Small studies suggest an association of donor-specific anti-human leukocyte antigen (HLA) antibodies (DSAs) with primary graft failure (GF) following haploidentical stem cell transplantation, but primary graft rejection (GR) was not discriminated from primary poor graft function (PGF). In this study, we aimed to determine the association of DSAs with primary GF, including GR and PGF, in patients who underwent unmanipulated haploidentical blood and marrow transplantation. A total of 345 subjects were prospectively recruited and randomly selected as training group (n = 173) and validation group (n = 172). Patient plasma/serum was screened. For HLA antibody positive samples with a median fluorescent intensity (MFI) >500, DSAs were further tested using a LABScreen Single Antigen Kit (One Lambda). A total of 342 patients (99.1 %) achieved sustained myeloid engraftment. The median times to neutrophil engraftment and platelet engraftment were 13 days (range, 8–28 days) and 18 days (range, 6–330 days), respectively. The cumulative incidence of primary GF was 6.4 ± 1.3 % and included GR (0.9 ± 0.5 %) and PGF (5.5 ± 1.2 %). Of the 345 cases tested, 39 (11.3 %) were DSA positive. Multivariate models showed that DSAs (MFI ≥ 10,000) were correlated to primary GR (P < 0.001) and that DSAs (MFI ≥ 2000) were strongly associated with primary PGF (P = 0.005). All patients were classified into three groups for analysis. Group A included cases that were DSA negative and those with a DSA MFI <2000 (n = 316), group B included cases with a 2000 ≤ MFI < 10,000 (n = 19), and group C included cases with a MFI ≥10,000 (n = 10). The DSAs were associated with an increased incidence of the primary GF (3.2 vs. 31.6 vs. 60 %, for groups A, B, and C, respectively, P < 0.001), transplant-related mortality (TRM) rate (17.2 vs. 14.7 vs. 33.3 %, for groups A, B, and C, respectively, P = 0.022), and inferior overall survival (OS, 77.3 vs. 85.3 vs. 44.4 %, for groups A, B, and C, respectively, P = 0.015). The primary GF was independently associated with a higher incidence of TRM (P < 0.001), inferior disease-free survival (P < 0.001), and OS (P < 0.001). The findings confirmed the effect of DSAs on primary GF, including GR and PGF, and survival. Our results suggest incorporating DSAs in the algorithm for haploidentical donor selection.

This study compared the effects of pre-transplantation minimal residual disease (pre-MRD) on outcomes in AML patients who underwent human leukocyte antigen-matched sibling donor transplantation (MSDT) or who received unmanipulated haploidentical allografts. A retrospective study (n = 339) and a prospective study (n = 340) were performed. MRD was determined using multiparameter flow cytometry. Either after retrospective or prospective analysis, patients with negative pre-MRD (pre-MRDneg) had a lower incidence of relapse than those with positive pre-MRD (pre-MRDpos) in MSDT settings (P < 0.001 for all), but relapse was comparable in Haplo-SCT settings for patients with pre-MRDneg versus pre-MRDpos (P = 0.866 and 0.161, respectively). In either the retrospective (n = 65) or the prospective study (n = 76), pre-MRDpos subjects receiving Haplo-SCT experienced a lower incidence of relapse than those who underwent MSDT (P < 0.001 and p = 0.017, respectively). Of the patients with pre-MRDpos in either the total (n = 141) or the subgroup excluding cases which received donor lymphocyte infusion (DLI; n = 105), those who underwent MSDT had a higher incidence of relapse than those receiving haplo-SCT (P < 0.01 for all). Multivariate analysis showed that, for pre-MRDpos cases, haplo-SCT was associated with a low incidence of relapse and with better LFS and OS in either retrospective group, prospective group, combination groups, or subgroup not including cases which received DLI. The results indicated that, for pre-MRD-positive AML patients, haplo-SCT was associated with lower incidence of relapse and better survival, suggesting a stronger anti-leukemia effect.

Background: Maintenance therapy with imatinib during the post-transplant period has been used for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL); however, its efficacy has not been demonstrated. A study was designed to investigate the safety of imatinib and its efficacy in preventing hematological relapse and improving disease-free survival (DFS) when administered after allogeneic hematopoietic stem cell transplantation (allo-HCT). Methods: Patients with Ph + ALL that received allo-HCT were enrolled in the study. Real-time quantitative reverse-transcription polymerase chain reaction (qRT-PCR) was used to detect BCR-ABL transcript levels. Imatinib therapy was initiated if patient neutrophil counts were > 1.0 × 10⁹/L and platelet counts were > 50.0 × 10⁹/L, or if they displayed either elevated BCR-ABL transcript levels in two consecutive tests, or a BCR-ABL transcript level ≥ 10^-2 after initial engraftment. Patients receiving imatinib after relapse were assigned to the non-imatinib group. The imatinib treatment was scheduled for 3–12 months, until BCR-ABL transcript levels were negative at least for three consecutive tests or complete molecular remission was sustained for at least 3 months. Results: A total of 82 patients were enrolled. Sixty-two patients initiated imatinib therapy post-HCT. Imatinib therapy was initiated at a median time of 70 days post-HCT. Grade 3–4 adverse events (AEs) occurred in 17.7% of patients. Ten patients (16.1%) terminated imatinib therapy owing to AEs. Among the patients in imatinib and non-imatinib groups, the estimated 5-year relapse rate was 10.2% and 33.1% (p = 0.016), and the 5-year probability of DFS was 81.5% and 33.5% (p = 0.000) with the median follow-up of 31 months (range, 2.5-76 months) and 24.5 months (range, 4–72 months), respectively. Multivariate analysis identified imatinib maintenance therapy post-HCT as an independent prognostic factor for DFS (p = 0.000, hazard ratio [HR] =4.8) and OS (p = 0.000, HR = 6.2). Conclusions: These results indicate that relapse rate can be reduced and DFS may be improved in Ph + ALL patients with imatinib maintenance therapy after HCT. BCR-ABL monitoring by qRT-PCR can guide maintenance therapy with imatinib including initiation time and treatment duration after allo-HCT.

The optimal dose of rabbit antithymocyte globulin (ATG, ImtixSangstat) minimizing infections without increasing graft-versus-host disease (GVHD) is unknown in T cell-replete, G-CSF-primed haploidentical hematopoietic stem cell transplantation (haplo-HSCT). Four hundred and eight patients were enrolled in this multicenter study to evaluate the effect of 7.5 mg/kg and 10.0 mg/kg rabbit ATG on viral infections and GVHD prophylaxis after haplo-HSCT. The primary endpoint was EBV DNAemia within 1 year posttransplantation. The 1-year incidence of EBV DNAemia was 20.7% (95% confidence interval, 15.4–26.5) and 40.0% (33.3–46.6) in the 7.5 mg/kg and 10.0 mg/kg groups, respectively (P < 0.001). The 100-day cumulative incidence of grade II to IV aGVHD was 27.1% (21.1–33.4) and 25.4% (19.6–31.5) in the 7.5 mg/kg and 10.0 mg/kg ATG groups, respectively (P = 0.548). The 2-year incidence of chronic GVHD was 34.6% (27.8–41.4) and 36.2% (29.1–43.2) in the 7.5 mg and 10.0 mg groups (P = 0.814). The 1-year incidence of CMV DNAemia was 73.4% (67.2–79.4) and 83.4% (77.5–87.9) in the 7.5 mg/kg and 10.0 mg/kg groups (P = 0.038). The 3-year overall survival posttransplantation was 69.5% (63.2–75.8) and 63.5% (56.2–70.8), and the disease-free survival was 62.2% (55.3–69.1) and 60.3% (53.0–67.6) in the 7.5 mg/kg and 10.0 mg/kg groups, respectively (OS: P = 0.308; DFS: P = 0.660). The counts of EBV- and CMV-specific cytotoxic T cells (CTLs) were higher in the 7.5 mg/kg group than in the 10.0 mg/kg group early posttransplantation. Compared with 10.0 mg/kg, 7.5 mg/kg ATG for GVHD prophylaxis was associated with reduced EBV and CMV infections without increased incidence of GVHD in haplo-HSCT, probably by affecting EBV- and CMV-specific CTLs. clinicaltrials.gov, NCT01883180 . Registered 14 June 2013.

Persons with acute leukemia relapsing after allotransplant and who respond to anti-leukemia interventions are at high risk of a second relapse. We studied the impact of minimal residual disease (MRD)- and graft-vs.-host disease (GvHD)-guided multiple consolidation chemotherapy and donor lymphocyte infusions (DLIs) to prevent second relapse in patients with acute leukemia relapsing post-transplant and who achieved complete remission after induction chemotherapy and DLI. Forty-seven subjects with acute leukemia relapsing after an allotransplant and who achieved complete remission after post-relapse induction chemotherapy and DLI were eligible. The use of consolidation chemotherapy and DLI was guided by the results of MRD testing and whether or not DLI caused acute and/or chronic GvHD. Outcomes were compared with those of 34 similar historical controls who did not receive consolidation chemotherapy and DLIs after induction chemotherapy and DLI. One-year cumulative incidence of relapse (CIR; 22 % 95 % confidence interval (10, 35 %) vs. 56 % (39, 73 %); P < 0.0001), leukemia-free survival (LFS; 71 % (57, 84 %) vs. 35 % (19, 51 %); P < 0.0001), and survival (78 % (66, 90 %) vs. 44 % (27, 61 %); P < 0.0001) was significantly better in subjects than controls. In multivariate analyses, no chronic GvHD after therapy (hazard ratio (HR) = 3.56 (1.09, 11.58); P = 0.035) and a positive MRD test after therapy (HR = 21.04 (4.44, 94.87); P < 0.0001) were associated with an increased CIR. These data suggest MRD- and GvHD-guided multiple consolidation chemotherapy and DLIs reduce CIR and increase LFS and survival compared with controls in persons relapsing after allotransplant for acute leukemia. ChiCTR-ONC-12002912 . Donor lymphocyte infusion for the treatment of leukemia relapse following allogeneic hematopoeitic stem cell transplant.

Background: Compared with HLA-matched sibling donor (MSD) transplant, the outcomes of haploidentical donor (HID) transplant for refractory acute leukemia need to be further explored. In this study, we compared the outcomes of HID with MSD for refractory acute leukemia. Patients and methods: This study population came from two prospective multicenter trials (NCT01883180, NCT02673008). Two hundred and seventy-eight patients with refractory acute leukemia were enrolled in this study, including 119 in HID group and 132 in MSD group. Sequential intensified conditioning was employed in all patients, and donor lymphocyte infusion (DLI) was administered in patients in the absence of active GVHD and according to minimal residual disease (MRD) from day + 60 post-transplantation for preventing relapse. Results: The complete remission of leukemia by day + 30 post-transplant were 94% and 93%, respectively, in HID and MSD groups (p = .802). The 1-year incidence of grades II–IV acute GVHD was 62% and 54% (p = .025), and 3-year incidence of chronic GVHD was 55% and 55% (p = .789), respectively, in two groups. HID transplant had lower incidence of first episode of MRD positivity and relapse than MSD transplant (28% vs 45%, p = .006; 26% vs 38%, p = .034). There was higher infection-related mortality in HID than MSD (8% vs 2%, p = .049) within the first 100 days’ post-transplant. The 5-year overall survival was 46% and 42% (p = .832), respectively; the 5-year disease-free survival was 43% and 39% (p = .665), in HID and MSD groups, respectively. Conclusions: HID transplant has lower relapse, but higher infection-related mortality and similar survival rates in refractory acute leukemia by the strategy of sequential intensified conditioning followed by DLI compared with MSD transplant.