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

AbstractWe 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 transplantation from MUD

Myeloablative Conditioning with PBSC Grafts for T Cell-Replete Haploidentical Donor Transplantation Using Posttransplant Cyclophosphamide

Relapse is the main cause of treatment failure after nonmyeloablative haploidentical transplant (haplo-HSCT). In an attempt to reduce relapse, we have developed a myeloablative (MA) haplo-HSCT approach utilizing posttransplant cyclophosphamide (PT/Cy) and peripheral blood stem cells as the stem cell source. We summarize the results of two consecutive clinical trials, using a busulfan-based (n=20) and a TBI-based MA preparative regimen (n=30), and analyze a larger cohort of 64 patients receiving MA haplo-HSCT. All patients have engrafted with full donor chimerism and no late graft failures. Grade III-IV acute GVHD and moderate-severe chronic GVHD occurred in 23% and 30%, respectively. One-year NRM was 10%. Predicted three-year overall survival, disease-free survival, and relapse were 53%, 53%, and 26%, respectively, in all patients and 79%, 74%, and 9%, respectively, in patients with a low/intermediate disease risk index (DRI). In multivariate analysis, DRI was the most significant predictor of survival and relapse. Use of TBI (versus busulfan) had no significant impact on survival but was associated with significantly less BK virus-associated hemorrhagic cystitis. We contrast our results with other published reports of MA haplo-HSCT PT/Cy in the literature and attempt to define the comparative utility of MA haplo-HSCT to other methods of transplantation

Mobilized Peripheral Blood Stem Cells Versus Unstimulated Bone Marrow As a Graft Source for T-Cell-Replete Haploidentical Donor Transplantation Using Post-Transplant Cyclophosphamide.

Purpose T-cell-replete HLA-haploidentical donor hematopoietic transplantation using post-transplant cyclophosphamide was originally described using bone marrow (BM). With increasing use of mobilized peripheral blood (PB), we compared transplant outcomes after PB and BM transplants. Patients and Methods A total of 681 patients with hematologic malignancy who underwent transplantation in the United States between 2009 and 2014 received BM (n = 481) or PB (n = 190) grafts. Cox regression models were built to examine differences in transplant outcomes by graft type, adjusting for patient, disease, and transplant characteristics. Results Hematopoietic recovery was similar after transplantation of BM and PB (28-day neutrophil recovery, 88% v 93%, P = .07; 100-day platelet recovery, 88% v 85%, P = .33). Risks of grade 2 to 4 acute (hazard ratio [HR], 0.45; P \u3c .001) and chronic (HR, 0.35; P \u3c .001) graft-versus-host disease were lower with transplantation of BM compared with PB. There were no significant differences in overall survival by graft type (HR, 0.99; P = .98), with rates of 54% and 57% at 2 years after transplantation of BM and PB, respectively. There were no differences in nonrelapse mortality risks (HR, 0.92; P = .74) but relapse risks were higher after transplantation of BM (HR, 1.49; P = .009). Additional exploration confirmed that the higher relapse risks after transplantation of BM were limited to patients with leukemia (HR, 1.73; P = .002) and not lymphoma (HR, 0.87; P = .64). Conclusion PB and BM grafts are suitable for haploidentical transplantation with the post-transplant cyclophosphamide approach but with differing patterns of treatment failure. Although, to our knowledge, this is the most comprehensive comparison, these findings must be validated in a randomized prospective comparison with adequate follow-up

Reduced-Intensity Allogeneic Transplantation Provides High Event-Free and Overall Survival in Patients with Advanced Indolent B Cell Malignancies: CALGB 109901

CALGB conducted a Phase II study to evaluate the safety and efficacy of a reduced-intensity conditioning regimen with allogeneic transplantation to treat patients with recurrent low grade B cell malignancies. Patients over age 18 with a diagnosis of relapsed, chemotherapy-sensitive disease underwent transplantation with a matched sibling donor and conditioning with cyclophosphamide (1 g/m2/d × 3) and fludarabine phosphate (25 mg/m2/d × 5). GVH prophylaxis included cyclosporine or tacrolimus plus low-dose methotrexate. Forty-four evaluable patients with a median age of 53 and median of two prior regimens were accrued. Sixteen patients had follicular NHL and 28 had histologies including 7 indolent B cell lymphomas, 4 mantle cell, 15 chronic lymphocytic leukemia, and 2 prolymphocytic leukemia pts. The six-month treatment-related mortality (TRM) was 2.4% and three-year TRM was 9%. Three-year event-free and overall survival were.75 and .81 for the follicular patients, .59 and .71 for the CLL/PLL patients, and .55 and .64 for the other histologies. The incidence of grade 2–4 acute graft vs host disease (GVHD) was 29% and extensive chronic GVHD was 18%. This report demonstrates that allogeneic sibling transplantation with a reduced intensity conditioning regimen is safe and efficacious for patients with advanced indolent B cell malignancies enrolled on a Cooperative Group study

Reduced-Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation for Patients with Hematologic Malignancies Who Relapse following Autologous Transplantation: A Multi-institutional Prospective Study from the Cancer and Leukemia Group B (CALGB trial 100002)

We prospectively treated 80 patients with relapse of malignancy or secondary myelodysplasia after autologous hematopoietic cell transplantation (AHCT) with allogeneic hematopoietic cell transplantation (allo-HCT) using a reduced-intensity conditioning (RIC) regimen of fludarabine 150 mg/m2 plus intravenous busulfan 6.4 mg/kg. Both sibling (MSD) and unrelated donors (MUD) were allowed. Patients transplanted from MUD donors received more intensive graft-versus-host disease (GVHD) prophylaxis, including rabbit anti-thymocyte globulin 10 mg/kg, mycophenolate mofetil, and an extended schedule of tacrolimus. With a median follow-up of 3.1 years (0.9 to 5.8), TRM at 6 months and 2 years was 8% and 23% respectively. Neither TRM nor the rates of acute GVHD were different in those with sibling or MUD donors. Donor CD3 cell chimerism > 90% at day +30 was achieved more often in patients with MUD than with MSD donors, 70% versus 23% (p<0.0001). Median EFS was higher in patients who achieved early full donor chimerism (14.2 versus 8 mo, p = 0.0395). Allo-HCT using this RIC regimen can be performed with low TRM in patients who have received a prior AHCT. Efforts to improve early donor CD3 chimerism may improve EFS

HLA-Identical Sibling Allogeneic Transplants versus Chemotherapy in Acute Myelogenous Leukemia with t(8;21) in First Complete Remission: Collaborative Study between the German AML Intergroup and CIBMTR

AbstractWe studied the role of HLA-matched sibling hematopoietic cell transplantation (HCT) in treating t(8;21) acute myelogenous leukemia (AML) in first remission. Outcomes of 118 patients receiving HCT and reported to the Center for International Blood and Marrow Transplant Research were compared with 132 similar patients receiving chemotherapy selected from 8 German AML Intergroup multicenter trials. Characteristics of the cohorts were similar except that chemotherapy recipients were significantly older. To adjust for time to treatment bias, outcomes were compared using left-truncated Cox regression models. Transplants were associated with higher treatment-related mortality (TRM; relative risk [RR] 6.76, 95% confidence interval [CI] 2.95-15.45, P < .001), lower relapse (RR 0.47, 95% CI 0.25-0.85, P = .01), and similar relapse-free survival (P = .2). Loss of sex chromosomes (LOS) in addition to t(8;21) had a negative impact on overall survival (OS) in patients receiving chemotherapy. Patients without LOS experienced shorter survival after HCT comparing to chemotherapy (RR 3.05, P = .02), whereas patients with LOS had similar survival regardless of postremission therapy. In both cohorts, white blood cell count (WBC) at diagnosis >25 × 109/L was associated with a higher relapse risk (RR = 2.09, P = .03), lower relapse-free (RR = 1.9, P = .008), and OS (RR = 1.91, P = .01). In this cohort of patients with t(8;21) AML, HCT did not improve OS, because reduction of relapse was offset by high TRM. In the group without LOS, survival after chemotherapy was far superior to HCT. These results suggest that patients with t(8;21) AML without poor prognostic factors have higher rates of survival after chemotherapy as a post remission therapy compared to HCT

Haploidentical vs. sibling, unrelated, or cord blood hematopoietic cell transplantation for acute lymphoblastic leukemia

The role of haploidentical hematopoietic cell transplantation (HCT) using posttransplant cyclophosphamide (PTCy) for acute lymphoblastic leukemia (ALL) is being defined. We performed a retrospective, multivariable analysis comparing outcomes of HCT approaches by donor for adults with ALL in remission. The primary objective was to compare overall survival (OS) among haploidentical HCTs using PTCy and HLA-matched sibling donor (MSD), 8/8 HLAmatched unrelated donor (MUD), 7 /8 HLA-MUD, or umbilical cord blood (UCB) HCT. Comparing haploidentical HCT to MSD HCT, we found that OS, leukemia-free survival (LFS), nonrelapse mortality (NRM), relapse, and acute graft-versus-host disease (aGVHD) were not different but chronic GVHD (cGVHD) was higher in MSD HCT. Compared with MUD HCT, OS, LFS, and relapse were not different, but MUD HCT had increased NRM (hazard ratio [HR], 1.42; P = .02), grade 3 to 4 aGVHD (HR, 1.59; P = .005), and cGVHD. Compared with 7/8 UD HCT, LFS and relapse were not different, but 7/8 UD HCT had worse OS (HR, 1.38; P = .01) and increased NRM (HR, 2.13; P <_ .001), grade 3 to 4 aGVHD (HR, 1.86; P = .003), and cGVHD (HR, 1.72; P <_ .001). Compared with UCB HCT, late OS, late LFS, relapse, and cGVHD were not different but UCB HCT had worse early OS (<_18 months; HR, 1.93; P < .001), worse early LFS (HR, 1.40; P = .007) and increased incidences of NRM (HR, 2.08; P < .001) and grade 3 to 4 aGVHD (HR, 1.97; P < .001). Haploidentical HCT using PTCy showed no difference in survival but less GVHD compared with traditional MSD and MUD HCT and is the preferred alternative donor HCT option for adults with ALL in complete remission

Reduced-Intensity Allografting as First Transplantation Approach in Relapsed/Refractory Grades One and Two Follicular Lymphoma Provides Improved Outcomes in Long-Term Survivors

Comparison of long-term outcomes in patients with refractory/relapsed grade 1-2 follicular lymphoma (FL) after allogeneic (allo-HCT) vs. autologous hematopoietic cell transplantation (auto-HCT) in the rituximab-era