Unrelated Donor Transplantation in Children with Thalassemia using Reduced-Intensity Conditioning: The URTH Trial

Allogeneic hematopoietic stem cell transplantation (HSCT) can cure transfusion-dependent thalassemia (TDT). In a multicenter trial we investigated the efficacy of reduced-intensity conditioning (RIC) before unrelated donor (URD) HSCT in children with TDT. Thirty-three children, ages 1 to 17 years, received bone marrow (BM) or umbilical cord blood (UCB) allografts. Median time to neutrophil engraftment was 13 days (range, 10 to 25) and 24 days (range, 18 to 49) and platelet engraftment 23 days (range, 12 to 46) and 50 days (range, 31 to 234) after BM and UCB allografts, respectively. With a median follow-up of 58 months (range, 7 to 79), overall and thalassemia-free survival was 82% (95% CI, .64% to .92%) and 79% (95% CI, .6% to .9%), respectively. The cumulative incidence of grades II to IV acute graft-versus-host disease (GVHD) after BM and UCB allografts was 24% and 44%; the 2-year cumulative incidence of chronic extensive GVHD was 29% and 21%, respectively; 71% of BM and 91% of UCB recipients discontinued systemic immunosuppression by 2 years. Six patients who had Pesaro risk class 2 (n?=?5) and class 3 (n?=?1) died of GVHD (n?=?3), viral pneumonitis (n?=?2) and pulmonary hemorrhage (n?=?1). Outcomes after this RIC compared favorably with URD HSCT outcomes for TDT and supported engraftment in 32 of 33 patients. Efforts to reduce GVHD and infectious complications are being pursued further.     

Haploidentical Transplantation with Post-Transplant Cyclophosphamide versus Unrelated Donor Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-Analysis

Hematopoietic stem cell transplantation (HSCT) is the standard treatment for patients with high-risk hematologic malignancies. Only approximately 25% of siblings are HLA-matched, and thus alternative donors—unrelated or haploidentical—are usually the only options available. This meta-analysis aimed to compare haploidentical HSCT with post-transplantation cyclophosphamide and unrelated donor (URD) HSCT. We searched the PubMed and Cochrane databases for pertinent studies indexed between 2008 and 2018. Twenty observational studies (with a total of 1783 haploidentical HSCT recipients and 6077 URD HSCT recipients) were included. Results for overall survival, graft-versus-host disease (GVHD), nonrelapse mortality (NRM), and relapse incidence were pooled. Measures of association used were hazard ratios and risk differences. The median age was 51 years for haploidentical transplant recipients and 52 years for URD transplant recipients. Peripheral blood stem cell (PBSC) grafts were more frequent in the URD transplant recipients (85%) than in the haploidentical transplant recipients (31%). Overall survival was not different between the 2 groups. NRM was lower for haploidentical transplantation. All forms of GVHD (acute grades II-IV and III-IV and moderate, severe, and extensive chronic) were lower with haploidentical donor HSCT. The risk of chronic GVHD was fairly proportional to the differential use of PBSC grafts across studies, however. All included studies were retrospective, representing the major limitation of this meta-analysis. In conclusion, haploidentical HSCT for hematologic malignancies achieved the same overall survival as URD HSCT, with a lower incidence of GVHD and NRM. The increased frequency of PBSC use in the unrelated donor group could partially explain the higher cGVHD rate. Haploidentical transplantation with post-transplantation cyclophosphamide should strongly be considered as the first option for adult patients with hematologic malignancies who do not have matched sibling donors in experienced centers. This systematic review has been registered at PROSPERO (65790).     

Comparable Outcomes after Hematopoietic Stem Cell Transplantation from Mother Donors and Matched Unrelated Donors in Patients with Hematopoietic Malignancies

Haploidentical transplantations have achieved comparable survival as HLA fully matched unrelated donors (URDs). When choosing the best donor for HLA haploidentical transplantations, most institutions prioritize using young male donors over mother donors. In a retrospective study we compared outcomes in mother donor and URD transplantations. We found that both 2-year overall survival and 2-year leukemia-free survival were comparable between the mother donor group and URD group (74.8% versus 72.9%, P = .937, and 71.7% versus 67.0%, P = .580, respectively). Higher incidences of grades II to IV acute graft-versus-host disease (GVHD) and chronic GVHD were observed in the mother donor group than in the URD group (43.5% versus 14.0%, P = .001, and 62.2% versus 38.7%, P = .007, respectively). The 2-year cumulative incidences of relapse were significantly decreased in the mother donor group (7.6% versus 20.9%, P = .036). These findings suggest mother donor transplantations could achieve comparable survival with URD transplantations and exhibited decreased rates of relapse but increased rates of GVHD, indicating that mother donors would be a suitable choice for patients without an identical sibling donor.     

Searching for unrelated donor hematopoietic stem cells: availability and speed of umbilical cord blood versus bone marrow.

Unrelated donor (URD) umbilical cord blood (UCB) has several potential advantages over URD BM for hematopoietic stem cell transplantation. To examine the efficiency of donor identification for each of these URD stem cell sources, we reviewed the search processes for all pediatric and adult URD transplantation referrals to the University of Minnesota during a period of 1 year. Of 171 consecutive referrals for URD transplantation, 108 patients proceeded to a formal URD search with selection of at least 1 donor. Significantly more formal UCB searches(54%) than BM searches (21%) were performed for patients who required urgent transplantation (P < .01). At least one 4-6/6 HLA-antigen matched UCB graft but no suitable BM graft was identified for 21 of the 108 patients (19%). The median time required to obtain a URD BM donor (from formal search to clearance of a BM donor) was 49 days (range, 32-293 days) compared to a UCB search time (from formal search to a donor unit chosen) of only 13.5 days (range, 2-387 days). For patients undergoing both BM and UCB searches, 29 more days (95% confidence interval, 21-37 days) were required to identify and clear a URD BM donor than a UCB donor (P < .01). For the 76 patients who proceeded to transplantation, patients receiving UCB received a transplant a median of 25 days more rapidly than did those receiving BM (P < .01). These data confirm that the availability of banked cryopreserved URD UCB grafts allows transplantations for patients with no available BM donor and that URD UCB grafts areavailable considerably faster than are URD BM grafts. Faster availability is a particular advantage for patients requiring urgent transplantation. These unique features of UCB transplantation must be considered in comparisons of the outcomes of UCB versus BM transplant recipients and in the design of prospective trials comparing URD sources.     

Comparative Analysis of Calcineurin Inhibitor–Based Methotrexate and Mycophenolate Mofetil–Containing Regimens for Prevention of Graft-versus-Host Disease after Reduced-Intensity Conditioning Allogeneic Transplantation

The combination of a calcineurin inhibitor (CNI) such as tacrolimus (TAC) or cyclosporine (CYSP) with methotrexate (MTX) or with mycophenolate mofetil (MMF) has been commonly used for graft-versus-host disease (GVHD) prophylaxis after reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (alloHCT), but there are limited data comparing efficacy of the 2 regimens. We evaluated 1564 adult patients who underwent RIC alloHCT for acute myelogenous leukemia (AML) and acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), and myelodysplastic syndrome (MDS) from 2000 to 2013 using HLA-identical sibling (matched related donor [MRD]) or unrelated donor (URD) peripheral blood graft and received CYSP or TAC with MTX or MMF for GVHD prophylaxis. Primary outcomes of the study were acute and chronic GVHD and overall survival (OS). The study divided the patient population into 4 cohorts based on regimen: MMF-TAC, MMF-CYSP, MTX-TAC, and MTX-CYSP. In the URD group, MMF-CYSP was associated with increased risk of grade II to IV acute GVHD (relative risk [RR], 1.78; P < .001) and grade III to IV acute GVHD (RR, 1.93; P = .006) compared with MTX-TAC. In the URD group, use of MMF-TAC (versus MTX-TAC) lead to higher nonrelapse mortality. (hazard ratio, 1.48; P = .008). In either group, no there was no difference in chronic GVHD, disease-free survival, and OS among the GVHD prophylaxis regimens. For RIC alloHCT using MRD, there are no differences in outcomes based on GVHD prophylaxis. However, with URD RIC alloHCT, MMF-CYSP was inferior to MTX-based regimens for acute GVHD prevention, but all the regimens were equivalent in terms of chronic GVHD and OS. Prospective studies, targeting URD recipients are needed to confirm these results.     

Comparable Outcomes of First-Line Hematopoietic Stem Cell Transplantation from Unrelated and Matched Sibling Donors in Adult Patients with Aplastic Anemia: A Retrospective Single-Center Study

To explore the feasibility of upfront unrelated donor (URD) hematopoietic stem cell transplantation (HSCT) in the treatment of adult aplastic anemia (AA), we conducted a retrospective, single-center study and compared the outcomes of adult patients who underwent first-line URD HSCT or matched sibling donor (MSD) HSCT between August 2012 and June 2018. In all, 23 URD HSCT recipients had an increased cumulative incidence of grade II acute graft-versus-host disease (aGVHD) (21.7% versus 3.4%; P =.007), but similar rates of secondary graft failure (8.7 ± 6.0% versus 6.9 ± 3.4%; P = .764), chronic GVHD (cGVHD) (18.2% versus 8.8%; P = .285), extensive cGVHD (9.1% versus 3.5%; P = .328), 5-year estimated overall survival (87.0% versus 94.2%; P = .501), and 5-year estimated failure-free survival (82.0% versus 89.3%; P = .404) compared with 58 MSD HSCT recipients treated during the same period. After using propensity score matching to reduce the influence of potential confounders, the 2 groups were well balanced in terms of pretransplantation clinical factors. The median survival time was similar, and no significant differences in the aforementioned outcomes were observed between the 2 groups. Our results suggest that URD HSCT may be an effective and feasible option for first-line therapy in adult AA patients who lack an MSD.     

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.     

Unrelated Donor Transplant Recipients Given Thymoglobuline Have Superior GRFS When Compared to Matched Related Donor Recipients Undergoing Transplantation without ATG

Recipients of allogeneic hematopoietic stem cell transplantation (HSCT) from unrelated donors (URDs) and mismatched related donors (MMRDs) typically have a higher incidence of acute and chronic graft-versus-host disease (GVHD) compared with matched related donors (MRDs). Anti-T-cell globulins (ATGs) are often used to reduce GVHD in these recipients. We report the outcomes of 211 adult peripheral blood stem cell transplant recipients with myeloid malignancies who received a standardized transplant protocol, in which ATG (Thymoglobuline 4.5 mg/kg) was administered to recipients of URD and MMRD (n = 147) but not MRD (n = 64) transplant. For all patients, incidence of acute GVHD grades 2 to 4 was 21.4%, and chronic GVHD was 35.0%. Two-year overall survival was 63.2% (95% confidence interval, 55.8% to 71.5%), relapse-free survival was 55.3% (47.4% to 64.6%), and GVHD-free, relapse-free survival (GRFS) was 30.7% (23.2% to 40.8%). There were no differences between recipients of MRDs and other donors in relapse, nonrelapse mortality, and overall and relapse-free survival. However, compared with MRD, recipients from URDs and MMRDs had reduced moderate to severe chronic GVHD (10.4% versus 30.1%, P= .002), less chronic GVHD requiring systemic therapy (19.4% versus 38.9%, P = .006), and superior 2-year GRFS (35.5% versus 20.0%, P = .003). In this retrospective review of nonrandomized transplant groups, outcomes of HSCT performed using an URD with ATG during conditioning were superior to transplant from an MRD without ATG. The addition of Thymoglobuline to conditioning in HSCT from MRD should be further examined in prospective trials.     

Chronic graft-versus-host disease (cGVHD) following unrelated donor hematopoietic stem cell transplantation (HSCT): higher response rate in recipients of unrelated donor (URD) umbilical cord blood (UCB).

We present a comparative analysis of clinical presentation and response to treatment in 170 patients with chronic graft versus host disease (cGVHD) (123 following transplant from an unrelated donor [URD] and 47 from umbilical cord blood [UCB]). URD transplant recipients were significantly younger (median age 25 versus 39 years, P = .002; and the donor grafts were mostly HLA matched (67% versus 10%, P < .0001). UCB recipients had more frequent responses (complete remission [CR] + partial remission [PR]) to treatment (URD 48% versus UCB 74% at 2 months [P = .005]; 49% versus 78% at 6 months [P = .001] and 51% versus 72% at 1 year [P = .03] in the URD and UCB groups, respectively). Nonrelapse mortality (NRM) after diagnosis of cGVHD was worse after URD grafts. (1 year NRM 27% [19%-35%] URD versus 11% [2%-20%] UCB, P = .055). Separate multivariate analyses were performed in each cohort. In both, thrombocytopenia and no CR or PR at 2 months were independently associated with increased mortality. In addition, progressive onset of cGVHD was a significant predictor of increased mortality in URD cohort. These data suggest that cGVHD following UCB transplant may be more responsive to therapy and also lead to a lower NRM.     

Reduced-Intensity Conditioning Followed by Related and Unrelated Allografts for Hematologic Malignancies: Expanded Analysis and Long-Term Follow-Up

Reduced-intensity conditioning (RIC) extends the curative potential of allogeneic hematopoietic cell transplantation (HCT) to patients with hematologic malignancies unable to withstand myeloablative conditioning. We prospectively analyzed the outcomes of 292 consecutive patients, median age 58 years (range, 19 to 75) with hematologic malignancies treated with a uniform RIC regimen of cyclophosphamide, fludarabine, and total body irradiation (200 cGy) with or without antithymocyte globulin and cyclosporine and mycophenolate mofetil graft-versus-host disease (GVHD) prophylaxis followed by allogeneic HCT at the University of Minnesota from 2002 to 6. Probability of 5-year overall survival was 78% for patients with indolent non-Hodgkin lymphoma, 53% for chronic myelogenous leukemia, 55% for Hodgkin lymphoma, 40% for acute myelogenous leukemia, 37% for myelodysplastic syndrome, 29% for myeloma, and 14% for myeloproliferative neoplasms. Corresponding outcomes for relapse were 0%, 13%, 53%, 37%, 39%, 75%, and 29%, respectively. Disease risk index (DRI) predicted both survival and relapse with superior survival (64%) and lowest relapse (16%) in those with low risk score compared with 24% survival and 57% relapse in those with high/very-high risk scores. Recipient cytomegalovirus (CMV)-positive serostatus was protective from relapse with the lowest rates in those also receiving a CMV-positive donor graft (29%). The cumulative incidence of 2-year nonrelapse mortality was 26% and was lowest in those receiving a matched sibling graft at 21%, with low (21%) or intermediate (18%) HCT-specific comorbidity index, and was similar across age groups. The incidence of grades II to IV acute GVHD was 43% and grades III to IV 27%; the highest rates were found in those receiving an unrelated donor (URD) peripheral blood stem cell (PBSC) graft, at 50%. Chronic GVHD at 1 year was 36%.Future approaches incorporating alternative GVHD prophylaxis, particularly for URD PBSC grafts, and targeted post-transplant antineoplastic therapies for those with high DRI are indicated to improve these outcomes.     

Comparison of Outcomes after Two Standards-of-Care Reduced-Intensity Conditioning Regimens and Two Different Graft Sources for Allogeneic Stem Cell Transplantation in Adults with Hematologic Diseases: A Single-Center Analysis

Recent advances in allogeneic stem cell transplantation (allo-HSCT) have included the advent of reduced-intensity conditioning (RIC) regimens to decrease the toxicity of myeloablative allo-SCT and the use of double umbilical cord blood (dUCB) units as a graft source in adults lacking a suitable donor. The FB2A2 regimen (fludarabine 30 mg/kg/day for 5-6 days + i.v. busulfan 3.6 mg/kg/day for 2 days + rabbit antithymocyte globulin 2.5 mg/kg/day for 2 days) supported by peripheral blood stem cells (PBSCs) and the TCF regimen (fludarabine 200 mg/m² for 5 days + cyclophosphamide 50 mg/kg for 1 day + low-dose [2 Gy] total body irradiation) supported by dUCB units are currently the most widely used RIC regimens in many centers and could be considered standard of care in adults eligible for an RIC allo-SCT. Here we compared, retrospectively, the outcomes of adults patients who received the FB2A2-PBSC RIC regimen (n = 52; median age, 59 years; median follow-up, 19 months) and those who received the dUCB-TCF RIC regimen (n = 39; median age, 56 years; median follow-up, 20 months) for allo-SCT between January 2007 and November 2010. There were no significant between-group differences in patient and disease characteristics. Cumulative incidences of engraftment, acute grade II-IV and chronic graft-versus-host disease were similar in the 2 groups. The median time to platelet recovery, incidence of early death (before day +100), and 2-year nonrelapse mortality were significantly higher in the dUCB-TCF group (38 days versus 0 days [P <.0001]; 20.5% versus 4% [P = .05], and 26.5% versus 6% [P = .02], respectively). The groups did not differ in terms of 2-year overall survival (62% for FB2A2-PBSC versus 61% for dUCB-TCF), disease-free survival (59% versus 50.5%), or relapse incidence (35.5% versus 23%). In multivariate analysis, the presence of a lymphoid disorder was associated with a significantly higher 2-year overall survival (hazard ratio, 0.42; 95% confidence interval, 0.20-0.87; P = .02), whereas patients receiving a FB2A2-PBSC allo-SCT had a significantly lower 2-year nonrelapse mortality (hazard ratio, 0.24; 95% confidence interval, 0.1-0.7; P = .01). There were no factors associated with higher 2-year disease-free survival or lower relapse incidence. This study suggests that the dUCB-TCF regimen provides a valid alternative in adults lacking a suitable donor and eligible for RIC allo-SCT. Prospective and randomized studies are warranted to establish the definitive role of dUCB RIC allo-SCT in adults. In addition, strategies for decreasing nonrelapse mortality after dUCB RIC allo-SCT are urgently needed.     

Sirolimus,Tacrolimus, and Low-Dose Methotrexate as Graft-versus-Host Disease Prophylaxis in Related and Unrelated Donor Reduced-Intensity Conditioning Allogeneic Peripheral Blood Stem Cell Transplantation

We assessed the combination of sirolimus, tacrolimus, and low-dose methotrexate as acute graft-versus-host disease (aGVHD) prophylaxis after reduced-intensity conditioning (RIC) allogeneic peripheral blood stem cell (PBSC) transplantation from matched related (MRD, n = 46) and unrelated (URD, n = 45) donors. All patients received fludarabine and intravenous busulfan conditioning followed by transplantation of mobilized PBSC. The median time to neutrophil engraftment was 13 days. The cumulative incidence of grade II-IV and III-IV aGVHD were 16% and 7%, respectively. There was no difference in the incidence of aGVHD between MRD and URD cohorts. Two-year cumulative incidence of extensive chronic GVHD (cGVHD) was 40%. Relapse-free survival (RFS) at 2 years was 34%: 21% in MRD and 45% in URD. Overall survival (OS) at 2 years was 59%: 47% in MRD and 67% in URD. High levels (>90%) of donor derived hematopoiesis were achieved in 59% of patients early after transplantation. The addition of sirolimus to tacrolimus and low-dose methotrexate as GVHD prophylaxis following RIC with fludarabine and low-dose intravenous busulfan is associated with rapid engraftment, low rates of aGVHD, and achievement of high levels of donor chimerism.     

Partially CD3+-Depleted Unrelated and Haploidentical Donor Peripheral Stem Cell Transplantation Has Favorable Graft-versus-Host Disease and Survival Rates in Pediatric Hematologic Malignancy

Most children who may benefit from stem cell transplantation lack a matched related donor. Alternative donor transplantations with an unrelated donor (URD) or a partially matched related donor (PMRD) carry an increased risk of graft-versus-host-disease (GVHD) and mortality compared with matched related donor transplantations. We hypothesized that a strategy of partial CD3⁺/CD19⁺ depletion for URD or PMRD peripheral stem cell transplantation (PSCT) would attenuate the risks of GVHD and mortality. We enrolled 84 pediatric patients with hematologic malignancies at the Children's Hospital of Philadelphia and the Children's Hospital of Wisconsin between April 2005 and February 2015. Two patients (2.4%) experienced primary graft failure. Relapse occurred in 23 patients (27.4%; cumulative incidence 26.3%), and 17 patients (20.2%) experienced nonrelapse mortality (NRM). Grade III-IV acute GVHD was observed in 18 patients (21.4%), and chronic GVHD was observed and graded as limited in 24 patients (35.3%) and extensive in 8 (11.7%). Three-year overall survival (OS) was 61.8% (95% confidence interval [CI], 50.2% to 71.4%) and event-free survival (EFS) was 52.0% (95% CI, 40.3% to 62.4%). Age ≥15 years was associated with decreased OS (P= .05) and EFS (P= .05). Relapse was more common in children in second complete remission (P = .03). Partially CD3⁺-depleted alternative donor PSCT NRM, OS, and EFS compare favorably with previously published studies of T cell-replete PSCT. Historically, T cell-replete PSCT has been associated with a higher incidence of extensive chronic GVHD compared with limited chronic GVHD, which may explain the comparatively low relapse and NRM rates in our study cohort despite similar overall rates of chronic GVHD. Partial T cell depletion may expand donor options for children with malignant transplantation indications lacking a matched related donor by mitigating, but not eliminating, chronic GVHD.     

Peripheral blood as a preferable source of stem cells for salvage transplantation in patients with graft failure after cord blood transplantation: a retrospective analysis of the registry data of the Japanese society for hematopoietic cell transplantation

To compare the different stem cell sources used in salvage transplantation for graft failure (GF) after cord blood transplantation (CBT), we retrospectively analyzed data of 220 patients who developed GF after undergoing CBT between January 2001 and December 2007 and underwent a second hematopoietic stem cell transplantation (HSCT) within 3 months. The donor sources for salvage HSCT were cord blood (n = 180), peripheral blood stem cells (PBSCs; n = 24), and bone marrow (BM; n = 16). The cumulative incidence of neutrophil engraftment on day 30 after the second HSCT was 39% with CB, 71% with PBSCs, and 75% with BM. Multivariate analysis revealed that PBSC and BM grafts were associated with a significantly higher engraftment rate than CB (hazard ratio [HR], 7.77; P < .001 and HR, 2.81; P = .016, respectively). Although the incidence of grade II-IV acute?graft-versus-host disease was significantly higher in the PBSC group than in the CB group (HR, 2.83; P?= .011), the incidence of 1-year nonrelapse mortality was lower in the PBSC group than in the CB group (HR, 0.43; P = .019), and 1-year overall survival was superior in the PBSC group compared with the CB group (HR, 0.45; P = .036). Our results suggest that PBSC is the preferable source of stem cells in salvage HSCT for GF after CBT.     

Reduced-Intensity Allogeneic Transplant in Patients Older Than 55 Years: Unrelated Umbilical Cord Blood Is Safe and Effective for Patients without a Matched Related Donor

The lower morbidity and mortality of reduced-intensity conditioning (RIC) regimens have allowed allogeneic hematopoietic cell transplantation (HCT) in older patients. Unrelated umbilical cord blood (UCB) has been investigated as an alternative stem cell source to suitably HLA matched related (MRD) and adult volunteer unrelated donors. We hypothesized that RIC HCT using UCB would be safe and efficacious in older patients, and compared the treatment-related mortality (TRM) and overall survival (OS) of RIC HCT in patients older than 55 years using either MRD (n = 47) or, in patients with no 5 of 6 or 6 of 6 HLA compatible related donors, UCB (n = 43). RIC regimen consisted of total-body irradiation (TBI; 200 cGy) and either cyclophosphamide and fludarabine (n = 69), or busulfan and fludarabine (n = 16) or busulfan and cladribine (n = 5). The median age of MRD and UCB cohorts was 58 (range, 55-70) and 59 (range, 55-69) years, respectively. acute myelogenous leukemia/myelodysplastic syndrome (AML/MDS) (50%) was the most common diagnosis. All MRD grafts were 6 of 6 HLA matched to the recipient. Among patients undergoing UCB HCT, 88% received 2 UCB units to optimize cell dose and 93% received 1-2 HLA mismatched grafts. The median follow-up for survivors was 27 (range: 12-61) months. The 3-year probabilities of progression-free survival (PFS; 30% versus 34%, P = .98) and OS (43% versus 34%, P = .57) were similar for recipients of MRD and UCB. The cumulative incidence of grade II-IV acute graft-versus-host (aGVHD) disease (42% versus 49%, P = .20) and TRM at 180-days (23% versus 28%, P = .36) were comparable. However, UCB recipients had a lower incidence of chronic graft-versus-host disease (cGVHD) at 1 year (40% versus 17%, P = .02). On multivariate analysis, graft type had no impact on TRM or survival, and the HCT comorbidity index score was the only factor independently predictive for these endpoints. Our study supports the use of HLA mismatched UCB as an alternative graft source for older patients who need a transplant but do not have an MRD. The use of RIC and UCB extends the availability of transplant therapy to older patients previously excluded on the basis of age and lack of a suitable MRD. A careful review of existing comorbidities is necessary when considering older patients for HCT.     

Allogeneic Transplantation with Reduced-Intensity Conditioning for Hodgkin and non-Hodgkin Lymphoma: Importance of Histology for Outcome

Allogeneic stem cell transplantation (SCT) with reduced-intensity conditioning (RIC) has the potential to lead to long-term remissions for patients with lymphoma. However, the role of RIC SCT in the treatment of lymphoma is still unclear. Specifically, the relative benefit of RIC SCT across lymphoma histologies and the prognostic factors in this population are incompletely defined. We retrospectively analyzed the outcomes of 87 patients with advanced lymphoma who underwent RIC SCT at the Dana-Farber Cancer Institute over a 6-year period with a homogeneous conditioning regimen consisting of fludarabine and low-dose busulfan. Thirty-six patients had Hodgkin disease (HD) and 51 had non-Hodgkin lymphoma (NHL). Sixty-eight percent had undergone prior autologous transplantation. The 1-year cumulative incidence of nonrelapse mortality was 13%, and the 3-year cumulative incidence of progression was 49%. The incidence of grade 3-4 acute GVHD was 11%. The 2-year cumulative incidence of chronic GVHD was 68%, and its development was associated with a decreased risk of progression and an improved progression-free survival (PFS). Three-year overall survival (OS) was 56% for patients with HD, 81% for indolent NHL, 42% for aggressive NHL, and 40% for mantle cell lymphoma. The corresponding figures for 3-year PFS were 22%, 59%, 22%, and 30%, respectively. Multivariate analysis identified elevated pretransplantation lactate dehydrogenase (LDH) as an adverse factor for PFS, while indolent NHL histology was favorable. For OS, advanced age and elevated pretransplantation LDH were adverse factors, whereas indolent NHL histology was favorable. Low early donor chimerism was not predictive of poor outcome in univariate or multivariate analyses. Moreover, progression was not associated with loss of chimerism. These results emphasize the importance of lymphoma histology for patients undergoing RIC SCT, as well as the lack of relevance of donor chimerism for outcome in this patient population.     

Immune Reconstitution and Infection Patterns after Early Alemtuzumab and Reduced Intensity Transplantation for Nonmalignant Disorders in Pediatric Patients

Hematopoietic stem cell transplantation (HSCT) is a therapeutic option for many nonmalignant disorders (NMD) and is curative or prevents disease progression. Reduced-intensity conditioning (RIC) in HSCT for NMD may reduce regimen-related acute toxicities and late complications. Myeloablation is often replaced by immune suppression in RIC regimens to support donor engraftment. The pace of immune reconstitution after immune suppression by RIC regimens is influenced by agents used, donor source, and graft-versus-host disease prophylaxis/treatment. In a multicenter trial (NCT 00920972) of HSCT for NMD, a RIC regimen consisting of alemtuzumab, fludarabine, and melphalan was substituted for myeloablation. Alemtuzumab was administered early (days ?21 to ?19) to mitigate major lymphodepletion of the incoming graft and the risk of graft rejection. Immune reconstitution and infectious complications were prospectively monitored for 1-year post-HSCT. Seventy-one patients met inclusion criteria for this report and received marrow or peripheral blood stem cell transplants. Immune reconstitution and infections are reported for related donor (RD) and unrelated donor (URD) transplants at 3 time-points (100days, 6 months, and 1 year post-HSCT). Natural killer cell recovery was rapid, and numbers normalized in both cohorts by day +100. Mean CD3, CD4, and CD8 T-lymphocyte numbers normalized by 6 months after RD HSCT and by 1 year in the URD group. CD4 and CD8 T-lymphocyte counts were significantly higher in patients who received RD HSCT at 6 months and at 1 year, respectively, post-HSCT compared with patients who received URD HSCT. The pace of CD19 B-cell recovery was markedly different between RD and URD cohorts. Mean B-cell numbers were normal by day 100 after RD HSCT but took 1 year post-HSCT to normalize in the URD cohort. Despite these differences in immune reconstitution, the timing and nature of infections did not differ between the groups, presumably because of comparable T-lymphocyte recovery. Immune reconstitution occurred at a faster pace than in prior reports using RIC with T-cell depletion. The incidence of infections was similar for both cohorts and occurred most frequently in the first 100days post-HSCT. Viral and fungal infections occurred at a lower incidence in this cohort, with “early” alemtuzumab compared with regimens administering serotherapy in the peritransplantation period. Patients were susceptible to bacterial infections primarily in the first 100days irrespective of donor source and had no increase in mortality from the same. The overall mortality rate from infections was 1.4% at 1 year. Close monitoring and prophylaxis against bacterial infections in the first 100days post-HSCT is necessary but is followed by robust immune reconstitution, especially in the T-cell compartment.     

Haploidentical/mismatched hematopoietic stem cell transplantation without in vitro T cell depletion for T cell acute lymphoblastic leukemia

The outcome of T cell acute lymphoblastic leukemia (T-ALL) is poorly understood. Allogeneic hematopoietic stem cell transplantation (HSCT) remains 1 of the best options to cure T-ALL. However, many patients cannot find an HLA-matched donor. Our institute established a new protocol for haplo-identical HSCT. Busulfan, cyclophosphamide, cytosine arabinoside, and methyl CCNU plus antithymocyte globulin was used for conditioning therapy. Seventy-two patients diagnosed with T-ALL underwent transplantation from haploidentical donor family members. The incidence rates of grades II to IV acute graft-versus-host disease (aGVHD) and of grades III and IV aGVHD were 49% ± 12% and 19% ± 12%, respectively. The cumulative incidence rate for chronic GVHD (cGVHD) at 2 years after HSCT was 41% ± 12%. After a median follow-up of 12 months, 15 patients had relapsed, 14 died from relapse, and 41 patients were still alive without disease recurrence. The probability of leukemia-free survival (LFS) was 44.2% ± 7.4% at 3 years. Patients transplanted during their first complete remission (CR1) had a lower relapse rate (18.8% versus 37.5%, P = .049, with a relative risk [RR] = 0.247, P = .007), a lower nonrelapse mortality (NRM) rate (16.6% versus 50.0%, P = .046, with an RR = 0.279, P = .024), and better LFS (54.8% versus 12.5%, P = .001, with an RR = 0.315, P = .004) compared with patients transplanted beyond CR1. This study confirmed that haploidentical/mismatched HSCT could be an alternative treatment choice for T-ALL.     

Peripheral Blood Hematopoietic Stem Cells for Transplantation of Hematological Diseases from Related,Haploidentical Donors after Reduced-Intensity Conditioning

In a multicenter collaboration, we carried out T cell–replete, peripheral blood stem cell (PBSC) transplantations from related, HLA-haploidentical donors with reduced-intensity conditioning (RIC) and post-transplantation cyclophosphamide (Cy) as graft-versus-host disease (GVHD) prophylaxis in 55 patients with high-risk hematologic disorders. Patients received 2 doses of Cy 50 mg/kg i.v. on days 3 and 4 after infusion of PBSC (mean, 6.4 × 10⁶/kg CD34⁺ cells; mean, 2.0 × 10⁸/kg CD3⁺ cells). The median times to neutrophil (500/μL) and platelet (>20,000/μL) recovery were 17 and 21 days respectively. All but 2 of the patients achieved full engraftment. The 1-year cumulative incidences of grade II and grade III acute GVHD were 53% and 8%, respectively. There were no cases of grade IV GVHD. The 2-year cumulative incidence of chronic GHVD was 18%. With a median follow-up of 509 days, overall survival and event-free survival at 2 years were 48% and 51%, respectively. The 2-year cumulative incidences of nonrelapse mortality and relapse were 23% and 28%, respectively. Our results suggest that PBSC can be substituted safely and effectively for bone marrow as the graft source for haploidentical transplantation after RIC.     

Busulfan Dose Intensity and Outcomes in Reduced-Intensity Allogeneic Peripheral Blood Stem Cell Transplantation for Myelodysplastic Syndrome or Acute Myeloid Leukemia

Comparisons of myeloablative conditioning versus reduced-intensity conditioning (RIC) have demonstrated a tradeoff between relapse and toxicity. Dose intensity across RIC regimens vary and may affect treatment outcomes. In this retrospective analysis, we investigated the effect of i.v. busulfan dosing (total dose 3.2 mg/kg versus 6.4 mg/kg) in RIC regimens that combined fludarabine and busulfan on outcomes in patients who were undergoing hematopoietic stem cell transplantation (HSCT) for myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). A total of 217 consecutive patients with MDS or AML underwent first busulfan and fludarabine RIC peripheral blood stem cell transplantation from well-matched related or unrelated donors at our institutions between 2004 and 2009. Of the 217 patients, 135 patients received Bu1 (3.2 mg/kg of busulfan) and 82 patients received Bu2 (6.4 mg/kg of busulfan), both with daily fludarabine (30 mg/m²/day for 4 days). The choice of RIC regimen was based on temporal institutional standard, enrollment on protocols, and physician choice. Patients had similar characteristics with a few notable differences: Patients who received Bu1 were younger (median age 61 versus 64 years, P < . 001), received more single-antigen mismatched unrelated grafts (14.1% versus 1.2%, P < . 001), received more sirolimus-based graft-versus-host disease (GVHD) prophylaxis regimens (63% versus 45%, P < .0001), received less antithymocyte globulin for GVHD prophylaxis (0% versus 22%, P < .001), and had less enrollment on a clinical trial that used prophylactic rituximab for the prevention of chronic GVHD (2.2% versus 11.0%, P = .011). Clinical disease status was similar between the groups. Median follow-up for survivors was 4.4 years for Bu1 and 3.2 years for Bu2. Because of the differences in characteristics, the 2 groups were compared with the adjustment of a propensity score that predicted Bu2 to account for measured differences. The day +200 cumulative incidence rates of grades II to IV acute GVHD (Bu1, 17%, versus Bu2, 8.5%; hazard ratio [HR], .56; 95% confidence interval [CI], .22 to 1.41; P = .22) or grades III to IV acute GVHD (Bu1, 6.7%, versus Bu2, 4.9%) were not different. The 2-year cumulative incidence of chronic GVHD was not significantly different between Bu1 and Bu2 (41.5% versus 28%, respectively; HR, .70; CI, .42 to 1.17; P = .09). Two-year nonrelapse mortality rates were similar for Bu1 and Bu2 (8.9% versus 9.8%, respectively; HR, .80; CI, .29 to 2.21; P = .67). Two-year progression-free survival and overall survival were also similar between Bu1 and Bu2 (progression-free survival: 40.6% versus 39.3%, respectively; HR, .82; CI, .57 to 1.30; P = .33; and overall survival: 47.4% versus 48.8%, respectively; HR, .96; CI, .64 to 1.44; P = .85). Subset analysis defined by clinical disease and cytogenetic risk with the propensity risk score applied suggest that in patients with high clinical disease risk and nonadverse cytogenetics, the higher dose busulfan RIC regimen may be of marginal benefit (2-year progression-free survival: HR, .54; CI, .29 to 1.03; P = .062). For the majority of patients with MDS or AML undergoing busulfan and fludarabine RIC peripheral blood stem cell transplantation, however, the dose of busulfan (3.2 mg/kg versus 6.4 mg/kg) is not associated with significant differences in overall outcomes.