Advances In Hematopoietic Stem Cell Transplantation Research Articles

The Contemporary Role of Hematopoietic Stem Cell Transplantation in the Management of Chronic Myeloid Leukemia: Is It the Same in All Settings?

Hematopoietic stem cell transplantation (HSCT) for chronic myeloid leukemia (CML) patients has transitioned from the standard of care to a treatment option limited to those with unsatisfactory tyrosine kinase inhibitor (TKI) responses and advanced disease stages. In recent years, the threshold for undergoing HSCT has increased. Most CML patients now have life expectancies comparable to the general population, and therefore, the goal of therapy is shifting toward achieving treatment-free remission (TFR). While TKI discontinuation trials in CML show potential for achieving TFR, relapse risk is high, affirming allogeneic HSCT as the sole curative treatment. HSCT should be incorporated into treatment algorithms from the time of diagnosis and, in some patients, evaluated as soon as possible. In this review, we will look at some of the recent advances in HSCT, as well as its indication in the era of aiming for TFR in the presence of TKIs in CML.

A dynamic time-to-event model for prediction of acute graft-versus-host disease in patients after allogeneic hematopoietic stem cell transplantation.

Acute graft-versus-host disease (aGvHD) is a major cause of death for patients following allogeneic hematopoietic stem cell transplantation (HSCT). Effective management of moderate to severe aGvHD remains challenging despite recent advances in HSCT, emphasizing the importance of prophylaxis and risk factor identification. In this study, we analyzed data from 1479 adults who underwent HSCT between 2005 and 2017 to investigate the effects of aGvHD prophylaxis and time-dependent risk factors on the development of grades II-IV aGvHD within 100 days post-HSCT. Using a dynamic longitudinal time-to-event model, we observed a non-monotonic baseline hazard overtime with a low hazard during the first few days and a maximum hazard at day 17, described by Bateman function with a mean transit time of approximately 11 days. Multivariable analysis revealed significant time-dependent effects of white blood cell counts and cyclosporine A exposure as well as static effects of female donors for male recipients, patients with matched related donors, conditioning regimen consisting of fludarabine plus total body irradiation, and patient age in recipients of grafts from related donors on the risk to develop grades II-IV aGvHD. Additionally, we found that higher cumulative hazard on day 7 after allo-HSCT are associated with an increased incidence of grades II-IV aGvHD within 100 days indicating that an individual assessment of the cumulative hazard on day 7 could potentially serve as valuable predictor for later grades II-IV aGvHD development. Using the final model, stochastic simulations were performed to explore covariate effects on the cumulative incidence over time and to estimate risk ratios. Overall, the presented model showed good descriptive and predictive performance and provides valuable insights into the interplay of multiple static and time-dependent risk factors for the prediction of aGvHD.

Posttransplant complications in patients with marrow failure syndromes: are we improving long-term outcomes?

Inherited bone marrow failure syndromes (IBMFS) encompass a group of rare genetic disorders characterized by bone marrow failure, non-hematologic multisystemic comorbidities, disease defining congenital anomalies, and a susceptibility to myelodysplastic syndrome, acute myeloid leukemia, and in some instances solid tumors. The most common IBMFS include Fanconi anemia, Shwachman-Diamond syndrome, Diamond-Blackfan anemia, and telomere biology disorders/ dyskeratosis congenita. Allogeneic hematopoietic stem cell transplant (HCT) is a well-established curative treatment to correct the hematological manifestations but does not halt or reverse the nonhematological complications and may hasten them. With advances in HCT and in our ability to care for patients with IBMFS, an increasing number of survivors are making it imperative to not only diagnose but also treat late effects from the pre-, peri-, and post-HCT course and complications relating to the natural history of the syndrome. As the field of HCT evolves to allow for the incorporation of alternate graft sources, for expansion of donor options to include unrelated and mismatched donors, and for use of reduced-intensity conditioning or reduced toxicity myeloablative regimens, we have yet to determine if these advances modify the disease-specific course. While long-term outcomes of these patients are often included under one umbrella, this article seeks to address disease-specific post-HCT outcomes within IBMFS.

Pitfalls and Successes in Trials in Older Transplant Patients with Hematologic Malignancies.

Recent medical advances have allowed a greater number of older patients to undergo hematopoietic stem cell transplantation (HSCT) and participate in HSCT trials. In this review, we outline recent advances in HSCT that have made this possible, general setbacks, and their effects on the landscape of HSCT trials in older adults. Reduced-intensity conditioning regimens and a more physiological approach to transplant candidate selection have given older patients an opportunity to participate in HSCT trials. However, difficulties in allogeneic donor selection, post-transplant complications, and the misalignment of trial goals with patient goals may pose challenges for future trial recruitment and success. While increasing amounts of evidence show that older adults may benefit from participation in HSCT trials, clinicians, investigators, and patients must carefully weigh the benefits with potential repercussions.

Hematopoietic cell transplantation in severe combined immunodeficiency: The SCETIDE 2006-2014 European cohort

Hematopoietic stem cell transplantation (HSCT) represents a curative treatment for patients with severe combined immunodeficiency (SCID), a group of monogenic immune disorders with an otherwise fatal outcome. We performed a comprehensive multicenter analysis of genotype-specific HSCT outcome, including detailed analysis of immune reconstitution (IR) and the predictive value for clinical outcome. HSCT outcome was studied in 338 patients with genetically confirmed SCID who underwent transplantation in 2006-2014 and who were registered in the SCETIDE registry. In a representative subgroup of 152 patients, data on IR and long-term clinical outcome were analyzed. Two-year OS was similar with matched family and unrelated donors and better than mismatched donor HSCT (P<.001). The 2-year event-free survival (EFS) was similar in matched and mismatched unrelated donor and less favorable in mismatched related donor (MMRD) HSCT (P< .001). Genetic subgroups did not differ in 2-year OS (P= .1) and EFS (P=.073). In multivariate analysis, pretransplantation infections and use of MMRDs were associated with less favorable OS and EFS. With a median follow-up of 6.2 years (range, 2.0-11.8 years), 73 of 152 patients in the IR cohort were alive and well without Ig dependency. IL-2 receptor gamma chain/Janus kinase 3/IL-7 receptor-deficient SCID, myeloablative conditioning, matched donor HSCT, and naive CD4 T lymphocytes >0.5×10e3/μL at+1 year were identified as independent predictors of favorable clinical and immunologic outcome. Recent advances in HSCT in SCID patients have resulted in improved OS and EFS in all genotypes and donor types. To achieve a favorable long-term outcome, treatment strategies should aim for optimal naive CD4 T lymphocyte regeneration.

The Binns Program for Cord Blood Research: A Novel Program for Cord Blood Procurement in an Academic Setting for Biomedical Research

<h3>Introduction</h3> Umbilical cord blood (UCB) is a vital source of hematopoietic stem and progenitor cells (HSPCs). Since 1991, UCB has been collected and stored in public cord blood banks to be primarily used as a source for allogeneic hematopoietic stem cell transplantation (HSCT). Since the seminal UCB transplant reported in 1988 by Gluckman et al., UCB has contributed to advances in HSCT and clinical trials. However, UCB-derived cells remain costly and difficult to procure for pre-clinical research. Here we present a protocol for a multidisciplinary, self-sustaining cord blood program dedicated to biomedical research: The Binns Program for Cord Blood Research, piloted at the Stanford University School of Medicine. <h3>Objectives</h3> The primary objective of this study was to educate others on the benefits of implementing a self-sustaining cord blood program that increases biomedical research throughout the medical community. <h3>Methods</h3> Eligible donors are identified using IRB-approved inclusion criteria. UCB samples are then collected in utero, with informed consent, by obstetric providers at the time of delivery. Within 24-48 hours of isolation, deidentified samples are processed into three fractions: (1) plasma, (2) hematopoietic stem and progenitor cells (HSPCs) by immunomagnetic separation, and (3) non-HSPC cellular flow-through. UCB-derived fractions are then distributed to researchers upon request. <h3>Results</h3> Between November 2015 and April 2019, 1,385 women gave informed consent to donate their cord blood following delivery. Of those participants, 1,147 (83%) samples were collected and 927 (81%) distributed for research purposes. The median post-enrichment cell count per cord following positive selection for CD34+ HSPCs was 1.25 × 10⁶ (Figure 1). Corresponding median post-enrichment sample purity was 90% following single-step purification. By October 2016, a protocol had been developed and optimized for the Binns Program to begin providing UCB-derived products to six laboratories. Now, the program supports 47 laboratories across Stanford. The research being supported spans a broad array of topics including normal and abnormal hematopoiesis, genetic engineering, and novel approaches to HCST. <h3>Conclusions</h3> After initial start-up funding, the Binns Program became self-sustaining, representing a feasible model for cord blood banking to support the advancement of research by providing fresh or cryopreserved UCB-derived cells to the research community. We hope this model may be useful for other institutions and centers where the need to support research is high and the traditional model for public cord blood banking may not be a suitable option.

The Impact of Hematopoietic Stem Cell Transplantation on Work and Productivity Loss in Patients with Acute Leukemia: Results from a Rapid Review

Introduction: Acute lymphocytic leukemia (ALL) and acute myeloid leukemia (AML) are both hematological malignancies characterized by rapid onset. While AML is more common than ALL, both typically receive cytotoxic chemotherapy in first line. Upon complete remission, patients will be considered for allogeneic hematopoietic stem cell transplant (HSCT). The economic burden of malignant blood disorders was recently studied in Europe, with an estimated €3.6 billion in productivity losses. The objective of this review is to evaluate the impact on productivity and understand the societal burden of HSCT in ALL and AML patients. Methods: A rapid review was conducted to identify real-world evidence reporting work and productivity loss associated with ALL and AML, including the impact of HSCT. A search of PubMed was executed for citations published between April 1, 2014 to April 1, 2019 and limited to English language. Eligible studies examined outcomes on work productivity in patients diagnosed with ALL, AML, or combined hematological malignancies, with no geographical restriction. A single reviewer screened all identified citations and extracted key data from included papers. Results: A total of 13 unique real-world data studies were identified. Seven studies examined the impact of hematological cancers (including ALL and AML) with varied return-to-work outcomes reported. Of these, 3 studies observed positive return-to-work outcomes over time, while 4 reported decreased employment among patients when compared to the general population, although 2 of the 4 studies were focused on childhood hematological cancer survivors. A total of 6 studies examined the impact of HSCT on work productivity. Two studies reported opposing results in unemployment in adult survivors of childhood hematological cancers who received HSCT. The remaining 4 studies found a general decrease in employment or increase in low-income status among adult patients when comparing pre-HSCT to post-HSCT; however, 2 of these studies reported most patients were still employed post-HSCT, with 62% returning to work over 1 year post-HSCT and 77% of patients returning to work 5 years post-HSCT. Overall, there was a trend towards work reintroduction as an important outcome post-HSCT. Further, recurring themes included structural changes in the current delivery of health services or potential interventions to help rehabilitation post-transplantation and optimize employment. Conclusions: Work productivity outcomes are important facets of long-term survivorship care in patients with hematological cancers. Although there was a limited number of studies identified, results from the current rapid review indicate that while productivity is lower in patients with AML or ALL, including those treated with HSCT, a substantial proportion of patients are still actively employed. Future research should be directed toward understanding the causes of unemployment post-HSCT to help prevent adverse financial outcomes following this life-saving procedure. In terms of limitations, none of the identified studies compared work productivity outcomes of those who received HSCT to those who did not receive HSCT, among patients with hematological cancer. Four of the studies only examined patients pre- and post-HSCT and the remaining 2 studies compared patients to the general population; thus, the effect of HSCT could not be discerned from the effect of the disease. While HSCT is a costly and resource-intensive procedure, it remains the only potentially curative intervention for most hematological cancers. Advances in HSCT have dramatically improved clinical outcomes in cancer patients; resulting in lowered HSCT-related morbidity and mortality. Future studies with direct comparisons of patients with hematological cancer who received HSCT to those who did not receive HSCT would be desirable to estimate the indirect costs of impact of work productivity in these patients; however, ability to receive HSCT may remain confounded by variables that are challenging to measure, such as disease state, donor availability, HSCT reimbursement policies, and patient preference. Disclosures Scory: Medlior Health Outcomes Research: Employment. Shaw:Medlior Health Outcomes Research: Employment. Cowling:Medlior Health Outcomes Research: Employment. Peloquin:Pfizer Inc: Employment, Equity Ownership. Welch:Pfizer Inc: Employment, Equity Ownership. Charaan:Pfizer Inc: Employment, Equity Ownership. Brown:Pfizer: Employment, Equity Ownership.

Allogeneic hematopoietic stem cell transplantation in advanced stage mycosis fungoides and Sézary syndrome: a concise review.

Mycosis fungoides and Sézary syndrome encompass over 70% of all cases of cutaneous T-cell lymphoma (CTCL). While early stage disease has excellent long-term survival rates, advanced stage disease (IIB-IV) carries a poor prognosis with a median 5-year overall survival rate of approximately 50%. Early stage and advanced stage disease have different treatment algorithms with systemic therapy being indicated upfront in the later. The role of allogeneic hematopoietic stem cell transplant (HSCT) has gained considerable interest in recent years as a treatment option for CTCL given the increasingly promising long-term outcomes in an otherwise incurable disease. Herein, we provide a brief update on the current advances in HSCT followed by a concise review of the role of HSCT for CTCL. We conclude with our recommendations to approaching HSCT as a curative treatment option for CTCL.

Emerging Therapeutic Approaches for Diamond Blackfan Anemia.

Diamond Blackfan Anemia (DBA) is an inherited erythroid aplasia with onset in childhood. Patients carry heterozygous mutations in one of 19 Ribosomal Protein (RP) genes, that lead to defective ribosome biogenesis and function. Standard treatments include steroids or blood transfusions but the only definitive cure is allogeneic Hematopoietic Stem Cell Transplantation (HSCT). Although advances in HSCT have greatly improved the success rate over the last years, the risk of adverse events and mor-tality is still significant.Clinical trials employing gene therapy are now in progress for a variety of monogenic diseases and the development of innovative stem cell-based strategies may open new alternatives for DBA treatment as well. In this review, we summarize the most recent progress toward the implementation of new thera-peutic approaches for this disorder. We present different DNA- and RNA-based technologies as well as new candidate pharmacological treatments and discuss their relevance and potential applicability for the cure of DBA.

Manejo infectológico de la aplasia medular severa en pacientes pediátricos

La aplasia medular es una enfermedad poco frecuente en pediatría, siendo el tratamiento de elección en las formas severas el trasplante de células progenitoras hematopoyéticas (TCPH). Gracias a los avances en TCPH, los nuevos tratamientos inmunosupresores y al adecuado tratamiento de sostén, se ha logrado en las últimas décadas una franca disminución de la mortalidad asociada a esta patología. Es por ello que uno de los principales desafíos consiste en prevenir la aparición de infecciones asociadas a la neutropenia severa y prolongada que padecen estos pacientes, siendo actualmente las infecciones bacterianas y fúngicas una de las principales causas de morbimortalidad. Por otra parte, la mayoría de las guías de manejo y tratamiento de sostén se basan en recomendaciones de expertos, siendo la evidencia escasa, más aún en pediatría. Gran parte de las recomendaciones de tratamiento empírico se basan en guías de neutropenia febril de pacientes hemato-oncológicos. A su vez, existe gran variabilidad, de acuerdo al centro de atención, en cuanto al uso de antimicrobianos para profilaxis primaria, debiéndose tener en cuenta la mayor propensión a presentar infecciones invasivas por hongos filamentosos y, en el caso de pacientes con linfopenia marcada, de enfermedad por P jirovecii a la hora de valorar la indicación de profilaxis de estos pacientes.Se detallarán a continuación las principales recomendaciones sobre manejo de prevención de infecciones y tratamiento precoz de pacientes pediátricos con aplasia medular severa.

Transplantation for bone marrow failure: current issues.

The preferred treatment of idiopathic aplastic anemia (AA) is allogeneic hematopoietic stem cell transplantation (HSCT) from a human leukocyte antigen (HLA)-identical sibling donor. Transplantation from a well-matched unrelated donor (MUD) may be considered for patients without a sibling donor after failure of immunosuppressive therapy, as may alternative transplantation (mismatched, cord blood or haplo-identical HSCT) for patients without a MUD. HSCT may also be contemplated for congenital disorders in cases of pancytopenia or severe isolated cytopenia. Currently, HSCT aims are not only to cure patients but also to avoid long-term complications, notably chronic graft-versus-host disease (GVHD), essential for a good quality of life long term. This paper summarizes recent advances in HSCT for idiopathic and inherited AA disorders. The effect of age on current transplantation outcomes, the role of transplantation in paroxysmal nocturnal hemoglobinuria, and the prevention of GVHD are also discussed. Emerging strategies regarding the role of up-front unrelated donor and alternative donor HSCT in idiopathic AA, along with advances in the treatment of clonal evolution in Fanconi anemia, are also examined.

Outcomes in hepatitis C virus seropositive lymphoma and myeloma patients after autologous stem cell transplantation.

Hematopoietic stem cell transplantation (HSCT) is the cornerstone therapy for many hematological disorders. Advances in HSCT with better supportive care and earlier referral for HSCT have led to an increase in the number of patients undergoing HSCT. However, the post-HSCT period is often accompanied by infections and complications involving the liver, the lungs and the hematopoietic system.

Allogeneic Hematopoietic Stem Cell Transplantation (HCT) for Acute Myeloid Leukemia (AML) Not in First Remission

Background: Approximately 60 - 80% of AML patients achieve a complete remission [CR] with one or two cycles of induction chemotherapy, leaving many patients with refractory AML [PIF]. Unfortunately, the majority of patients in CR1 ultimately relapse. With salvage therapy, only 30-50% achieve CR2. Those with PIF or relapsed AML have shortened survival and few therapeutic options.Risk stratification is primarily based on karyotype, however other factors including age, initial white blood cell count, secondary AML and mutational status are also utilized to determine prognosis. HCT is an effective option for treatment of AML with intermediate/high risk features in CR1. It has also been utilized in refractory or relapsed disease. Advances in HCT over the last decade have improved overall survival (OS) and extended this option to older patients.Our aim is to characterize outcomes after HCT for AML patients who are not in CR1.Methods: We analyzed 136 AML patients who were not in CR1 at the time of HCT from 2004 - 2013. The conditioning regimen was fludarabine and myeloablative doses of PK targeted busulfan. IWG AML response criteria were used to define disease status at the time of transplant. Cytogenetic risk was based on the NCCN AML guidelines. OS is defined as the time from HCT until the time of death from any cause. Disease free survival (DFS) is defined as the time from HCT to the time of relapse or death from any cause.Results: Disease status consisted of 74 (54.4%) in CR2, 6 (4.4%) in CR3 or beyond, 27 (18.9%) were PIF, 21 (15.4%) with relapsed AML (REL) that was treated but still present at time of transplant, and 8 (5.7%) who received either no treatment or a hypomethylating agent (HMA). Median age was 52.0 (21.8 - 72.5) years, and 80 (59%) were male. Time from most recent treatment to HCT was < 1 month in 8 (5.8%), 1-3 months in 75 (55.8%), >3 months in 50 (36.8%) and not applicable in 3. Ninety-six (70.6%) had de novo AML, while 40 (29.4%) had secondary AML. Cytogenetic risk was favorable in 32 (23.5%), intermediate in 57 (42%), poor in 40 (29.4%) and unknown in 7 (5.1%). Graft-versus-host disease prophylaxis was tacrolimus with methotrexate or sirolimus, or mycophenolate mofetil. Donors included 41 (30.2%) matched related, 2 (1.4%) mismatched related, 65 (47.8%) matched unrelated and 28 (20.6%) mismatched unrelated donors. Peripheral blood stem cells were used in 97.2% of cases.Two year OS, DFS, cumulative incidence (CI) of relapse and CI-NRM for all patients was 45.3%, 35.2%, 47.1% and 18.2%, respectively. Two-year DFS stratified by disease status at time of HCT was 41.9%, 33.3%, 25.9%, 33.3% and 12.5% in CR2, CR3 or beyond, PIF, REL and HMA, respectively(p=0.011 for CR2 vs HMA) (Figure 1). Two-year DFS stratified by cytogenetic risk was 43.8%, 31.6%, 37.1% and 14.3% in favorable, intermediate, poor and unknown, respectively (p>0.05) (Figure2). CI-Rel stratified by disease status was 43.2%, 16.7%, 66.7%, 42.9% and 50% in CR2, CR3 or greater, PIF, REL and HMA, respectively (Figure 3).Conclusions: We analyzed 136 AML patients after undergoing HST outside of CR1 and the cumulative incidence of relapse at two years was 47%. Relapse was highest in those with primary induction failure or residual disease after either no or low intensity therapy. These data suggest that patients with active disease at the time of transplant fare worse than those who are transplanted in remission, highlighting the importance of effective upfront therapies in order to obtain the maximum potential benefit from HCT. Cytogenetic risk stratification did not significantly impact outcomes, although those with favorable risk cytogenetics trend towards higher 2-year DFS vs those with intermediate or poor-risk disease. Trials looking at the impact of maintenance therapy post-transplant may be valuable in this patient population.Table 1Disease Status @ HSCTCR2CR3 or beyondPIFRESHMA/untreated2 years41.9% (30.6 - 52.8)33.3% (4.6 - 67.6)25.9% (11.5 - 43.1)33.3% (14.9 - 53.1)12.5% (0.7 - 42.3)Table 2Cytogenetic Risk GroupFavorableIntermediateUnfavorableUnknown2 years43.8% (26.5 - 59.8)31.6% (20.1 - 43.7)37.1% (22.5 - 51.8)14.3% (0.7 - 46.5)Table 3Cumulative Incidence of RelapseCR2 (1)CR3 or beyond (2)PIF (3)REL (4)HMA/untreated (5)2 years43.2% (32.2 - 54.6)16.7% (0.0 - 53.5)66.7% (48.1 - 82.9)42.9% (23.0 - 64.0)50.0% (18.1 - 81.9) [Display omitted] [Display omitted] [Display omitted] DisclosuresSweet:Novartis Pharmaceuticals: Speakers Bureau; Ariad Pharmaceuticals: Consultancy, Speakers Bureau; Karyopharm Therapeutics Inc: Research Funding; Incyte: Research Funding. Lancet:Celgene: Consultancy, Research Funding; Seattle Genetics: Consultancy; Boehringer-Ingelheim: Consultancy; Pfizer: Research Funding; Kalo-Bios: Consultancy; Amgen: Consultancy. Perkins:PDL Biopharma: Research Funding. Field:PDL Biopharma: Research Funding.

Hematopoietic Stem Cell Transplantations for Primary Immune Deficiencies: 3 Decades of Experience From a Tertiary Medical Center.

Hematopoietic stem cell transplantation (HSCT) remains the leading treatment for the majority of severe primary immune deficiency (PID). This study aims to analyze changes in outcome over time. We conducted a retrospective analysis of HSCT in children with PID in a tertiary medical center over the period of 1983 to 2012. We identified 93 children with PID with a median follow-up of 3.6 years (range, 29 d to 21.2 y) after HSCT. The 2-year survival rates after HSCT for children with severe combined immune deficiency, hemophagocytic lymphohistiocytosis/lymphoproliferative disease, Wiskott-Aldrich syndrome, granulocyte defect, and undefined PID were 65.7%±6.8%, 80%±10.3%, 83.3%±15.2%, 75%±12.5%, and 25%±21.7%, respectively. Survival was associated with year of HSCT and matching. The hazard ratio (HR) (95% CI) for HSCT done in 1983 to 1999 compared with 2000 to 2012 and for matched (related and unrelated) compared with mismatched donor were 2.14 (0.99 to 4.653) and 3.07 (1.46 to 6.4), respectively. Survival was not associated with age, sex of the recipient, underlying PID, conditioning regimen, and presence of acute graft-versus-host disease. After adjustment to the underlying PID, donor and use of fludarabine-based conditioning, the HR (95% CI) for HSCT from the year 2000 was 4.69 (range, 1.4 to 15.45). Advances in HSCT over time have improved the survival of children with PID.

Aplastic anemia: therapeutic updates in immunosuppression and transplantation

Abstract Advances in hematopoietic stem cell transplantation (HSCT) and immunosuppressive therapy (IST) have improved survival in severe aplastic anemia (SAA) from 10%-20% in the 1960s to 80%-90% today. A matched sibling HSCT is the treatment of choice in younger patients, whereas IST is often used in older patients or in those who lack a histocompatible sibling. Graft rejection, GVHD, and poor immune reconstitution (with associated infectious complications) limit the success of HSCT, whereas lack of response, relapse, and clonal evolution limit the success of IST. The historically high rate of graft rejection in SAA is now less problematic in the matched setting, but with greater rates observed with unrelated and umbilical cord donors. The correlation of increasing age with the risk of GVHD and the significant morbidity and mortality of this transplantation complication continue to affect the decision to pursue HSCT versus IST as initial therapy in adults with SAA. Outcomes with matched unrelated donor HSCT have improved, likely due to better donor selection, supportive care, and improved transplantation protocols. Results with mismatched unrelated donor and umbilical HSCT are not as favorable, with higher rates of graft rejection, GVHD, and infectious complications. Investigation of several upfront alternative IST protocols has not improved outcomes beyond horse antithymocyte globulin and cyclosporine. More recently, the role of alemtuzumab in SAA has been better defined and an oral thrombomimetic, eltrombopag, is showing promising activity in refractory cases. The most recent advances in HSCT and IST in SAA are discussed in this review.

Aplastic anemia: therapeutic updates in immunosuppression and transplantation.

Advances in hematopoietic stem cell transplantation (HSCT) and immunosuppressive therapy (IST) have improved survival in severe aplastic anemia (SAA) from 10%-20% in the 1960s to 80%-90% today. A matched sibling HSCT is the treatment of choice in younger patients, whereas IST is often used in older patients or in those who lack a histocompatible sibling. Graft rejection, GVHD, and poor immune reconstitution (with associated infectious complications) limit the success of HSCT, whereas lack of response, relapse, and clonal evolution limit the success of IST. The historically high rate of graft rejection in SAA is now less problematic in the matched setting, but with greater rates observed with unrelated and umbilical cord donors. The correlation of increasing age with the risk of GVHD and the significant morbidity and mortality of this transplantation complication continue to affect the decision to pursue HSCT versus IST as initial therapy in adults with SAA. Outcomes with matched unrelated donor HSCT have improved, likely due to better donor selection, supportive care, and improved transplantation protocols. Results with mismatched unrelated donor and umbilical HSCT are not as favorable, with higher rates of graft rejection, GVHD, and infectious complications. Investigation of several upfront alternative IST protocols has not improved outcomes beyond horse antithymocyte globulin and cyclosporine. More recently, the role of alemtuzumab in SAA has been better defined and an oral thrombomimetic, eltrombopag, is showing promising activity in refractory cases. The most recent advances in HSCT and IST in SAA are discussed in this review.

Effect of Physical Activity (PA) Interventions On Health-Related Quality of Life (HRQoL) Post Hematopoietic Stem Cell Transplantation (HSCT): A Systematic Review and Meta-Analysis

AbstractAbstract 1968 Background:Recent advances in HSCT have resulted in improved overall and relapse-free survival and decreased incidence of serious complications. Improved survival has prompted an increased focus on enhancing HRQoL. There is an accumulating body of evidence emphasizing that physical activity (PA) may be one modifiable lifestyle factor associated with decreased negative side effects related to HSCT and improved HRQoL. We sought to summarize the available evidence related to the effects of PA participation and HRQoL in HSCT recipients. Methods:We searched electronic databases including Pubmed/MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and conference proceedings from American Society of Hematology and American Society of Clinical Oncology to April 1, 2012. No language or publication date limits were used. Studies were eligible for inclusion if they were randomized controlled trials (RCTs) or quasi-experimental trials with a control group comparing exercise interventions with placebo-control or standard of care in adult HSCT recipients. Exercise was defined as any form of PA that was performed on a repeated basis for a fixed time frame over a fixed time interval. Included studies were required to have a HRQoL measure as a primary (1o) or secondary (2o) outcome. Change in global HRQoL from pre to post-intervention for intervention and control groups were compared using a DerSimonian and Laird random effects model. Heterogeneity was assessed by calculating the Q- and I2 statistics. Meta-regression was performed for the following study characteristics: total number (no.) of study participants; mean age; % female; average body mass index (BMI); mean exercise duration in minutes per session; intervention length in weeks; % adherence; type of transplant (allo- or combination of allo- and auto-transplants); and whether HRQoL was a 1o or 2o outcome. Sensitivity analysis assessed the cumulative effect of studies by publication year and no. of participants. Influential analysis was conducted to determine change in pooled effect estimate by removing one study at a time. Publication bias was assessed the Begg's rank correlation and Egger's regression test and plot. Results:Of the 1606 studies originally identified, 7 studies involving 420 patients who underwent HSCT (of which 208 were assigned to exercise or PA intervention) met all inclusion criteria. One study was excluded from the final analysis as it was identified as an extreme outlier. All 6 remaining studies used the European Organization of Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) measurement tool thus weighted mean differences (WMD) were calculated for ease of interpretation. Participation in an exercise intervention resulted in an increase in global HRQoL with a WMD of 4.72 points (95% CI: −0.04, 9.47; P = 0.05). The proportion of variability in WMD attributed to intra-study heterogeneity was 65% (95% CI: 15%, 85%; P = 0.02) and was due primarily to variation in exercise intervention protocols and study quality. Meta-regression identified that whether HRQoL was a 1o or 2o outcome significantly affected the pooled effect estimate (P=0.02). Sensitivity analysis did not reveal any important trends. Influential analysis demonstrated that the study with the most influence when removed was Baumann A, where WMD decreased to 2.86 points (95% CI: −1.25, 8.57). There was no statistical evidence of publication bias by assessment with the Egger’s regression test (coefficient for bias 2.35, 95% CI −1.90 to, 6.59, P = 0.20) and Begg’s rank correlation test (Z-score 0.75 with continuity correction, P = 0.45). Conclusions:This analysis summarizes the best available evidence regarding effect of exercise participation on overall self-reported HRQoL in adult HSCT recipients. The pooled estimate, after excluding outliers, showed that exercise participation resulted in a 4.72 point increase in the global HRQoL score on the EORTC QLQ-C30 measure, which was borderline statistically significant (P =0.05). This effect estimate is similar in magnitude to pivotal meta-analyses of exercise interventions in breast cancer survivors. Substantial heterogeneity existed among included trials. Larger RCTs with a strong focus on study quality and long-term effects of exercise participation should be conducted. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Pulmonary function testing prior to hematopoietic stem cell transplantation

The pretransplant pulmonary function test plays an important role in the management of noninfectious pulmonary complications after hematopoietic stem cell transplantation (HCT). Although these tests are widely used as standard preoperative assessments in the nontransplant population, common conditions associated with the HCT patient requires that particular attention be given to interpretation of pulmonary function testing (PFT) results, such as comparison of serial pulmonary function tests and evaluation of the diffusion capacity. Although their utility in helping to predict the likelihood of developing post transplant pulmonary complications and mortality is not well established, current data indicate that pretransplant PFTs are important as a reference for the interpretation of post transplant PFTs and for identifying patients at high risk for developing pulmonary complications and/or mortality after HCT. Future studies of pretransplant pulmonary function should consider the advances in HCT, so that pretransplant PFTs will become a useful tool in pretransplant risk assessment and help the transplant oncologist to determine the most appropriate conditioning regimen for a patient with compromised lung function.