Cord blood transplantation is associated with good outcomes in secondary Acute Myeloid Leukaemia in first remission.

BACKGROUND: We conducted a retrospective survey within the European Society for Blood and Marrow Transplantation (EBMT) registry to assess the outcomes of cord blood transplantation (CBT) in secondary acute myeloid leukaemia (sAML). METHODS: Inclusion criteria consisted of ≥18 years of age, sAML, first CBT between 2002 and 2016, and either first complete remission (CR) or active disease at CBT. RESULTS: One hundred forty-six patients met the study inclusion criteria. Status at transplantation was first CR (n = 97), primary refractory sAML (n = 30) or relapsed (n = 19) sAML. Neutrophil engraftment was achieved in 118 patients while the remaining 25 patients (17%) failed to engraft. This includes 13% of patients transplanted in first CR versus 30% of those transplanted with active disease (P = 0.008). Two-year incidences of relapse were 25% in first CR patients versus 36% in those with advanced disease (P = 0.06) while 2-year incidences of nonrelapse mortality were 35% and 49% (P = 0.03), respectively. At 2-year overall survival, leukaemia-free survival and graft-versus-host disease (GVHD)-free relapse-free survival were 42% vs. 19% (P < 0.001), 40% vs. 16% (P < 0.001), and 26% vs. 12% (P = 0.002) in first CR patients versus those with advanced disease, respectively. CONCLUSIONS: We report here the first study of CBT in a large cohort of sAML patients. Main observation was that CBT rescued approximately 40% of patients with sAML in first CR.

Occurrence of graft-versus-host disease increases mortality after umbilical cord blood transplantation for acute myeloid leukaemia: a report from Eurocord and the ALWP of the EBMT.

BACKGROUND: The efficacy of umbilical cord blood transplantation (UCBT) as treatment for acute myeloid leukaemia (AML) relies on immune-mediated graft-versus-leukaemia effects. Previous studies have suggested a strong association between graft-versus-host disease (GVHD) occurrence and graft-versus-leukaemia effects after allogeneic hematopoietic cell transplantation. METHODS: Here, we evaluated the kinetics of relapse rate in correlation with GVHD occurrence after UCBT. The kinetics of relapse rate over time in correlation to GVHD occurrence were assessed by calculating the relapse rate per patient-year within sequential 90-day intervals. The impact of GVHD on relapse and mortality was further studied in multivariate Cox models handling GVHD as a time-dependent covariate. RESULTS: The study included data from 1068 patients given single (n = 567) or double (n = 501) UCBT. The proportion of patients with grade II, III and IV acute GVHD was 20%, 7% and 4%, respectively. At 2 years, the cumulative incidence of chronic GVHD was 42%, the cumulative incidence of relapse was 32%, and overall survival was 32% as well. Relapse rates declined gradually over time during the first 30 months after transplantation. There was a possible suggestion that grade II-IV acute (HR = 0.8, P = 0.1) and chronic (HR = 0.65, P = 0.1) GVHD decreased relapse risk. However, grade II-IV acute GVHD significantly increased early (the first 18 months after UCBT) mortality (HR = 1.3, P = 0.02), whilst chronic GVHD increased each early (HR = 2.7, P < 0.001) and late (HR = 4.9, P < 0.001) mortality after UCBT. CONCLUSIONS: The occurrence of grade II-IV acute or chronic GVHD each increases overall mortality after UCBT for AML mitigating the possible graft-versus-leukemia effect of GVHD.

Regulatory T-cell depletion does not prevent emergence of new CD25+ FOXP3+ lymphocytes after antigen stimulation in culture.

BACKGROUND: The removal of human regulatory T (T(reg)) cells from a cellular product prior to the induction of a T-cell response has the potential to boost the total yield of antigen (Ag)-specific CD4(+) and CD8(+) T cells. METHODS: We examined the effect of this manipulation on the generation of human anti-cytomegalovirus (CMV) T-cell responses. Furthermore, we examined the clonotypic composition of Ag-specific CD4(+)FOXP3(+) and CD4(+)FOXP3(-) T cells. RESULTS: We found that the immunomagnetic depletion of CD25(+) cells had an unpredictable effect on outcome, with total yields of CMV-specific T cells either increasing or decreasing after the removal of these cells. The depletion of CD25(+) cells both removed a proportion of Ag-specific T cells and failed to eliminate a substantial population of T(reg) cells. Furthermore, using a novel T-cell receptor clonotyping technique, we found that Ag recognition induces the expression of FOXP3 in a proportion of specific T cells; these FOXP3-expressing Ag-specific CD4(+) and CD8(+) T cells were no longer capable of producing inflammatory cytokines. DISCUSSION: The depletion of CD25(+) cells from the starting population has a variable effect on the total yield of Ag-specific T cells, a proportion of which invariably acquire FOXP3 expression and lose effector function.

Rapid natural killer cell recovery determines outcome after T-cell-depleted HLA-identical stem cell transplantation in patients with myeloid leukemias but not with acute lymphoblastic leukemia.

Natural killer (NK) cells are the first lymphocytes to recover after allogeneic stem cell transplantation (SCT) and can exert powerful graft-versus-leukemia (GVL) effects determining transplant outcome. Conditions governing NK cell alloreactivity and the role of NK recovery in sibling SCT are not well defined. NK cells on day 30 post-transplant (NK30) were measured in 54 SCT recipients with leukemia and donor and recipient killer immunoglobulin-like receptor (KIR) genotype determined. In univariate analysis, donor KIR genes 2DL5A, 2DS1, 3DS1 (positive in 46%) and higher numbers of inhibitory donor KIR correlated with higher NK30 counts and were associated with improved transplant outcome. NK30 counts also correlated directly with the transplant CD34 cell dose and inversely with the CD3+ cell dose. In multivariate analysis, the NK30 emerged as the single independent determinant of transplant outcome. Patients with NK30 >150/microl had less relapse (HR 18.3, P=0.039), acute graft-versus-host disease (HR 3.2, P=0.03), non-relapse mortality (HR 10.7, P=0.028) and improved survival (HR 11.4, P=0.03). Results suggest that T cell-depleted SCT might be improved and the GVL effect enhanced by selecting donors with favorable KIR genotype, and by optimizing CD34 and CD3 doses.

Is there any role for physical therapy in chronic GvHD?

Chronic GvHD is the leading cause of non-relapse mortality in recipients of hematopoietic cell transplantation. Although the benefit of physical therapy (PT) has been reported in some GvHD studies, a literature gap is identified in demonstrating the exact role of different types of PT interventions and their impact on GvHD outcomes. An electronic search was undertaken using 13 peer-reviewed databases from 1994 to 2016. JADAD scoring method was used to score the quality of articles. PT interventions utilized for non-GvHD aspects of transplantation were excluded. Out of the 4775 articles on the electronic search, 297 articles were reviewed out of which 3 fulfilled the selection criteria. Moderately high evidence for effectiveness of supervised PT intervention was found, whereas moderate evidence for a self-administered exercise program was established. No safety concerns with PT were observed in any of the studies, however none of the studies were conducted to directly evaluate safety and effectiveness specifically in GvHD patients. PT is a safe but understudied therapy for GvHD. Limited evidence on the effectiveness of most PT interventions is available through randomized control trials. Well-designed trials are urgently needed for musculoskeletal GvHD especially with focused PT interventions.

Risks factors and timing of genital human papillomavirus (HPV) infection in female stem cell transplant survivors: a longitudinal study.

This longitudinal single-center study describes the timing and risk factors for genital human papillomavirus (HPV) disease in women after allogeneic hematopoietic cell transplantation (HCT). Between 1994 and 2014, 109 females underwent HCT of whom 82 surviving transplant for >1 year had regular, comprehensive genital tract assessment and treatment of HPV disease. The cumulative proportions of any genital HPV infection at 1, 3, 5, 10 and 20 years were 4.8%, 14.9%, 28.1%, 36.7% and 40.9%, respectively. Demographic, disease-related factors, chronic GvHD (cGvHD) and its treatment were analyzed for their association with persistent, multifocal or severe genital HPV disease. Pre-transplant HPV disease was strongly associated with any posttransplant HPV (odds ratio (OR)=6.5, 95% confidence interval (CI)=1.65-25.85, P=0.008). Having either extensive or genital cGvHD was associated with increased risk of any HPV disease (OR=5.7, 95% CI=1.90-17.16, P=0.002) and a higher risk for severe genital dysplasia (CIN II-III/VIN II-III; OR=13.1, 95% CI=1.59-108.26, P=0.017), but no one developed HPV-related genital cancer. Persistent, multifocal or severe HPV disease occurred more frequently than in healthy populations. Women with extensive cGvHD, genital cGvHD or pre-transplant HPV are at greatest risk for post-transplant HPV disease. Early initiation of annual screening, comprehensive genital tract assessment and active management are cornerstones of their gynecology care.

Pulmonary function following total body irradiation (with or without lung shielding) and allogeneic peripheral blood stem cell transplant.

Our purpose was to determine if total body irradiation (TBI) with lung dose reduction protects against subsequent radiation-induced deterioration in pulmonary function. Between July 1997 and August 2004, 181 consecutive patients with hematologic malignancies received fractionated TBI before allogeneic peripheral blood stem cell transplant. The first 89 patients were treated to a total dose of 13.6 Gy. Thereafter, total body dose was decreased to 12 Gy with lung dose reduction to 9 or 6 Gy. All patients underwent pulmonary function test evaluation before treatment, 90 days post-treatment, then annually. Median follow-up was 24.0 months. Eighty-nine patients were treated with lung shielding, and 92 without. At 1-year post transplant, there was a small but significant difference in lung volume measurements between patients with lung shielding and those without. This was not observed at the 2-year time point. When stratified by good (>100% predicted) or poor (

Stem cell transplantation with reduced-intensity conditioning regimens: a review of ten years experience with new transplant concepts and new therapeutic agents.

The realization in the 1990s that allogeneic stem cell transplants (SCT) have a potentially curative graft-versus-leukemia (GVL) effect in addition to the antileukemic action of myeloablative conditioning regimens was a major stimulus for the development of reduced-intensity conditioning (RIC) regimens, aimed primarily at securing engraftment to provide the GVL effect, while minimizing regimen-related toxicity. It is now over 10 years since RIC regimens were heralded as a new direction in the field of SCT. Over the last decade much has been learned about the ways in which the conditioning regimen can be tailored to provide adequate immunosuppression, and modulated to deliver a chosen degree of antimalignant treatment. The huge literature of clinical data with RIC transplantation now permits us to more clearly define the success and limitations of the approach. This review examines the origins of RIC SCT, explores the degree to which the initial expectations and purpose of the approach have been realized, and outlines some ways forward for the field.

Halfway there: the past, present and future of haploidentical transplantation.

In recent years, the use of haploidentical donors for hematopoietic cell transplantation has expanded rapidly. Approximately 50% of patients requiring hematopoietic cell transplant lack a traditional donor. The use of HLA haploidentical-related donors is attractive due to nearly universal availability of this graft source. We summarize the current and future need for haploidentical donors and detail the rise of post-transplant cyclophosphamide as the dominant haploidentical approach. Further, we examine ongoing controversies in the field of haploidentical transplant, including conditioning regimens and graft source. Finally, we review the evidence available from preliminary comparative studies and discuss future direction of research.

Hyperglycemia as a possible risk factor for mold infections-the potential preventative role of intensified glucose control in allogeneic hematopoietic stem cell transplantation.

Diabetes mellitus (DM) is well-known as a disorder that increases the risk of infectious diseases. Various reports have shown that innate immunity is impaired in patients with DM, which is considered to be a major cause of increased risk of infectious diseases. However, there is a paucity of data about the actual risk of mold infections in patients with DM. Several treatment procedures, such as solid organ transplantation and hematopoietic stem cell transplantation (HSCT), are intrinsically associated with a high risk of mold infections and also correlated with an increased risk of post-transplant DM. Therefore, we could assume that organ transplant recipients or HSCT recipients with DM are at quite high risk of mold infections. Here, we aim to summarize the information about the increased risk of mold infections in patients with DM, and propose possible interventions such as intensive glucose control to reduce this risk in patients with DM.

Posttransplant maintenance therapy in multiple myeloma: the changing landscape.

Transplant-eligible patients with multiple myeloma (MM) now have extended survival after diagnosis owing to effective modern treatment strategies that include new agents in induction therapy, autologous stem cell transplant (ASCT), consolidation therapy and posttransplant maintenance therapy. Standard of care for newly diagnosed, fit patients includes ASCT and, often nowadays, posttransplant maintenance. Several large studies have shown the efficacy of maintenance with thalidomide, lenalidomide and bortezomib in the treatment scheme of MM with regards to prolonging progression-free survival and, to a lesser degree, overall survival. Herein we discuss the data currently available to support the use of maintenance therapy in patients after ASCT as well as the newer available agents that may be a part of its changing landscape in the years to come.

Clinical management of genital chronic GvHD.

Chronic GvHD (cGvHD) of the genital tract is an underreported and infrequently recognized complication of allogeneic hematopoietic cell transplantation in both male and female long-term survivors. Its pathophysiology, clinical manifestations and management are not well understood, and studies are limited. We thus provide a comprehensive review of genital cGvHD in both men and women, as well as discuss related issues of sexual health and viral reactivation. We further provide guidance on screening, management and long-term follow-up, as well as future priority areas of study.

Is myeloablative dose intensity necessary in allogeneic hematopoietic cell transplantation for lymphomas?

The advent of novel immunotherapy and tyrosine kinase inhibitors has ushered a new era in the treatment of Hodgkin and non-Hodgkin lymphomas. Allogeneic hematopoietic cell transplantation remains, however, a vital component in the management and potential cure of lymphomas, especially in the relapsed setting. Considering the biological and clinical heterogeneity of various subtypes of lymphomas, the optimal intensity of conditioning regimens remains controversial. Reduced intensity conditioning regimens have broadened applicability of the procedure to older and frail patients. Observational studies suggest that although reduced intensity allografting is associated with higher risk of relapse, overall survival is comparable and in some cases even better, than observed with myeloablative regimens. Here, we review the available published data pertaining to allogeneic hematopoietic cell transplantation using reduced intensity or myeloablative conditioning for various lymphoma histologies. Owing to the lack of randomized prospective trials, recommendations are mainly based on registry and single-institution studies. Special emphasis must be given to implementing strategies to prevent relapse when using reduced intensity regimens. Identifying particular patients who may benefit from myeloablative regimens in lymphomas remains to be better defined.

Pre-existing invasive fungal infection is not a contraindication for allogeneic HSCT for patients with hematologic malignancies: a CIBMTR study.

Patients with prior invasive fungal infection (IFI) increasingly proceed to allogeneic hematopoietic cell transplantation (HSCT). However, little is known about the impact of prior IFI on survival. Patients with pre-transplant IFI (cases; n=825) were compared with controls (n=10247). A subset analysis assessed outcomes in leukemia patients pre- and post 2001. Cases were older with lower performance status (KPS), more advanced disease, higher likelihood of AML and having received cord blood, reduced intensity conditioning, mold-active fungal prophylaxis and more recently transplanted. Aspergillus spp. and Candida spp. were the most commonly identified pathogens. 68% of patients had primarily pulmonary involvement. Univariate and multivariable analysis demonstrated inferior PFS and overall survival (OS) for cases. At 2 years, cases had higher mortality and shorter PFS with significant increases in non-relapse mortality (NRM) but no difference in relapse. One year probability of post-HSCT IFI was 24% (cases) and 17% (control, P<0.001). The predominant cause of death was underlying malignancy; infectious death was higher in cases (13% vs 9%). In the subset analysis, patients transplanted before 2001 had increased NRM with inferior OS and PFS compared with later cases. Pre-transplant IFI is associated with lower PFS and OS after allogeneic HSCT but significant survivorship was observed. Consequently, pre-transplant IFI should not be a contraindication to allogeneic HSCT in otherwise suitable candidates. Documented pre-transplant IFI is associated with lower PFS and OS after allogeneic HSCT. However, mortality post transplant is more influenced by advanced disease status than previous IFI. Pre-transplant IFI does not appear to be a contraindication to allogeneic HSCT.

Autologous hematopoietic cell transplantation for multiple myeloma patients with renal insufficiency: a center for international blood and marrow transplant research analysis.

Autologous hematopoietic cell transplantation (AHCT) in multiple myeloma (MM) patients with renal insufficiency (RI) is controversial. Patients who underwent AHCT for MM between 2008 and 2013 were identified (N=1492) and grouped as normal/mild (⩾60 mL/min), N=1240, moderate (30-59), N=185 and severe RI (<30), N=67 based on Modification of Diet in Renal Disease. Multivariate analyses of non-relapse mortality (NRM), relapse, PFS and overall survival (OS) were performed. Of the 67 patients with severe RI, 35 were on dialysis prior to AHCT. Patients received melphalan 200 mg/m2 (Mel 200) in 92% (normal/mild), 75% (moderate) and 33% (severe) RI; remainder received 140 mg/m2 (Mel 140). Thirty four of 35 patients with severe RI achieved post-AHCT dialysis independence. The 5-year PFS for normal, moderate and severe RI was 35 (95% CI, 31-38)%, 40 (31-49)% and 27 (15-40)%, respectively, (P=0.42); 5-year OS for normal, moderate and severe RI was 68 (65-71)%, 68 (60-76)% and 60 (46-74)%, respectively, (P=0.69). With moderate RI, 5-year PFS for high-dose melphalan 140 mg/m2 was 18 (6-35)% and for Mel 200 was 46 (36-57)% (P=0.009). With severe RI, 5-year PFS Mel 140 was 25 (11-41) % and for Mel 200 was 32 (11-58)% (P=0.37). We conclude that AHCT is safe and effective in patients with MM with RI.

Metabolic syndrome and cardiovascular disease following hematopoietic cell transplantation: screening and preventive practice recommendations from CIBMTR and EBMT.

Metabolic syndrome (MetS) is a constellation of cardiovascular risk factors that increases the risk of cardiovascular disease, diabetes mellitus and all cause mortality. Long-term survivors of hematopoietic cell transplantation (HCT) have a substantial risk of developing MetS and cardiovascular disease, with the estimated prevalence of MetS being 31-49% among HCT recipients. Although MetS has not yet been proven to impact cardiovascular risk after HCT, an understanding of the incidence and risk factors for MetS in HCT recipients can provide the foundation to evaluate screening guidelines and develop interventions that may mitigate cardiovascular-related mortality. A working group was established through the Center for International Blood and Marrow Transplant Research and the European Group for Blood and Marrow Transplantation with the goal of reviewing literature and recommend practices appropriate to HCT recipients. Here we deliver consensus recommendations to help clinicians provide screening and preventive care for MetS and cardiovascular disease among HCT recipients. All HCT survivors should be advised of the risks of MetS and encouraged to undergo recommended screening based on their predisposition and ongoing risk factors.

What do we need to know about allogeneic hematopoietic stem cell transplant survivors?

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment for over 70 benign and malignant hematologic and immunological processes. Over the past several decades, significant technological and post-transplant supportive advances have been made, resulting in a decrease in early transplant mortality and continued growth in the population of allo-HSCT survivors. With the expansion in the number of long-term survivors, as well as of those considering a transplant, the focus of transplant medicine has been shifted significantly to include a more prominent role for the care of the 'long-term' survivor. These patients have survived the acute critical phase of transplantation and have potentially achieved remission from their primary disease, yet allo-HSCT patients do not return to pre-transplant health status. For survivors >2 years removed, the time of transplant all-cause mortality is four- to nine-fold higher than age-matched peers within the general population. These patients represent a distinct, high-risk population that must be monitored for long-term transplant complications, including chronic GvHD (cGvHD), multi-organ dysfunctions and secondary malignancies. This article will review in a non-exhaustive manner, the approach to long-term care of an allo-HSCT recipient.

Next-generation long-term transplant clinics: improving resource utilization and the quality of care through health information technology.

By the year 2020, potentially one-half a million hematopoietic cell transplant (HCT) recipients will need long-term follow-up care to address not only chronic GvHD but also multiple other late consequences of transplant. Despite this increase in patients, there will not be a concomitant increase in the HCT workforce. Thus, the future of long-term patient management will require a new 'next-generation' clinical model that utilizes technological solutions to make the care of the HCT patient efficient, safe and cost-effective. Guideline-based decision support will be embedded in clinical workflows. Documentation requirements will be reduced as automated data collection from electronic medical records (EMRs) will populate registries and provide feedback for a rapid learning health system. Interoperable EMRs will disseminate treatment protocols to multiple care providers in a distributed long-term clinic model, such that providers outside of the transplant center can provide services closer to the patient. Patients will increase their participatory role through patient portals and mobile devices. At Vanderbilt, we have responded to some of these future challenges by embedding guideline-based decision support, structuring clinical documentation and being early adopters of communication technology. This manuscript describes the current state of some of these innovations, and a vision for the future of the long-term transplant clinic.

Childhood to adult transition and long-term follow-up after blood and marrow transplantation.

The use of hematopoietic stem cell transplantation or blood and marrow transplantation (BMT) is on the increase worldwide. With BMT's increasing utilization and increasing success, the number of BMT survivors in the United States alone is expected to surpass 500 000 by the year 2030. BMT survivors are susceptible to a host of long-term side effects and complications. The pediatric and adolescent and young adult (AYA) populations comprise an increasing proportion of BMT survivors. Though these populations are both at risk of a specific set of sequelae and faced with the additional challenge of transitioning to adult care, no previous literature has addressed their specific challenges. In this review, we illustrate with clinical vignettes the need for focused and specific survivorship clinics for pediatric/AYA BMT survivors. We then focus on the following areas pertaining to pediatric BMT survivorship and care: (1) psychological health, (2) neurocognition, (3) endocrine health, (4) infertility resources, (5) issues in transition from pediatric to adult clinicians, (6) preventative services and (7) cost of care issues.

Venous thromboembolism in hematopoietic stem cell transplant recipients.

Venous thromboembolism (VTE) is an increasingly recognized problem in the post-hematopoietic stem cell transplantation (HSCT) setting, with a lack of high-quality evidence-based data to recommend best practices. Few patients with hematologic malignancies and even fewer post-HSCT patients were included in randomized trials of VTE prophylaxis and treatment. Prior VTE, GVHD, infections and indwelling venous catheters are risk factors for thrombosis. The increasing use of post-transplant maintenance therapy with lenalidomide in patients with multiple myeloma adds to this risk after autologous HSCT. These patients are also at high risk of bleeding complications because of prolonged thrombocytopenia and managing the competing risks of bleeding and thrombosis can be challenging. This review aims to provide a practical, clinician-focused approach to the prevention and treatment of VTE in the post-HSCT setting.