Dataset Information

Reduced-Intensity Haploidentical Bone Marrow Transplantation with Post-Transplant Cyclophosphamide for Solid Tumors in Pediatric and Young Adult Patients.

ABSTRACT: High-risk, recurrent, or refractory solid tumors in pediatric, adolescent, and young adult (AYA) patients have an extremely poor prognosis despite current intensive treatment regimens. We piloted an allogeneic bone marrow transplant platform using reduced-intensity conditioning (RIC) and partially HLA-mismatched (haploidentical) related donors for this population of pediatric and AYA solid tumor patients. Sixteen patients received fludarabine, cyclophosphamide, melphalan, and low-dose total body irradiation RIC haploidentical BMT (haploBMT) followed by post-transplantation cyclophosphamide (PTCy), mycophenolate mofetil, and sirolimus. All assessable patients were full donor chimeras on day 30 with a median neutrophil recovery of 19 days and platelet recovery of 21 days. One patient (7%) exhibited secondary graft failure associated with concomitant infection. The median follow-up time was 15 months. Overall survival was 88%, 56%, and 21% at 6, 12, and 24 months, respectively. Median survival from transplant date was 14 months with a median progression-free survival 7 months. We observed limited graft-versus-host disease in 3 patients and nonrelapse mortality in 1 patient. We demonstrated that RIC haploBMT with PTCy is feasible and has acceptable toxicities in patients with incurable pediatric and AYA solid tumors; thus, this approach serves as a platform for post-transplant strategies to prevent relapse and optimize progression-free survival.

SUBMITTER: Llosa NJ

PROVIDER: S-EPMC5986177 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Publications

Reduced-Intensity Haploidentical Bone Marrow Transplantation with Post-Transplant Cyclophosphamide for Solid Tumors in Pediatric and Young Adult Patients.

Llosa Nicolas J NJ Cooke Kenneth R KR Chen Allen R AR Gamper Christopher J CJ Klein Orly R OR Zambidis Elias T ET Luber Brandon B Rosner Gary G Siegel Nicholas N Holuba Mary Jo MJ Robey Nancy N Hayashi Masanori M Jones Richard J RJ Fuchs Ephraim E Holdhoff Matthias M Loeb David M DM Symons Heather J HJ

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 20170812 12

High-risk, recurrent, or refractory solid tumors in pediatric, adolescent, and young adult (AYA) patients have an extremely poor prognosis despite current intensive treatment regimens. We piloted an allogeneic bone marrow transplant platform using reduced-intensity conditioning (RIC) and partially HLA-mismatched (haploidentical) related donors for this population of pediatric and AYA solid tumor patients. Sixteen patients received fludarabine, cyclophosphamide, melphalan, and low-dose total body ...[more]

PMID: 28807769

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Project description:Post-transplantation cyclophosphamide (PT-CY) is the most widely applied graft-versus-host disease (GVHD) prophylaxis regimen in T-cell replete haploidentical bone marrow transplantation (haplo-BMT). Although PT-CY has met with great success in the haplo-BMT arena by suppressing GVHD, patients without acute GVHD have high relapse rates. One strategy to reduce relapse rates being explored by others is a dosage reduction of PT-CY. We have taken a different approach in evaluating whether partially replacing PT-CY with post-transplantation bendamustine (PT-BEN) would be advantageous, an idea based on our preclinical research identifying several beneficial immunomodulatory properties of BEN. We therefore initiated and completed a Phase Ia trial to evaluate the progressive substitution of PT-CY with PT-BEN (ClinicalTrials.gov identifier NCT02996773). We compared outcomes between 13 patients with high-risk hematologic malignancies who received PT-CY/BEN and 31 contemporaneous haplo-BMT recipients treated with the same myeloablative conditioning regimens but receiving only PT-CY. We found that partial replacement of PT-CY with PT-BEN (PT-CY/BEN) on day +4 was well tolerated and associated with significantly earlier trilineage engraftment. We also report favorable trends toward significant improvements on univariate and multivariate analyses with PT-CY/BEN compared with PT-CY with respect to rates of chronic GVHD (hazard ratio [HR], .08; 95% confidence interval [CI], .005 to 1.11; P = .06), and GVHD-free relapse-free survival (GRFS) (HR, .22; 95% CI, .05 to .86; P = .039). Our human trial has now transitioned to Phase Ib, which will further evaluate the safety and potential benefits of PT-CY/BEN. Herein we also expand our pediatric, adolescent, and young adult experience to 31 patients, demonstrating overall survival, progression-free survival, and GRFS at 3 years of 85.6%, 76.1%, and 58.2%, respectively, in a largely racial/ethnic minority cohort. PT-CY/BEN appears to be a promising treatment option that requires further evaluation.

Project description:In the coronavirus disease 19 (COVID-19) pandemic era, the number of haploidentical hematopoietic cell transplantations (HCTs) with peripheral blood (PB) grafts increased significantly compared with HCTs with bone marrow (BM) grafts, which may be associated with adverse outcomes. We compared outcomes of HCT in BM graft and PB graft recipients age ≥18 years with hematologic malignancies who underwent T cell- replete haploidentical HCT and received graft-versus-host disease (GVHD) prophylaxis with post-transplantation cyclophosphamide, tacrolimus, and mycophenolate mofetil. Among the 264 patients, 180 (68%) received a BM graft and 84 (32%) received a PB graft. The median patient age was 50 years in both groups. The majority (n = 199; 75%) received reduced-intensity conditioning. The rate of acute leukemia or myelodysplastic syndrome was higher in the BM graft recipients compared with the PB graft recipients (85% [n = 152] versus 55% [n = 46]; P < .01). The median times to neutrophil and platelet engraftment and the incidence of grade II-IV and grade III-IV acute GVHD (aGVHD) were comparable in the 2 groups. Among the patients with grade II-IV aGVHD, the rate of steroid-refractory aGVHD was 9% (95% confidence interval [CI], 5% to 18%) in the BM group versus 32% (95% CI, 19% to 54%) in the PB group (hazard ratio [HR], 3.7, 95% CI, 1.5 to 9.3; P = .006). At 1 year post-HCT, the rate of chronic GVHD (cGVHD) was 8% (95% CI, 4% to 13%) in the BM group versus 22% (95% CI, 14% to 36%) in the PB group (HR, 3.0; 95% CI, 1.4-6.6; P = .005), and the rate of systemic therapy-requiring cGVHD was 2.5% (95% CI, 1% to 7%) versus 14% (95% CI, 7% to 27%), respectively (HR, 5.6; 95% CI, 1.7 to 18; P = .004). The PB group had a significantly higher risk of bacterial and viral infections, with no appreciable advantage in the duration of hospitalization, immune reconstitution, relapse, nonrelapse mortality, or survival. Our data suggest a benefit of the use of BM grafts over PB grafts for haplo-HCT.

Project description:Classic Hodgkin lymphoma (cHL) patients with relapsed or refractory disease may benefit from allogeneic hematopoietic cell transplantation (allo-HCT), but many lack a matched sibling donor (MSD). Herein, we compare outcomes of 2 reduced-intensity conditioning (RIC) HCT platforms in cHL: T cell-replete related donor haploidentical (haplo) HCT with a post-transplant cyclophosphamide (PTCy)-based approach versus an MSD/calcineurin inhibitor (CNI)-based approach. The study included 596 adult patients who underwent a first RIC allo-HCT for cHL between 2008 and 2016 using either a haplo-PTCy (n = 139) or MSD/CNI-based (n = 457) approach. Overall survival (OS) was the primary endpoint. Secondary endpoints included acute graft-versus-host disease (aGVHD) and chronic GVHD (cGVHD), nonrelapse mortality (NRM), relapse/progression, and progression-free survival (PFS). On multivariate analysis, there was no significant difference between haplo/PTCy and MDS/CNI-based approaches in terms of OS (hazard ratio [HR], 1.07; 95% confidence interval [CI], .79 to 1.45; P = .66) or PFS (HR, .86; 95% CI, .68 to 1.10; P = .22). Haplo/PTCy was associated with a significantly higher risk of grades II to IV aGVHD (odds ratio [OR], 1.73, 95% CI, 1.16 to 2.59; P = .007), but the risk of grades III to IV aGVHD was not significantly different between the 2 cohorts (OR, .61; 95% CI, .29 to 1.27; P = .19). The haplo/PTCy platform provided a significant reduction in cGVHD risk (HR, .45; 95% CI, .32 to .64; P < .001), and a significant reduction in relapse risk (HR, .74; 95% CI, .56 to .97; P = .03). There was a statistically nonsignificant trend toward higher NRM with a haplo/PTCy approach (HR, 1.65; 95% CI, .99 to 2.77; P = .06). Haplo/PTCy-based approaches are associated with lower incidences of cGVHD and relapse, with PFS and OS outcomes comparable with MSD/CNI-based approaches. There was a leaning toward higher NRM with a haplo/PTCy-based platform. These data show that haplo/PTCy allo-HCT in cHL results in survival comparable with MSD/CNI-based allo-HCT.

Dataset Information

Reduced-Intensity Haploidentical Bone Marrow Transplantation with Post-Transplant Cyclophosphamide for Solid Tumors in Pediatric and Young Adult Patients.

Publications

Reduced-Intensity Haploidentical Bone Marrow Transplantation with Post-Transplant Cyclophosphamide for Solid Tumors in Pediatric and Young Adult Patients.

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