Total Body Irradiation–Based Myeloablative Haploidentical Stem Cell Transplantation Is a Safe and Effective Alternative to Unrelated Donor Transplantation in Patients Without Matched Sibling Donors

Abstract

We enrolled 30 patients on a prospective phase II trial utilizing a total body irradiation (TBI)-based myeloablative preparative regimen (fludarabine 30 mg/m2/day × 3 days and TBI 150 cGy twice per day on day -4 to -1 [total dose 1200 cGy]) followed by infusion of unmanipulated peripheral blood stem cells from a haploidentical family donor (haplo). Postgrafting immunosuppression consisted of cyclophosphamide 50 mg/kg/day on days 3 and 4, mycophenolate mofetil through day 35, and tacrolimus through day 180. Median patient age was 46.5 years (range, 24 to 60). Transplantation diagnosis included acute myelogenous leukemia (n = 16), acute lymphoblastic leukemia (n = 6), chronic myelogenous leukemia (n = 5), myelodysplastic syndrome (n = 1), and non-Hodgkin's lymphoma (n = 2). Using the Dana Farber/Center for International Blood and Marrow Transplant Research/Disease Risk Index (DRI), patients were classified as low (n = 4), intermediate (n = 12), high (n = 11), and very high (n = 3) risk. All patients engrafted with a median time to neutrophil and platelet recovery of 16 and 25 days, respectively. All evaluable patients achieved sustained complete donor T cell and myeloid chimerism by day +30. Acute graft-versus-host disease (GVHD) grades II to IV and III and IV was seen in 43% and 23%, respectively. The cumulative incidence of chronic GVHD was 56% (severe in 10%). After a median follow-up of 24 months, the estimated 2-year overall survival (OS), disease-free survival (DFS), nonrelapse mortality, and relapse rate were 78%, 73%, 3%, and 24%, respectively. Two-year DFS and relapse rate in patients with low/intermediate risk disease was 100% and 0%, respectively, compared with 39% and 53% for patients with high/very high risk disease. When compared with a contemporaneously treated cohort of patients at our institution receiving myeloablative HLA-matched unrelated donor (MUD) transplantation (acute myelogenous leukemia [n = 17], acute lymphoblastic leukemia [n = 15], chronic myelogenous leukemia [n = 7], myelodysplastic syndrome [n = 7], non-Hodgkin lymphoma [n = 1], chronic lymphoblastic leukemia [n = 1]), outcomes were statistically similar, with 2-yr OS and DFS being 78% and 73%, respectively after haplo transplantation versus 71% and 64%, respectively, after MUD transplantation. In patients with DRI low/intermediate risk disease, 2-yr DFS was superior after haplo compared with MUD transplantations (100% versus 74%, P = .032), whereas there was no difference in DFS in patients with high/very high risk disease (39% versus 37% for haplo and MUD respectively, P = .821). Grade II to IV acute GVHD was seen less often after haplo compared with MUD transplantation (43% versus 63%, P = .049), as was moderate-to-severe chronic GVHD (22% versus 58%, P = .003). Myeloablative haplo transplantation using this regimen is a valid option for patients with advanced hematologic malignancies who lack timely access to a conventional donor. Outcomes appear at least equivalent to those seen in contemporaneous patients who underwent transpl...

Post-relapse survival after haploidentical transplantation vs matched-related or matched-unrelated hematopoietic cell transplantation

“…These findings are consistent with previously published reports from our institution and others. 2,16,19 One-year PRS was inferior among HIDT patients compared with MUD and MRD (17% vs 40% vs 46%, respectively). PRS was not significantly different between the three donor groups when the analysis was restricted to patients who did not receive DLI after relapse.…”

“…We currently have a clinical trial with fludarabine-and melphalan-based conditioning to assess if higher intensity (compared with non-ablative fludarabine/cyclophosphamide/TBI) in the HIDT setting can yield lower relapses as has been shown with MRDT and MUDT in the BMTCTN 0901 trial. 16,30 Other local strategies we are using include post-transplant maintenance therapy such as hypomethylating agents for high-risk MDS and AML patients, 20 clinical trials with FLT-3 inhibitors for AML patients who harbor the FLT-3 ITD mutation and MRD monitoring, especially for patients with Philadelphia-positive ALL. 29 Clinical trials using one or combination of different strategies aiming at preventing relapse and/or using molecular and cellular targets for post-relapse treatment are currently being investigated in many centers with the hope of better disease control after allogeneic HCT.…”

“…Myeloablative HIDT were performed using two different regimens consecutively developed at our institution. 15,16 Eight patients received a regimen 1: fludarabine 25 mg/m 2 IV once per day on days − 6 to − 2, busulfan 110-130 mg/m 2 IV once per day on days − 7 to − 4 and cyclophosphamide 14.5 mg/kg IV once per day on days − 3 and − 2 and 50 mg/kg once per day on days +3 and +4. Seven patients received regimen 2: fludarabine 30 mg/m 2 once per day on days -7 to − 5, TBI 150 cGy two times daily on days − 4 to − 1 (total dose 1200 cGy) with the same post-transplant therapy as regimen 1.…”

Erratum: Modern approaches to HLA-haploidentical blood or marrow transplantation.

“…128 Unlike in preclinical studies, 107 tolerance was still induced when CsA was started before PTCy, as evidenced by low rates of grade II-IV acute GVHD (12%) and chronic GVHD (26% in this study). 128 Another study published this year, 130 which used TBI-based myeloablative conditioning with PBSCs for haploBMT, showed an excellent survival rate (78%), with low rates of NRM (3%) and relapse (24% for all patients and 0% for patients with low-risk or intermediate-risk disease) after 2 years of follow up, albeit with higher rates of acute (23% grade III-IV) and chronic (56% overall and 22% moderate or severe) GVHD. An alternative 'two-step' approach to myeloablative PTCy-haploBMT has involved TBIbased conditioning, a fixed peripheral blood T-cell dose on pretransplantation day 6, cyclophosphamide at 60 mg/kg per day on pretransplantation days 3 and 2, and a CD34 + -selected PBSC allograft on day 0.…”

“…132 Several groups have explored the use of PBSCs rather than bone marrow for PTCyhaploBMT in an attempt to further improve engraftment and reduce relapse. 129,130,133,134 However, the effects of this substitution are currently unclear, particularly as heterogeneity between studies makes a definitive assessment of the effects on relapse challenging. Graft failure rates seem to be similar or, at most, only slightly improved by the use of PBSCs.…”