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Allogeneic hematopoietic stem cell transplantation (HSCT) is an integral therapy for patients with hematological malignancies, myelodysplasia, and bone marrow failure. Its use has been increasing over the past decade, as understanding of the treatment and its related toxicities has led to changes in patient selection, conditioning regimens, and post-transplant care. Older (age ≥65 years) patients are often considered unfit for transplantation; however, more recent data suggest that older patients, when selected appropriately, tolerate transplantation well. We report our institutional experience with HSCT in patients aged ≥70 years. A cohort of 22 patients underwent HSCT. Median overall survival was 5.16 years [95% confidence interval (CI): 1.5-8.7 years], and median post-transplant survival was 2.2 years (myelodysplastic syndrome: median 1.3 years, 95% CI: 4.7 months-2.2 years; acute myeloid leukemia: median not reached). Thirty-day mortality following HSCT was 9.5% (n = 2). These data provide further support for the use of HSCT in selected older patients, and highlight the impact of HSCT on overall survival among a patient cohort primarily of acute myeloid leukemia and myelodysplasia., (Published by Elsevier Ltd.)

Background: Patients with diffuse large B-cell lymphoma that is refractory to primary and second-line therapies or that has relapsed after stem-cell transplantation have a poor prognosis. The chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel targets and eliminates CD19-expressing B cells and showed efficacy against B-cell lymphomas in a single-center, phase 2a study., Methods: We conducted an international, phase 2, pivotal study of centrally manufactured tisagenlecleucel involving adult patients with relapsed or refractory diffuse large B-cell lymphoma who were ineligible for or had disease progression after autologous hematopoietic stem-cell transplantation. The primary end point was the best overall response rate (i.e., the percentage of patients who had a complete or partial response), as judged by an independent review committee., Results: A total of 93 patients received an infusion and were included in the evaluation of efficacy. The median time from infusion to data cutoff was 14 months (range, 0.1 to 26). The best overall response rate was 52% (95% confidence interval, 41 to 62); 40% of the patients had complete responses, and 12% had partial responses. Response rates were consistent across prognostic subgroups. At 12 months after the initial response, the rate of relapse-free survival was estimated to be 65% (79% among patients with a complete response). The most common grade 3 or 4 adverse events of special interest included cytokine release syndrome (22%), neurologic events (12%), cytopenias lasting more than 28 days (32%), infections (20%), and febrile neutropenia (14%). Three patients died from disease progression within 30 days after infusion. No deaths were attributed to tisagenlecleucel, cytokine release syndrome, or cerebral edema. No differences between response groups in tumor expression of CD19 or immune checkpoint-related proteins were found., Conclusions: In this international study of CAR T-cell therapy in relapsed or refractory diffuse large B-cell lymphoma in adults, high rates of durable responses were produced with the use of tisagenlecleucel. (Funded by Novartis; JULIET ClinicalTrials.gov number, NCT02445248 .).

The Revised International Staging System (R-ISS) and the International Myeloma Working Group 2014 (IMWG 2014) are newer staging systems used to prognosticate multiple myeloma (MM) outcomes. We hypothesized that these would provide better prognostic differentiation for newly diagnosed multiple myeloma (MM) compared with ISS. We analyzed the Center for International Blood and Marrow Transplant Research database from 2008 to 2014 to compare the 3 systems (N = 628) among newly diagnosed MM patients undergoing upfront autologous hematopoietic cell transplantation (AHCT). The median follow-up of survivors was 48 (range, 3 to 99) months. The R-ISS provided the greatest differentiation between survival curves for each stage (for overall survival [OS], the differentiation was 1.74 using the R-ISS, 1.58 using ISS, and 1.60 using the IMWG 2014) . Univariate analyses at 3 years for OS showed R-ISS I at 88% (95% confidence interval [CI], 83% to 93%), II at 75% (95% CI, 70% to 80%), and III at 56% (95% CI, 3% to 69%; P < .001). An integrated Brier score function demonstrated the R-ISS had the best prediction for PFS, though all systems had similar prediction for OS. Among available systems, the R-ISS is the most optimal among available prognostic tools for newly diagnosed MM undergoing AHCT. We recommend that serum lactate dehydrogenase and cytogenetic data be performed on every MM patient at diagnosis to allow accurate prognostication., (Copyright © 2018. Published by Elsevier Inc.)

High-grade B cell lymphoma with MYC and BCL2 rearrangements (double hit) has a poor prognosis with standard R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). We report here a treatment algorithm of DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab) followed by BEAM (carmustine, etoposide, cytarabine, melphalan) autologous transplant in 36 cases of previously untreated double hit lymphoma (DHL) from 2010 to 2015. A high risk International Prognostic Index (IPI) was present in 42% of cases. At median follow-up of 38 months, the 2-year progression free survival (PFS) and overall survival (OS) were 69% (95% CI 54-84%) and 71% (95% CI 56-86%). Eight cases were refractory to induction with 1-year OS 20%, and no factors were predictive for primary refractory disease. Of 28 responders, 17 proceeded to transplant while 11 were observed, primarily due to age and co-morbidities. By 24-week landmark analysis after diagnosis, the 2-year PFS and OS were both 94% (95% CI 83-100%) vs 79% (95% CI 52-100%) for transplant vs observation (p = .59 for both PFS and OS). There was no significant benefit to consolidative transplant in our series, and primary refractory DHL needs novel approaches.

The purpose of this report is to analyze long-term clinical outcomes of patients exposed to plerixafor plus granulocyte colony-stimulating factor (G-CSF) for stem cell mobilization. This was a study of patients with non-Hodgkin lymphoma (NHL; n = 167) and multiple myeloma (MM; n = 163) who were enrolled in the long-term follow-up of 2 pivotal phase III studies (NCT00741325 and NCT00741780) of 240 µg/kg plerixafor plus 10 µg/kg G-CSF, or placebo plus 10 µg/kg G-CSF to mobilize and collect CD34 + cells for autologous hematopoietic stem cell transplantation. Overall survival (OS) and progression-free survival (PFS) were evaluated over a 5-year period following the first dose of plerixafor or placebo. The probability of OS was not significantly different in patients with NHL or MM treated with plerixafor or placebo (NHL: 64%; 95% confidence interval [CI], 56% to 71% versus 56%; 95% CI, 44% to 67%, respectively; MM: 64%; 95% CI, 54% to 72% versus 64%; 95% CI, 53% to 73%, respectively). In addition, there was no statistically significant difference in the probability of PFS over 5 years between treatment groups in patients with NHL (50%; 95% CI, 44% to 67% for plerixafor versus 43%; 95% CI, 31% to 54% for placebo) or those with MM (17%; 95% CI, 10% to 24% for plerixafor versus 30%; 95% CI, 21% to 40% for placebo). In this long-term follow-up study, the addition of plerixafor to G-CSF for stem cell mobilization did not affect 5-year survival in patients with NHL or patients with MM., (Copyright © 2018. Published by Elsevier Inc.)

This study describes short-term and long-term healthcare resource utilization (HRU) and costs following an allogeneic hematopoietic stem cell transplant (HSCT) in adult patients with diffuse large B-cell lymphoma (DLBCL) in a real-world setting. Among 101 patients with DLBCL receiving an allogeneic HSCT, HRU and direct healthcare costs for up to three years after the allogeneic HSCT are described. HRU and costs were substantial, with the most intensive HRU and highest healthcare costs observed during the first year after HSCT (38 inpatient days; 68 days with office visits and average healthcare costs of $455,741). Although HRU and costs decreased over time, they remained high even in the third year after HSCT (four inpatient days; 27 days with office visits and average healthcare costs of $72,957). Overall, this study showed that the economic burden following an allogeneic HSCT in DLBCL patients is significant.

Chronic lymphocytic leukemia (CLL) is a common hematologic malignancy with many highly effective therapies. Chemorefractory disease, often characterized by deletion of chromosome 17p, has historically been associated with very poor outcomes, leading to the application of allogeneic hematopoietic stem cell transplantation (allo-HCT) for medically fit patients. Although the use of allo-HCT has declined since the introduction of novel targeted therapy for the treatment of CLL, there remains significant interest in understanding factors that may influence the efficacy of allo-HCT, the only known curative treatment for CLL. The potential benefit of transplantation is most likely due to the presence of alloreactive donor T cells that mediate the graft-versus-leukemia (GVL) effect. The recognition of potentially tumor-specific antigens in the context of class I and II major histocompatibility complex on malignant B lymphocytes by donor T cells may be influenced by subtle differences in the highly polymorphic HLA locus. Given previous reports of specific HLA alleles impacting the incidence of CLL and the clinical outcomes of allo-HCT for CLL, we sought to study the overall survival and progression-free survival of a large cohort of patients with CLL who underwent allo-HCT from fully HLA-matched related and unrelated donors at Center for International Blood and Marrow Transplant Research transplantation centers. We found no statistically significant association of allo-HCT outcomes in CLL based on previously reported HLA combinations. Additional study is needed to further define the immunologic features that portend a more favorable GVL effect after allo-HCT for CLL., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Extra-Nodal natural killer/T-cell lymphoma (ENKL) is a rare lymphoma representing approximately 5-10% of T-cell non-Hodgkin lymphomas diagnosed in the United States each year. Patients with advanced stage III/IV ENKL and relapsed refractory ENKL have a poor prognosis even despite aggressive therapy and stem cell transplantation (SCT). We conducted a review of the management of 37 patients with advanced-stage and relapsed/refractory ENKL in a predominantly non-Asian cohort evaluating both chemotherapy and SCT outcomes., Patients and Methods: We evaluated clinical outcomes in all patients treated for advanced stage III/IV or relapsed/refractory ENKL at MD Anderson cancer center between 2000-2014. Next, we collected stem cell transplant data from four transplant institutions to further evaluate outcomes of both allogeneic (allo-SCT) and autologous (auto-SCT) stem cell transplantation in ENKL., Results: OS and PFS were 73% and 45% at one year, and 30% and 19% at 3-years, respectively. SMILE chemotherapy was more effective in maintaining a CR compared to CHOP (83% vs 17%). Only achievement of CR was prognostic for OS (HR 0.245, p=0.002) and PFS (HR 0.072, p) CONCLUSION: Our results suggest that achievement of a CR is imperative in patients with advanced ENKL, and is desirable for any patient for whom auto-SCT is utilized. SMILE-based chemotherapy appeared effective in attaining a CR, and was also an effective salvage regimen. For patients attaining a first CR, auto-SCT should be strongly considered, but should definitely be utilized in patients attaining CR2. For patients with refractory disease, allo-SCT can be considered in a selected group of patients., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Patient-centered medical home models are fundamental to the advanced alternative payment models defined in the Medicare Access and Children's Health Insurance Plan Reauthorization Act (MACRA). The patient-centered medical home is a model of healthcare delivery supported by alternative payment mechanisms and designed to promote coordinated medical care that is simultaneously patient-centric and population-oriented. This transformative care model requires shifting reimbursement to include a per-patient payment intended to cover services not previously reimbursed such as disease management over time. Payment is linked to quality measures, including proportion of care delivered according to predefined pathways and demonstrated impact on outcomes. Some medical homes also include opportunities for shared savings by reducing overall costs of care. Recent proposals have suggested expanding the medical home model to specialized populations with complex needs because primary care teams may not have the facilities or the requisite expertise for their unique needs. An example of a successful care model that may provide valuable lessons for those creating specialty medical home models already exists in many hematopoietic cell transplantation (HCT) centers that deliver multidisciplinary, coordinated, and highly specialized care. The integration of care delivery in HCT centers has been driven by the specialty care their patients require and by the payment methodology preferred by the commercial payers, which has included bundling of both inpatient and outpatient care in the peritransplant interval. Commercial payers identify qualified HCT centers based on accreditation status and comparative performance, enabled in part by center-level comparative performance data available within a national outcomes database mandated by the Stem Cell Therapeutic and Research Act of 2005. Standardization across centers has been facilitated via voluntary accreditation implemented by Foundation for the Accreditation of Cell Therapy. Payers have built on these community-established programs and use public outcomes and program accreditation as standards necessary for inclusion in specialty care networks and contracts. Although HCT centers have not been described as medical homes, most HCT providers have already developed the structures that address critical requirements of MACRA for medical homes., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Introduction: Multiple myeloma (MM) is an incurable plasma cell malignancy, in which aggressive relapses might require salvage cytotoxic infusional chemotherapy. Several clinical trials that reported the efficacy of bortezomib led to institutional practice changes in which vincristine was replaced with bortezomib in the modified hyperCVAD regimen, creating a new treatment regimen, named "bortezomib-hyperCAD.", Patients and Methods: We retrospectively describe the effectiveness and tolerability of 2 chemotherapy regimens among 33 patients with relapsed and/or refractory MM. Patients who received ≥ 1 cycle of modified hyperCVAD or bortezomib-hyperCAD between 2011 and 2015 were assessed., Results: The median number of cycles administered in each arm was 2. The overall response rate was 40% (6 partial responses) in the modified hyperCVAD group and 44.4% (1 complete response, 1 very good partial response, and 6 partial responses) in the bortezomib-hyperCAD group (Fisher exact P = .80). Median progression-free survival (PFS) and median overall survival (OS) for patients in the modified hyperCVAD group was 6.3 months and 11.1 months, respectively. This was comparable with patients in the bortezomib-hyperCAD group, who had a median PFS of 6.6 months and a median OS of 13.8 months (log rank P = .54 and .66, respectively). There was no statistically significant association between treatment arm and febrile neutropenia, emergency department visits, hospitalizations, or peripheral neuropathy (all Fisher exact P values > .05)., Conclusion: Overall effectiveness and tolerability outcomes were similar between modified hyperCVAD and bortezomib-hyperCAD, with both regimens showing an impressive response rate among refractory and heavily pretreated patients with relapsed MM., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose Several open-label randomized studies have suggested that in vivo T-cell depletion with anti-T-lymphocyte globulin (ATLG; formerly antithymocyte globulin-Fresenius) reduces chronic graft-versus-host disease (cGVHD) without compromising survival. We report a prospective, double-blind phase III trial to investigate the effect of ATLG (Neovii Biotech, Lexington, MA) on cGVHD-free survival. Patients and Methods Two hundred fifty-four patients 18 to 65 years of age with acute leukemia or myelodysplastic syndrome who underwent myeloablative HLA-matched unrelated hematopoietic cell transplantation (HCT) were randomly assigned one to one to placebo (n =128 placebo) or ATLG (n = 126) treatment at 27 sites. Patients received either ATLG or placebo 20 mg/kg per day on days -3, -2, -1 in addition to tacrolimus and methotrexate as GVHD prophylaxis. The primary study end point was moderate-severe cGVHD-free survival. Results Despite a reduction in grade 2 to 4 acute GVHD (23% v 40%; P = .004) and moderate-severe cGVHD (12% v 33%; P < .001) in ATLG recipients, no difference in moderate-severe cGVHD-free survival between ATLG and placebo was found (2-year estimate: 48% v 44%, respectively; P = .47). Both progression-free survival (PFS) and overall survival (OS) were lower with ATLG (2-year estimate: 47% v 65% [ P = .04] and 59% v 74% [ P = .034], respectively). Multivariable analysis confirmed that ATLG was associated with inferior PFS (hazard ratio, 1.55; 95% CI, 1.05 to 2.28; P = .026) and OS (hazard ratio, 1.74; 95% CI, 1.12 to 2.71; P = .01). Conclusion In this prospective, randomized, double-blind trial of ATLG in unrelated myeloablative HCT, the incorporation of ATLG did not improve moderate-severe cGVHD-free survival. Moderate-severe cGVHD was significantly lower with ATLG, but PFS and OS also were lower. Additional analyses are needed to understand the appropriate role for ATLG in HCT.

Allogeneic hematopoietic stem cell transplantation (HSCT) is a critically important therapy for hematological malignancies, inborn errors of metabolism, and immunodeficiency disorders, yet complications such as graft-vs.-host disease (GvHD) limit survival. Development of anti-GvHD therapies that do not adversely affect susceptibility to infection or graft-vs.-tumor immunity are hampered by the lack of a physiologically relevant, preclinical model of allogeneic HSCT. Here we show a spectrum of diverse clinical HSCT outcomes including primary and secondary graft failure, lethal GvHD, and stable, disease-free full donor engraftment using reduced intensity conditioning and mobilized peripheral blood HSCT in unrelated, fully MHC-matched Mauritian-origin cynomolgus macaques. Anti-GvHD prophylaxis of tacrolimus, post-transplant cyclophosphamide, and CD28 blockade induces multi-lineage, full donor chimerism and recipient-specific tolerance while maintaining pathogen-specific immunity. These results establish a new preclinical allogeneic HSCT model for evaluation of GvHD prophylaxis and next-generation HSCT-mediated therapies for solid organ tolerance, cure of non-malignant hematological disease, and HIV reservoir clearance.

Background: In the CALGB (Alliance) 100104 study, lenalidomide versus placebo after autologous stem-cell transplantation (ASCT) was investigated for patients with newly diagnosed myeloma. That study showed improved time to progression and overall survival and an increase in second primary malignancies for lenalidomide at a median follow-up of 34 months. Here we report an updated intention-to-treat analysis of CALGB (Alliance) 100104 at a median follow-up of 91 months., Methods: Patients were eligible for this randomised, double-blind, placebo-controlled, phase 3 trial if they had symptomatic disease requiring treatment; had received, at most, two induction regimens; and had achieved stable disease or better in the first 100 days after ASCT. We randomly assigned patients to either lenalidomide or placebo groups using permuted block randomisation, with a fixed block size of six. Randomisation was stratified by three factors: normal or elevated β2 microglobulin concentration at registration (≤2·5 mg/L vs >2·5 mg/L), previous use or non-use of thalidomide during induction therapy, and previous use or non-use of lenalidomide during induction therapy. The starting dose was two capsules (10 mg) per day, escalated to three capsules (15 mg) per day after 3 months. The primary endpoint was time to progression (time of progressive disease or death from any cause), with intention-to-treat analysis. This study is registered with ClinicalTrials.gov, identifier NCT00114101. New patients are no longer being recruited, but some patients remain on treatment and in follow-up., Findings: Between April 14, 2005, and July 2, 2009, 460 patients were randomly assigned to receive either lenalidomide (n=231) or placebo (n=229). After three interim analyses, the study was unblinded at a median follow-up of 18 months, at which point 86 (67%) of 128 patients without progressive disease in the placebo group chose to cross over to the lenalidomide group. The median follow-up for the updated survival analysis, as of Oct 19, 2016, was 91 months (IQR 83·6-103·1). The median time to progression was 57·3 months (95% CI 44·2-73·3) for the lenalidomide group and 28·9 months (23·0-36·3) for the placebo group (hazard ratio 0·57, 95% CI 0·46-0·71; p<0·0001). The most common grade 3-4 adverse events were neutropenia (116 [50%] patients in the lenalidomide group and 41 [18%] patients in the placebo group) and thrombocytopenia (34 [15%] patients in the lenalidomide group and 12 [5%] patients in the placebo group). 18 (8%) haematological and 14 (6%) solid tumour second primary malignancies were diagnosed after randomisation and before disease progression in the lenalidomide group, compared with three (1%) haematological and nine (4%) solid tumour second primary malignancies in the placebo group. Three haematological and five solid tumour second primary malignancies in the placebo group were in the crossover subgroup., Interpretation: Despite an increase in haematological adverse events and second primary malignancies, lenalidomide maintenance therapy after ASCT significantly improved time to progression and could be considered a standard of care., Funding: The National Cancer Institute., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Cellular therapies and other regenerative medicines are emerging as potentially transformative additions to modern medicine, but likely at a staggering financial cost. Public health care systems' budgets are already strained by growing and aging populations, and many private insurer's budgets are equally stretched. The current systems that most payers employ to manage their cash flow are not structured to absorb a sudden onslaught of very expensive prescriptions for a large portion of their covered population. Despite this, developers of new regenerative medicines tend to focus on the demands of regulators, not payers, in order to be compliant throughout the clinical trials phases, and to develop a product that ultimately will be approvable. It is not advisable to assume that an approved product will automatically become a reimbursed product, as examples from current practice in hematopoietic stem cell transplantation in the U.S. demonstrate; similarly, in Europe numerous Advanced-therapy Medicinal Products achieved market authorization but failed to secure reimbursement (e.g., Glybera, Provenge, ChondroCelect, MACI). There are however strategies and approaches that developers can employ throughout clinical development, in order to generate clinical and health economic data which will be necessary to demonstrate the value proposition of the new product and help ensure market access for patients; furthermore, performance based managed entry agreements coupled with post-launch evidence generation can help overcome challenges around product uncertainty at launch and reduce market access delays. Stem Cells Translational Medicine 2017;6:1723-1729., (© 2017 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)

Purpose The optimal regimen intensity before allogeneic hematopoietic cell transplantation (HCT) is unknown. We hypothesized that lower treatment-related mortality (TRM) with reduced-intensity conditioning (RIC) would result in improved overall survival (OS) compared with myeloablative conditioning (MAC). To test this hypothesis, we performed a phase III randomized trial comparing MAC with RIC in patients with acute myeloid leukemia or myelodysplastic syndromes. Patients and Methods Patients age 18 to 65 years with HCT comorbidity index ≤ 4 and < 5% marrow myeloblasts pre-HCT were randomly assigned to receive MAC (n = 135) or RIC (n = 137) followed by HCT from HLA-matched related or unrelated donors. The primary end point was OS 18 months post-random assignment based on an intent-to-treat analysis. Secondary end points included relapse-free survival (RFS) and TRM. Results Planned enrollment was 356 patients; accrual ceased at 272 because of high relapse incidence with RIC versus MAC (48.3%; 95% CI, 39.6% to 56.4% and 13.5%; 95% CI, 8.3% to 19.8%, respectively; P < .001). At 18 months, OS for patients in the RIC arm was 67.7% (95% CI, 59.1% to 74.9%) versus 77.5% (95% CI, 69.4% to 83.7%) for those in the MAC arm (difference, 9.8%; 95% CI, -0.8% to 20.3%; P = .07). TRM with RIC was 4.4% (95% CI, 1.8% to 8.9%) versus 15.8% (95% CI, 10.2% to 22.5%) with MAC ( P = .002). RFS with RIC was 47.3% (95% CI, 38.7% to 55.4%) versus 67.8% (95% CI, 59.1% to 75%) with MAC ( P < .01). Conclusion OS was higher with MAC, but this was not statistically significant. RIC resulted in lower TRM but higher relapse rates compared with MAC, with a statistically significant advantage in RFS with MAC. These data support the use of MAC as the standard of care for fit patients with acute myeloid leukemia or myelodysplastic syndromes.

This study aims to provide a detailed analysis of allogeneic stem cell transplantation (allo-SCT) outcomes in a large T-cell acute lymphoblastic leukemia (T-ALL) cohort with a specific emphasis on the effects of pre-transplant minimal residual disease (MRD) and disease subtype, including the aggressive early-thymic precursor (ETP) subtype. Data from 102 allo-SCT patients with a diagnosis of T-ALL from three centers were retrospectively analyzed. Patients were grouped into four T-ALL subtypes: ETP, early, cortical and mature. At 3 years, overall survival (OS), PFS, non-relapse mortality and cumulative incidence (CI) progression were 35, 33, 11 and 55%, respectively. Patients transplanted in first complete remission (CR1) had a 3-year OS of 62% versus those transplanted in CR2 or greater (24%) (hazards ratio 1.6, P=0.2). Patients with MRD positivity at the time of transplant had significantly higher rates of progression compared with those with MRD negativity (76 vs 34%, hazards ratio 2.8, P=0.006). There was no difference in OS, PFS or cumulative incidence (CI) progression between disease subtypes, including ETP (n=16). ETP patients transplanted in CR1 (n=10) had OS of 47%, comparable to other disease subtypes, suggesting that allo-SCT can overcome the poor prognosis associated with ETP. MRD status at transplant was highly predictive of disease relapse, suggesting novel therapies are necessary to improve transplant outcomes.

Importance: Bone marrow or peripheral blood from unrelated donors may be used for hematopoietic cell transplantation. Information about the relative success of transplantation with these 2 graft sources would help physicians and patients choose between them., Objective: To compare patient-reported outcomes between patients randomized to receive 1 of 2 graft types for unrelated donor transplantation., Design, Setting, and Participants: This follow-up of a randomized clinical trial included English- or Spanish-speaking patients 16 years or older participating in a multicenter randomized clinical trial of unrelated donor bone marrow (BM) vs peripheral blood (PB) (N = 551) in hematopoietic cell transplantation for hematologic neoplasms. Patient-reported outcomes were collected from patients at enrollment and 0.5, 1, 2, and 5 years after transplantation., Interventions: Unrelated donor BM or PB hematopoietic cell transplantation., Main Outcomes and Measures: Functional Assessment of Cancer Therapy-Bone Marrow Transplant, Mental Health Inventory, occupational functioning, Lee Chronic Graft-vs-Host Disease Symptom Scale., Results: At 5 years after transplantation, 102 BM and 93 PB participants were alive and eligible for assessment (age ≥40 years or older: 104 [53.5%] male: 101 [51.8%]). The mean (SE) Mental Health Inventory Psychological Well-Being scores (78.9 [1.7] vs 72.2 [1.9]; P = .01; higher better) and Lee chronic graft-vs-host disease symptom scores (13.1 [1.5] vs 19.3 [1.6]; P = .004; lower better) were significantly better for BM recipients, adjusting for baseline scores and missing data. Recipients of BM were also more likely to be working full or part-time than recipients of PB (odds ratio, 1.5; 95% CI, 1.2-2.0; P = .002), adjusting for work status before transplantation. With a median follow-up of 73 months (range, 30-121 months) for survivors, no differences in survival (40% vs 39%; P = .84), relapse (32% vs 29%; P = .47), or treatment-related mortality (29% vs 32%; P = .44) between BM and PB were observed., Conclusions and Relevance: Recipients of unrelated donor BM had better psychological well-being, less burdensome chronic GVHD symptoms, and were more likely to return to work than recipients of PB at 5 years after transplantation. Bone marrow should be the standard of care for these types of transplant procedures., Trial Registration: clinicaltrials.gov Identifier: NCT00075816.

We sought to confirm the prognostic importance of simple clinically available biomarkers of C-reactive protein, serum albumin, and ferritin prior to allogeneic hematopoietic cell transplantation. The study population consisted of 784 adults with acute myeloid leukemia in remission or myelodysplastic syndromes undergoing unrelated donor transplant reported to the Center for International Blood and Marrow Transplant Research. C-reactive protein and ferritin were centrally quantified by ELISA from cryopreserved plasma whereas each center provided pre-transplant albumin. In multivariate analysis, transplant-related mortality was associated with the pre-specified thresholds of C-reactive protein more than 10 mg/L (P=0.008) and albumin less than 3.5 g/dL (P=0.01) but not ferritin more than 2500 ng/mL. Only low albumin independently influenced overall mortality. Optimal thresholds affecting transplant-related mortality were defined as: C-reactive protein more than 3.67 mg/L, log(ferritin), and albumin less than 3.4 g/dL. A 3-level biomarker risk group based on these values separated risks of transplant-related mortality: low risk (reference), intermediate (HR=1.66, P=0.015), and high risk (HR=2.7, P<0.001). One-year survival was 74%, 67% and 56% for low-, intermediate- and high-risk groups. Routinely available pre-transplant biomarkers independently risk-stratify for transplant-related mortality and survival., (Copyright© Ferrata Storti Foundation.)

Conventional cytogenetics and interphase fluorescence in situ hybridization (FISH) identify high-risk multiple myeloma (HRM) populations characterized by poor outcomes. We analyzed these differences among HRM versus non-HRM populations after upfront autologous hematopoietic cell transplantation (autoHCT). Between 2008 and 2012, 715 patients with multiple myeloma identified by FISH and/or cytogenetic data with upfront autoHCT were identified in the Center for International Blood and Marrow Transplant Research database. HRM was defined as del17p, t(4;14), t(14;16), hypodiploidy (<45 chromosomes excluding -Y) or chromosome 1 p and 1q abnormalities; all others were non-HRM. Among 125 HRM patients (17.5%), induction with bortezomib and immunomodulatory agents (imids) was higher compared with non-HRM (56% versus 43%, P < .001) with similar pretransplant complete response (CR) rates (14% versus 16%, P .1). At day 100 post-transplant, at least a very good partial response was 59% in HRM and 61% in non-HRM (P = .6). More HRM patients received post-transplant therapy with bortezomib and imids (26% versus 12%, P = .004). Three-year post-transplant progression-free (PFS) and overall survival (OS) rates in HRM versus non-HRM were 37% versus 49% (P < .001) and 72% versus 85% (P < .001), respectively. At 3 years, PFS for HRM patients with and without post-transplant therapy was 46% (95% confidence interval [CI], 33 to 59) versus 14% (95% CI, 4 to 29) and in non-HRM patients with and without post-transplant therapy 55% (95% CI, 49 to 62) versus 39% (95% CI, 32 to 47); rates of OS for HRM patients with and without post-transplant therapy were 81% (95% CI, 70 to 90) versus 48% (95% CI, 30 to 65) compared with 88% (95% CI, 84 to 92) and 79% (95% CI, 73 to 85) in non-HRM patients with and without post-transplant therapy, respectively. Among patients receiving post-transplant therapy, there was no difference in OS between HRM and non-HRM (P = .08). In addition to HRM, higher stage, less than a CR pretransplant, lack of post-transplant therapy, and African American race were associated with worse OS. In conclusion, we show HRM patients achieve similar day 100 post-transplant responses compared with non-HRM patients, but these responses are not sustained. Post-transplant therapy appeared to improve the poor outcomes of HRM., (Copyright © 2016 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Aim: To assess the 5-year healthcare resource utilization (HRU) and direct payer costs following allogeneic hematopoietic stem cell transplants (HSCTs) in acute lymphoblastic leukemia pediatric patients using data from two large US administrative databases., Patients & Methods: Among the 209 patients with acute lymphoblastic leukemia, HRU and costs were described over the up to 5 years after the HSCT., Results: HRU and costs following the HSCTs were substantial. The highest average costs and most intensive HRU were observed within the first year following the HSCTs (49 outpatient visits; 29 laboratory service visits; 68 inpatient days), with a first year cost of US$683,099 and substantial costs over the following years., Conclusion: HRU and direct costs associated with allogeneic HSCTs are substantial., Competing Interests: Financial & competing interests disclosure Funding for this research was provided by Novartis Pharmaceuticals Corporation. RT Maziarz is an employee of the Oregon Health & Science University who provided and received payment for consultant services to Novartis Pharmaceuticals Corporation. This potential conflict of interest has been reviewed and managed by OHSU. SK Thomas and L Chen are employees of Novartis Pharmaceuticals Corporation and own stock/stock options. G Gauthier, J Heroux, M Zhdanava, A Guérin and EQ Wu are employees of Analysis Group Inc., which has received consultancy fees from Novartis Pharmaceuticals Corporation for this project. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Writing assistance was utilized in the production of this manuscript. Shelley Batts, an employee of Analysis Group Inc., aided with formatting and editing this manuscript. Analysis Group Inc., has received consultancy fees from Novartis Pharmaceuticals Corporation for this project.

Acute biphenotypic leukemias or mixed phenotype acute leukemias (MPAL) are rare and considered high risk. The optimal treatment and the role of allogeneic hematopoietic stem cell transplantation (alloHCT) are unclear. Most prior case series include only modest numbers of patients who underwent transplantation. We analyzed the outcome of 95 carefully characterized alloHCT patients with MPAL reported to the Center for International Blood and Marrow Transplant Research between 1996 and 2012. The median age was 20 years (range, 1 to 68). Among the 95 patients, 78 were in first complete remission (CR1) and 17 were in second complete remission (CR2). Three-year overall survival (OS) of 67% (95% confidence interval [CI], 57 to 76), leukemia-free survival of 56% (95% CI, 46 to 66), relapse incidence of 29% (95% CI, 20 to 38), and nonrelapse mortality of 15% (95% CI, 9 to 23) were encouraging. OS was best in younger patients (<20 years), but no significant differences were observed between those 20 to 40 years of age and those who were 40 years or older. A matched-pair analysis showed similar outcomes comparing MPAL cases to 375 acute myelogenous leukemia or 359 acute lymphoblastic leukemia cases. MPAL patients had more acute and a trend for more chronic graft-versus-host disease. No difference was observed between patients who underwent transplantation in CR1 versus those who underwent transplantation in CR2. AlloHCT is a promising treatment option for pediatric and adult patients with MPAL with encouraging long-term survival., (Copyright © 2016 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Risk factors for non-Aspergillus mold infection (NAMI) and the impact on transplant outcome are poorly assessed in the current era of antifungal agents. Outcomes of 124 patients receiving allogeneic hematopoietic cell transplantation (HCT) diagnosed with either mucormycosis (n=72) or fusariosis (n=52) between days 0 and 365 after HCT are described and compared with a control cohort (n=11 856). Patients with NAMI had more advanced disease (mucormycois: 25%, fusariosis: 23% and controls: 18%; P=0.004) and were more likely to have a Karnofsky performance status (KPS) <90% at HCT (mucormycosis: 42%, fusariosis: 38% and controls: 28%; P=0.048). The 1-year survival after HCT was 22% (15-29%) for cases and was significantly inferior compared with controls (65% (64-65%); P<0.001). Survival from infection was similarly dismal regardless of mucormycosis: 15% (8-25%) and fusariosis: 21% (11-33%). In multivariable analysis, NAMI was associated with a sixfold higher risk of death (P<0.0001) regardless of the site or timing of infection. Risk factors for mucormycosis include preceding acute GvHD, prior Aspergillus infection and older age. For fusariosis, increased risks including receipt of cord blood, prior CMV infection and transplant before May 2002. In conclusion, NAMI occurs infrequently, is associated with high mortality and appears with similar frequency in the current antifungal era.

Unlabelled: Multipotent adult progenitor cells (MAPCs) are adult adherent stromal stem cells currently being assessed in clinical trials for acute graft versus host disease with demonstrated immunomodulatory capabilities and the potential to ameliorate detrimental autoimmune and inflammation-related processes. Anti-CD3/anti-CD28 (3/28) activation of T cells within the peripheral blood mononuclear cell (PBMC) compartment was performed in the presence or absence of MAPCs. Liquid chromatography-coupled tandem mass spectrometry was used to characterize the differential secretion of proteins, and transcriptional profiling was used to monitor mRNA expression changes in both cell populations. Overall, 239 secreted and/or ectodomain-shed proteins were detected in the secretomes of PBMCs and MAPCs. In addition, 3/28 activation of PBMCs induced differential expression of 2,925 genes, and 22% of these transcripts were differentially expressed on exposure to MAPCs in Transwell. MAPCs exposed to 3/28-activated PBMCs showed differential expression of 1,247 MAPC genes. Crosstalk was demonstrated by reciprocal transcriptional regulation. Secretome proteins and transcriptional signatures were used to predict molecular activities by which MAPCs could dampen local and systemic inflammatory responses. These data support the hypothesis that MAPCs block PBMC proliferation via cell cycle arrest coupled to metabolic stress in the form of tryptophan depletion, resulting in GCN2 kinase activation, downstream signaling, and inhibition of cyclin D1 translation. These data also provide a plausible explanation for the immune privilege reported with administration of donor MAPCs. Although most components of the major histocompatibility complex class II antigen presentation pathway were markedly transcriptionally upregulated, cell surface expression of human leukocyte antigen-DR is minimal on MAPCs exposed to 3/28-activated PBMCs., Significance: This study documents experiments quantifying solution-phase crosstalk between multipotent adult progenitor cells (MAPCs) and peripheral blood mononuclear cells. The secretome and transcriptional changes quantified suggest mechanisms by which MAPCs are hypothesized to provide both local and systemic immunoregulation of inflammation. The potential impact of these studies includes development of a robust experimental framework to be used for preclinical evaluation of the specific mechanisms by which beneficial effects are obtained after treatment of patients with MAPCs., (©AlphaMed Press.)

The Haematopoietic Cell Transplantation-Comorbidity Index (HCT-CI) was designed as a predictor of non-relapse mortality after HCT. Chronic graft-versus-host disease (GVHD) contributes to mortality after HCT. Here, we investigated whether the HCT-CI could predict development of chronic GVHD or post-chronic GVHD mortality. We retrospectively analysed data from 2909 patients treated with allogeneic HCT for malignant and non-malignant haematological conditions at four institutions. In Cox regression models adjusted for potential confounders, increasing HCT-CI was not statistically significantly associated with the development of chronic GVHD [hazard ratio (HR) = 1·02, P = 0·34]. Yet, the index was associated with an increased risk of non-relapse mortality (HR = 1·29, P < 0·0001) as well as overall mortality (HR = 1·25, P < 0·001) following the development of chronic GVHD. The association between HCT-CI and post-chronic GVHD mortality was similar regardless of donor type or stem cell source. HCT-CI scores could be incorporated in the design of clinical trials for treatment of chronic GVHD., (© 2015 John Wiley & Sons Ltd.)

Background: Previously, early results were reported for allogeneic hematopoietic cell transplantation (HCT) after nonmyeloablative conditioning with 2 Gy of total body irradiation with or without fludarabine and/or rituximab in 33 patients with mantle cell lymphoma (MCL)., Methods: This study examined the outcomes of 70 patients with MCL and included extended follow-up (median, 10 years) for the 33 initial patients. Grafts were obtained from human leukocyte antigen (HLA)-matched, related donors (47%), unrelated donors (41%), and HLA antigen-mismatched donors (11%)., Results: The 5-year incidence of nonrelapse mortality was 28%. The relapse rate was 26%. The 5-year rates of overall survival (OS) and progression-free survival (PFS) were 55% and 46%, respectively. The 10-year rates of OS and PFS were 44% and 41%, respectively. Eighty percent of surviving patients were off immunosuppression at the last follow-up. The presence of relapsed or refractory disease at the time of HCT predicted a higher rate of relapse (hazard ratio [HR], 2.94; P = .05). Despite this, OS rates at 5 (51% vs 58%) and 10 years (43% vs 45%) were comparable between those with relapsed/refractory disease and those undergoing transplantation with partial or complete remission. A high-risk cytomegalovirus (CMV) status was the only independent predictor of worse OS (HR, 2.32; P = .02). A high-risk CMV status and a low CD3 dose predicted PFS (HR, 2.22; P = .03)., Conclusions: Nonmyeloablative allogeneic HCT provides a long-term survival benefit for patients with relapsed MCL, including those with refractory disease or multiple relapses., (© 2015 American Cancer Society.)

The haematopoietic cell transplantation-specific comorbidity index (HCT-CI) was developed in a single centre as a weighted scoring system to predict risks of non-relapse mortality (NRM) following allogeneic haematopoietic cell transplantation. Information on the performance of the HCT-CI in multi-centre studies is lacking in the literature. To that end, a collaborative multicentre retrospective study was initiated. Comorbidity data from 2523 consecutive recipients of human leucocyte antigen-matched grafts from five different US institutions were analysed. Among all patients, HCT-CI scores of 0 vs. 1-2 vs. ≥3 were associated with 2-year NRM rates of 14%, 23% and 39% (P < 0·0001), respectively, and 2-year overall survival (OS) rates of 74%, 61% and 39%, respectively (P < 0·0001). Using regression models, increasing HCT-CI scores were independently associated with increases in hazard ratios for NRM and worse survival within individual institutions. The HCT-CI retained independent capacity for association with outcomes within different age as well as conditioning intensity groups. C-statistic estimates for the prognostic power of the HCT-CI for NRM and OS were 0·66 and 0·64, respectively. The estimates within each institution were overall similar. The HCT-CI is a valid tool for capturing comorbidities and predicting mortality after haematopoietic cell transplantation across different institutions., (© 2015 John Wiley & Sons Ltd.)

Serositis is a rare manifestation of chronic GvHD (cGvHD). No risk factors or laboratory changes associated with this syndrome have been recognized to date, and outcomes have not been described in a large series. We searched our institutional database for patients undergoing allogeneic hematopoietic cell transplant identified as having serositis or pericarditis. Laboratory studies from prior to diagnosis, at diagnosis and post diagnosis of serositis, as well as outcomes from invasive procedures were included. Twenty patients met criteria for cGvHD-associated serositis, and all but three patients had a prior diagnosis of cGvHD. Fifteen were male, and the complication occurred in the setting of immunosuppressant taper in 12 cases. Ten patients required invasive interventions, including pericardial window or stripping. A significant increase in blood monocytes and decrease in serum albumin were identified at diagnosis compared with pre-diagnosis. Out of 20 patients, 17 were treated with steroids, with 12 demonstrating a complete response. These data suggest that cGvHD-associated serositis occurs mainly in the setting of treated as opposed to de novo cGvHD and biomarkers associated with the syndrome include a decrease in albumin and an increase in absolute monocyte count. Outcome data from larger series are required to better understand the optimal management of this rare complication.

We conducted a multicenter, phase 1 dose escalation study evaluating the safety of the allogeneic multipotent adult progenitor cell (MAPC, MultiStem, Athersys, Inc., Cleveland, OH) stromal product administered as an adjunct therapy to 36 patients after myeloablative allogeneic hematopoietic cell transplantation (HCT). Patients received increasing doses of MAPC (1, 5, or 10 million cells per kilogram recipient weight) as a single i.v. dose on day +2 after HCT (n = 18), or once weekly for up to 5 doses (1 or 5 million cells per kilogram; n = 18). Infusional and regimen-related toxicities were assessed for 30 days after the last MAPC dose. Of 36 allogeneic HCT donors (17 related and 19 unrelated), 35 were 6/6 HLA matched. MAPC infusions were well tolerated without associated infusional toxicity, graft failure, or increased incidence of infection. Median times to neutrophil (n = 36) and platelet (n = 31) engraftment were 15 (range, 11 to 25) and 16 (range, 11 to 41) days, respectively. The overall cumulative incidences of grades II to IV and III and IV acute graft-versus-host disease (GVHD) at day 100 were 37% and 14%, respectively (n = 36). In the group that received the highest single MAPC dose (10 million cells/kg), day 100 incidence of grade II to IV GVHD was 11.1% (1 of 9) with no observed cases of grade III and IV GVHD. We found no evidence for MHC class II allogeneic antibody induction, although some patients showed an increase in serum anticlass I titers compared with baseline. MAPC contribution to blood chimerism was negligible. These phase I data support the safety of stromal stem cell therapy and suggest that MAPC should be tested prospectively as a novel therapeutic option for GVHD prophylaxis after HCT., (Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Cyclophosphamide (Cy) in combination with busulfan (Bu) or total body irradiation (TBI) is the most commonly used myeloablative conditioning regimen in patients with chronic myeloid leukemia (CML). We used data from the Center for International Bone Marrow Transplantation Research to compare outcomes in adults who underwent hematopoietic cell transplantation for CML in first chronic phase after myeloablative conditioning with Cy in combination with TBI, oral Bu, or intravenous (i.v.) Bu. Four hundred thirty-eight adults received human leukocyte antigen (HLA)-matched sibling grafts and 235 received well-matched grafts from unrelated donors (URD) from 2000 through 2006. Important differences existed between the groups in distribution of donor relation, exposure to tyrosine kinase inhibitors, and year of transplantation. In multivariate analysis, relapse occurred less frequently among patients receiving i.v. Bu compared with TBI (relative risk [RR], .36; P = .022) or oral Bu (RR, .39; P = .028), but nonrelapse mortality and survival were similar. A significant interaction was detected between donor relation and the main effect in leukemia-free survival (LFS). Among recipients of HLA-identical sibling grafts, but not URD grafts, LFS was better in patients receiving i.v. Bu (RR, .53; P = .025) or oral Bu (RR, .64; P = .017) compared with TBI. In CML in first chronic phase, Cy in combination with i.v. Bu was associated with less relapse than TBI or oral Bu. LFS was better after i.v. or oral Bu compared with TBI., (Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

The BuFluTBI conditioning regimen was designed with the primary goal of reducing non-relapse mortality (NRM) while maximizing primary disease control in patients ineligible for myeloablative conditioning. Patients with hematologic malignancies for whom limited long-term survival was expected with standard therapy were administered an outpatient conditioning regimen of busulfan 3.2 mg/kg IV on day -5, fludarabine 30 mg/m(2) IV on days -4, -3, -2, and 200 cGy of total body irradiation (TBI) followed by stem cell infusion from related or unrelated donors. GVHD prophylaxis included cyclosporine and mycophenolate mofetil. 147 patients were enrolled from 2005-2011; 59% with myeloid disease and 41% with lymphoid disease. The median age was 64, and the median comorbidity index (HCT-CI) score was 3. Overall survival (OS), with 3.2 years median follow-up, was 60% at 1 year and 48% at 2 years, with projected OS 37% at 5 years. Relapse rates were 29% at 1 year and 33% at 2 years, with relapse mortality of 13% at 1 year, and 20% at 2 years. Nonrelapse mortality (NRM) at 1 year was 27% and 33% at 2 years. 54% of patients developed grade II-IV aGVHD and 67% of patients developed cGVHD within 2 years. On multivariate analysis, HCT-CI score 4 or greater, pre-transplant KPS less than 90, delayed platelet engraftment of more than 15 days, and grade II-IV aGVHD were found to be independent predictors of poor survival. There was no difference in OS or PFS between lymphoid and myeloid malignancies. BuFluTBI is an efficacious NMA regimen, active in both myeloid and lymphoid disease, and is ideally suited for use in patients age 65 and older or with an HCT-CI of 4 or greater., (Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

We sought to determine whether differences in chronic graft-versus-host disease (GVHD) rates would lead to survival differences by comparing 2463 peripheral blood (PB) and 1713 bone marrow (BM) hematopoietic cell transplant recipients. Patients had acute leukemia, chronic myeloid leukemia (CML), or myelodysplastic syndrome, and they received myeloablative conditioning regimens and calcineurin-inhibitor GVHD prophylaxis. There were no significant differences in long-term survival after transplantation of PB and BM, except for patients in first chronic phase CML. For these patients, the 5-year rate of survival was lower after transplantation of PB compared with transplantation of BM (35% versus 56%, P = .001). Although mortality risks were higher in patients with chronic GVHD after both PB (hazard ratio [HR], 1.58; P < .001) and BM (HR 1.73; P < .001) transplantations, its effect on mortality did not differ by graft type (P = .42). BM is the preferred graft for first chronic phase CML, whereas as either graft is suitable for other leukemias., (Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

We analyzed the outcomes of patients who survived disease-free for 1 year or more after a second allogeneic hematopoietic cell transplantation (HCT) for relapsed acute leukemia or myelodysplastic syndromes between 1980 and 2009. A total of 1285 patients received a second allogeneic transplant after disease relapse; among these, 325 were relapse free at 1 year after the second HCT. The median time from first to second HCT was 17 and 24 months for children and adults, respectively. A myeloablative preparative regimen was used in the second transplantation in 62% of children and 45% of adult patients. The overall 10-year conditional survival rates after second transplantation in this cohort of patients who had survived disease-free for at least 1 year was 55% in children and 39% in adults. Relapse was the leading cause of mortality (77% and 54% of deaths in children and adults, respectively). In multivariate analyses, only disease status before second HCT was significantly associated with higher risk for overall mortality (hazard ratio, 1.71 for patients with disease not in complete remission before second HCT, P < .01). Chronic graft-versus-host disease (GVHD) developed in 43% and 75% of children and adults after second transplantation. Chronic GVHD was the leading cause of nonrelapse mortality, followed by organ failure and infection. The cumulative incidence of developing at least 1 of the studied late effects within 10 years after second HCT was 63% in children and 55% in adults. The most frequent late effects in children were growth disturbance (10-year cumulative incidence, 22%) and cataracts (20%); in adults they were cataracts (20%) and avascular necrosis (13%). Among patients with acute leukemia and myelodysplastic syndromes who receive a second allogeneic HCT for relapse and survive disease free for at least 1 year, many can be expected to survive long term. However, they continue to be at risk for relapse and nonrelapse morbidity and mortality. Novel approaches are needed to minimize relapse risk and long-term transplantation morbidity in this population., (Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Variability in transplantation benefits may directly affect outcomes of individuals undergoing autologous or allogeneic hematopoietic stem cell transplantation procedures. The Financial Working Group of the National Marrow Donor Program-sponsored System Capacity Initiative addressed the issue of variable benefits and reviewed multiple transplantation benefit packages from both public and private payer organizations. On completion of the review, a consensus was obtained on defining a recipient benefit package that avoids major coverage gaps that could negatively influence patient outcomes. The recommendation was to encourage adoption of these benefits at a national level by payers, benefit brokers/consultants, and sales teams., (Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

We describe outcomes after allogeneic hematopoietic cell transplantation (HCT) for mycosis fungoides and Sezary syndrome (MF/SS). Outcomes of 129 subjects with MF/SS reported to the Center for the International Blood and Marrow Transplant from 2000-2009. Median time from diagnosis to transplant was 30 (4-206) months and most subjects were with multiply relapsed/ refractory disease. The majority (64%) received non-myeloablative conditioning (NST) or reduced intensity conditioning (RIC). NST/RIC recipients were older in age compared with myeloablative recipients (median age 51 vs 44 years, P=0.005) and transplanted in recent years. Non-relapse mortality (NRM) at 1 and 5 years was 19% (95% confidence interval (CI) 12-27%) and 22% (95% CI 15-31%), respectively. Risk of disease progression was 50% (95% CI 41-60%) at 1 year and 61% (95% CI 50-71%) at 5 years. PFS at 1 and 5 years was 31% (95% CI 22-40%) and 17% (95% CI 9-26%), respectively. OS at 1 and 5 years was 54% (95% CI 45-63%) and 32% (95% CI 22-44%), respectively. Allogeneic HCT in MF/SS results in 5-year survival in approximately one-third of patients and of those, half remain disease-free.

Purpose: Age has long been used as a major factor for assessing suitability for allogeneic hematopoietic cell transplantation (HCT). The HCT-comorbidity index (HCT-CI) was developed as a measure of health status to predict mortality risk after HCT. Whether age, comorbidities, or both should guide decision making for HCT is unknown., Patients and Methods: Data from 3,033 consecutive recipients of HLA-matched grafts from five institutions contributed to this analysis. Patients were randomly divided into a training set to develop weights for age intervals and a validation set to assess the performance of prognostic models., Results: In the training set, patients age 20 to 39 years, 40 to 49 years, 50 to 59 years, and ≥ 60 years had hazard ratios for nonrelapse mortality (NRM) of 1.21 (P = .29), 1.48 (P = .04), 1.75 (P = .004), and 1.84 (P = .005), respectively, compared with those age younger than 20 years. Consequently, age ≥ 40 years was assigned a weight of 1 to be added to the HCT-CI to constitute a composite comorbidity/age index. In the validation set, the composite comorbidity/age score had statistically significantly higher c-statistic estimates for prediction of NRM (0.664 v 0.556; P < .001) and survival (0.682 v 0.560; P < .001) compared with age, respectively. Patients with comorbidity/age scores of 0 to 2 had comparable mortality risks regardless of conditioning regimens. Patients with scores of 3 to 4 and ≥ 5 had statistically significant higher mortality risks after high-dose versus nonmyeloablative regimens., Conclusion: Age is a poor prognostic factor. The proposed composite measure allows integration of both comorbidities and age into clinical decision making and comparative-effectiveness research of HCT., (© 2014 by American Society of Clinical Oncology.)

Introduction/background: High-dose melphalan (HDM) followed by autologous stem cell transplant (ASCT) for light chain amyloidosis (AL) was performed in 31 patients at Oregon Health and Science University between 2005 and 2012. Fifteen patients had cardiac involvement., Patients and Methods: Patients received melphalan 200 mg/m(2) or dose-adjusted HDM (100-140 mg/m(2)) depending on high risk features. Thirteen patients proceeded directly to ASCT after diagnosis, 12 patients received a bortezomib-containing regimen, and 6 received a variety of other induction regimens., Results: The day 100 treatment-related mortality was 9.6%. Overall hematologic (ORR) and organ response rates (OR) in the whole cohort after ASCT were 77% and 58%. ORR and OR in the bortezomib pretreated group were 92% and 75% vs. 69% and 54% in the group that received no pretreatment. The median time to maximum hematologic response after ASCT was reduced in the group that received bortezomib induction (3 vs. 14 months). Overall cardiac response rate was 60%; 100% in patients pretreated with bortezomib and 43% in those without induction treatment. With a median follow-up of 2.9 years, the 3-year progression-free and overall survival rates in the entire cohort were 66% and 73% and in those with cardiac involvement, 73% and 80%., Conclusion: We observed that bortezomib-based induction is well tolerated in patients with and without cardiac involvement and suggest that this approach be studied in prospective multi-institutional trials., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Allogeneic hematopoietic cell transplantation (HCT) can cure some chronic lymphocytic leukemia (CLL) subjects. This study compared outcomes of myeloablative (MA) and reduced-intensity conditioning (RIC) transplants from HLA-matched sibling donors (MSD) for CLL. From 1995 to 2007, information regarding 297 CLL subjects was reported to the Center of International Blood and Marrow Transplant Research; of these, 163 underwent MA and 134 underwent RIC MSD HCT. The MA subjects underwent transplantation less often after 2000 and less commonly received antithymocyte globulin (4% versus 13%, P = .004) or prior antibody therapy (14% versus 53%; P < .001). RIC was associated with a greater likelihood of platelet recovery and less grade 2 to 4 acute graft-versus-host disease compared with MA conditioning. One- and 5-year treatment-related mortality (TRM) were 24% (95% confidence intervals [CI], 16% to 33%) versus 37% (95% CI, 30% to 45%; P = .023), and 40% (95% CI, 29% to 51%) versus 54% (95% CI, 46% to 62%; P = .036), respectively, and the relapse/progression rates at 1 and 5 years were 21% (95% CI, 14% to 29%) versus 10% (95% CI, 6% to 15%; P = .020), and 35% (95% CI, 26% to 46%) versus 17% (95% CI, 12% to 24%; P = .003), respectively. MA conditioning was associated with better progression-free (PFS) (relative risk, .60; 95% CI, .37 to .97; P = .038) and 3-year survival in transplantations before 2001, but for subsequent years, RIC was associated with better PFS and survival (relative risk, 1.49 [95% CI, .92 to 2.42]; P = .10; and relative risk, 1.86 [95% CI, 1.11 to 3.13]; P = .019). Pretransplantation disease status was the most important predictor of relapse (P = .003) and PFS (P = .0007) for both forms of transplantation conditioning. MA and RIC MSD transplantations are effective for CLL. Future strategies to decrease TRM and reduce relapses are warranted., (Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Whether the hematopoietic cell transplantation comorbidity index (HCT-CI) can provide prognostic information about development of acute graft-versus-host disease (GVHD) and subsequent mortality is unknown. Five institutions contributed information on 2985 patients given human leukocyte antigen-matched grafts to address this question. Proportional hazards models were used to estimate the hazards of acute GVHD and post-GVHD mortality after adjustment for known risk variables. Higher HCT-CI scores predicted increased risk of grades 3 to 4 acute GVHD (P < .0001 and c-statistic of 0.64), and tests of interaction suggested that this association was consistent among different conditioning intensities, donor types, and stem cell sources. Probabilities of grades 3 to 4 GVHD were 13%, 18%, and 24% for HCT-CI risk groups of 0, 1 to 4, and ≥5. The HCT-CI was statistically significantly associated with mortality rates following diagnosis of grade 2 (hazard ratio [HR] = 1.24; P < .0001) or grades 3 to 4 acute GVHD (HR = 1.19; P < .0001). Patients with HCT-CI scores of ≥3 who developed grades 3 to 4 acute GVHD had a 2.63-fold higher risk of mortality than those with scores of 0 to 2 and did not develop acute GVHD. Thus, pretransplant comorbidities are associated with the development and severity of acute GVHD and with post-GVHD mortality. The HCT-CI could be useful in designing trials for GVHD prevention and could inform expectations for GVHD treatment trials., (© 2014 by The American Society of Hematology.)

There are limited data on the outcomes of autologous or allogeneic hematopoietic cell transplantation (HCT) in diffuse large B cell lymphoma transformed from follicular lymphoma. We analyzed transplantation outcomes in 141 subjects with biopsy-proven diffuse large B-cell lymphoma transformed from follicular lymphoma reported to the Center for International Blood and Marrow Transplant Research between 1990 and 2009. Two groups were identified: autologous HCT (auto-HCT; n = 108) and allogeneic HCT (allo-HCT; n = 33). Fewer auto-HCTs were done for transformed follicular lymphoma in 2003 to 2009, with a shift favoring allo-HCT. Auto-HCT was associated with a 1-year nonrelapse mortality (NRM) of 8% (95% confidence interval [CI], 4% to 14%), 5-year progression-free survival of 35% (95% CI, 26% to 45%), and 5-year overall survival of 50% (95% CI, 40% to 59%). In contrast, allo-HCT was associated with a 1-year NRM of 41% (95% CI, 23% to 58%), 5-year progression-free survival of 18% (95% CI, 6% to 35%), and 5-year overall survival of 22% (95% CI, 8% to 41%). Auto-HCT for transformed follicular lymphoma achieves sustained remission in a high proportion of subjects. The high NRM of allo-HCT offset any benefit that might be associated with this transplantation modality., (Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Because the outcome of allogeneic hematopoietic cell transplantation (HCT) is predominantly influenced by disease type and status, it is essential to be able to stratify patients undergoing HCT by disease risk. The Disease Risk Index (DRI) was developed for this purpose. In this study, we analyzed 13,131 patients reported to the Center for International Blood and Marrow Transplant Research who underwent HCT between 2008 and 2010. The DRI stratified patients into 4 groups with 2-year overall survival (OS) ranging from 64% to 24% and was the strongest prognostic factor, regardless of age, conditioning intensity, graft source, or donor type. A randomly selected training subgroup of 9849 patients was used to refine the DRI, using a multivariable regression model for OS. This refined DRI had improved prediction ability for the remaining 3282 patients compared with the original DRI or other existing schemes. This validated and refined DRI can be used as a 4- or 3-group index, depending on the size of the cohort under study, for prognostication; to facilitate the interpretation of single-center, multicenter, or registry studies; to adjust center outcome data; and to stratify patients entering clinical trials that enroll patients across disease categories., (© 2014 by The American Society of Hematology.)

Allogeneic hematopoietic cell transplantation (HCT) offers curative therapy for many patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). However, post-HCT relapse remains a major problem, particularly in patients with high-risk cytogenetics. In this prospective phase II trial, we assessed the efficacy and toxicity of treosulfan, fludarabine, and 2 Gy total body irradiation (TBI) as conditioning for allogeneic HCT in patients with MDS or AML. Ninety-six patients with MDS (n = 36: 15 refractory cytopenia with multilineage dysplasia, 10 refractory anemia with excess blasts type 1, 10 refractory anemia with excess blasts type 2, 1 chronic myelomonocytic leukemia type 1) or AML (n = 60: 35 first complete remission [CR], 18 second CR, 3 advanced CR, 4 refractory relapse) were enrolled; median age was 51 (range, 1 to 60) years. Twelve patients had undergone a prior HCT with high-intensity conditioning. Patients received 14 g/m(2)/day treosulfan i.v. on days -6 to -4, 30 mg/m(2)/day fludarabine i.v. on days -6 to -2, and 2 Gy TBI on day 0, followed by infusion of hematopoietic cells from related (n = 27) or unrelated (n = 69) donors. Graft-versus-host disease prophylaxis consisted of tacrolimus and methotrexate. With a median follow-up of 30 months, the 2-year overall survival (OS), relapse incidence, and nonrelapse mortality were 73%, 27%, and 8%, respectively. The incidences of grades II to IV (III to IV) acute and chronic graft-versus-host disease were 59% (10%) and 47%, respectively. Two-year OS was not significantly different between MDS patients with poor-risk and good/intermediate-risk cytogenetics (69% and 85%, respectively) or between AML patients with unfavorable and favorable/intermediate-risk cytogenetics (64% and 76%, respectively). In AML patients, minimal residual disease (MRD; n = 10) at the time of HCT predicted higher relapse incidence (70% versus 18%) and lower OS (41% versus 79%) at 2 years, when compared with patients without MRD. In conclusion, treosulfan, fludarabine, and low-dose TBI provided effective conditioning for allogeneic HCT in patients with MDS or AML and resulted in low relapse incidence, regardless of cytogenetic risk. In patients with AML, MRD at the time of HCT remained a risk factor for post-HCT relapse., (Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

We conducted a nested case-control study within a cohort of 6244 patients to assess risk factors for avascular necrosis (AVN) of bone in children and adolescents after allogeneic transplantation. Eligible patients were ≤21 years of age, received their first allogeneic transplant between 1990 and 2008 in the United States, and had survived ≥ 6 months from transplantation. Overall, 160 patients with AVN and 478 control subjects matched by year of transplant, length of follow-up and transplant center were identified. Patients and control subjects were confirmed via central review of radiology, pathology, and/or surgical procedure reports. Median time from transplant to diagnosis of AVN was 14 months. On conditional logistic regression, increasing age at transplant (≥5 years), female gender, and chronic graft-versus-host disease (GVHD) were significantly associated with increased risks of AVN. Compared with patients receiving myeloablative regimens for malignant diseases, lower risks of AVN were seen in patients with nonmalignant diseases and those who had received reduced-intensity conditioning regimens for malignant diseases. Children at high risk for AVN include those within the age group where rapid bone growth occurs as well as those who experience exposure to myeloablative conditioning regimens and immunosuppression after hematopoietic cell transplantation for the treatment of GVHD. More research is needed to determine whether screening strategies specifically for patients at high risk for developing AVN with early interventions may mitigate the morbidity associated with this complication., (Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Background Aims: Targeted recruitment of leukocytes to sites of inflammation is a crucial event in normal host defense against pathogens, and attachment to and rolling on activated endothelial cells is a prerequisite first step for eventual leukocyte extravasation into sites of inflammation. These key events are mediated by interactions between glycosylated ligands expressed on leukocytes and selectins expressed on activated endothelium. Cell surface expression of selectin ligands on leukocytes is regulated by the rate-limiting enzyme fucosyltransferase VII (Fut7), and in its absence extravasation of leukocytes is severely inhibited. Multipotent adult progenitor cells (MAPCs) are an adherent cell population isolated from adult bone marrow. Intravenous administration of MAPCs provided functional improvement in multiple pre-clinical models of injury or disease, but the mechanisms by which these outcomes were achieved remain poorly understood., Methods: In vitro cell analysis studies including fluorescence-activated cell sorting, messenger RNA analysis, T-cell proliferation assays and endothelial cell binding assays were performed., Results: The in vitro cell analysis studies characterized the ability of MAPCs to secrete factors that transcriptionally attenuate expression of Fut7 in T cells, blocking the terminal fucosylation event in the biosynthesis of selectin ligands and reducing T-cell binding to endothelial cells., Conclusions: This study presents the first example of a distinct regulatory mechanism involving transcriptional down-regulation of Fut7 by MAPCs that could modulate the trafficking behavior of T cells in vivo., (Copyright © 2014 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

High-dose therapy with autologous stem cell transplant (autoSCT) is standard therapy for relapsed/refractory Hodgkin lymphoma, although the optimal conditioning regimen remains uncertain. We conducted a retrospective analysis of 100 consecutive patients with relapsed/refractory Hodgkin lymphoma who underwent autoSCT between 1998 and 2009. There were 60 patients who received busulfan, melphalan and thiotepa (BuMelTt) conditioning and 40 who received other common regimens. There were no significant differences in patient characteristics between the two groups. With a median follow-up of 4.3 years, the 5-year overall survival (OS) was superior for patients who received BuMelTt versus other conditioning (73% vs. 44%, p = 0.05). BuMelTt was also associated with an improved 5-year progression-free survival (66% vs. 37%, p = 0.03). There were no differences in length of hospitalization, febrile neutropenia, hepatic veno-occlusive disease or 100-day non-relapse mortality (NRM). There were more cases of severe mucositis but fewer episodes of bacteremia with BuMelTt. Our results suggest that BuMelTt may be a superior conditioning regimen for autoSCT in Hodgkin lymphoma.

An allogeneic hematopoietic cell transplantation from an HLA-identical donor after high-dose (myeloablative) pretransplantation conditioning is an effective therapy for some people with chronic lymphocytic leukemia (CLL). Because CLL is a highly radiosensitive cancer, we hypothesized that total body irradiation (TBI) conditioning regimens may be associated with better outcomes than those without TBI. To answer this, we analyzed data from 180 subjects with CLL receiving myeloablative doses of TBI (n = 126) or not (n = 54), who received transplants from an HLA-identical sibling donor between 1995 and 2007 and reported to the Center for International Blood & Marrow Transplant Research. At 5 years, treatment-related mortality was 48% (95% confidence interval [CI], 39% to 57%) versus 50% (95% CI, 36% to 64%); P = NS. Relapse rates were 17% (95% CI, 11% to 25%) versus 22% (95% CI, 11% to 35%); P = NS. Five-year progression-free survival and overall survival were 34% (95% CI, 26% to 43%) versus 28% (95% CI, 15% to 42%); P = NS and 42% (95% CI, 33% to 51%) versus 33% (95% CI, 19% to 48%); P = NS, respectively. The single most common cause of death in both cohorts was recurrent/progressive CLL. No variable tested in the multivariate analysis was found to significantly affect these outcomes, including having failed fludarabine. Within the limitations of this study, we found no difference in HLA-identical sibling transplantation outcomes between myeloablative TBI and chemotherapy pretransplantation conditioning in persons with CLL., (Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Purpose: To examine the outcomes of patients with chemotherapy-sensitive mantle-cell lymphoma (MCL) following a first hematopoietic stem-cell transplantation (HCT), comparing outcomes with autologous (auto) versus reduced-intensity conditioning allogeneic (RIC allo) HCT and with transplantation applied at different times in the disease course., Patients and Methods: In all, 519 patients who received transplantations between 1996 and 2007 and were reported to the Center for International Blood and Marrow Transplant Research were analyzed. The early transplantation cohort was defined as those patients in first partial or complete remission with no more than two lines of chemotherapy. The late transplantation cohort was defined as all the remaining patients., Results: Auto-HCT and RIC allo-HCT resulted in similar overall survival from transplantation for both the early (at 5 years: 61% auto-HCT v 62% RIC allo-HCT; P = .951) and late cohorts (at 5 years: 44% auto-HCT v 31% RIC allo-HCT; P = .202). In both early and late transplantation cohorts, progression/relapse was lower and nonrelapse mortality was higher in the allo-HCT group. Overall survival and progression-free survival were highest in patients who underwent auto-HCT in first complete response. Multivariate analysis of survival from diagnosis identified a survival benefit favoring early HCT for both auto-HCT and RIC allo-HCT., Conclusion: For patients with chemotherapy-sensitive MCL, the optimal timing for HCT is early in the disease course. Outcomes are particularly favorable for patients undergoing auto-HCT in first complete remission. For those unable to achieve complete remission after two lines of chemotherapy or those with relapsed disease, either auto-HCT or RIC allo-HCT may be effective, although the chance for long-term remission and survival is lower.

Introduction: Early reports demonstrated the safety of adherent mesenchymal stromal cell (MSC) infusions in the hematopoietic stem cell transplantation (HCT) setting, as well as clinical efficacy for treatment of steroid refractory acute graft-versus-host disease (GVHD); however, two large, Phase III randomized, placebo-controlled trials of MSC for initial therapy or steroid refractory GVHD failed to meet their primary endpoints of durable complete response. Subset analyses demonstrated efficacy in selected patient populations, contributing to recent approvals of MSC for pediatric patients in Canada and New Zealand., Areas Covered: In this review, we discuss the biologic and immunomodulatory properties of MSC and potential mechanisms involved. We review the results of prior clinical trials incorporating MSC for GVHD treatment or prophylaxis, the recent approvals in Canada and New Zealand, as well as future directions in the field., Expert Opinion: The role of MSC infusions, in the prophylaxis and/or treatment of GVHD after HCT, continues to be under active investigation. Whether, and how, to incorporate MSC infusions is unclear, and ongoing questions include the source tissue type and culture methods, the timing and dosage of MSC product infusions, as well as the optimal clinical trial design and endpoints for assessment of clinical response.