Myeloablative Unrelated Cord Blood Transplantation in Adolescents and Young Adults with Acute Leukemia

Outcomes for adolescents and young adults (AYAs) with leukemia differ from other age groups and are still under-represented in clinical research. The aim of this study was to analyze outcomes of umbilical cord blood transplant (UCBT) in AYAs with acute leukemia reported to Eurocord/European Society for Blood and Marrow Transplantation. Patients (N = 504) had acute lymphoblastic (59%) or myeloid leukemia (41%), were aged 15 to 25 years, and received UCBT after myeloablative conditioning regimens between 2004 and 2016. The primary endpoint was 3-year overall survival (OS). Median follow-up was 3.9 years. Transplant was single in 58% and double UCBT in 42%. Three-year OS was 45% and leukemia free survival (LFS) was 41%. Cumulative incidence functions (CIFs) of nonrelapse mortality (NRM) and relapse were 31% and 28%, respectively. CIF of acute graft-versus-host disease (GVHD) grades II to IV at day 100 was 28%. Three-year CIF of chronic GVHD was 25%. In adjusted analysis, better disease status at UCBT (hazard ratio [HR], 2.74; P < .001) and more recent UCBT (HR, 1.43; P = .01) were associated with increased OS, and a similar effect of these factors was observed on LFS. Contrastingly, the use of antithymocyte globulin had a negative effect in LFS. The risk of acute GVHD grades II to IV increased with the use of double UCBT (HR, 1.65; P = .02) and decreased with more recent transplant period (HR, .65; P = .02) and antithymocyte globulin use (HR, .55; P = .01). Outcomes of AYA UCBT improved in more recent years, becoming comparable with pediatric results. Demonstrating the feasibility of UCBT in AYAs facilitates stem cell source selection and provides the basis for future prospective studies.     

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.     

Comparison of Autologous Stem Cell Transplantation versus Haploidentical Donor Stem Cell Transplantation for Favorable- and Intermediate-Risk Acute Myeloid Leukemia Patients in First Complete Remission

Stem cell transplantation (SCT) is an attractive postremission treatment option for patients with intermediate-risk acute myeloid leukemia (AML) and for some favorable-risk AML patients with additional nongenetic risk factors. Autologous SCT (auto-SCT) and haploidentical donor SCT (haplo-SCT) are the widely used alternatives in cases of a lack of a HLA-matched donor. However, limited data have been published on the direct comparison between these 2 transplant types. Based on the transplant database in our center, we conducted a retrospective study involving patients with favorable- and intermediate-risk AML in first complete remission (CR1), according to the National Comprehensive Cancer Network guideline. Patients with extramedullary disease or those achieving CR by more than 2 cycles were excluded. In total, 195 patients were included in the study, 88 of whom underwent auto-SCT and 107 haplo-SCT. In the entire cohort analyses the impact of high relapse incidence in the auto-SCT group was compensated by low nonrelapse mortality (NRM), which resulted in a comparable overall survival (OS) (79.0%?±?4.6% versus 80.1%?±?5.0%, P?=?.769) and relapse-free survival (RFS) (66.1%?±?5.2% versus 77.4%?±?4.8%, P?=?.079) compared with those observed in the haplo-SCT group. However, for patients with intermediate-risk AML, NRM was similar between the groups, and haplo-SCT exhibited superior survival. In case of post-SCT relapse, patients with intermediate-risk AML showed markedly inferior 3-year OS compared with that shown by patients with favorable-risk AML (23.3%?±?9.8% versus 60.8%?±?14.3%, P?=?.011). In the multivariate analyses, minimal residual disease (MRD) measured by flow cytometry and gene mutation status before transplantation were independent predictors for both OS and RFS. We concluded that both auto-SCT and haplo-SCT were acceptable options for postremission treatment of patients with favorable- and intermediate-risk AML. Haplo-SCT yielded a better outcome in patients with intermediate-risk AML, but the relapse after SCT still led to a poor outcome. Clearance of MRD before SCT could improve the prognosis after transplantation.     

Single-Unit versus Double-Unit Umbilical Cord Blood Transplantation in Children and Young Adults with Residual Leukemic Disease

We previously reported in a French prospective randomized study that transplantation of 2 unrelated cord blood (UCB) units instead of 1 unit does not decrease the risk of transplantation failure but may enhance alloreactivity. Here we evaluated the influence of pretransplantation minimal residual disease (MRD) on leukemia relapse and survival after single- versus double-UCB transplantation (UCBT). Among 137 children and young adults who underwent UCBT in this randomized study, 115 had available data on MRD assessment done immediately before initiation of the pretransplantation conditioning regimen. MRD was considered positive at a level of ≥10^?4, which was the case of 43 out of 115 patients. Overall, the mean 3-year survival probability was 69.1 ± 4.4%, and it was not significantly influenced by the MRD level: 70.7 ± 5.4% in MRD-negative (<10^?4) patients (n?=?72), 71.1 ± 9.4% in MRD-positive patients with 10^?4 ≤ MRD <10^?3 (n?=?26) and 58.8 ± 11.9% in MRD-positive patients with ≥10^?3 (n?=?17). In the MRD-positive group, the mean risk of relapse was significantly lower in the double-UCBT arm compared with the single-UCBT arm (10.5 ± 7.2% versus 41.7 ± 10.4%; P?=?.025) leading to a higher mean 3-year survival rate (82.6 ± 9.3% versus 53.6 ± 10.3%; P?=?.031). This difference was observed only in patients who had not received antithymocyte globulin during their conditioning regimen. In the MRD-negative group, there was no differencebetween the single- and the double-UCBT arms. We conclude that even in cases of positive pretransplantation MRD, UCBT in children and young adults with acute leukemia yields a high cure rate, and that a double-unit strategy may enhance the graft-versus-leukemia effect and survival in these patients.     

Allogeneic Stem Cell Transplantation from HLA-Mismatched Donors for Pediatric Patients with Acute Lymphoblastic Leukemia Treated According to the 2003 BFM and 2007 International BFM Studies: Impact of Disease Risk on Outcomes

Allogeneic hematopoietic stem cell transplantation (HSCT) is beneficial for pediatric patients with relapsed or (very) high-risk acute lymphoblastic leukemia (ALL) in remission. A total of 1115 consecutive patients were included in the ALL SCT 2003 BFM study and the ALL SCT 2007 I-BFM study and were stratified according to relapse risk (standard versus high versus very high risk of relapse) and donor type (matched sibling versus matched donor versus mismatched donor). A total of 148 patients (60% boys; median age, 8.7 years; B cell precursor ALL, 75%) were transplanted from mismatched donors, which was defined as either less than 9/10 HLA-compatible donors or less than 5/6 unrelated cord blood after myeloablative conditioning regimen (total body irradiation based, 67%) for high relapse risk (HRR; n?=?42) or very HRR (VHRR) disease (n?=?106). The stem cell source was either bone marrow (n?=?31), unmanipulated peripheral stem cells (n?=?28), T cell ex vivo depleted peripheral stem cells (n?=?59), or cord blood (n?=?25). The median follow-up was 5.1 years. The 4-year rates of overall survival (OS) and event-free survival were 56%?±?4% and 52%?±?4%, respectively, for the entire cohort. Patients transplanted from mismatched donors for HRR disease obtained remarkable 4-year OS and event-free survival values of 82%?±?6% and 80%?±?6%, respectively, whereas VHRR patients obtained values of 45%?±?5% and 42%?±?5% (P?<?.001), respectively. The cumulative incidence of relapse was 29%?±?4% and that of nonrelapse mortality 19%?±?3%. The cumulative incidence of limited and extensive chronic graft-versus-host disease was 13%?±?3% and 15%?±?4%, respectively, among the 120 patients living beyond day 100. Multivariate analysis showed that OS was lower for transplanted VHRR patients (P?=?.002; hazard ratio [HR], 3.62; 95% confidence interval [CI], 1.60 to 8.20) and for patients beyond second complete remission (CR2) versus first complete remission (P?<?.001; HR, 3.68; 95% CI, 1.79 to 7.56); relapse occurred more frequently in patients with VHRR disease (P?=?.026; HR, 3.30; 95% CI, 1.16 to 9.60) and for those beyond CR2 (P?=?.005; HR, 4.16; 95% CI, 1.52 to 10.59). Nonrelapse mortality was not significantly higher for cytomegalovirus-positive recipients receiving cytomegalovirus-negative grafts (P?=?.12; HR, 1.96; 95% CI, .84 to 4.58). HSCT with a mismatched donor is feasible in pediatric ALL patients but leads to inferior results compared with HSCT with better matched donors, at least for patients transplanted for VHRR disease. The results are strongly affected by disease status. The main cause of treatment failure is still relapse, highlighting the urgent need for interventional strategies after HSCT for patients with residual leukemia before and/or after transplantation     

Second Hematopoietic Stem Cell Transplantation for Post-Transplantation Relapsed Acute Leukemia in Children: A Retrospective EBMT-PDWP Study

Outcome data were collected from the European Society for Blood and Marrow Transplantation registry on 373 children from 120 centers with relapsed leukemia (214 with acute lymphoblastic leukemia [ALL] and 159 with acute myelogenous leukemia [AML]) who underwent second allogeneic hematopoietic stem cell transplantation (HSCT) between 2004 and 2013. Overall survival (OS) was 38% at 2 years and 29% at 5 years, and leukemia-free survival (LFS) was 30% at 2 years and 25% at 5 years. Median follow-up after second HSCT was 36.4 months in the ALL group and 50.2 months in the AML group. In the ALL group, OS was 43% at 2 years and 33% at 5 years, and LFS was 34% at 2 years and 31% at 5 years. In the AML group, OS was 32% at 2 years and 24% at 5 years, and LFS was 24% at 2 years and 17% at 5 years. The 2-year nonrelapse mortality (NRM) rate was 22% in the ALL group and 18% in the AML group. Favorable prognostic factors (P?<?.05) for OS and LFS included >12 months between transplantations and chronic graft-versus-host disease after the first HSCT (in both groups), complete response before the second HSCT (ALL group only), and age >12 years (AML group only). Findings were more consistent over time in the ALL group, with no significant differences between 2-year and 5-year rates of relapse, NRM, and LFS. Children with relapsed acute leukemias have a substantial likelihood of long-term survival following second HSCT. Given the many novel targeted and immunomodulation therapies currently under development, it is important to identify specific patient subpopulations that may benefit from a second HSCT compared with those better suited to new approaches.     

Poor Outcome with Nonmyeloablative Conditioning Regimen before Cord Blood Transplantation for Patients with High-Risk Acute Myeloid Leukemia Compared with Matched Related or Unrelated Donor Transplantation

Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is recommended for patients with high-risk acute myeloid leukemia (AML). In many situations, a matched related (MRD) or matched unrelated donor (MUD) is lacking, in which case unrelated cord blood units (UCB) provide an alternative. We analyzed the outcome of consecutive high-risk AML patients prepared with reduced-intensity conditioning (RIC) regimens and allografted with UCB (n = 32) and compared their outcome with high-risk AML patients who underwent transplantation with MRD/MUD (n = 49) in the same period of time. Grade III to IV acute graft-versus-host disease (GVHD) occurred slightly more frequently in the UCB group (25%) than in the MRD/MUD group (8%) (P = .069). Conversely, we found a lower incidence of extensive chronic GVHD in the UCB group (6%) than in the MRD/MUD group (20%, P = .085). Nonrelapse mortality at 4 years was 16% and 22% in the UCB and MRD/MUD groups, respectively (P = .529). The cumulative incidence of relapse at 4 years was significantly higher in the UCB group (60%) than in the MRD/MUD group (27%, P = .006). Leukemia-free survival (LFS) and overall survival (OS) at 4 years were 25% and 34%, respectively, in the UCB group and 50% and 56%, respectively, in the MRD/MUD group (LFS, P = .029; OS, P = .072). Multivariate analyses adjusted by cytogenetics and disease status at the time of Allo-HSCT revealed that use of UCB remained an independent predictive factor of shorter LFS (hazard ratio, 2.0; 95% confidence interval, 1.1 to 3.6; P = .018), and was associated with a trend for shorter OS (hazard ratio, 1.7; 95% confidence interval, .9 to 3.2; P = .093). Whereas UCB provides an alternative for patients with high-risk AML lacking an MRD/MUD, the high incidence of relapse after RIC-based UCB Allo-HSCT is a concern. Attempts to improve leukemic control with UCB Allo-HSCT are warranted, as well as the evaluation of other alternative donors in this context.     

Effect of Antithymocyte Globulin Source on Outcomes of HLA-Matched Sibling Allogeneic Hematopoietic Stem Cell Transplantation for Patients with Severe Aplastic Anemia

We wanted to evaluate efficacy of porcine antithymocyte globulin (ATG) in HLA-matched sibling donor allogeneic hematopoietic stem cell transplantation (MSD-HSCT) for patients with severe aplastic anemia (SAA). The clinical data of 113 SAA patients who received MSD-HSCT from January 2005 to November 2016 were analyzed retrospectively. Of these, 58 patients received rabbit ATG as a part of conditioning regimen (R-ATG group), whereas the other 55 patients received porcine ATG (P-ATG group). Patient baseline characteristics and donor conditions of the 2 groups were similar, except patients were older and more received peripheral blood stem cell transplantation in the P-ATG group. All patients engrafted in 2 groups. There were significant differences in the incidence of acute (20.7%?±?5.3% versus 43.4%?±?7.0%, P?=?.015) and chronic graft-versus- host disease (GVHD; 20.1%?±?5.8% versus 46.0%?±?7.9%, P?=?.003) between the R-ATG and P-ATG groups. However, there were no significant differences in terms of 3-year overall survival (93.1%?±?3.3% versus 84.4%?±?5.7%, P?=?.235), grades III to IV acute GVHD (3.4%?±?2.4% versus 12.3%?±?4.7%, P?=?.098), moderate to severe chronic GVHD (12.6%?±?4.9% versus 11.5%?±?4.9%, P?=?.905), or graft rejection (7.4%?±?3.6% versus 5.5%?±?3.1%, P?=?.852). There was also no significant difference with regard to the incidence of severe bacterial infection (P?=?.075), invasive fungal disease (P?=?.701), or cytomeglovirus viremia (P?=?.770). P-ATG showed satisfactory efficacy and safety compared with R-ATG in the setting of MSD-HSCT for SAA patients. P-ATG could be a potential alternative preparation for R-ATG, further offering the advantage of lower costs.     

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.     

Outcomes after Second Hematopoietic Cell Transplantation in Children and Young Adults with Relapsed Acute Leukemia

Children with acute leukemia who relapse after hematopoietic cell transplantation (HCT) have few therapeutic options. We studied 251 children and young adults with acute myelogenous or lymphoblastic leukemia who underwent a second HCT for relapse after their first HCT. The median age at second HCT was 11 years, and the median interval between first and second HCT was 17 months. Most of the patients (n?=?187; 75%) were in remission, received a myeloablative conditioning regimen (n?=?157; 63%), and underwent unrelated donor HCT (n?=?230; 92%). The 2-year probability of leukemia-free survival (LFS) was 33% after transplantation in patients in remission, compared with 19% after transplantation in patients not in remission (P?=?.02). The corresponding 8-year probabilities were 24% and 10% (P?=?.003). A higher rate of relapse contributed to the difference in LFS. The 2-year probability of relapse after transplantation was 42% in patients in remission and 56% in those in relapse (P?=?.05). The corresponding 8-year probabilities were 49% and 64% (P?=?.04). These data extend the findings of others showing that patients with a low disease burden are more likely to benefit from a second transplantation. Late relapse led to a 10% decrement in LFS beyond the second year after second HCT. This differs from first HCT, in which most relapses occur within 2 years after HCT.     

Unrelated cord blood transplantation in adult and pediatric acute lymphoblastic leukemia: effect of minimal residual disease on relapse and survival

Data on pretransplantation minimal residual disease (MRD) and outcomes of umbilical cord blood transplantation (UCBT) are limited. Out of the 143 patients with acute lymphoblastic leukemia (ALL) who underwent UCBT at the University of Minnesota between 2004 and 2010, we evaluated 86 patients with available MRD assessment data by 4- and 8-color flow cytometry analysis immediately before transplantation. Ten patients (11.6%) were MRD-positive, and 76 were MRD-negative (88.4%). Most of the patients (82%) received myeloablative conditioning. GVHD prophylaxis consisted of cyclosporine and mycophenolate mofetil. In multivariate analysis, age, disease status (complete remission [CR] 1 versus CR2/CR3), disease group (precursor B cell ALL versus Philadelphia chromosome-positive ALL versus T cell ALL), and time to transplantation had no impact on relapse. Patients with MRD before UCBT had a greater incidence of relapse at 2 years (relapse rate, 30%; 95% confidence interval [CI], 4%-56%) and lower 3-year disease-free survival (30%; 95% CI, 7%-58%) compared with those without MRD (relapse rate, 16%; 95% CI, 8%-25%; P = .05; disease-free survival, 55%; 95% CI, 43%-66%; P = .02). Our data suggest that in patients with ALL, achieving an MRD-negative state before UCBT improves outcomes.     

Allogeneic Stem Cell Transplantation versus Tyrosine Kinase Inhibitors Combined with Chemotherapy in Patients with Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia

Here we compare outcomes between the tyrosine kinase inhibitors (TKIs) plus chemotherapy regimen and allogeneic hematopoietic stem cell transplantation (transplantation cohort) in patients with Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+?ALL) and explore factors associated with prognosis. Data from 145 Ph+?ALL patients were analyzed retrospectively. Patients were treated with imatinib plus chemotherapy and then transplantation or continuous TKIs with chemotherapy based on patient preference. A total of 145 Ph+?ALL patients were recruited for this study (median age, 37 years; range, 14 to 65). Among these patients, 81 were men (55.9%) and 86 underwent IKZF1 detection, which identified 59 patients (68.6%) with IKZF1 deletions. After treatment 136 patients (95.8%) achieved complete remission (CR) eventually. With a median follow-up of 33 months (range, 4 to 114) for CR patients, 77 patients (57.9%) underwent transplantation and 56 (42.1%) received continuous TKIs with chemotherapy. At the 4-year follow-up the cumulative incidence of relapse (CIR), disease-free survival (DFS), and overall survival (OS) were 29.4% (95% confidence interval [CI], 24.9% to 34.4%), 60.9% (95% CI, 56.5% to 65.3%), and 69.2% (95% CI, 65.1% to 73.3%), respectively. Multivariate analysis showed that WBC?counts <?30?×?10⁹/L at diagnosis (hazard ratio [HR], 4.2; 95% CI, 1.9 to 9.2; P??<?.001; HR, 2.6; 95% CI, 1.4 to 4.9; P?=?.003; HR, 2.7; 95% CI, 1.4 to 5.4; P?=?.003), 3-log reduction of BCR-ABL levels from baseline after 2 consolidation cycles (HR, 4.4; 95% CI, 1.9 to 9.9; P?<?.001; HR, 3.1; 95% CI, 1.7 to 5.9; P? <?.001; HR, 3.5; 95% CI, 1.9 to 8.7; P?=?.001; defined as “minimal residual disease low level”), and transplantation (HR, 5.0; 95% CI, 2.2 to 11.2; P??<?.001; HR, 3.3; 95% CI, 1.7 to 6.4; P???<?.001; HR, 4.1; 95% CI, 1.9 to 8.7; P???<?.001) were the favorable factors of CIR, DFS, and OS. According to the first 2 risk factors, CR patients were divided into 3 groups: low risk (no factor, n?=?42, 31.6%), intermediate risk (1 factor, n?=?73, 54.9%), and high risk (2 factors, n?=?18, 13.5%). In the low-risk group at the 4-year follow up no significant difference existed between the transplant and nontransplant arms for the probabilities of CIR (8.5% versus 7.7%, P?=?.671), DFS (88.2% versus 83.9%, P?=?.426), and OS (96.6% versus 83.3%, P?=?.128). In the intermediate- and high-risk groups at the 4-year follow-up, CIR (23.6% versus 36.9%, P?=?.017; 37.5% versus 100.0%, P???<.001), DFS (62.4% versus 43.8%, P?=?.048; 56.2% versus 0%, P???<.001), and OS (76.1% versus 47.7%, P?=?.037; 51.4% versus 6.3%, P?=?.001) rates were significantly better in the transplant arm than in the nontransplant arm. In surviving patients of the low-risk group, no difference in complete molecular response (CMR) rates (85.7% versus 72.7%, P?=?.379) between the transplant and nontransplant arms was found. However, in the intermediate-risk group the proportion of CMR was significantly higher in the transplant arm than in the nontransplant arm (82.8% versus 42.9%, P?=?.006). In the high-risk group 4 of 7 transplant patients (57.1%) were in CMR, and no patients survived in the nontransplant arm. Allogeneic hematopoietic stem cell transplantation confers significant survival advantages for Ph+?ALL patients compared with TKIs plus chemotherapy, especially in intermediate- and high-risk patients.     

Treatment of Acute Leukemia with Unmanipulated HLA-Mismatched/Haploidentical Blood and Bone Marrow Transplantation

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains one of the best therapeutic options to cure acute leukemia (AL). However, many patients have no human leukocyte antigen (HLA)-matched donor. Recently, we developed a new method for HLA-mismatched/haploidentical transplantation without in vitro T cell depletion (TCD). This method combined granulotyce-colony stimulating factor (G-CSF)-primed bone marrow and peripheral blood with intensive immunosuppression. We analyzed the outcome of 250 consecutive patients with AL who underwent HLA-mismatched/haploidentical transplantation with 1-3 mismatched loci of HLA-A, B, and DR from family donors via our new transplant protocol. Two hundred forty-nine patients achieved sustained, full donor chimerism. The incidence of grade 2-4 acute graft-versus-host disease (aGVHD) was 45.8%, and that of grades 3 and 4 was 13.4%, which was not associated with the extent of HLA disparity. The cumulative incidence of total chronic GVHD (cGVHD) was 53.9% and that of extensive cGVHD was 22.6% in 217 evaluable patients. One hundred forty-one of the 250 patients survived free of disease recurrence at a median of 1092 days (range: 442-2437 days) of follow-up. Seventeen patients received DLI as a treatment for relapse after transplantation and 7 patients achieved leukemia-free survival (LFS). The 3-year probability of LFS for acute myelogenous leukemia (AML) was 70.7% and 55.9%, and for acute lymphoblastic leukemia (ALL) it was 59.7% and 24.8% in standard-risk and high-risk groups, respectively. Lower LFS were associated with diagnosis of acute leukemia in the high-risk group (P = .001, relative risk [RR], 95% confidence interval [CI]: 2.94[1.535-5.631]) and the occurrence of aGVHD of grades 3 and 4 (P = .004). HLA-mismatched/haploidentical HSCT was feasible with unmanipulated blood and bone marrow harvest.     

Unmanipulated Haploidentical Hematopoietic Stem Cell Transplantation Achieved Outcomes Comparable With Matched Unrelated Donor Transplantation in Young Acquired Severe Aplastic Anemia

Salvage haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is considered in patients with severe aplastic anemia (SAA) if a matched unrelated donor (MUD) is unavailable. However, studies on haplo- and MUD transplantation in SAA are lacking. The present study retrospectively analyzed the outcomes of 89 young SAA patients who underwent unmanipulated alternative HSCT between September 2012 and September 2016 at our single center. Forty-one patients received haploidentical donors and forty-eight patients MUDs for HSCT. Most were heavily transfused and refractory to previous immunotherapy. The median durations for myeloid engraftment in the haplo- and MUD cohorts were 14 (range, 10 to 21) and 13 (range, 10 to 18) days, respectively. Compared with the MUD cohort, haplo-HSCT cohorts had an increased cumulative incidence of acute graft-versus-host disease (GVHD) grades II to IV (43.9%?±?7.8% versus 12.5%?±?4.8%, P?=?.001) and grades III to IV (21.1%?±?6.7% versus 6.6%?±?3.7%, P?=?.045) and similar limited chronic GVHD (47.7%?±?8.5% versus 38.5%?±?7.3%, P?=?.129) and extensive chronic GVHD (12.1%?±?6.8% versus 9.1%?±?4.3%, P?=?.198). The median follow-up time of the surviving patients was 26 months (range, 6 to 45). No significant differences were observed between haplo-HSCT and MUD HSCT cohorts in 3-year overall survival (80.3%?±?5.1% versus 89.6%?±?7.0%, P?=?.210), disease-free survival (76.4%?±?5.1% versus 89.4%?±?7.7%, P?=?.127), and GVHD-free failure-free survival (79.0%?±?8.6% versus 71.6%?±?9.3%, P?=?.976). Thus, haplo-HSCT, as salvage therapy, achieved similar outcomes as MUD HSCT in young SAA patients, thereby rendering it as an effective and safe option for SAA.     

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.     

Allogeneic Hematopoietic Stem Cell Transplantation in Adult Acute Lymphocytic Leukemia: Impact of Donor Source on Survival

We studied the relative impact of donor source on outcomes following myeloablative hematopoietic stem cell transplantation (HSCT) for adult patients with acute lymphocytic leukemia (ALL). In this single center study, 138 patients aged 18-61 (median 31) years underwent myeloablative conditioning followed by allogeneic HSCT. Stem cell source was an HLA matched related donor (MRD) in 90, HLA matched unrelated donor (URD:M) in 15, HLA mismatched unrelated donor (URD:MM) in 14, and HLA 0-2 (A, B, DRB1) mismatched umbilical cord blood (UCB) in 19 patients. At the time of HSCT, 70 patients were in first clinical remission (CR1), 57 in CR2, and 11 in ≥CR3. Twenty-one patients had T-lineage disease; 43 patients (31%) had high-risk cytogenetics of either t(9;22) (n = 33), t(4;11) or t(1,19) abnormalities, with the remainder (69%) having normal cytogenetics. White blood cell count (WBC) ≥30 × 10⁹/L at diagnosis was documented in 33%. Demographics and disease characteristics were similar in all 4 groups except all UCB recipients were treated since 1996 and received growth factors. Overall survival (OS) at 3 years for the UCB group was 66% (95% confidence interval [CI] 44%-89%) compared to 27% (95% CI 17%-36%) in the MRD group, and only 13% (95% CI 0%-31%) and 14% (95% CI 0%-33%) in the URD:M and URD:MM groups, respectively. Similarly leukemia free survival (LFS) at 3 years was better in the UCB group at 61% (95% CI 38%-84%) than 27% (95% CI 18%-36%) in the MRD and only 13% (95% CI 0%-31%) in the URD:M group and 14% (95%CI 0%-33%) in URD:MM group. Relapse rates at 3 years were 5% (95% CI 0%-15%) in the UCB group compared to 26% (95% CI 16%-35%) in the MRD, 20% (95% CI 1%-39%) in the URD:M groups, and 0% in the URD:MM groups. Transplant-related mortality (TRM) at 3 years was the lowest in the UCB group at 34% and higher in the other donor groups: MRD 47%, URD:M 67%, and URD:MM 86%. In multiple regression analysis, 5 independent risk factors were significantly associated with poorer OS and LFS: use of URD:MM (relative risk [RR] 2.5, 95% CI, 1.2-5.1, P = .01), ≥CR3 at HSCT (RR 3.5, 95% CI, 1.2-9.6, P = .02), WBC ≥30 × 10⁹/l (RR 1.9, 95% CI, 1.2-3.0, P = .01) at diagnosis, recipient and donor (R/D) cytomegalovirus (CMV) seropositive (RR 3.8, 95% CI, 2.0-7.4, P < .01), and ≥2 induction regimens to achieve initial CR (RR 3.5, 95% CI, 1.2-9.6, P = .02). Graft-versus-host disease (GVHD) was associated with improved LFS (RR 0.4, 95% CI, 0.2-0.6, P < .01). When compared with URD:M, OS with UCB was better (RR 0.3, 95% CI, 0.1-0.7, P = .01), supporting the use of UCB as an alternative stem cell source for adults with ALL.     

Comparison of outcomes after HLA-matched sibling and unrelated donor transplantation for children with high-risk acute lymphoblastic leukemia

We compared outcomes after 94 HLA-matched sibling, 168 unrelated donor bone marrow (BM; n = 81 matched and n = 88 mismatched), and 86 cord blood transplantations in patients age 1 to 15 years with acute?lymphoblastic leukemia (ALL) in second complete remission (CR). All patients had their first BM relapse within 3 years from diagnosis. Cox regression models were constructed to examine for differences in transplant outcome by donor source. Risks of grade 2 to 4 acute graft-versus-host disease (aGVHD) and chronic graft-versus-host disease (cGVHD), when compared to HLA-matched sibling transplants, were higher after matched unrelated donor BM (relative risk [RR], 2.42; P = .001; RR, 5.12; P < .001, respectively), mismatched BM (RR, 3.24; P < .001; RR, 5.19; P < .001, respectively), and cord blood (RR, 2.67; P < .001; RR, 2.54; P = .024, respectively) transplants. Although nonrelapse mortality was higher after transplantation of mismatched unrelated donor BM and cord blood, there were no differences in leukemia-free survival (LFS) between HLA-matched sibling and any of the unrelated donor transplantations. The 3-year probabilities of LFS were 50% after HLA-matched sibling and 44% after matched unrelated BM, and 44% after mismatched unrelated BM and 43% after cord blood transplantation. Our observations support transplantation of BM or cord blood from a suitably matched unrelated donor or cord blood for patients without an HLA-matched sibling with ALL in second CR.     

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.     

Impact on Outcomes of Human Leukocyte Antigen Matching by Allele-Level Typing in Adults with Acute Myeloid Leukemia Undergoing Umbilical Cord Blood Transplantation

This retrospective study analyzed the impact of directional donor-recipient human leukocyte antigen (HLA) disparity using allele-level typing at HLA-A, -B, -C, and -DRB1 in 79 adults with acute myeloid leukemia (AML) who received single-unit umbilical cord blood (UCB) transplant at a single institution. With extended high-resolution HLA typing, the donor-recipient compatibility ranged from 2/8 to 8/8. HLA disparity showed no negative impact on nonrelapse mortality (NRM), graft-versus-host (GVH) disease or engraftment. Considering disparities in the GVH direction, the 5-year cumulative incidence of relapse was 44% and 22% for patients receiving an UCB unit matched ≥ 6/8 and < 6/8, respectively (P = .04). In multivariable analysis, a higher HLA disparity in the GVH direction using extended high-resolution typing (Risk ratio [RR] 2.8; 95% confidence interval [CI], 1.5 to 5.1; P = .0009) and first complete remission at time of transplantation (RR 2.1; 95% CI, 1.2 to 3.8; P = .01) were the only variables significantly associated with an improved disease-free survival. In conclusion, we found that in adults with AML undergoing single-unit UCBT, an increased number of HLA disparities at allele-level typing improved disease-free survival by decreasing the relapse rate without a negative effect on NRM.     

Haploidentical Transplantation for Older Patients with Acute Myeloid Leukemia and Myelodysplastic Syndrome

Allogeneic stem cell transplantation with HLA-matched donors is increasingly used for older patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). It remains unclear if haploidentical stem cell transplantation (haploSCT) is a suitable option for older patients with this disease. We analyzed 43 patients with AML/MDS (median age, 61 years) who underwent a haploSCT at our institution. All patients received a fludarabine-melphalan–based reduced-intensity conditioning regimen and post-transplant cyclophosphamide-based graft-versus-host disease (GVHD) prophylaxis. Except for 1 patient who had early death, the remaining 42 patients (98%) engrafted donor cells. The cumulative incidences of grades II to IV and III to IV acute GVHD at 6 months were 35% and 5%, respectively, and chronic GVHD at 2 years was 9%. After a median follow-up of 19 months, 2-year overall survival, progression-free survival (PFS), and relapse incidence were 42%, 42%, and 24%, respectively. Best PFS (74% at 2 years) was seen in patients with intermediate-/good-risk cytogenetics, in first or second remission (hazard ratio, .4; P?=?.05), and with a younger donor (≤40 years; hazard ratio, .2; P?=?.01). In conclusion, these data suggest that haploidentical transplantation is safe and effective for older AML/MDS patients. Disease status, cytogenetics, and younger donor age are predictors for improved survival in older patients receiving a haploidentical transplant.