Unrelated Cord Blood Transplantation for Acute Leukemia Diagnosed in the First Year of Life: Outcomes and Risk Factor Analysis

Infant acute leukemia still has a poor prognosis, and allogeneic hematopoietic stem cell transplantation is indicated in selected patients. Umbilical cord blood (UCB) is an attractive cell source for this population because of the low risk of chronic graft-versus-host disease (GVHD), the strong graft-versus-leukemia effect, and prompt donor availability. This retrospective, registry-based study reported UCB transplantation (UCBT) outcomes in 252 children with acute lymphoblastic leukemia (ALL; n?=?157) or acute myelogenous leukemia (AML; n?=?95) diagnosed before 1 year of age who received a single-unit UCBT after myeloablative conditioning between 1996 and 2012 in European Society for Blood and Marrow Transplantation centers. Median age at UCBT was 1.1 years, and median follow-up was 42 months. Most patients (57%) received a graft with 1 HLA disparity and were transplanted in first complete remission (CR; 55%). Cumulative incidence function (CIF) of day 100 acute GVHD (grades II to IV) was 40%?±?3% and of 4-year chronic GVHD was 13%?±?2%. CIF of 1-year transplant-related mortality was 23%?±?3% and of 4-year relapse was 27%?±?3%. Leukemia-free-survival (LFS) at 4 years was 50%?±?3%; it was 40% and 66% for those transplanted for ALL and AML, respectively (P?=?.001). LFS was better for patients transplanted in first CR, regardless of diagnosis. In multivariate model, diagnosis of ALL (P?=?.001), advanced disease status at UCBT (<.001), age at diagnosis younger than 3 months (P?=?.012), and date of transplant before 2004 were independently associated with worse LFS. UCBT is a suitable option for patients diagnosed with infant acute leukemia who achieve CR. In this cohort, patients with AML had better survival than those with ALL.     

Myeloablative Cord Blood Transplantation in Adults with Acute Leukemia: Comparison of Two Different Transplant Platforms

We compared the clinical outcomes of adults with acute leukemia that received single-unit umbilical cord blood transplantation (sUCBT) after conditioning with a busulfan/antithymocyte globulin (BU-ATG)–based regimen at University Hospital La Fe (n = 102) or double-unit UCBT (dUCBT) after conditioning with a total body irradiation (TBI)–based regimen at the University of Minnesota (n = 91). Nonrelapse mortality, relapse and disease-free survival were similar in the 2 groups. Multivariate analyses, showed more rapid neutrophil (hazard ratio [HR], .6; 95% confidence interval [CI], .45 to .80; P = .0006) and platelet recovery (HR, .59; 95% CI, .43 to.83; P = .002) after the BU-ATG-based conditioning and sUCBT. Although there was a lower risk of acute graft-versus-host disease (GVHD) grade II to IV (HR, 2.81; 95% CI, 1.75 to 4.35; P < .001) after BU-ATG and sUCBT, the incidences of grade III to IV acute and chronic GVHD were similar between the 2 groups. Regarding disease-specific outcomes, disease-free survival in both acute myeloid leukemia and acute lymphoblastic leukemia (ALL) patients were not significantly different; however, a significantly lower relapse rate was found in patients with ALL treated with TBI and dUCBT (HR, .3; 95% CI, .12 to .84; P = .02). In the context of these specific treatment platforms, our study demonstrates that sUCB and dUCBT offer similar outcomes.     

Updated Comparison of 7/8 HLA Allele-Matched Unrelated Bone Marrow Transplantation and Single-Unit Umbilical Cord Blood Transplantation as Alternative Donors in Adults with Acute Leukemia

The outcomes of 7/8 allele-matched unrelated bone marrow transplantation (7/8 UBMT) and umbilical cord blood transplantation (UCBT) have been improving. We retrospectively analyzed adults with acute leukemia who underwent their first 7/8 UBMT or UCBT in Japan. Between January 2008 and December 2017, a total of 4150 patients were recorded, including 488 who underwent 7/8 UBMT and 3662 who underwent UCBT. Only 32 patients with 7/8 UBMT had graft-versus-host-disease (GVHD) high-risk HLA mismatched pairs. Overall survival at 3 years was 54% for 7/8 the UBMT group and 46% for the UCBT group, a nonsignificant difference in multivariate analysis (hazard ratio [HR], 1.01; 95% confidence interval [CI], .88 to 1.17; P = .89). The 7/8 UBMT and UCBT groups showed a similar nonrelapse mortality rate (HR, 1.16; 95% CI, .96 to 1.45; P = .16) and relapse rate (HR, .85; 95% CI, .71 to 1.02; P = .08). However, the UCBT group had a lower risk of grade II-IV acute GVHD (HR, .76; 95% CI, .65 to .88; P < .001) and chronic GVHD (HR, .77; 95% CI, .66- .91; P = .002) compared with the 7/8 UBMT group. In stratified analyses combining disease risk with conditioning intensity, 7/8 UBMT showed superior overall survival to UCBT in standard risk and myeloablative conditioning (HR, .72; 95% CI, .56 to .93; P = .014). Both 7/8 UBMT and UCBT are appropriate alternative donor procedures. The stem cell source can be selected on the basis of disease risk, patient tolerability, or concerns regarding GVHD.     

Alternative Donor Transplantation for Older Patients with Acute Myeloid Leukemia in First Complete Remission: A Center for International Blood and Marrow Transplant Research-Eurocord Analysis

We studied patients with acute myeloid leukemia (AML) over age 50 and in first complete remission (CR1) after adult unrelated donor (URD) (n = 441, 8/8 HLA matched; n = 94, 7/8 HLA matched) or umbilical cord blood (UCB; n = 205) transplantations. UCB recipients achieved CR1 within 8 weeks less often, and received reduced-intensity conditioning and cyclosporine-based graft-versus-host disease (GVHD) prophylaxis more often. Neutrophil recovery was slower in UCB (69% by day 28) compared with 8/8 HLA-matched URD (97%) and 7/8 HLA-matched (91%) (P < .001) recipients. Three-year transplantation-related mortality (TRM) was higher and leukemia-free survival (LFS) lower with UCB (35% and 28%, respectively) versus 8/8 HLA-matched URD (27% and 39%, respectively). TRM was higher in 7/8 HLA-matched URD (41%, P = .01), but LFS was similar at 34% (P = .39). Three-year chronic GVHD was the lowest in UCB (28%) versus 53% and 59% in 8/8 and 7/8 HLA-matched URD recipients, respectively. Three-year survival was 43% in 8/8 HLA-matched URD (95% confidence interval [CI], 38% to 48%), 30% in UCB (95% CI, 23% to 37%) (P = .002) and 37% in 7/8 URD (95% CI, 27 to 46). Allotransplantation for AML in CR1 with any of these grafts extends LFS for over one third of older patients. In the absence of an 8/8 HLA-matched URD or when transplantation is needed urgently, UCB can provide extended survival. Less frequent chronic GVHD with UCB transplantation may be of particular value for older patients.     

A meta-analysis of unrelated donor umbilical cord blood transplantation versus unrelated donor bone marrow transplantation in acute leukemia patients

Umbilical cord blood has emerged as an alternative stem cell source to bone marrow or peripheral blood stem cells. Umbilical cord blood transplantation (UCBT) is also potentially curative for acute leukemia. However, the effect of unrelated donor bone marrow transplantation (UBMT) and UCBT on the outcome of patients with acute leukemia has not been systematically reviewed. In the present meta-analysis, we systematically searched Cochrane Library, MEDLINE, EMBASE, and CNKI up to May 2011. Two reviewers extracted data independently. Seven studies totaling 3389 patients have been assessed. Pooled results found that the incidence of engraftment failure and transplantation-related mortality were higher in UCBT than in UBMT, and relative risks (RRs) were 4.27 (95% confidence interval [CI], 2.94-6.21) and 1.27 (95% CI, 1.01-1.59), respectively. The rates of acute and chronic graft-versus-host disease (GVHD) in the UCBT group were significantly lower than that in the UBMT group, and RRs were 0.71 (95% CI, 0.65-0.79) and 0.69 (95% CI, 0.52-0.91), respectively. The relapse rate was similar between the UCBT and UBMT group. The leukemia-free survival (LFS) and overall survival (OS) were significantly lower in the UCBT group than in the UBMT group; RRs were 1.14 (95% CI, 1.07-1.22) and hazard ratios (HRs) were 1.31 (95% CI, 1.16-1.48), respectively. Subgroup analysis showed that in patients with acute lymphoblastic leukemia (ALL), the survival was similar between UCBT and UBMT.     

Prospective Randomized Study Comparing Myeloablative Unrelated Umbilical Cord Blood Transplantation versus HLA-Haploidentical Related Stem Cell Transplantation for Adults with Hematologic Malignancies

In this prospective randomized study, we compared the outcomes of single-unit umbilical cord blood transplantation (UCBT) and unmanipulated haploidentical stem cell transplantation (haplo-SCT) with post-transplantation cyclophosphamide (PTCy) in adults with hematologic malignancies. All patients received a myeloablative conditioning (MAC) regimen consisting of thiotepa, busulfan, and fludarabine, with antithymocyte globulin (ATG) added for UCBT recipients. Nineteen patients were randomized to UCBT and the other 26 to haplo-HSCT. Four patients (15%) allocated to the haplo-HSCT arm lacked a suitable donor and were crossed over to the UCBT arm. Finally, 23 underwent UCBT and 22 underwent haplo-HSCT. The cumulative incidence of neutrophil recovery was 87% at a median of 19 days (range, 13 to 24 days) in the UCBT arm versus 100% at a median of 17 days (range, 13 to 25 days) in the haplo-SCT arm (P = .04). Platelet recovery was 70% at a median of 40 days (range, 18 to 129 days) in the UCBT arm versus 86% at a median of 24 days (range, 12 to 127 days) in the haplo-HCT arm (P = .02). Rates of acute graft-versus-host disease (GVHD) grade II-IV or grade III-IV, overall chronic GVHD, and extensive chronic GVHD in the UCBT and Haplo-SCT arms were 43% versus 36% (P = .8), 9% versus 9% (P = 1), 66% versus 43% (P = .04), and 41% versus 23% (P = .2), respectively. Two-year nonrelapse mortality and relapse in the 2 arms were 52% versus 23% (P = .06) and 17% versus 23% (P = .5), respectively. Two-year disease-free survival, overall survival, and GVHD/relapse-free survival in the 2 arms were 30% versus 54% (P = .2), 35% versus 59% (P = .1), and 17% versus 40% (P = .04), respectively. Our data show that in the context of an MAC regimen, haplo-SCT with PTCy provides improved outcomes compared with ATG-containing single-unit UCBT.     

Transplantation from Matched Siblings Using Once-Daily Intravenous Busulfan/Fludarabine with Thymoglobulin: A Myeloablative Regimen with Low Nonrelapse Mortality in All But Older Patients with High-Risk Disease

Two hundred patients received hematopoietic stem cell transplantation (HSCT) from matched sibling donors (MSD) after myeloablative conditioning including fludarabine (Flu) and once-daily intravenous busulfan (Bu). Thymoglobulin (TG) was added to methotexate (MTX) and cyclosporine (CsA) as graft-versus-host disease (GVHD) prophylaxis. For low-risk (acute leukemia CR1/CR2, CML CP1) patients projected 5-year nonrelapse mortality (NRM) and overall survival (OS) were 4% and 76% for those ≤45 years old (n = 54) and 6% and 83% for those >45 (n = 31). For high-risk (HR) patients NRM was 6% versus 27% (18% at 1 year) (P = .04) and OS 64% versus 37% (P = .47) in younger (n = 40) and older (n = 75) patients, respectively. To correct for imbalance in HR diagnoses each of 17 younger HR patients were matched with 2 older HR (OHR) patients by diagnosis and details of stage, and thereafter for other risk factors. For the younger HR and OHR patients, respectively, OS was 70% versus 37% (P = .02) and NRM 0 versus 34% (P = .02). When outcomes of OHR patients were compared with the other 3 groups combined NRM was 27% versus 5%, respectively (P = .002). Incidence of acute graft-versus-host disease (aGVHD) grade II-IV, aGVHD grade III-IV, and chronic GVHD (cGVHD) was 23% versus 10% (P = .02), 4% versus 2% (P = ns), and 66% versus 41% (P = .001), respectively. Nine of 14 nonrelapse deaths in the OHR group were related to GVHD or its treatment compared with 3 of 6 in all others (P value for GVHD related death = .01). Multivariate analysis of OS and DFS correcting for potentially confounding pretransplant factors identified only the OHR patients as having significantly increased risk (relative risk [RR] 3.32, confidence interval [CI] 1.71-6.47, P < .0001, and RR 3.32, CI 1.71-6.43, P < .0001, respectively). The effect of age on NRM is only apparent in HR patients, and is not explained by heterogeneity in diagnoses. Older HR patients experience more GVHD and more GVHD-related death than others, but NRM is no higher than reported with many nonmyeloablative regimens.     

Allogeneic transplantation for adult acute leukemia in first and second remission with a novel regimen incorporating daily intravenous busulfan, fludarabine, 400 CGY total-body irradiation, and thymoglobulin.

A myeloablative conditioning regimen incorporating daily intravenous busulfan, fludarabine, and 400 cGy total-body irradiation was given before allogeneic stem cell transplantation (SCT) to 64 adults with acute leukemia in first and second remission. Graft-versus-host disease (GVHD) prophylaxis included methotrexate, cyclosporine A, and rabbit antithymocyte globulin (Thymoglobulin). For 31 matched related (MRD) and 33 alternate donor (AD) SCT the incidence of acute GVHD grade II-IV was 11% +/- 6% versus 35% +/- 9% (P = .047), acute GVHD grade III-IV was 0% versus 10% +/- 6% (P = .09), and chronic GVHD was 40% +/- 9% versus 66% +/- 9% (P = NS), respectively. Overall transplant-related mortality (TRM) was 3% +/- 2%. Projected disease-free (DFS) and overall survival (OS) at 3 years for acute myelogenous leukemia (AML) (n = 36) are the same at 83% +/- 6%, and for acute lymphoblastic leukemia (ALL) (n = 28) are 65% +/- 10% and 78% +/- 8%, respectively. For MRD SCT DFS is 77% +/- 9%, OS 87% +/- 6%, for AD SCT the respective figures are 71% +/- 8% and 74% +/- 8%. OS and DFS in patients without and with high-risk features are 100% versus 71% +/- 7% (P = .007) and 88% +/- 8% versus 68% +/- 7% (P = .04), respectively. This combination appears relatively well tolerated, gives equivalent final outcomes from MRD and AD, and may be a reasonable alternative to conventional myeloablative regimens.     

Cytotoxic T-Lymphocyte Antigen-4 Single Nucleotide Polymorphisms Are Not Associated with Outcomes after Unrelated Donor Transplantation: A Center for International Blood and Marrow Transplant Research Analysis

Cytotoxic T-lymphocyte antigen-4 (CTLA-4) plays an essential role in T cell homeostasis by restraining immune responses. AG and GG genotypes of donor CTLA-4 SNP rs4553808 in patients after unrelated donor hematopoietic stem cell transplantations (HSCT) have been shown to be an independent predictor of inferior relapse-free survival (RFS) and overall survival (OS) compared with those with the AA genotype, in single-center studies. We tested the hypothesis that SNP rs4553808 is associated with RFS, OS, nonrelapse mortality (NRM) and the cumulative incidence of acute graft-versus-host disease (GVHD) and chronic GVHD in adults with acute myeloid leukemia and advanced myelodysplastic syndrome undergoing a first 8/8 or 7/8 HLA-matched unrelated donor HSCT. Multivariable analysis adjusting for relevant donor and recipient characteristics showed no significant association between SNP rs4553808 and OS, RFS, NRM, and incidence of acute and chronic GVHD. An exploratory analysis of other CTLA-4 SNPs, as well as studying the interaction with antithymocyte globulin, also demonstrated no significant associations. Our results indicate that CTLA-4 SNPs are not associated with HSCT outcomes.     

CD3+ cell dose and disease status are important factors determining clinical outcomes in patients undergoing unmanipulated haploidentical blood and marrow transplantation after conditioning including antithymocyte globulin.

Haploidentical transplantation is a feasible alternative for patients with life-threatening hematologic diseases who lack a matched donor. Factors affecting the clinical outcomes of haploidentical transplantation remain under investigation. We analyzed 157 consecutive patients with leukemia who underwent transplantation with nonmanipulated granulocyte colony-stimulating factor (G-CSF)-mobilized marrow and peripheral blood cells (G-BMPBs) from haploidentical donors after receiving myeloablative chemotherapy (Ara-C + BuCy + antithymocyte globulin). Follow up observations after transplantation were made from 48 days to 1191 days (median, 448 days). Multivariate analysis indicated that the cohort given higher doses of CD3(+) cells (> or = 177 x 10(6) /kg) in allograft transplantation had a significantly lower treatment-related mortality (TRM) (relative risk [RR] = 0.35; 95% CI = 0.16-0.77; P = .0090), better leukemia-free survival (LFS) (RR = 0.46; 95% CI = 0.26-0.84; P = .0106), and better overall survival (OS) (RR = 0.42; 95% CI = 0.23-0.78; P = .0058). Inversely, advanced-stage disease was a strong predictor of greater posttransplantation relapse (RR = 3.48; 95% CI = 1.26- 9.60; P = .0159), worse LFS (RR = 2.56; 95% CI = 1.33-4.95; P = .0050), and worse OS (RR = 2.77; 95% CI = 1.39-5.53; P = .0038). A high number of CD3(+) cells (> 177 x 10(6)/kg) given to patients resulted in statistically less TRM and more intensive graft versus leukemia effect without producing more severe grades of GVHD, all resulting in a significantly better overall clinical outcome from haploidentical transplantation.     

T Cell Clonal Dynamics Determined by High-Resolution TCR-β Sequencing in Recipients after Allogeneic Hematopoietic Cell Transplantation

Delayed reconstitution of the immune system is a long-recognized complication after allogeneic hematopoietic cell transplantation (HCT). Specifically, loss of T cell diversity has been thought to contribute to infectious complications, graft-versus-host disease (GVHD), and disease relapse. We performed serial high-resolution next-generation sequencing of T cell receptor (TCR)-β in 99 related or unrelated donor (57 unrelated, 42 related) allogeneic HCT recipients (55 with reduced-intensity conditioning, 44 with myeloablative conditioning) during the first 3 months after HCT using the immunoSEQ Assay. We measured T cell fraction, clonality (1- Peilou's evenness) and Daley-Smith richness from recipient samples at multiple time points. In agreement with previous studies, we found that although absolute T cell numbers recover relatively quickly after HCT, T cell repertoire diversity remains diminished. Restricted diversity was associated with conditioning intensity, use of antithymocyte globulin, and donor type. Increased number of expanded clones compared to donor T cell clones at day +30 was associated with the incidence of acute GVHD (hazard ratio [HR], 1.11; P = .00005). Even after exclusion of the 12 patients who developed acute GVHD before day +30, the association between acute GVHD and increased clonal expansion at day +30 remained (HR, 1.098; P = .041), indicating that increased clonal T cell expansion preceded the development of acute GVHD. Our results highlight T cell clonal expansion as a potential novel biomarker for acute GVHD that warrants further study.     

Donor Killer Immunoglobulin-Like Receptor (KIR) Genotype-Patient Cognate KIR Ligand Combination and Antithymocyte Globulin Preadministration Are Critical Factors in Outcome of HLA-C-KIR Ligand-Mismatched T Cell–Replete Unrelated Bone Marrow Transplantation

We previously reported the potent adverse effects of killer immunoglobulin-like receptor (KIR) ligand mismatch (KIR-L-MM) on the outcome of T cell–replete unrelated hematopoietic stem cell transplantation (UR-HSCT) through the Japan Marrow Donor Program. Other UR-HSCT studies have yielded inconsistent results. To address this discrepancy, we evaluated candidate factors contributing to the effects of KIR-L-MM on transplantation outcomes in retrospectively selected hematologic malignancy cases with uniform graft-versus-host disease (GVHD) prophylaxis (n = 1489). KIR-L-MM in the graft-versus-host direction (KIR-L-MM-G) was associated with a higher incidence of acute GVHD (aGVHD; P < .002) and a lower overall survival (OS; P < .0001) only without the preadministration of antithymocyte globulin (ATG). Furthermore, in KIR-L-MM-G, the donor KIR2DS2 gene with the patient cognate C1 ligand was associated with a higher incidence of aGVHD (P = .012). Multivariate analysis by Cox proportional hazard models suggested that donor 2DS2 and ATG preadministration were critical factors in grade III-IV aGVHD (hazard ratio = 1.96; 95% confidence interval = 1.01-3.80; P = .045, and hazard ratio = 0.56; 95% confidence interval = 0.31-0.99; P = .047, respectively). These results indicate that the adverse effects of KIR-L-MM-G depend on combination of donor-activating KIR genotype-patient cognate KIR ligand type and no ATG preadministration, thereby suggesting the importance of these factors in UR-HSCT and in leukemia treatment using natural killer (NK) cell alloreactivity.     

Thiotepa,Busulfan, and Fludarabine Conditioning Regimen in T Cell-Replete HLA-Haploidentical Hematopoietic Stem Cell Transplantation

We report the outcomes of 51 patients who underwent unmanipulated haploidentical hematopoietic stem cell transplantation (haplo-HSCT) with post-transplantation cyclophosphamide (PT-Cy) and antithymocyte globulin (ATG), from peripheral blood stem cells (PBSCs) or bone marrow, after receipt of a TBF (thiotepa, busulfan, and fludarabine) conditioning regimen. Their median age was 55 years (range, 16 to 72 years). Hematologic diagnoses included acute leukemias (n = 31), lymphoid neoplasm (n = 12), myeloproliferative neoplasm (n = 5), and myelodysplastic syndromes (n = 3). Thirty-seven patients (73%) were in complete remission. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and mycophenolate for all patients, associated with ATG in 39 patients (76.5%). The median time to neutrophil engraftment was 17 days (range, 12 to 34 days). The cumulative incidences of grade II-IV and grade III-IV acute GVHD were 27.5% and 14%, respectively. In patients receiving a PBSC graft and ATG prophylaxis, grade II-IV aGVHD occurred in 16% of patients. The use of ATG and a lower thiotepa dose (5 mg/kg versus 10 mg/kg) were associated with a reduced cumulative incidence of grade II-IV acute GVHD (P = .03 and .005, respectively). The 2-year cumulative incidence of chronic GVHD was 29% and was significantly reduced to 13% with the lower thiotepa dose (P = .002). After a median follow-up of 25 months (range, 12 to 62 months), the cumulative incidences of nonrelapse mortality, relapse, overall survival (OS), disease-free survival (DFS), and GVHD-free, relapse-free survival (GFRFS) were 20%, 22.5%, 67%, 58%, and 51%, respectively. Pretransplantation disease status (complete remission versus others) was the main factor associated with OS, DFS, and GFRFS. In conclusion, the TBF conditioning regimen is an appealing platform in the haplo-HSCT setting with PT-Cy in terms of engraftment rate, toxicity, and disease control. We found no benefit of a thiotepa dose of 10 mg/kg compared with a dose of 5 mg/kg. ATG reduced the risk of acute GVHD without comprising outcomes.     

Outcomes of Advanced Hodgkin Lymphoma after Umbilical Cord Blood Transplantation: A Eurocord and EBMT Lymphoma and Cellular Therapy & Immunobiology Working Party Study

Allogeneic stem cell transplantation is an alternative for patients with relapsed or refractory Hodgkin lymphoma (HL), but only limited data on unrelated umbilical cord blood transplantation (UCBT) are available. We analyzed 131 adults with HL who underwent UCBT in European Society for Blood and Marrow Transplantation centers from 2003 to 2015. Disease status at UCBT was complete remission (CR) in 59 patients (47%), and almost all patients had received a previous autologous stem cell transplantation. The 4-year progression-free survival (PFS) and overall survival (OS) were 26% (95% confidence interval [CI], 19% to 34%) and 46% (95% CI, 37% to 55%), respectively. Relapse incidence was 44% (95% CI, 36% to 54%), and nonrelapse mortality (NRM) was 31% (95% CI, 23% to 40%) at 4 years. In multivariate analysis refractory/relapsed disease status at UCBT was associated with increased relapse incidence (hazard ratio [HR], 3.14 [95% CI, 1.41 to 7.00], P?=?.005) and NRM (HR, 3.61 [95% CI, 1.58 to 8.27], P?=?.002) and lower PFS (HR, 3.45 [95% CI, 1.95 to 6.10], P < .001) and OS (HR, 3.10 [95% CI, 1.60 to 5.99], P?=?.001). Conditioning regimen with cyclophosphamide?+?fludarabine?+?2 Gy total body irradiation (Cy+Flu+2GyTBI) was associated with decreased risk of NRM (HR, .26 [95% CI, .10 to .64], P?=?.004). Moreover, Cy+Flu+2GyTBI conditioning regimen was associated with a better OS (HR, .25 [95% CI, .12 to .50], P < .001) and PFS (HR, .51 [95% CI, .27 to .96], P?=?.04). UCBT is feasible in heavily pretreated patients with HL. The reduced-intensity conditioning regimen with Cy+Flu+2GyTBI is associated with a better OS and NRM. However, outcomes are poor in patients not in CR at UCBT.     

Higher Peak Tacrolimus Concentrations after Allogeneic Hematopoietic Stem Cell Transplantation Increase the Risk of Endothelial Cell Damage Complications

Noninfectious transplantation-related complications (TRCs) such as graft-versus-host disease (GVHD) and endothelial cell damage (TRC-EC) are critical after allogeneic hematopoietic stem cell transplantation. Tacrolimus (TAC) is used to control GVHD. Hypertension and renal failure are common adverse events after TAC treatment. Higher blood concentrations of TAC would be expected to reduce the risk of GVHD but may increase TRC-EC. TRC-EC often develops in patients with GVHD; thus, it is difficult to clinically determine the proper intensity of immunosuppression. We therefore evaluated the impact of weekly mean/peak TAC blood concentrations (PTCs) on TRC-EC occurrence and prognosis. Patients (N = 295) who received TAC as a GVHD prophylaxis at our institute from 2009 to 2016 were eligible for this retrospective study. Forty-three patients were diagnosed with TRC-EC: 8 with sinusoidal obstructive syndrome, 28 with transplant-associated microangiopathy, and 7 with idiopathic pneumonia syndrome. The cumulative incidence of TRC-EC at 12 months was 13.8% (95% confidence interval [CI] 10.1% to 18.1%). After multivariate analysis high PTCs during days 22 to 28 (hazard ratio [HR] 2.47; 95% CI, 1.37 to 4.45; P < .01) and grades II to IV acute GVHD (HR, 5.61; 95% CI, 2.99 to 10.53; P < .01) were associated with TRC-EC occurrence. The probability of overall survival (OS) at 12 months was 67.7% (95% CI, 61.7% to 73.0%). After multivariate analysis TRC-EC diagnosis (HR, 2.47, 95% CI, 1.59 to 3.83; P < .01) and high-risk disease (HR, 1.75; 95% CI, 1.17 to 2.61; P < .01) were significantly associated with poor OS. In conclusion, higher PTC during days 22 to 28 increased the risk of TRC-EC. TRC-EC development was associated with poor OS.     

Effects of Priming with Recombinant Human Granulocyte Colony–Stimulating Factor on Conditioning Regimen for High-Risk Acute Myeloid Leukemia Patients Undergoing Human Leukocyte Antigen–Haploidentical Hematopoietic Stem Cell Transplantation: A Multicenter Randomized Controlled Study in Southwest China

HLA-haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is an effective and immediate treatment for high-risk acute myeloid leukemia (HR-AML) patients lacking matched donors. Relapse remains the leading cause of death for HR-AML patients after haplo-HSCT. Accordingly, the prevention of relapse remains a challenge in the treatment of HR-AML. In a multicenter randomized controlled trial in southwestern China, 178 HR-AML patients received haplo-HSCT with conditioning regimens involving recombinant human granulocyte colony–stimulating factor (rhG-CSF) or non–rhG-CSF. The cumulative incidences of relapse and graft-versus-host disease (GVHD), 2-year leukemia-free survival (LFS), and overall survival (OS) were evaluated. HR-AML patients who underwent the priming conditioning regimen with rhG-CSF had a lower relapse rate than those who were treated with non-rhG-CSF (38.2%; 95% confidence interval [CI], 28.1% to 48.3% versus 60.7%, 95% CI, 50.5% to 70.8%; P < .01). The cumulative incidences of acute GVHD, chronic GVHD, transplantation-related toxicity, and infectious complications appeared to be equivalent. In total, 53 patients in the rhG-CSF–priming group and 31 patients in the non-rhG-CSF–priming group were still alive at the median follow-up time of 42 months (range, 24 to 80 months). The 2-year probabilities of LFS and OS in the rhG-CSF–priming and non-rhG-CSF–priming groups were 55.1% (95% CI, 44.7% to 65.4%) versus 32.6% (95% CI, 22.8% to 42.3%) (P < .01) and 59.6% (95% CI, 49.4% to 69.7%) versus 34.8% (95% CI, 24.9% to 44.7%) (P < .01), respectively. Multivariate analyses indicated that the 2-year probability of LFS of patients who achieved complete remission (CR) before transplantation was better than that of patients who did not achieve CR. The 2-year probability of LFS of patients with no M4/M5/M6 subtype was better than that of patients with the M4/M5/M6 subtype in the G-CSF–priming group (67.4%; 95% CI, 53.8% to 80.9% versus 41.9%; 95% CI, 27.1% to 56.6%; P < .05). This study suggests that the rhG-CSF–priming conditioning regimen is an acceptable choice for HR-AML patients, especially for the patients with no M4/M5/M6 subtype who achieved CR before transplantation.     

Allogeneic Hematopoietic Cell Transplantation from Unrelated Donors in Multiple Myeloma: Study from the Italian Bone Marrow Donor Registry

To evaluate trends in allografting from unrelated donors, we conducted a study on 196 consecutive myeloma patients transplanted between 2000 and 2009 in Italy. Twenty-eight percent, 37%, and 35%, respectively, received myeloablative, reduced-intensity, and nonmyeloablative conditioning. In these 3 cohorts, 1-year and 5-year transplantation-related mortalities were 28.8% and 37.0%, 20.3% and 31.3%, and 25.0% and 30.3%, respectively (P = .745). Median overall survival (OS) and event-free survival from transplantation for the 3 cohorts were 29 and 10 months, 11 and 6 months, and 32 and 13 months, respectively (P = .039 and P = .049). Overall cumulative incidences of acute and chronic graft-versus-host-disease (GVHD) were 46.1% and 51.1%. By Cox multivariate analyses, chronic GVHD was significantly associated with longer OS (hazard ratio [HR], .51; P = .009), whereas the use of peripheral blood stem cells was borderline significant (HR, .55; P = .051). Better response posttransplantation was associated with longer event-free survival (HR, 2.13 to 4.25; P < .001). Acute GVHD was associated with poorer OS (HR, 2.53; P = .001). This analysis showed a strong association of acute and chronic GVHD and depth of response posttransplantation with clinical outcomes. Long-term disease control remains challenging regardless of the conditioning. In the light of these results, prospective trials may be designed to better define the role of allografting from unrelated donors in myeloma.     

Peripheral Blood Stem Cells versus Bone Marrow for T Cell–Replete Haploidentical Transplantation with Post-Transplant Cyclophosphamide in Hodgkin Lymphoma

Haploidentical stem cell transplantation (haplo-SCT) with post-transplant cyclophosphamide (PT-Cy) represents a potential curative strategy for patients with Hodgkin lymphoma (HL) when a matched related or unrelated donor is not available. The role of graft source, either bone marrow (BM) or peripheral blood stem cells (PBSCs), in this setting has not been fully elucidated. We performed a retrospective study on 91 patients with HL to compare the outcome after BM (n = 53) or PBSC (n = 38) transplant. Eighty-nine patients engrafted with no difference between BM and PBSCs in terms of median time for neutrophil (20 versus 20 days, P = .405) and platelet (26 versus 26.5 days, P = .994) engraftment. With a median follow-up of 40.2 months, 100-day cumulative incidences of grades II to IV acute graft-versus host disease (GVHD) and grades II to IV acute GVHD were 24% and 4%, respectively. Graft source was not associated with a different risk of acute GVHD both by univariate and multivariate analyses. Consistently, 1-year cumulative incidence of chronic GVHD was 7% with no differences between the 2 graft types (P = .761). Two-year rates of overall survival (OS), progression-free survival (PFS), nonrelapse mortality, and GVHD/relapse-free survival (GRFS) were 67%, 58%, 20%, and 52%, respectively. By univariate analysis, pretransplant disease status was the main variable affecting all outcomes. By multivariate analysis, PBSCs resulted in a protective factor for OS (hazard ratio [HR], .29; P = .006), PFS (HR, .38; P = .001), and GRFS (HR, .44; P = .020). The other independent variables affecting the final outcome were pretransplant disease status and hematopoietic cell transplant–specific comorbidity index. In conclusion, when planning a haplo-SCT with PT-Cy for patients with poor-risk HL, graft type is an important variable to take into account when selecting the best available donor.     

Comparable Long-Term Outcome after Allogeneic Stem Cell Transplantation from Sibling and Matched Unrelated Donors in Patients with Acute Myeloid Leukemia Older Than 50 Years: A Report on Behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation

Allogeneic stem cell transplantation (SCT) is potentially curative therapy in acute myeloid leukemia (AML). Marked improvement has been achieved with SCT from matched unrelated donors (MUDs) in recent years. However, there are limited data comparing the long-term outcomes (beyond 10 years) after SCT from sibling donors and MUDs in older patients with AML. We analyzed these outcomes in a large cohort of patients with AML (n = 1134), age ≥50 years, who were alive and leukemia-free 2 years after SCT from matched siblings (n = 848) or MUDs (n = 286), with a median follow-up of 8.9 years. The median age was 56 and 58 years after SCT from siblings and MUDs, respectively (P = .005). In the sibling group, 77%, 12%, and 11% were in first complete remission (CR1), second complete remission (CR2), and active leukemia at SCT compared with 50%, 25%, and 25% in the MUD group, respectively (P < .001). Sixty-one percent of siblings and 62% of MUDs had reduced-intensity conditioning (P = .78). The 10-year leukemia-free survival (LFS) of patients surviving leukemia-free 2 years after SCT was 72% and 62%, respectively (P = .30). Multivariate analysis identified active leukemia at SCT (hazard ratio [HR], 1.86; P = .0001) or CR2 (HR, 1.51; P = .02) compared with CR1, female recipients (HR, 0.71; P = .006), adverse cytogenetics (HR, 2.52; P = .01), and prior graft-versus-host disease (HR, 1.31; P = .04) as independent factors predicting LFS. Donor and conditioning type were not significant. The cumulative incidence was 15% and 17% (P = .97) for late relapse mortality and 13% and 21% for late nonrelapse mortality, respectively (P = .15). In conclusion, long-term LFS is similar, and patients who are leukemia-free 2 years after SCT can expect favorable outcomes with both donor types.     

Haploidentical Transplants with Post-Transplant Cyclophosphamide for Relapsed or Refractory Hodgkin Lymphoma: The Role of Comorbidity Index and Pretransplant Positron Emission Tomography

Disease relapse remains an unmet medical need for patients with Hodgkin lymphoma (HL) receiving an allogeneic hematopoietic cell transplantation (HCT). With the aim of identifying patients at high risk for post-transplant relapse, we retrospectively reviewed 41 HL patients who had received haploidentical (haplo) nonmyeloablative (NMA) HCT with high dose post-transplant cyclophosphamide (PT-Cy) for graft-versus-host (GVHD) prophylaxis. Primary refractory disease, relapse within 6 months from autologous stem cell transplantation, age, pretransplant chemotherapy, HCT comorbidity index (HCT-CI), sex mismatch, tumor burden and pretransplant fluorodeoxyglucose positron emission tomography (FDG-PET) status, assessed by Deauville score, were analyzed as variables influencing outcomes. All but 1 patient engrafted: median time to neutrophil and platelet recovery was 15 (interquartile range, 13 to 23) days and 19 (interquartile range, 12 to 28) days, respectively. Cumulative incidence of severe (grade III to IV) acute graft-versus-host disease (GVHD) and 3-year moderate-severe chronic GVHD was 2.4% and 11.8%, respectively. The 3-year overall (OS), progression free (PFS), and graft relapse-free survival (GRFS) were 75.6%, 43.9%, and 39%, respectively. On multivariate analysis, 3-year OS was significantly worse in patients with HCT-CI ≥3 (hazard ratio [HR], 5.0; 95% confidence interval [CI], 1.1 to 21.8; P?=?.03). Three-year relapse rate, 3-year PFS, and 3-year GRFS were significantly worse in patients with HCT-CI ≥3 (HR, 3.5; 95% CI, 1.3 to 9.3; P = .01; HR, 3.3; 95% CI, 1.2 to 9.0; P?=?.02; and HR, 4.2; 95% CI, 1.7 to 9.9; P?=?.001, respectively) and in patients with a Deauville score ≥4 on pretransplant FDG-PET (HR, 4.4; 95% CI, 1.6-12.4; P?=?.005, HR, 3.8; 95% CI, 1.5 to 9.7; P?=?.005; and 3.2; 95% CI, 1.3 to 7.9; P?=?.01, respectively). On univariate analysis, 3-year NRM was significantly worse only in patients with a HCT-CI ≥3 (HR, 17.6; 95% CI, 1.4 to 221.0). Among relapsed or refractory HL patients undergoing haplo NMA HCT with PT-Cy, pretransplant FDG-PET with a Deauville score ≥4 and HCT-CI ≥3 identified patients at high risk of relapse. Moreover, an HCT-CI ≥3 was associated with higher NRM and lower OS.