Marrow Hematopoietic Cell Transplantation Research Articles

Three-Year Outcomes in Recipients of Mismatched Unrelated Bone Marrow Donor Transplants Using Post-Transplantation Cyclophosphamide: Follow-Up from a National Marrow Donor Program-Sponsored Prospective Clinical Trial

The use of post-transplantation cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis has resulted in reductions in GVHD and improved outcomes in allogeneic hematopoietic cell transplantation (HCT) using HLA-mismatched related donors. We report the 3-year outcomes of the first multicenter prospective clinical trial using PTCy in the setting of mismatched unrelated donor (MMUD) bone marrow HCT. The study enrolled 80 patients, treated with either myeloablative conditioning (MAC; n=40) or reduced-intensity conditioning (RIC; n=40), with the primary endpoint of 1-year overall survival (OS). The median follow-up for this study was 34 months (range, 12 to 46 months) in the RIC group and 36 months (range, 18 to 49 months) in the MAC group. Three-year OS and nonrelapse mortality were 70% and 15%, respectively, in the RIC group and 62% and 10% in the MAC group. No GVHD was reported after 1 year. The incidence of relapse was 29% in the RIC group and 51% in the MAC group. OS did not differ based on HLA match grade (63% in the 7/8 strata and 71% in the 4 to 6/8 strata). These encouraging outcomes, which were sustained for 3 years post-HCT, support the continued exploration of MMUD HCT using a PTCy platform. Important future areas to address include relapse reduction and furthering our understanding of optimal donor selection based on HLA and non-HLA factors.

Anti-CD45 Radioimmunotherapy Followed By Haploidentical Allogeneic Hematopoietic Cell Transplantation for Advanced Acute Leukemia or High-Risk MDS

Background: Although hematopoietic cell transplantation (HCT) may offer the best chance for cure for patients with relapsed/refractory hematologic malignancies, many of these patients will relapse after HCT. Escalating doses of total body irradiation (TBI) or chemotherapy prior to HCT can decrease relapse, but incurs higher toxicity, resulting in no survival benefit. Therefore, there is a need to reduce relapse without increasing the toxicity of the conditioning regimen prior to HCT. In addition, many potentially curable candidates for HCT do not have a fully human leukocyte antigen (HLA) matched donor. This is an especially challenging hurdle for many ethnic minority patients, yet nearly all patients have a related donor identical for one HLA haplotype (i.e., haploidentical). Radioiodinated anti-CD45 radioimmunotherapy (RIT) has been shown to deliver high-doses of radiation specifically to hematolymphoid organs, while sparing normal tissues. We report a phase I/II study using iodine-131 (131I)-anti-CD45 antibody (BC8) combined with pre- and post-transplant cyclophosphamide, and reduced intensity conditioning prior to haploidentical HCT.Methods and Patients: Eligible patients over the age of 18 had relapsed or refractory acute myeloid leukemia (AML), acute lymphoid leukemia (ALL), or high-risk (>5% active marrow blasts) myelodysplastic syndrome (MDS). Patients received a 131I-anti-CD45 dosimetry dose, followed by serial gamma-camera imaging for organ dosimetry estimates. One to two weeks later a therapeutic dose delivering escalating doses (12 to 26 Gy) to the liver (the normal organ that received the highest dose) was administered, followed by fludarabine (FLU; 30 mg/m2 on day -6 to -2), cyclophosphamide (CY; 14.5 mg/m2 on day -6 and -5), 200 cGy TBI on day -1, and subsequent haploidentical marrow HCT on day 0. For GVHD prophylaxis, patients received CY (50 mg/kg) on day+3 plus standard tacrolimus and mycophenolate mofetil.Results: A total of 25 patients have been treated (21 with advanced AML, 3 with ALL and 1 with high-risk MDS). Ten patients were in florid refractory relapse with 6-20% abnormal marrow blasts while 9 were in remission with minimal residual disease (MRD) 0.03-5.4% by flow cytometry, and only 6 were in remission and MRD negative by flow cytometry. All 24 patients who had marrow aspiration on day 28 after HCT achieved a morphologic remission, with only two patients showing MRD by flow cytometry (0.002 -1.8% abnormal blasts). There were no graft failures, and all patients with chimerism studies (n=15) had 100% donor CD3+ and CD33+ cell engraftment at day 28 after haploidentical HCT. Median time to neutrophil engraftment (ANC>500/ml for 3 consecutive days) was 15 (range, 12-19) days. Median time to platelet engraftment (platelets >20,000/ml for 7 consecutive days without transfusion support) was 23 (19-44) days. The maximum tolerated dose was not determined and there were no unexpected adverse events, as the most frequent grade ≥3 adverse events were infections/neutropenic fevers (32), gastrointestinal (22), and laboratory abnormalities (cytopenias 18; metabolic 16). Five patients had grades 3-4 acute GVHD. Twelve patients relapsed with median time to relapse of 2.4 months. Most deaths have been from relapse (11), and infections (2). Eight (32%) patients were alive at a median follow up of 4 years after HCT (range 1 to 9 years). Overall survival at one and three year was 42% and 26%, and progression-free survival was 40% and 25%, respectively (Figure).Conclusions: Although patients with active disease are not traditionally referred for HCT, the use of 131I-anti-CD45 RIT prior to a haploidentical HCT may facilitate improved survival for these patients. Given these results, anti-CD45 RIT prior to HCT using haploidentical donors warrants further investigation for patients with advanced leukemia and high-risk MDS. [Display omitted] DisclosuresOrozco:Actinium Pharmaceuticals: Other: Research Funding to Institution for sponsored Clinical Trials. Shadman:PLEXXIKON: Research Funding; AbbVie: Other: advisory board; Genentech: Consultancy, Research Funding; Emergent: Research Funding; TG Therapeutics: Research Funding; Gilead: Research Funding; Acerta Pharma: Research Funding; Celgene: Research Funding; Pharmacyclics: Other: advisory board, Research Funding; Merck: Research Funding. Gopal:Seattle Genetics: Consultancy, Research Funding. Pagel:Actinium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

Post-Transplant Cyclophosphamide and Tacrolimus–Mycophenolate Mofetil Combination Prevents Graft-versus-Host Disease in Allogeneic Peripheral Blood Hematopoietic Cell Transplantation from HLA-Matched Donors

Allogeneic hematopoietic cell transplant (HCT) remains the only curative therapy for many hematologic malignancies but it is limited by high nonrelapse mortality (NRM), primarily from unpredictable control of graft-versus-host disease (GVHD). Recently, post-transplant cyclophosphamide demonstrated improved GVHD control in allogeneic bone marrow HCT. Here we explore cyclophosphamide in allogeneic peripheral blood stem cell transplantation (alloPBSCT). Patients with high-risk hematologic malignancies received alloPBSCT from HLA-matched unrelated/related donors. GVHD prophylaxis included combination post-HCT cyclophosphamide 50 mg/kg (days +3 and +4) and tacrolimus/mofetil mycophenolate (T/MMF) (day +5 forward). The primary objective was the cumulative incidence of acute and chronic GVHD. Between March 2011 and May 2015, 35 consecutive patients received the proposed regimen. MMF was stopped in all patients at day +28; the median discontinuation of tacrolimus was day +113. Acute and chronic GVHD cumulative incidences were 17% and 7%, respectively, with no grade IV GVHD events, only 2 patients requiring chronic GVHD immunosuppression control, and no deaths from GVHD. Two-year NRM, overall survival, event-free survival, and chronic GVHD event-free survival rates were 3%, 77%, 54%, and 49%, respectively. The graft-versus-tumor effect was maintained as 5 of 15 patients (33%) who received HCT with evidence of disease experienced further disease response. A post-transplant cyclophosphamide + T/MMF combination strategy effectively prevented acute and chronic GVHD after alloPBSCT from HLA-matched donors and achieved an unprecedented low NRM without losing efficacy in disease control or impaired development of the graft-versus-tumor effect. This trial is registered at clinicaltrials.gov as NCT02300571.

Long-term Tolerance Toward Haploidentical Vascularized Composite Allograft Transplantation in a Canine Model Using Bone Marrow or Mobilized Stem Cells.

The development of safe and reliable protocols for the transplantation of the face and hands may be accomplished with animal modeling of transplantation of vascularized composite allografts (VCA). Previously, we demonstrated that tolerance to a VCA could be achieved after canine recipients were simultaneously given marrow from a dog leukocyte antigen-identical donor. In the present study, we extend those findings across a dog leukocyte antigen mismatched barrier. Eight recipient dogs received total body irradiation (4.5 cGy), hematopoietic cell transplantation (HCT), either marrow (n = 4) or granulocyte-colony stimulating factor mobilized peripheral blood stem cells (n = 4), and a VCA transplant from the HCT donor. Post grafting immunosuppression consisted of mycophenolate mofetil (28 days) and cyclosporine (35 days). In 4 dogs receiving bone marrow, 1 accepted both its marrow transplant and demonstrated long-term tolerance to the donor VCA (>52 weeks). Three dogs rejected both their marrow transplants and VCA at 5 to 7 weeks posttransplant. Dogs receiving mobilized stem cells all accepted their stem cell transplant and became tolerant to the VCA. However, 3 dogs developed graft-versus-host disease, whereas 1 dog rejected its stem cell graft by week 15 but exhibited long-term tolerance toward its VCA (>90 weeks). The data suggest that simultaneous transplantation of mobilized stem cells and a VCA is feasible and leads to tolerance toward the VCA in a haploidentical setting. However, there is a higher rate of donor stem cell engraftment compared with marrow HCT and an increase in the incidence of graft-versus-host disease.

Fludarabine Is Superior to Cladribine When Added to Busulfan and Low Dose TBI as Reduced Intensity Conditioning for Allogeneic Hematopoietic Cell Transplantation (HCT): A Prospective Randomized Trial.

Purine analogues have been combined with alkylator/irradiation as immunosuppressive and anti-tumor conditioning prior to allogeneic hematopoietic stem cell transplantation (HCT) though differing purine analogues have not been compared. We prospectively tested Fludarabine (F) 40 mg/m2/d x 5d vs. Cladribine (C) 10 mg/m2/d x 5d plus Busulfan (Bu) (2mg/kg q12h x 2d) and total body irradiation (T) 200cGy followed by cyclosporine and mycophenylate mofetil in 19 recipients of matched sibling peripheral blood stem cell and 13 unrelated donor (URD) marrow HCT. Patients in each randomly assigned cohort [FBuT vs. CbuT] were similar in age (median 52 years in both groups), diagnosis (leukemia/MDS 38 vs. 31%; lymphoid malignancy 57 vs 69%), extensive pre-HCT therapy (56 vs. 63%), high risk disease status (81 vs. 93%) and Karnofsky (median 90 in each)[all p= NS] though fewer FBuT were URD recipients 25% vs. CBuT 56%, p=0.07. Engraftment was prompt in both groups (median 11 vs. 12 days), but the cumulative incidence of neutrophil engraftment was 75% (95% C.I. 54–96%) using CBuT vs. 100% with FBuT (p<0.01) and randomization was halted. Platelet recovery was prompt (median FBuT 18 vs CBuT 24 days) and after FBuT 75% (95% C.I. 49–100) vs. CBuT 69% (43–95) recovered platelets > 50,000/μL by day +180, p=0.19. The cumulative incidence of GVHD after FBuT vs. CbuT was similar (acute grade II/IV 56 vs. 69%, p=0.26) and (chronic 50 vs. 31%, p=0.27). Transplant related mortality at day +180 was also similar [FBuT 25% (4–46) vs. CbuT 38% (14–61), p=0.47]. Survival was equivalent: at 1 year 50% in each group; at 3 years FBuT 25% vs. CBuT 38%, p=0.55. Multivariate analyses adjusted for age, donor type, diagnosis and stage as well as conditioning regimen showed lower relative risk (RR) of engraftment with CBuT (RR 0.6 (95% C.I. 0.2–1.3) p=0.16) and with URD RR 0.4 (0.2–1.0) p=0.04). RR of Platelet recovery was equivalent with FBuT (RR 0.7 (0.3–1.7) p=0.45) but inferior with URD (RR .16 (.05–.5) p<0.01). RR of GHVD II/IV similar with FBuT RR 1.1, p=0.95, but more frequent with URD RR 2.0, p=.2 and high risk status patients (RR 4.5, 1.5–13.5, =<0.01). Prevalence of remission (CR or PR) at 18 months was high and was similar in both groups (FBuT 100% vs CBuT 86%, p=NS). These data suggest that older patients with advanced hematologic malignancies can achieve satisfactory post-transplant outcomes using either of these combination/reduced intensity conditioning regimens. Fludarabine may be superior to cladribine as a component of pre-HCT conditioning with Bu/TBI due to reduced risks of graft failure. Further modifications of the regimen may confirm universal engraftment with even lower peri-transplant morbidity.