Severe Infections after Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplantation in Adults: Comparison of Cord Blood Transplantation with Peripheral Blood and Bone Marrow Transplantation

We evaluated the occurrence of severe infections in 192 consecutive adult recipients of volunteer unrelated donor allogeneic hematopoietic stem cell transplants, with a detailed analysis of severe infections after receipt of cord blood transplants (CBTs; n = 48) or bone marrow transplants (BMTs)/peripheral blood stem cell transplants (PBSCTs; n = 144). At a 3-year median follow-up, CBT recipients had a higher risk of developing any severe infection (85% versus 69% in BMT/PBSCT recipients, P < .01). CBT recipients had a higher incidence of severe bacterial infections before day +100, but at 3 years the risks of these and other infections were similar in the CBT and BMT/PBSCT groups. In addition, the 100-day and 3-year incidences of infection-related mortality (IRM) did not differ between groups (P = .2 and .5, respectively). In multivariate analysis, the most significant risk factor for IRM in all 192 patients was monocytopenia (.2 × 10⁹/L). In CBT recipients, only neutropenia (.2 × 10⁹/L) on day +30 and low nucleated cell dose infusion (<2 × 10⁷/kg) showed a trend for increased IRM (P = .05 in both cases). Stem cell source had no effect on day +100 or 3-year nonrelapse mortality (NRM), cytomegalovirus infection, cytomegalovirus disease (7% versus 6%), or overall survival (36% versus 39%, respectively). The number of mismatches in HLA (A, B, and DRB1) had no effect on any outcome in CBT recipients. In contrast, in the BMT/PBSCT group, the presence of any mismatch by low or high-resolution HLA typing (A, B, C, and DRB1) increased NRM and decreased overall survival (P < .01). IRM was the primary or secondary cause of death in 61% and 59% of CBT and BMT/PBSCT recipients who died, respectively. Our results confirm the relevance of severe infectious complications as source of severe morbidity and NRM after volunteer unrelated donor hematopoietic stem cell transplantation in adults, but suggest that CBT recipients have a similar risk of dying from an infection if an accurate selection of a cord blood unit is done.     

Listeriosis in Recipients of Allogeneic Bone Marrow Transplants from Unrelated Donors

 Two cases of listeriosis in patients submitted to matched unrelated donor bone marrow transplantation are reported. The patients developed listerial septicemia and listerial septicemia with meningitis and encephalitis 39 and 29 days after transplantation, respectively. Including the present two cases, 19 Listeria monocytogenes infections in related and unrelated donor allogeneic bone marrow transplant recipients have been reported to date. Infection occurred earlier in unrelated donor transplant recipients. Listeriosis is a rare complication in allogeneic bone marrow transplant recipients; however, the widespread practice of performing transplants from a donor-alternative to a human leukocyte antigen-compatible sibling and, in this setting, the need for intensified immunosuppression may predict an increasing and earlier occurrence of listeriosis.     

Lenalidomide Maintenance for High-Risk Multiple Myeloma after Allogeneic Hematopoietic Cell Transplantation

Allogeneic hematopoietic cell transplantation (alloHCT) with reduced-intensity conditioning is an appealing option for patients with high-risk multiple myeloma (MM). However, progression after alloHCT remains a challenge. Maintenance therapy after alloHCT may offer additional disease control and allow time for a graft-versus-myeloma effect. The primary objective of this clinical trial was to determine the tolerability and safety profile of maintenance lenalidomide (LEN) given on days 1 to 21 of 28 days cycles, with intrapatient dose escalation during 12 months/cycles after alloHCT. Thirty alloHCT recipients (median age, 54 years) with high-risk MM were enrolled at 8 centers between 2009 and 2012. The median time from alloHCT to LEN initiation was 96 days (range, 66 to 171 days). Eleven patients (37%) completed maintenance and 10 mg daily was the most commonly delivered dose (44%). Most common reasons for discontinuation were acute graft-versus-host disease (GVHD) (37%) and disease progression (37%). Cumulative incidence of grades III to IV acute GVHD from time of initiation of LEN was 17%. Outcomes at 18 months after initiation of maintenance were MM progression, 28%; transplantation-related mortality, 11%; and progression-free and overall survival, 63% and 78%, respectively. The use of LEN after alloHCT is feasible at lower doses, although it is associated with a 38% incidence of acute GVHD. Survival outcomes observed in this high-risk MM population warrant further study of this approach.     

Unrelated Donor Reduced-Intensity Allogeneic Hematopoietic Stem Cell Transplantation for Relapsed and Refractory Hodgkin Lymphoma

Myeloablative allogeneic hematopoietic cell transplantation (HCT) may cure patients with relapsed or refractory Hodgkin lymphoma (HL), but is associated with a high treatment-related mortality (TRM). Reduced-intensity and nonmyeloablative (RIC/NST) conditioning regimens aim to lower TRM. We analyzed the outcomes of 143 patients undergoing unrelated donor RIC/NST HCT for relapsed and refractory HL between 1999 and 2004 reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Patients were heavily pretreated, including autologous HCT in 89%. With a median follow-up of 25 months, the probability of TRM at day 100 and 2 years was 15% (95% confidence interval [CI] 10%-21%) and 33% (95% CI 25%-41%), respectively. The probabilities of progression free survival (PFS) and overall survival (OS) were 30% and 56% at 1 year and 20% and 37% at 2 years. The presence of extranodal disease and the Karnofsky Performance Scale (KPS) <90 were significant risk factors for TRM, PFS, and OS, whereas chemosensitivity at transplantation was not. Dose intensity of the conditioning regimen (RIC versus NST) did not impact outcomes. Unrelated donor HCT with RIC/NST can salvage some patients with relapsed/refractory HL, but relapse remains a common reason for treatment failure. Clinical studies should be aimed at reducing the incidence of acute graft-versus-host disease (GVHD) and relapse.     

Homing Characteristics of Donor T Cells after Experimental Allogeneic Bone Marrow Transplantation and Posttransplantation Therapy for Multiple Myeloma

Relapse and graft-versus-host disease remain major problems associated with allogeneic bone marrow (BM) transplantation (allo-BMT) and posttransplantation therapy in patients with multiple myeloma (MM) and other hematologic malignancies. A possible strategy for selectively enhancing the graft-versus-myeloma response and possibly reducing graft-versus-host disease is to increase the migration of alloreactive T cells toward the MM-containing BM. In the present study, we characterized the BM-homing behavior of donor-derived effector T cells in a novel allo-BMT model for the treatment of MM. We observed that posttransplantation immunotherapy consisting of donor lymphocyte infusion (DLI) and vaccination with minor histocompatibility antigen-loaded dendritic cells (DCs) was associated with prolonged survival compared with allo-BMT with no further treatment. Moreover, CD8⁺ effector T cells expressing inflammatory homing receptors, including high levels of CD44, LFA-1, and inflammatory chemokine receptors, were recruited to MM-bearing BM. This was paralleled by strongly increased expression of IFN-γ and IFN-γ–inducible chemokines, including CXCL9, CXCL10, and CXCL16, especially in mice treated with DLI plus minor histocompatibility antigen-loaded DC vaccination. Remarkably, expression of the homeostatic chemokine CXCL12 was reduced. Furthermore, IFN-γ and TNF-α induced BM endothelial cells to express high levels of the inflammatory chemokines and reduced or unaltered levels of CXCL12. Finally, presentation of CXCL9 by multiple BM endothelial cell-expressed heparan sulfate proteoglycans triggered transendothelial migration of effector T cells. Taken together, our data demonstrate that both post-transplantation DLI plus miHA-loaded DC vaccination and MM growth result in an increased expression of inflammatory homing receptors on donor T cells, decreased levels of the homeostatic BM-homing chemokine CXCL12, and strong induction of inflammatory chemokines in the BM. Thus, along with increasing the population of alloreactive T cells, post-transplantation immunotherapy also might contribute to a more effective graft-versus-tumor response by switching homeostatic T cell migration to inflammation-driven migration.     

Mismatched Related and Unrelated Donors for Allogeneic Hematopoietic Cell Transplantation for Adults with Hematologic Malignancies

Two parallel phase II trials in adults with hematologic malignancies demonstrated comparable survival after reduced-intensity conditioning and transplantation of either 2 HLA-mismatched umbilical cord blood (UCB) units or bone marrow from HLA-haploidentical relatives. Donor choice is often subject to physician practice and institutional preference. Despite clear preliminary evidence of equipoise between HLA-haploidentical related donor and double unrelated donor UCB transplantation, the actual prospect of being randomized between these 2 very different donor sources is daunting to patients and their treating physicians alike. Under these circumstances, it is challenging to conduct a phase III randomized trial in which patients are assigned to the UCB or haploidentical bone marrow arms. Therefore, we aimed to provide an evidence-based review and recommendations for selecting donors for adults without an HLA-matched sibling or an HLA-matched adult unrelated donor.     

Unrelated Donor Allogeneic Hematopoietic Cell Transplantation Is Underused as a Curative Therapy in Eligible Patients from the United States

Allogeneic hematopoietic cell transplantation (alloHCT) is a curative therapy for hematologic disorders including acute lymphoblastic and myeloid leukemia, chronic lymphocytic and myeloid leukemia, Hodgkin's and non-Hodgkin lymphoma, multiple myeloma, and myelodysplastic syndrome. To determine the utilization of alloHCT from unrelated donors (URDs) in the United States, we calculated the number of patients diagnosed with hematologic disorders age 20 to 74 years based on 2004 to 2008 Surveillance, Epidemiology and End Results and 2007 US Census data, estimated the percentage of patients who would be eligible for URD alloHCT after discounting the mortality rate during induction therapy and the rate of severe comorbidities, and compared these with the actual 2007 alloHCTs facilitated by the National Marrow Donor Program. We found that the number of URD alloHCT as a percentage of the estimated potential transplantations ranged from 11% for multiple myeloma to 54% for chronic myeloid leukemia, with an average percentage of 26% for all the disorders considered. In an analysis stratified by age groups (20 to 44, 45 to 64, and 65 to 74 years), the utilization of URD alloHCT was higher in younger patients than in older patients for all disorders. Of acute lymphoblastic and myeloid leukemia patients, approximately 66% underwent URD alloHCT later in the course of their disease (in second or greater complete remission). URD alloHCT is likely underused for potentially curable hematologic disorders, particularly in older patients. Understanding the reasons for low use of alloHCT may lead to strategies to expand the use of this curative therapy for more patients with hematologic disorders.     

Unrelated Donor Hematopoietic Cell Transplantation for Non-Hodgkin Lymphoma: Long-Term Outcomes

We analyzed the outcomes of 283 patients receiving unrelated donor allogeneic hematopoietic cell transplantation for non-Hodgkin lymphoma (NHL) facilitated by the Center for International Blood and Marrow Transplant Research/National Marrow Donor Program (CIBMTR/NMDP) between 1991 and 2004. All patients received myeloablative conditioning regimens. The median follow-up of survivors is 5 years. Seventy-three (26%) patients are alive. The day 100 probability of death from all causes is estimated at 39%. The cumulative incidence of developing grade III-IV acute graft-versus-host disease (aGVHD) at day 100 is 25%. The estimated 5-year survival and failure free survival are 24% (95% confidence interval [CI]: 19-30) and 22% (95% CI: 17-28), respectively. Factors adversely associated with overall survival (OS) included increasing age, decreased performance status, and refractory disease. Follicular lymphoma (FL) and peripheral T cell lymphoma had improved survival compared to aggressive B cell lymphomas. Factors adversely associated with progression-free survival (PFS) included performance status, histology, and disease status at transplant. Long-term failure-free survival is possible following unrelated donor transplantation for NHL, although early mortality was high in this large cohort.     

MHC-Resident Variation Affects Risks After Unrelated Donor Hematopoietic Cell Transplantation

Blood malignancies can be cured with hematopoietic cell transplantation from human leukocyte antigen (HLA)-matched unrelated donors; however, acute graft-versus-host disease (GVHD) affects up to 80% of patients and contributes to increased mortality. To test the hypothesis that undetected patient-donor differences for non-HLA genetic variation within the major histocompatibility complex (MHC) could confer risks after HLA-matched transplantation, we conducted a discovery-validation study of 4205 transplants for 1120 MHC region single-nucleotide polymorphisms (SNPs). Two SNPs were identified as markers for disease-free survival and acute GVHD. Among patients with two or more HLA-matched unrelated donors identified on their search, SNP genotyping of patients and their potential donors demonstrated that most patients have a choice of SNP-matched donors. In conclusion, the success of HLA-matched unrelated donor hematopoietic cell transplantation depends on non-HLA MHC region genetic variation. Prospective SNP screening and matching provides an approach for lowering risks to patients.     

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.     

Optimizing Antithymocyte Globulin Dosing for Unrelated Donor Allogeneic Hematopoietic Cell Transplantation Based on Recipient Absolute Lymphocyte Count

Antithymocyte globulin (ATG) is used as prophylaxis against graft-versus-host disease (GVHD). Current dosing regimens for ATG are empiric and weight-based, and do not account for patient-specific factors. Furthermore, the target of ATG, recipient T cells post-cytotoxic chemotherapy, is not a function of recipient weight. We hypothesized the recipient peripheral blood absolute lymphocyte count (ALC) on the day of ATG administration would interact with the dose of ATG administered to predict transplantation outcomes. We retrospectively analyzed 135 patients who received ATG for GVHD prophylaxis for unrelated allogeneic hematopoietic cell transplantation at 3 different doses: 10?mg/kg, 7.5?mg/kg, and 5?mg/kg. There was no difference in 2-year overall survival (OS) among ATG dosing groups; however, deaths from infectious complications were significantly higher with higher doses of ATG (3.7% versus 19% versus 26.7%; P?=?.02). Severity of chronic GVHD was lower with higher doses of ATG (28% versus 24% versus 4%; P?=?.03). In multivariate analysis, the median peripheral blood ALC on day of ATG administration and the total amount of ATG interacted to predict OS (hazard ratio, .09; P?=?.03). For low recipient ALC (10th percentile, or .56 × 10²/µL), a higher total ATG dose was associated with a greater risk of death, whereas for high recipient ALC (90th percentile, or 24.96 × 10²/µL), a higher ATG dose was associated with a lower risk of death. Our findings suggest that the interaction between ATG and its target, the recipient lymphocyte, could represent a new paradigm for ATG dosing.     

Relapse after Allogeneic Hematopoietic Cell Transplantation for Multiple Myeloma: Survival Outcomes and Factors Influencing Them

Many patients with multiple myeloma (MM) eventually relapse even after allogeneic hematopoietic cell transplantation (alloHCT) for curative intent. Over the past decade, outcomes for patients with MM have improved significantly with the availability of new therapies, including next-generation proteasome inhibitors, immunomodulatory agents, and, more recently, monoclonal antibodies. Although several published studies have evaluated the outcomes of alloHCT for MM, the data on survival outcomes in patients with MM experiencing disease relapse following alloHCT are limited. In addition, the predictors for postrelapse survival in these patients are not known. In this study, we examined the outcomes of a single-center cohort of 60 patients with MM who experienced relapse or progression after alloHCT. In addition, we evaluated the use of salvage regimens for treatment of relapsed MM and analyzed the predictors for improved postrelapse survival. After a median follow-up of 2.2 years from the time of relapse, the median duration of postrelapse survival was 1.8 years (95% confidence interval [CI], 1.2 to 5.0 years). Patients received a median of 3 lines of therapy (range, 0 to 10) for treatment of MM beyond the post-alloHCT relapse/progression. Multivariate analysis identified cytogenetic risk (standard risk versus high risk; hazard ratio [HR], .34; P = .01), time to relapse after alloHCT (>12 months versus ≤12 months: HR, .41; P = .04), and occurrence of acute graft-versus-host disease (GVHD) before relapse (GVHD versus no GVHD: HR, 2.89; P = .01) significantly affected postrelapse survival. These data illustrate that long-term myeloma control and survival is attainable in those relapsing/progressing after alloHCT and suggest that the synergism between novel therapies and the allogeneic immune platform is the key to improved survival in this high-risk patient population.     

Proinflammatory Cytokine and Adipokine Levels in Adult Unrelated Marrow Donors Are Not Associated with Hematopoietic Cell Transplantation Outcomes

Graft-versus-host disease (GVHD) is a frequent cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (allo-HCT). GVHD occurs when donor lymphocytes are activated by inflammatory cytokines and alloantigens. The role of donor biologic characteristics, such as basal inflammation, has not been investigated as a risk factor for GVHD but is theoretically transferrable to the recipient. We evaluated donor serum and plasma concentrations of cytokines and adipokines (IL-1β, IL-6, tumor necrosis factor [TNF]-α, leptin, suppression of tumorigenicity-2, and adiponectin) from test (n?=?210) and replication (n?=?250) cohorts of matched, unrelated transplant peripheral blood stem cell recipients identified through the Center for International Blood and Marrow Transplantation Research between 2000 and 2011 for hematologic malignancies. Hazard ratios were estimated for acute (grades II to IV and III to IV) and chronic GVHD, overall survival, disease-free survival, transplant-related mortality, and relapse for each cytokine or adipokine, adjusting for significant covariates. The lowest cytokine quartile was considered as the reference group for each model. To account for multiple testing P < .01 was considered the threshold for significance. In the test cohort a borderline significant association was identified between donor serum IL-1β concentrations and grades III to IV acute GVHD in the recipient (P = .01), and a significant inverse association was identified between donor TNF-α concentrations and chronic GVHD (P = .006). These findings were not validated in the replication cohort. Although the initial associations between cytokine levels and allo-HCT outcomes were not validated, the idea that donor characteristics may be transferable to the recipient remains an exciting area for future research.