Annie L. Oh

A phase 1 trial of autologous stem cell transplantation conditioned with melphalan 200 mg/m2 and total marrow irradiation (TMI) in patients with relapsed/refractory multiple myeloma

Abstract In this phase 1 study, we tested increasing doses of total marrow irradiation (TMI) in addition to standard intravenous melphalan at 200 mg/m2 (Mel200) in the conditioning regimen prior to autologous stem cell transplant (ASCT) for multiple myeloma (NCT02043847). Twelve patients aged 18–75 with relapsed myeloma were enrolled in the study and received Mel200 and TMI 3 Gy (n = 3), 6 Gy (n = 3), or 9 Gy (n = 6) prior to transplant. There were no grade 4 extra-hematologic toxicities and a maximum tolerated dose was not reached. Median time to neutrophil and platelet engraftment was 11 and 13 d, respectively. At day 90, 73% of patients were in CR or VGPR. Median progression free survival (PFS) was 449 d and median overall survival (OS) was 966 d. We conclude that TMI at a dose of 9 Gy can be safely combined with Mel200 in therapeutic regimens for autologous transplant. Initial clinical results will prompt a phase 2 study.

Renal dysfunction within 90 days of FluBu4 predicts early and late mortality

Myeloablative conditioning regimens with significant extramedullary toxicity result in high rates of renal dysfunction including acute kidney injury (AKI). Here we examine the incidence and impact of a reduced creatinine clearance (below 60 ml/min) before day 90 (early renal dysfunction, ERD) in patients receiving the reduced toxicity fludarabine/i.v. busulfan (FluBu4) regimen prior to allogeneic transplant. Of 91 patients receiving FluBu4, 62 (68%) developed ERD. ERD resulted in worse overall survival (OS, 2.2 years versus median not reached, p = 0.04) and progression-free survival (PFS, 1.6 years versus median not reached, p = 0.02). This was due to a higher relapse rate (34% versus 14%, p = 0.03) in the ERD group. In time-dependent Cox proportional hazards models adjusted for age, ERD was associated with worse OS (hazard ratio [HR] 2.67, 95% confidence interval [CI] 1.06–4.21, p = 0.043) and PFS (HR 2.52, 95% CI 1.17–4.28, p = 0.030). Patients with ERD surviving 1 year had an increased risk of chronic kidney disease (CKD, OR 10; 95% CI 1.4–112.6, p = 0.0181), which was associated with worse survival (3.2 years versus median not reached, p = 0.002). ERD after FluBu4 is therefore a poor prognostic sign resulting in increased relapse, worse OS, and high risk of CKD at 1 year.

Haploidentical Peripheral Blood Stem Cell Transplantation Demonstrates Stable Engraftment in Adults with Sickle Cell Disease

Abstract We report on the screening and development of haploidentical hematopoietic stem cell transplantation (HSCT) for adult patients with clinically aggressive sickle cell disease (SCD) at our institution. Of 50 adult SCD patients referred for HSCT between January 2014 and March 2017, 20% were denied by insurance. Of 41 patients initially screened, 10% lacked an available haploidentical donor, 29% had elevated donor-specific antibodies (DSAs), and 34% declined to proceed to HSCT. All 10 patients who were transplanted received peripheral blood stem cells. The initial 2 were conditioned with alemtuzumab/total body irradiation (TBI) 3 Gy followed by post-transplant cyclophosphamide and failed to engraft. The next 8 patients received the regimen developed at Johns Hopkins University with TBI 3 Gy. Granulocyte colony-stimulating factor was administered from day +12 in those with HbS < 30%. All 8 patients engrafted with a median time to neutrophil >.5 × 109/L of 22 days (range, 18 to 23). One patient subsequently lost the graft, and 7 (87.5%) maintained >95% donor cell chimerism at 1-year post-HSCT. Two patients developed acute graft-versus-host disease (GVHD) of at least grade II. One had chronic GVHD and died >1 year after HSCT of unknown causes. With a median follow-up of 16 months (range, 11 to 29), 7 patients (87.5%) are alive. Our findings suggest that limited insurance coverage, high rate of DSAs, and patient declining HSCT may limit the availability of haploidentical HSCT in adult SCD patients. The modified Hopkins regimen used here demonstrates high engraftment and low morbidity rates and should be tested in larger, multicenter, prospective clinical trials.