroid-refractory chronic graft-versus-host disease (cGVHD). A modified 3 + 3 study design was used with the primary endpoint to determine the maximum tolerated dose of BV in this population. Escalating doses of BV were planned, starting with .6 mg/kg every 3 weeks (dose level 0) and increasing by .3 mg/kg per dose level. BV was administered in 21-day cycles for up to 16 cycles of therapy. Nineteen patients were enrolled on the study, with 2 withdrawing consent before dosing. The median number of cycles of therapy was 4 (range, 1 to 16). Reasons for stopping therapy prematurely included toxicities (n = 9), patient decision (n = 3), lack of response (n = 2), and death (n = 1). There were 2 dose-limiting toxicities observed: posterior reversible encephalopathy syndrome (cohort 4, grade 3) and sepsis (cohort 4, grade 4). The maximum tolerated dose was not reached because the trial was prematurely closed due to toxicity. Seven patients (41%) developed grade 3 or 4 adverse events that were attributed to therapy, including 4 patients who developed moderate or severe peripheral neuropathy that led to cessation of treatment in each case. According to National Institutes of Health cGVHD response criteria, 8 patients (47%) experienced a partial response, whereas 9 patients (53%) had a lack of response. There were no complete responses observed. Eleven patients (65%) were able to decrease their systemic corticosteroid dose by ≥50% by 6 months after initiation of BV, including 3 patients who were able to stop corticosteroids completely. The median soluble CD30 level before therapy was 61.5 ng/mL (range, 7.8 to 474.9); however, we did not observe any association between soluble CD30 level and cGVHD severity at enrollment or clinical responses to BV. In conclusion, BV may have activity in treatment of steroid-refractory cGVHD, yet its use is limited by treatment-emergent toxicities, including peripheral neuropathy. Continued efforts to investigate targeted approaches to cGVHD that do not cause broad immunosuppression are needed.

Third-party fecal microbiota transplantation following allo-HCT reconstitutes microbiome diversity.

We hypothesized that third-party fecal microbiota transplantation (FMT) may restore intestinal microbiome diversity after allogeneic hematopoietic cell transplantation (allo-HCT). In this open-label single-group pilot study, 18 subjects were enrolled before allo-HCT and planned to receive third-party FMT capsules. FMT capsules were administered no later than 4 weeks after neutrophil engraftment, and antibiotics were not allowed within 48 hours before FMT. Five patients did not receive FMT because of the development of early acute gastrointestinal (GI) graft-versus-host disease (GVHD) before FMT (n = 3), persistent HCT-associated GI toxicity (n = 1), or patient decision (n = 1). Thirteen patients received FMT at a median of 27 days (range, 19-45 days) after HCT. Participants were able to swallow and tolerate all FMT capsules, meeting the primary study endpoint of feasibility. FMT was tolerated well, with 1 treatment-related significant adverse event (abdominal pain). Two patients subsequently developed acute GI GVHD, with 1 patient also having concurrent bacteremia. No additional cases of bacteremia occurred. Median follow-up for survivors is 15 months (range, 13-20 months). The Kaplan-Meier estimates for 12-month overall survival and progression-free survival after FMT were 85% (95% confidence interval, 51%-96%) and 85% (95% confidence interval, 51%-96%), respectively. There was 1 nonrelapse death resulting from acute GI GVHD (12-month nonrelapse mortality, 8%; 95% confidence interval, 0%-30%). Analysis of stool composition and urine 3-indoxyl sulfate concentration indicated improvement in intestinal microbiome diversity after FMT that was associated with expansion of stool-donor taxa. These results indicate that empiric third-party FMT after allo-HCT appears to be feasible, safe, and associated with expansion of recipient microbiome diversity. This trial was registered at www.clinicaltrials.gov as #NCT02733744.

Phase I trial of maintenance sorafenib after allogeneic hematopoietic stem cell transplantation for fms-like tyrosine kinase 3 internal tandem duplication acute myeloid leukemia.

The fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutation is associated with a high relapse rate for patients with acute myeloid leukemia (AML) even after allogeneic hematopoietic stem cell transplantation (HSCT). Sorafenib is a tyrosine kinase inhibitor, which inhibits the FLT3 tyrosine kinase and has shown encouraging activity in FLT3-ITD AML. We conducted a phase I trial of maintenance sorafenib after HSCT in patients with FLT3-ITD AML (ClinicalTrials.govNCT01398501). Patients received a variety of conditioning regimens and graft sources. A dose escalation 3 + 3 cohort design was used to define the maximum tolerated dose (MTD), with an additional 10 patients treated at the MTD. Sorafenib was initiated between days 45 and 120 after HSCT and continued for 12 28-day cycles. Twenty-two patients were enrolled (status at HSCT: first complete remission [CR1], n = 16; second complete remission [CR2], n = 3; refractory, n = 3). The MTD was established at 400 mg twice daily with 1 dose-limiting toxicity (DLT) observed (pericardial effusion). Two patients died of transplantation-related causes, both unrelated to sorafenib. Two patients stopped sorafenib after relapse and 5 stopped because of attributable toxicities after the DLT period. Median follow-up for surviving patients is 16.7 months after HSCT (range, 8.1 to 35.0). There was 1 case of grade II acute graft-versus-host disease (GVHD) after starting sorafenib and the 12-month cumulative incidence of chronic GVHD was 38% (90% confidence interval [CI], 21% to 56%). For all patients, 1-year progression-free survival (PFS) was 85% (90% CI, 66% to 94%) and 1-year overall survival (OS) was 95% (90% CI, 79% to 99%) after HSCT. For patients in CR1/CR2 before HSCT (n = 19), 1-year PFS was 95% (90% CI, 76% to 99%) and 1-year OS was 100%, with only 1 patient who relapsed. Sorafenib is safe after HSCT for FLT3-ITD AML and merits further investigation for the prevention of relapse.