Search

Study objectives: Reported risk factors for bronchiolitis obliterans (BO) in allogeneic hematopoietic stem-cell transplant recipients come from modest-sized studies and are limited to experiences of single institutions. We sought to [...]

Posttransplant cyclophosphamide (PTCy) graft-versus-host disease (GVHD) prophylaxis has enabled haploidentical (Haplo) transplantation to be performed with results similar to those after matched unrelated donor (MUD) transplantation with traditional prophylaxis. The relative value of transplantation with MUD vs Haplo donors when both groups receive PTCy/calcineurin inhibitor/mycophenolate GVHD prophylaxis is not known. We compared outcomes after 2036 Haplo and 284 MUD transplantations with PTCy GVHD prophylaxis for acute leukemia or myelodysplastic syndrome in adults from 2011 through 2018. Cox regression models were built to compare outcomes between donor types. Recipients of myeloablative and reduced-intensity regimens were analyzed separately. Among recipients of reduced-intensity regimens, 2-year graft failure (3% vs 11%), acute grades 2 to 4 GVHD (hazards ratio [HR], 0.70; P = .022), acute grades 3 and 4 GVHD (HR, 0.41; P = .016), and nonrelapse mortality (HR, 0.43; P = .0008) were lower after MUD than with Haplo donor transplantation. Consequently, disease-free (HR, 0.74; P = .008; 55% vs 41%) and overall (HR, 0.65; P = .001; 67% vs 54%) survival were higher with MUD than with Haplo transplants. Among recipients of myeloablative regimens, day-100 platelet recovery (95% vs 88%) was higher and grades 3 and 4 acute (HR, 0.39; P = .07) and chronic GVHD (HR, 0.66; P = .05) were lower after MUD than with Haplo donor transplantation. There were no differences in graft failure, relapse, nonrelapse mortality, and disease-free and overall survival between donor types with myeloablative conditioning regimens. These data extend and confirm the importance of donor-recipient HLA matching for allogeneic transplantation. A MUD is the preferred donor, especially for transplantations with reduced-intensity conditioning regimens.

We compared outcomes in 603 patients with myelodysplastic syndrome (MDS) after HLA-haploidentical relative (n = 176) and HLA-matched unrelated (n = 427) donor hematopoietic cell transplantation (HCT) from 2012 to 2017, using the Center for International Blood and Marrow Transplant Research database. All transplantations used reduced-intensity conditioning regimens. Total-body irradiation plus cyclophosphamide and fludarabine was the predominant regimen for HLA-haploidentical relative donor HCT, and graft-versus-host disease (GVHD) prophylaxis was uniformly posttransplantation cyclophosphamide, calcineurin inhibitor, and mycophenolate. Fludarabine with busulfan or melphalan was the predominant regimen for HLA-matched unrelated donor HCT, and GVHD prophylaxis was calcineurin inhibitor with mycophenolate or methotrexate. Results of multivariate analysis revealed higher relapse (hazard ratio [HR], 1.56; P = .0055; 2-year relapse rate, 48% vs 33%) and lower disease-free survival (DFS) rates after HLA-haploidentical relative donor HCT (HR, 1.29; P = .042; 2-year DFS, 29% vs 36%). However, overall survival (OS) rates did not differ between donor type (HR, 0.94; P = .65; 2-year OS, 46% for HLA-haploidentical and 44% for HLA-matched unrelated donor HCT) because of mortality associated with chronic GVHD. Acute grade 2 to 4 GVHD (HR, 0.44; P < .0001) and chronic GVHD (HR, 0.36; P < .0001) were lower after HLA-haploidentical relative donor HCT. By 2 years, probability of death resulting from chronic GVHD was lower after HLA-haploidentical relative compared with HLA-matched unrelated donor HCT (6% vs 21%), negating any potential survival advantage from better relapse control. Both donor types extend access to transplantation for patients with MDS; strategies for better relapse control are desirable for HLA-haploidentical relative donor HCT, and effective GVHD prophylaxis regimens are needed for unrelated donor HCT.

Bedside Tests To Exclude Pulmonary Embolism Study objective: Less than 35% of patients suspected of having pulmonary embolism (PE) actually have PE. Safe bedside methods to exclude PE could save [...]

The best conditioning regimen before allogeneic transplantation for high-risk diffuse large B-cell lymphoma (DLBCL) remains to be clarified. We analyzed data from 396 recipients of allotransplants for DLBCL receiving myeloablative (MAC; n = 165), reduced intensity (RIC; n = 143), or nonmyeloablative conditioning (NMAC; n = 88) regimens. Acute and chronic GVHD rates were similar across the groups. Five-year nonrelapse mortality (NRM) was higher in MAC than RIC and NMAC (56% vs 47% vs 36%; P = .007). Five-year relapse/progression was lower in MAC than in RIC/NMAC (26% vs 38% vs 40%; P = .031). Five-year progression-free survival (15%-25%) and overall survival (18%-26%) did not differ significantly between the cohorts. In multivariate analysis, NMAC and more recent transplant year were associated with lower NRM, whereas a lower Karnofsky performance score (< 90), prior relapse resistant to therapy, and use of unrelated donors were associated with higher NRM. NMAC transplants, no prior use of rituximab, and prior relapse resistant to therapy were associated with a greater risk of relapse/progression. In conclusion, allotransplantation with RIC or NMAC induces long-term progression-free survival in selected DLBCL patients with a lower risk of NRM but with higher risk of lymphoma progression or relapse.

We describe outcomes after human leukocyte antigen-matched sibling bone marrow transplantation (BMT) for 179 patients with β-thalassemia major. The median age at transplantation was 7 years and the median follow-up was 6 years. The distribution of Pesaro risk class I, II, and III categories was 2%, 42%, and 36%, respectively. The day 30 cumulative incidence of neutrophil recovery and day 100 platelet recovery were 90% and 86%, respectively. Seventeen patients had graft failure, which was fatal in 11. Six of 9 patients with graft failure are alive after a second transplantation. The day 100 probability of acute graft-versus-host disease and 5-year probability of chronic graft-versus-host disease was 38% and 13%, respectively. The 5-year probabilities of overall- and disease-free survival were 91% and 88%, respectively, for patients with Pesaro risk class II, and 64% and 62%, respectively, for Pesaro risk class III. In multivariate analysis, mortality risks were higher in patients 7 years of age and older and those with hepatomegaly before BMT. The leading causes of death were interstitial pneumonitis (n = 7), hemorrhage (n = 8), and veno-occlusive disease (n = 6). Proceeding to BMT in children younger than 7 years before development of end-organ damage, particularly in the liver, should improve results after BMT for β-thalassemia major.

We report the retrospective outcomes of unrelated donor (URD) transplants in 169 patients with acute lymphoblastic leukemia (ALL) in first complete remission (CR1) who received transplants between 1995 and 2004. Median age was 33 years (range, 16-59 years). A total of 50% had a white blood cell count (WBC) more than 30 × 109/L, 18% extramedullary disease, 42% achieved CR more than 8 weeks from diagnosis, 25% had adverse cytogenetics, and 19% had T-cell leukemia. A total of 41% were HLA well-matched, 41% partially matched with their donors, and 18% were HLA-mismatched. At 54-month median follow-up, incidences of acute grade 2-IV, III to IV, and chronic graft-versus-host disease were 50%, 25%, and 43%, respectively. Five-year treatment-related mortality (TRM), relapse, and overall survival were 42%, 20%, and 39%, respectively. In multivariate analyses, TRM was significantly higher with HLA-mismatched donors and T-cell depletion. Relapse risk was higher if the diagnostic WBC was more than 100 × 109/L. Factors associated with poorer survival included WBC more than 100 × 109/L, more than 8 weeks to CR1, cytomegalovirus seropositivity, HLA mismatching, and T-cell depletion. Nearly 40% of adults with ALL in CR1 survive 5 years after URD transplantation. Relapse risks were modest; TRM is the major cause of treatment failure. Selecting closely HLA-matched URD and reducing TRM should improve results.

We analyzed the outcome of 692 patients with severe aplastic anemia (SAA) receiving transplants from HLA-matched siblings. A total of 134 grafts were peripheral blood progenitor cell (PBPC) grafts, and 558 were bone marrow (BM) grafts. Rates of hematopoietic recovery and grades 2 to 4 chronic graft-versus-host disease (GVHD) were similar after PBPC and BM transplantations regardless of age at transplantation. In patients older than 20 years, chronic GVHD and overall mortality rates were similar after PBPC and BM transplantations. In patients younger than 20 years, rates of chronic GVHD (relative risk [RR] 2.82; P= .002) and overall mortality (RR 2.04; P= .024) were higher after transplantation of PBPCs than after transplantation of BM. In younger patients, the 5-year probabilities of overall survival were 73% and 85% after PBPC and BM transplantations, respectively. Corresponding probabilities for older patients were 52% and 64%. These data indicate that BM grafts are preferred to PBPC grafts in young patients undergoing HLA-matched sibling donor transplantation for SAA.

The addition of antithymocyte globulin (ATG) to a regimen of high-dose cyclophosphamide has been advocated to enhance engraftment after allogeneic bone marrow transplantation (BMT) for severe aplastic anemia (SAA). In a prospective clinical trial, 134 patients were randomly assigned to receive cyclophosphamide alone or in combination with ATG. All patients received T-cell–replete bone marrow from an HLA-matched sibling. With a median follow-up of 6 years, the 5-year probabilities of survival were 74% for the cyclophosphamide alone group and 80% for the cyclophosphamide plus ATG group (P= .44). Graft failure and graft-versus-host disease (GVHD) rates were similar in both groups. With the survival rates achieved, this study is not adequately powered to detect significant differences between the 2 treatment groups. In conclusion, the results of allogeneic BMT for SAA have improved over time related to advances in supportive care. The addition of ATG to the preparative regimen did not significantly improve the outcome.

Reported risk factors for bronchiolitis obliterans (BO) in allogeneic hematopoietic stem-cell transplant recipients come from modest-sized studies and are limited to experiences of single institutions. We sought to identify risk factors for BO using data from the International Bone Marrow Transplant Registry.

The effect of the organization and delivery of health care at medical centers, referred to as “center effects,” with clinical outcomes after hematopoietic stem cell transplantation (HSCT) is not clear. We examined the association between center and treatment provider factors and mortality after HSCT. We surveyed 163 (87% response rate) United States transplantation centers that performed HLA-identical sibling HSCT for leukemia or autologous HSCT for lymphoma between 1998 and 2000 among patients at least 18 years old. One hundred thirteen (69%) centers performed HLA-identical sibling transplantations, whereas 162 (99%) performed autologous transplantations. Factors associated with decreased 100-day mortality in the allogeneic setting include a higher patient-per-physician ratio (P= .003) and centers where physicians answer calls after office hours (P= .03). Medical school affiliation was not associated with increased 100-day mortality except in centers where students/residents are present without fellows (P= .02). Center effects were weaker in autologous HSCT at 1 year. Differences in 100-day mortality in patients receiving transplants in centers with favorable versus unfavorable factors were greater in allogeneic than autologous HSCT. Greater physician involvement in patient care is important in producing favorable outcomes after HSCT. To more clearly establish the role of the factors we identified, further studies are recommended.

Myeloablative allogeneic hematopoietic stem cell transplantation (allo-HSCT) is increasingly used in patients with lymphoma who experience disease relapse after autologous hematopoietic stem cell transplantation (auto-HSCT) because the allograft is tumor free and may induce a graft-versus-tumor effect. We analyzed 114 patients treated with this approach from 1990 to 1999 to assess disease progression, progression-free survival (PFS), and overall survival (OS). Cumulative incidence of disease progression at 3 years was 52%, whereas treatment-related mortality was 22%, lower than previously reported. Three-year probabilities of OS and PFS were 33% and 25%, respectively. With prolonged follow-up, however, nearly all patients experienced disease progression, and 5-year probabilities were 24% and 5%, respectively. Complete remission at the time of allo-HSCT and use of total body irradiation (TBI) in patients with non-Hodgkin lymphoma (NHL) were associated with lower rates of disease progression and higher rates of OS. In summary, allo-HSCT is feasible for patients with lymphoma who have relapses after auto-HSCT and can result in prolonged survival for some, but it is usually not curative. Most likely to benefit are patients who have HLA-matched sibling donors, are in remission, and have good performance status.

Allogeneic hematopoietic stem cell transplantation is the only curative therapy for myelodysplasia (MDS). To identify factors influencing transplantation outcome, we studied 452 recipients of HLA-identical sibling transplants for MDS from 1989 to 1997, reported to the International Bone Marrow Transplant Registry. Patients with treatment-related MDS or unclassified MDS were excluded. Median age was 38 years (range, 2-64 years). Sixty percent had refractory anemia with excess blasts (n?=?136) or with excess blasts in transformation (n?=?136). Conditioning regimens included total body irradiation in 199 (44%) cases. Marrow was T-cell depleted for 58 (13%) transplants. Cumulative incidences of neutrophil engraftment, grades II-IV acute graft-versus-host disease (GVHD), and chronic GVHD were 91% (95% confidence interval [CI], 88%-93%), 36% (95% CI, 31%-40%), and 39% (95% CI, 33%-44%), respectively. Three-year transplantation-related mortality (TRM), relapse, disease-free survival, and overall survival rates were 37% (95% CI, 32%-42%), 23% (95% CI, 19%-27%), 40% (95% CI, 36%-45%), and 42% (95% CI, 37%-47%), respectively. Multivariate analyses showed that young age and platelet counts higher than 100?×?109/L at transplantation were associated with lower TRM and higher disease-free and overall survival rates. Relapse incidence was higher in patients with high percentages of blasts in the marrow at transplantation or presentation, with high International Prognostic Scoring System scores at diagnosis, and with T-cell–depleted transplants. These findings indicate that transplantation from an HLA-identical sibling offers the possibility of long-term, disease-free survival to patients with MDS. Best candidates are younger patients with a low percentage of blasts and preserved platelet counts.

Sabloff: Lundbeck: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Canada: Membership on an entity's Board of Directors or advisory committees; Gilead: Research Funding; Alexion: Honoraria.

Ciurea: Spectrum Pharmaceuticals: Other: Advisory Board; Cyto-Sen Therapeutics: Equity Ownership. Seftel:Otsuka: Research Funding. Pulsipher:Medac: Other: Housing support for conference; Chimerix: Consultancy; Jazz Pharmaceutical: Consultancy; Novartis: Consultancy, Other: Study Steering Committee. Champlin:Ziopharm Oncology: Equity Ownership, Patents & Royalties; Intrexon: Equity Ownership, Patents & Royalties.

Bence-Bruckler: Lundbeck: Membership on an entity's Board of Directors or advisory committees.

BackgroundGraft-versus-host disease (GVHD) is a leading cause of morbidity and mortality in allogeneic hematopoietic stem cell transplantation (HSCT). Prophylactic in-vivo T-Cell depletion with antithymocyte globulin (ATG) has recently been reported as leading to decreased GVHD rates in matched unrelated and related donor HSCT, without increases in relapse or death. Understanding that higher rates of GVHD are observed with matched unrelated versus matched related donor HSCT, we have always had a local policy to give ATG as part of GVHD prophylaxis in patients undergoing HSCT from an unrelated donor. Here we report and compare clinical outcomes of patients who did and did not receive ATG at our transplant center using a unique, substantially lower ATG dose than previously reported.

No relevant conflicts of interest to declare.

Abstract 680

BACKGROUND: Non-secretory myeloma (NSM), where immunofixation fails to detect a monoclonal protein in serum and/or urine, accounts for <5% of cases of multiple myeloma (MM). The outcome of patients with NSM versus SM undergoing AuHCT has not been evaluated in clinical trials and patients with NSM are often excluded from clinical trials of MM therapy. METHODS: We compared the probabilities of treatment-related mortality (TRM), disease progression, progression-free survival (PFS) and overall survival (OS) after AuHCT for patients with NSM versus SM transplant between 1989 and 2003, reported to the CIBMTR. Immunofixation reports were reviewed to confirm the diagnosis of NSM. 110 patients with NSM were matched to 438 patients with SM using a propensity score (PS) approach. PS were calculated using age at transplant, Durie-Salmon stage at diagnosis, sensitivity to pretransplant therapy, time from diagnosis to transplant and year of transplant. A logistic regression model was fit and a numerical score derived for each case (NSM recipients). Controls (SM) were matched in random order to cases with similar PS. Multivariate Cox proportional hazards regression models were stratified on matched pairs. Recipients who had a planned second transplant (whether they received their 2nd transplant or not) were excluded. RESULTS: The two groups were similar with respect to disease characteristics at diagnosis (bone marrow plasmacytosis, ISS, renal function) and at transplant (performance status,β2-microglobulin, prior therapy and presence of bone disease). Patients with SM were more anemic and had lower serum albumin levels at diagnosis, while those with NSM were more likely to have preceding plasmacytoma and radiation therapy, presumably to the plasmacytoma. 5-year outcomes, with a median follow-up of 66 months (range, 1 – 177) were as follows: Outcome, Probability (95% CI) NSM SM P-value TRM, % 8 (3 – 14) 7 (5 – 10) 0.86 Disease progression, % 65 (55 – 75) 72 (67 – 76) 0.21 PFS, % 27 (18 – 37) 20 (16 – 25) 0.20 OS, % 51 (40 – 67) 43 (38 – 48) 0.22 In multivariate analysis, based on a Cox model stratified on matched pairs and adjusted for covariates not considered in the propensity score, we found no difference in outcome between the NSM and SM groups. The causes of death were similar between the two groups with disease progression accounting for 75% of deaths. CONCLUSION: In this large cohort of patients undergoing AuHCT, we found no difference in the outcome of patients with NSM compared to those with SM. With increasing use of the free light chain assay, the majority of patients with NSM are expected to have detectable light chain abnormalities thus making them oligosecretory rather than truly non-secretory. This group of patients is generally underrepresented in prospective clinical trials of MM. This study establishes that the post transplant outcomes of this subset of patients are not different and suggests that they should not be excluded from clinical trials.

Randomization in clinical trials involving comparison of patients receiving an allogeneic HSCT versus other treatments is challenged by limitated donor availability. Biologic assignment relies on the availability of suitable donors to determine assignment to allogeneic HSCT. BMT CTN 0102 is a phase III multicenter clinical trial that compares tandem autologous HSCT (auto-auto) to an autologous HSCT followed by a nonmyeloablative allogeneic HSCT (auto-allo) for the treatment of multiple myeloma after initial systemic therapy. Transplant arm assignment was determined by the availability of an HLA-matched sibling donor. Patients were stratified into high and standard risk groups. Absence of chromosome 13 deletion by standard karyotyping and beta-2 microglobulin (B2M) ≤ 4mg/L were defined as standard-risk disease (SRD). The trial was powered to detect differences in 3-year progression-free survival in patients with SRD. A total of 710 patients from 43 centers in the U.S. were enrolled from December 2001 to March 2007. Data from 596 patients with SRD were available for this analysis (sibling donor availability for other 28 SRD patients is not yet determined); 30% (n=178) were assigned to the auto-allo arm. The median ages were 55 and 52 years for the auto-auto and auto-allo arms, respectively (p=0.01). The proportions of African-American patients were 17% and 9% in the auto-auto and auto-allo arms, respectively (p=0.006). Most patients were Durie Salmon Stage III (66% and 70%, p=0.6), in partial remission (86% and 83%, p=0.6) and had Karnofsky Performance Scores ≥ 90 (76% and 77%, p=0.5) at time of study entry. Treatment arms were balanced for B2M, baseline cardiac and hepatic functions and CMV serological status. Median times from diagnosis, initiation of systemic therapy and stem cell mobilization to first transplant were 213, 191 and 27 days, respectively and the same in both arms. The interval from the first to second transplant was 98 days for the auto-auto arm and 105 days for the auto-allo arm (p=0.02). We conclude that biologic assignment resulted in two reasonably comparable treatment groups, although statistically significant differences in age, race and interval between first and second transplant were identified. The differences in age between the groups is related to donor availability, since patients younger than 55 years had on average significantly more living siblings than older patients. Importantly, full-sibling donor availability did not account for differences in race distribution. Because the clinical significance of all detectable differences is unknown, the planned statistical analysis will adjust for these discrepancies. These results confirm that biologic assignment is feasible and might be considered when standard randomization is prohibitive, as in allogeneic HSCT clinical trials.

In 2001, the Docket Report from the Food and Drug Administration expressed concerns regarding the potential of microbially contaminated hematopoietic stem cell products to produce morbidity and mortality in transplant recipients. This concern was the basis for development of regulatory standards for hematopoietic stem cell products. We surveyed a total of 2972 patients at 121 U.S. transplant centers that registered patients with the CIBMTR in the years 2000 and 2001. Information regarding microbial contamination of infused grafts was obtained from 94 transplant centers (80% response rate) for 2312 patients. 52 (2%) of 2286 infused grafts tested were culture positive for bacterial or fungal organisms. The microbial isolates included: coagulase negative staphylococcus (56%), gram negative organisms (15%), coagulase positive staphylococcus (10%), gram positive rods (10%), streptococcus (8%), and fungus (1%). Prophylactic antibiotics targeted at the contaminant were given to 17 of the 52 recipients of contaminated grafts. Antibiotic regimens included vancomycin alone (76%), aminoglycosides and vancomycin (12%), or cephalosporin and vancomycin (12%). 47 (50%) of the centers that participated have existing policies regarding contaminated products. Patients with non-malignant disorders or who received bone marrow were more likely to have a contaminated graft. No differences in age distribution, sex, race, type of transplant (allogeneic vs autologous) and year of transplant were noted between recipients of contaminated and non-contaminated grafts. The unadjusted 100-day survival of persons receiving contaminated grafts was 86% (95% Confidence Interval [CI] 72–93%) versus 81% (95% CI 80–83%) among those receiving non-contaminated grafts, p=0.35. In summary, about 2% of hematopoietic stem cell products infused for allogeneic or autologous transplantations in U.S. centers will test positive for microbial contamination, but such contamination does not increase posttransplant mortality. The absence of significant 100-day mortality among patients infused with contaminated grafts suggests that stringent regulatory policies regarding the use of contaminated hematopoietic cell products may not be indicated.