Allogeneic transplantation of bone marrow versus peripheral blood stem cells from HLA-identical sibling donors for hematological malignancies in 6064 adults from 2003 to 2020: different impacts on survival according to time period.

BACKGROUND: Mobilized peripheral blood stem cells (PBSC) have been widely used instead of bone marrow (BM) as the graft source for allogeneic hematopoietic cell transplantation (HCT). Although early studies demonstrated no significant differences in survival between PBSC transplantation (PBSCT) and BM transplantation (BMT) from human leukocyte antigen (HLA)-identical sibling donors to adults with hematological malignancies, recent results have been unclear. OBJECTIVE: The objective of this retrospective study was to compare overall survival (OS), relapse, non-relapse mortality (NRM), hematopoietic recovery and graft-versus-host disease (GVHD) between PBSCT and BMT according to the time period of HCT (2003-2008, 2009-2014, or 2015-2020). STUDY DESIGN: We retrospectively compared the outcomes after PBSCT versus BMT in 6064 adults with hematological malignancies using a Japanese registry database between 2003 and 2020. RESULTS: The adjusted probability of OS was significantly higher in BMT recipients compared to PBSCT recipients during the early period of 2003-2008 (adjusted hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.70-0.91; P < 0.001) and the middle period of 2009-2014 (adjusted HR, 0.80; 95% CI, 0.70-0.91; P < 0.001). However, during the late period of 2015-2020, the adjusted probability of OS was comparable between BMT and PBSCT recipients (adjusted HR, 0.94; 95% CI, 0.79-1.13; P = 0.564), which were mainly due to the reduction of NRM. There was no significant difference in the relapse rate between the groups, irrespective of the time period. Compared to BMT, PBSCT led to faster neutrophil and platelet recovery and the cumulative incidences of grades II-IV and grades III-IV acute and overall and extensive chronic GVHD were significantly higher in PBSCT recipients, irrespective of the time period. CONCLUSIONS: PBSCT and BMT had similar survival outcomes and relapse rates in adult patients with hematological malignancies during the late time period of 2015-2020 despite the hematopoietic recovery and acute and chronic GVHD being higher in PBSCT recipients in all time periods.

Longitudinal trajectory of frailty in blood or marrow transplant survivors: Report from the Blood or Marrow Transplant Survivor Study.

BACKGROUND: Blood or bone marrow transplantation (BMT) survivors with frailty are at a higher risk of subsequent mortality. Longitudinal trends in the frailty state are not known and could help identify vulnerable subpopulations at risk of subsequent adverse events. METHODS: This study included a cohort of 470 autologous and allogeneic BMT recipients who had survived ≥2 years after BMT and completed a baseline questionnaire (t1) at a median of 7.3 years after BMT and a follow-up questionnaire (t2) 13.2 years after t1. The main outcome was change in frailty state between t1 and t2. Frailty phenotype was defined as exhibiting ≥3 of the following characteristics: clinically underweight, exhaustion, low energy expenditure, slow walking speed, and muscle weakness. The following categories of change in frailty state were evaluated: worsened, improved, and stable. RESULTS: Of the 470 participants, 36.4% were aged ≥60 years at t1, and 50.6% were men. The prevalence of frailty increased from 4.8% at t1 to 9.6% at t2. Worsening was observed in 18.8% of patients, and improvement was reported in 9.7%. Pre-BMT exposure to vincristine (odds ratio [OR], 2.1; 95% CI, 1.3-3.39) was associated with worsening. Female sex (OR, 1.5; 95% CI, 0.93-2.4) was associated with a trend toward worsening. Pre-BMT exposure to vincristine (OR, 2.79; 95% CI, 1.44-5.43), a history of chronic graft-versus-host disease (OR, 2.58; 95% CI, 1.2-5.5), and grade 3 and 4 chronic health conditions at t1 (OR, 2.1; 95% CI, 1.08-4.33) were associated with frailty at t2. CONCLUSIONS: In a cohort of BMT survivors who were followed longitudinally for a median of 20.6 years from BMT, the frailty status worsened for approximately20% over a 13-year timespan. BMT survivors who are at risk for worsening frailty could benefit from targeted interventions.

Clinical characteristics and outcomes of bone marrow transplantation patients presenting to the ED of a tertiary care center.

BACKGROUND: Bone marrow transplantation is a breakthrough in the world of hematology and oncology. In our region, there is scarce literature studying emergency department visits among BMT patients, as well as their predictors of mortality. OBJECTIVES: This study aimed to assess the frequency, reasons, clinical characteristics and outcomes of patients presenting to the ED after a BMT, and to study the predictors of mortality in those patients. This study also compares those variables among the different types of BMT. METHODS: This was a retrospective cohort study conducted on all adult patients who have completed a successful BMT and visited the ED. RESULTS: Our study included 115 BMT patients, of whom 17.4% died. Those who died had a higher median number of ED visits than those who did not die. Around 36.5% presented with fever/chills with 29.6% diagnosed with pneumonia on discharge. We found that the odds of mortality were significantly higher among those who presented with dyspnea (p < .0005) and AMS (p = .023), among septic patients (p = .001), those who have undergone allogeneic BMT (p = .037), and those who were admitted to the ICU (p = .002). Moreover, the odds of mortality were significantly higher among hypotensive (p ≤0005) and tachycardic patients (p = .015). CONCLUSION: In our study, we have shown that BMT patients visit the ED very frequently and have high risk of in-hospital mortality. Moreover, our study showed a significant association between mortality and patients with dyspnea, AMS, sepsis, allogeneic BMT type, ICU admission, hypotension and tachycardia.

Exome chip analyses identify genes affecting mortality after HLA-matched unrelated-donor blood and marrow transplantation.

Although survival outcomes have significantly improved, up to 40% of patients die within 1 year of HLA-matched unrelated-donor blood and marrow transplantation (BMT). To identify non-HLA genetic contributors to mortality after BMT, we performed the first exome-wide association study in the DISCOVeRY-BMT cohorts using the Illumina HumanExome BeadChip. This study includes 2473 patients with acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome and 2221 10/10 HLA-matched donors treated from 2000 to 2011. Single-variant and gene-level analyses were performed on overall survival (OS), transplantation-related mortality (TRM), and disease-related mortality (DRM). Genotype mismatches between recipients and donors in a rare nonsynonymous variant of testis-expressed gene TEX38 significantly increased risk of TRM, which was more dramatic when either the recipient or donor was female. Using the SKAT-O test to evaluate gene-level effects, variant genotypes of OR51D1 in recipients were significantly associated with OS and TRM. In donors, 4 (ALPP, EMID1, SLC44A5, LRP1), 1 (HHAT), and 2 genes (LYZL4, NT5E) were significantly associated with OS, TRM, and DRM, respectively. Inspection of NT5E crystal structures showed 4 of the associated variants affected the enzyme structure and likely decreased the catalytic efficiency of the enzyme. Further confirmation of these findings and additional functional studies may provide individualized risk prediction and prognosis, as well as alternative donor selection strategies.

Late mortality after autologous blood or marrow transplantation in childhood: a Blood or Marrow Transplant Survivor Study-2 report.

Autologous blood or marrow transplantation (BMT) is a curative option for several types of childhood cancer. However, there is little information regarding the risk of late mortality. We examined all-cause mortality, relapse-related mortality (RRM), and nonrelapse-related mortality (NRM) in 2-year survivors of autologous BMT performed before age 22 between 1980 and 2010 at 1 of 2 US transplant centers. Vital status information was collected using medical records, National Death Index, and Accurint databases. Overall survival was calculated using Kaplan-Meier techniques. Cumulative incidence of mortality used competing risk methods. Standardized mortality ratio (SMR) was calculated using age-, sex-, and calendar-specific mortality rates from Centers for Disease Control and Prevention. Cox regression analysis was used to determine predictors of all-cause late mortality. Among the 345 2-year survivors, 103 deaths were observed, yielding an overall survival of 70.3% 15 years post-BMT. The leading causes of death included primary disease (50.0%), subsequent neoplasm (21.4%), and infection (18.2%). Overall, the cohort was at a 22-fold increased risk of late mortality (SMR, 21.8; 95% CI, 17.9-26.3), compared with the general population. Mortality rates remained elevated among the 10-year survivors (SMR, 20.6; 95% CI, 9.9-37.2) but approached those of the general population ≥15 years post-BMT. The 10-year cumulative incidence of RRM (14.3%) exceeded that of NRM (10.4%). The 10-year cumulative mortality rate declined over time (<1990, 35.1%; 1990-1999, 25.6%; 2000-2010, 21.8%; P = .05). In conclusion, childhood autologous BMT recipients have an increased risk of late mortality, compared with the general population. The late mortality rates have declined over the past 3 decades.

Haploidentical transplantation in high-risk pediatric leukemia: A retrospective comparative analysis on behalf of the Spanish working Group for bone marrow transplantation in children (GETMON) and the Spanish Grupo for hematopoietic transplantation (GETH).

A total of 192 pediatric patients, median age 8.6 years, with high-risk hematological malignancies, underwent haploidentical stem cell transplantation (haplo-HSCT) using post-transplantation cyclophosphamide (PT-Cy), or ex vivo T cell-depleted (TCD) graft platforms, from January 1999 to December 2016 in 10 centers in Spain. Some 41 patients received an unmanipulated graft followed by PT-Cy for graft-vs-host disease (GvHD) prophylaxis. A total of 151 patients were transplanted with CD3-depleted peripheral blood stem cells (PBSCs) by either CD34+ selection, CD3+ CD19+ depletion, TCRαß+ CD19+ depletion or CD45RA+ depletion, added to CD34+ selection for GvHD prophylaxis. The PBSCs were the only source in patients following ex vivo TCD haplo-HSCT; bone marrow was the source in 9 of 41 patients following PT-CY haplo-HSCT. Engraftment was achieved in 91.3% of cases. A donor younger than 30 years, and the development of chronic GvHD were positive factors influencing survival, whereas positive minimal residual disease (MRD) before transplant and lymphoid disease were negative factors. The probability of relapse increased with lymphoid malignancies, a donor killer-cell immunoglobulin-like receptor (KIR) haplotype A and positive MRD pretransplant. No difference was found in overall survival, disease-free survival or relapse incidence between the two platforms. Relapse is still of concern in both platforms, and it should be the focus of future efforts. In conclusion, both platforms for haplo-HSCT were effective and could be utilized depending on the comfort level of the center.

Long-Term Clinical Outcomes of Autologous Bone Marrow Mononuclear Cell Implantation in Patients With Severe Thromboangiitis Obliterans.

BACKGROUND: Patients with severe Buerger disease, also known as thromboangiitis obliterans (TAO), are at risk of major limb amputation. It has been shown that autologous bone marrow mononuclear cell (BM-MNC) implantation improves the condition of critical limb ischemia in TAO patients. This study was conducted to further clarify the long-term (>10 years) results of autologous BM-MNC implantation in patients with TAO.Methods and Results:An observational study was conducted of the long-term results of BM-MNC implantation in 47 lower limbs of 27 patients with TAO. The mean (±SD) follow-up period was 12.0±8.6 years. There was no major amputation event up to 10 years of follow-up in patients treated with BM-MNC implantation. The overall amputation-free survival rates were significantly higher in patients who underwent BM-MNC implantation than in internal controls and historical controls. There was no significant difference in amputation-free survival rates between the historical and internal controls. There was also no significant difference in overall survival between patients who underwent BM-MNC implantation and the historical controls. CONCLUSIONS: BM-MNC transplantation successfully prevented major limb amputation over a period of >10 years in patients with severe TAO who had no other therapeutic options.

Neonatal Cancer Epidemiology and Outcome: A Retrospective Study.

OBJECTIVE: Our study aimed at describing neonatal cancer incidence, distribution by type, location, outcome, and long-term toxicity, by comparison with tumors occurring later in infancy. METHODS: The authors led a single-center retrospective analysis of 118 cases of tumors diagnosed in the first year of life and compared tumors' types incidence, presentation, location, and outcome according to age group at diagnosis (below or over 28 d of life). RESULTS: The most frequent neonatal tumor types in our series were germ cell tumors, mainly teratoma, followed by neuroblastoma and renal tumors, whereas in children below 1 year of age, brain tumors, neuroblastoma, and leukemia were the most common types. Genetic predisposition syndromes were present in 14% of these infants and antenatal sonography enabled 68% of diagnosis for tumors presenting at birth. Other patients presented with mass syndrome, hydrops, or skin lesions. Six percent of neonates with cancer died from their malignancies, and up to 18% experienced a chronic health condition as a consequence of therapy. CONCLUSIONS: Tumor pattern differs in neonates and infants, with a higher percentage of benign tumors in children below 28 days of life. Yet, long-term therapy-related toxicity is significant in younger patients. Enhancing knowledge of neonatal tumors, their epidemiology, clinical presentation, genetic background, and prognosis should help promote better management and introduce follow-up programs to improve surviving rates and the quality of life of survivors.

Comparison of HLA Allele Mismatch and Antigen Mismatch in Unrelated Bone Marrow Transplantation in Patients with Leukemia.

We compared the effect of HLA single-antigen and single-allele mismatched unrelated bone marrow transplantation (UBMT) without in vivo/ex vivo T cell depletion. Becasue a single DRB1 mismatch is preferred among 1-allele or 1-antigen mismatched donors, we performed mismatched allele- or antigen-specific analyses with a single DRB1 mismatch as the reference. In adjusted comparison by multivariate analyses, an HLA-DRB1 single-allele mismatch resulted in a decreased risk of nonrelapse mortality (NRM; relative risk [RR], 1.33; 95% confidence interval [CI], 1.08 to 1.63, P = .006) compared with an HLA-DR single-antigen mismatch and conferred a decreased risk of NRM (RR, 1.25; 95% CI, 1.01 to 1.57; P = .025) and overall mortality (RR, 1.16; 95% CI, 1.00 to 1.37; P = .046) compared with an HLA-C single-antigen mismatch. Relative to an HLA-DRB1 single-allele mismatch, 2-mismatch transplants, including those with 1 or more antigen mismatches, resulted in a significantly increased risk of NRM (1-antigen/1-allele mismatch: RR, 1.68; 95% CI, 1.03 to 2.05; P < .001; 2-antigen mismatch: RR, 1.58; 95% CI, 1.04 to 2.02; P = .001) and overall mortality (1-antigen/1-allele mismatch: RR, 1.27; 95% CI, 1.09 to 1.47; P = .002; 2-antigen mismatch: RR, 1.27; 95% CI, 1.03 to 1.57; P = .02). NRM correlated with the combined number of mismatches and allele or antigen mismatches, with rates of 22%, 27%, 32%, 31%, and 38% at 4years for full match, single-allele mismatch, single-antigen mismatch, 2-allele mismatch, and 2 mismatches that included an antigen mismatch, respectively. Our results support the preference for an allele mismatch rather than an antigen mismatch in unrelated bone marrow donors with 1 DR mismatch or 2 mismatches for T cell-replete UBMT.

Late Mortality after Allogeneic Bone Marrow Transplantation in Childhood for Bone Marrow Failure Syndromes and Severe Aplastic Anemia.

Children with bone marrow failure syndromes and severe aplastic anemia (SAA) are treated with allogeneic blood or marrow transplantation (BMT). However, there is a paucity of studies examining late mortality risk after allogeneic BMT performed in childhood for bone marrow failure syndromes and SAA and evaluating how this risk differs between these diseases. We investigated cause-specific late mortality in 2-year survivors of allogeneic BMT for bone marrow failure syndromes and SAA performed before age 22years between 1974 and 2010 at 2 US transplantation centers. Vital status information was collected from medical records, the National Death Index, and Accurint databases. Overall survival was calculated using Kaplan-Meier techniques. The standardized mortality ratio (SMR) was calculated using age- sex-, and calendar-specific mortality rates from the Centers for Disease Control and Prevention. Among the 2-year survivors of bone marrow failure syndromes (n = 120) and SAA (n = 147), there were 15 and 19 deaths, respectively, yielding an overall survival of 86.4% for bone marrow failure syndromes and 93.1% for SAA at 15years post-BMT. Compared with the general population, patients with bone marrow failure syndromes were at a higher risk for premature death (SMR, 22.7; 95% CI, 13.1 to 36.2) compared with those with SAA (SMR, 4.5; 95% CI, 2.8 to 7.0) (P < .0001). The elevated relative risk persisted at ≥15years after BMT for both diseases. The hazard of all-cause late mortality was 2.9-fold (95% CI, 1.1 to 7.3) higher in patients with bone marrow failure syndromes compared with those with SAA. The high late mortality risk in recipients of allogeneic BMT in childhood for bone marrow failure syndromes calls for intensified life-long follow-up.

How I monitor long-term and late effects after blood or marrow transplantation.

Blood or marrow transplantation (BMT) is used with curative intent for hematologic malignancies. Conditional on surviving the first 2 years after BMT, 5-year survival generally exceeds 70%. However, the cumulative therapeutic exposures lead to premature onset of chronic health conditions, such that the 15-year cumulative incidence of severe or life-threatening chronic health conditions exceeds 40%, resulting in premature mortality. The high burden of morbidity, coupled with a long latency between BMT and the development of chronic health conditions necessitates life-long risk-based monitoring of the BMT survivors. The issues of how and when to screen BMT survivors for therapy-related complications and exacerbation of preexisting conditions are important and largely unanswered questions. For BMT survivors, screening recommendations must incorporate risks associated with pre-BMT therapy as well as risks related to transplant conditioning and graft-versus-host disease. Here, we describe our approach to monitoring BMT survivors for risk-based screening and early detection of key late-occurring or long-term complications using patient scenarios to illustrate our discussion.

Replication and validation of genetic polymorphisms associated with survival after allogeneic blood or marrow transplant.

Multiple candidate gene-association studies of non-HLA single-nucleotide polymorphisms (SNPs) and outcomes after blood or marrow transplant (BMT) have been conducted. We identified 70 publications reporting 45 SNPs in 36 genes significantly associated with disease-related mortality, progression-free survival, transplant-related mortality, and/or overall survival after BMT. Replication and validation of these SNP associations were performed using DISCOVeRY-BMT (Determining the Influence of Susceptibility COnveying Variants Related to one-Year mortality after BMT), a well-powered genome-wide association study consisting of 2 cohorts, totaling 2888 BMT recipients with acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome, and their HLA-matched unrelated donors, reported to the Center for International Blood and Marrow Transplant Research. Gene-based tests were used to assess the aggregate effect of SNPs on outcome. None of the previously reported significant SNPs replicated at P < .05 in DISCOVeRY-BMT. Validation analyses showed association with one previously reported donor SNP at P < .05 and survival; more associations would be anticipated by chance alone. No gene-based tests were significant at P < .05. Functional annotation with publicly available data shows these candidate SNPs most likely do not have biochemical function; only 13% of candidate SNPs correlate with gene expression or are predicted to impact transcription factor binding. Of these, half do not impact the candidate gene of interest; the other half correlate with expression of multiple genes. These findings emphasize the peril of pursing candidate approaches and the importance of adequately powered tests of unbiased genome-wide associations with BMT clinical outcomes given the ultimate goal of improving patient outcomes.

Impact of HLA Disparity in Haploidentical Bone Marrow Transplantation Followed by High-Dose Cyclophosphamide.

We studied the impact of HLA mismatching on the outcome of 318 consecutive patients who received an unmanipulated haploidentical bone marrow transplant, followed by post-transplant cyclophosphamide (PTCy). The number of HLA-mismatched antigens was tested for its impact on overall survival (OS) and nonrelapse mortality (NRM), whereas HLA mismatches in the graft-versus-host (GVH) direction were tested for prediction of graft-versus-host disease (GVHD and relapse. Finally, we studied whether graft rejection correlated with the number of HLA mismatched antigens in host-versus-graft (HVG) direction. Two hundred thirty-one donor-recipient pairs (72%) had 4/8 mismatches at the -A, -B, -C, -DRB1 HLA loci. HLA mismatches did not predict the 2-year OS (hazard ratio, .83; P = .58) and NRM (subhazard ratio, 1.08; P = .93). The cumulative incidence of acute GVHD (P = .13), 1-year chronic GVHD (P = .84), and relapse rate (P = .26) did not correlate with univectorial GVH mismatches. Similarly, no correlation was observed between the amount of HLA mismatch in the HVG direction and graft rejection. In multivariate analysis advanced disease at transplant was the strongest predictor of survival, NRM, relapse, and graft rejection. In conclusion, the degree of HLA mismatching should not be used as a criterion to select family haploidentical donors when using bone marrow as stem cell source and PTCy for GVHD prophylaxis.

Haploidentical Bone Marrow Transplantation with Post-Transplant Cyclophosphamide Using Non-First-Degree Related Donors.

Outcomes of nonmyeloablative (NMA) haploidentical (haplo) blood or marrow transplant (BMT) with post-transplantation cyclophosphamide (PTCy) using non-first-degree relatives are unknown. We evaluated 33 consecutive adult patients (median age, 56 years) with hematologic malignancies who underwent NMA haplo T cell-replete BMT with PTCy at Johns Hopkins using second- or third-degree related donors. Donors consisted of 10 nieces (30%), 9 nephews (27%), 7 first cousins (21%), 5 grandchildren (15%), and 2 uncles (6%). Thirty-one patients (94%) reached full donor chimerism by day 60. The estimated cumulative incidence (CuI) of grades II to IV acute graft-versus-host disease (aGVHD) at day 180 was 24% (90% confidence interval [CI], 9% to 38%). Only 1 patient experienced grades III to IV aGVHD. At 1 year the CuI of chronic GVHD was 10% (90% CI, 0% to 21%). The CuI of nonrelapse mortality at 1 year was 5% (90% CI, 0% to 14%). At 1 year the probability of relapse was 31% (90% CI, 12% to 49%), progression-free survival 64% (90% CI, 48% to 86%), and overall survival 95% (90% CI, 87% to 100%). The 1-year probability of GVHD-free, relapse-free survival was 57% (90% CI, 41% to 79%). NMA haplo BMT with PTCy from non-first-degree relatives is an acceptably safe and effective alternative donor platform, with results similar to those seen with first-degree relatives.

Grade II Acute Graft-versus-Host Disease and Higher Nucleated Cell Graft Dose Improve Progression-Free Survival after HLA-Haploidentical Transplant with Post-Transplant Cyclophosphamide.

Compared with standard graft-versus-host disease (GVHD) prophylaxis platforms, post-transplantation cyclophosphamide (PTCy) after T cell-replete HLA-haploidentical (haplo) bone marrow transplantation (BMT) reduces the risk of grades III to IV acute (a) and chronic (c) GVHD, but maintains similar rates of grade II aGVHD. Given that mild GVHD has been associated with reduced treatment failure in HLA-matched BMT, we evaluated the risk factors for and effects of GVHD on survival in 340 adults with hematologic malignancies who engrafted after nonmyeloablative haplo-BMT with PTCy, mycophenolate mofetil, and tacrolimus. The cumulative incidence at 100 days of grade II and grades III to IV aGVHD were 30% (95% confidence interval [CI], 25% to 35%) and 2% (95% CI, 1% to 4%), respectively. The 1-year cumulative incidence of cGVHD was 10% (95% CI, 7% to 13%). In landmark analyses at 100 days, the 4-year probabilities of overall survival (OS) and progression-free survival (PFS) were, 48% (95% CI, 41% to 56%) and 39% (95% CI, 32% to 47%) for patients without grades II to IV aGVHD, compared with 63% (95% CI, 53% to 73%) and 59% (95% CI, 50% to 71%) for patients with grade II aGVHD (P = .05 and P = .009). In multivariable modeling, when compared with patients who never experienced GVHD, the hazard ratio (HR) for OS and PFS in patients with grade II aGVHD was .78 (95% CI, .54 to 1.13; P = .19) and .69 (95% CI, .48 to .98; P = .04). Higher nucleated cell graft dose was also associated with improved OS (HR, .88; 95% CI, .78 to 1.00; P = .05) and PFS (HR, .89; 95% CI, .79 to 1.0; P = .05) and decreased risk of grades III to IV aGVHD (subdistribution HR, .66; 95% CI, .46 to .96; P = .03). PTCy reduces grades III to IV aGVHD and cGVHD, but retains similar incidence of grade II aGVHD, the development of which improves PFS. Higher nucleated cell graft dose goals may also improve survival after nonmyeloablative haplo-BMT with PTCy.

Bone marrow versus mobilized peripheral blood stem cells in haploidentical transplants using posttransplantation cyclophosphamide.

BACKGROUND: Incidence of graft-versus-host disease (GVHD) in haploidentical bone marrow (BM) transplants using posttransplantion cyclophosphamide (PT-Cy) is low, whereas GVHD using mobilized peripheral blood stem cells (PBSC) ranges between 30% and 40%. METHODS: To evaluate the effect of stem cell source in haploidentical transplantation with PT-Cy, we analyzed 451 patients transplanted for acute myeloid leukemia or acute lymphoblastic leukemia reported to the European Society for Blood and Marrow Transplantation. RESULTS: BM was used in 260 patients, and PBSC were used in 191 patients. The median follow-up was 21 months. Engraftment was lower in BM (92% vs 95%, P < 0.001). BM was associated with a lower incidence of stage II-IV and stage III-IV acute GVHD (21% vs 38%, P ≤ .01; and 4% vs 14%, P < .01, respectively). No difference in chronic GVHD, relapse, or nonrelapse mortality were found for PBSC or BM. The 2-year overall survival (OS) was 55% versus 56% (P = .57) and leukemia-free survival (LFS) was 49% versus 54% (P = .74) for BM and PBSC, respectively. On multivariate analysis, PBSC were associated with an increased risk of stage II-IV (hazard ratio [HR], 2.1; P < .001) and stage III-IV acute GVHD (HR, 3.8; P < .001). For LFS and OS, reduced intensity conditioning was the only factor associated with treatment failure (LFS: HR, 1.40; P = .04) and relapse (HR, 1.62; P = .02). CONCLUSION: In patients with acute leukemia in first or second remission receiving haploidentical transplantation with PT-Cy, the use of PBSC increases the risk of acute GVHD, whereas survival outcomes are comparable. Cancer 2018;124:1428-37. © 2018 American Cancer Society.

Autologous hematopoietic cell transplantation for HIV-related lymphoma: results of the BMT CTN 0803/AMC 071 trial.

Autologous hematopoietic cell transplant (AHCT) for HIV-infected patients is largely limited to centers with HIV-specific expertise. The Blood and Marrow Transplant Clinical Trials Network 0803/AIDS Malignancy Consortium 071 trial is a multicenter phase 2 study of AHCT for patients with HIV-related lymphoma (HRL). Eligible patients had chemotherapy-sensitive relapsed/persistent HRL, were >15 years of age, and had treatable HIV infection. Patients were prepared using carmustine, etoposide, cytarabine, and melphalan and received consistent management of peritransplant antiretroviral treatment. The primary endpoint was 1-year overall survival. Forty-three patients were enrolled; 40 underwent AHCT. Pretransplant HIV viral load was undetectable (<50 copies/mL) in 32 patients (80%); the median CD4 count was 249/µL (range, 39-797). At a median follow-up of 24.8 months, 1-year and 2-year overall survival probabilities were 87.3% (95% confidence interval [CI], 72.1-94.5) and 82% (95% CI, 65.9-91), respectively. The probability of 2-year progression-free survival was 79.8% (95% CI, 63.7-89.4). One-year transplant-related mortality was 5.2%. Median time to neutrophil and platelet recovery was 11 days and 18 days, respectively. Nine patients experienced a total of 13 unexpected grade 3-5 adverse events posttransplant (10 grade 3 and 3 grade 4 events). Twenty-two patients had at least 1 infectious episode posttransplant. At 1 year post-AHCT, median CD4(+) T-cell count was 280.3 (range, 28.8-1148.0); 82.6% had an undetectable HIV viral load. Trial patients were compared with 151 matched Center for International Bone Marrow Transplant Research controls. Outcomes between HIV-infected patients and controls were not statistically significantly different. HRL patients should be considered candidates for AHCT if they meet standard transplant criteria. The trial was registered at www.clinicaltrials.gov as #NCT01141712.

Early cytomegalovirus reactivation remains associated with increased transplant-related mortality in the current era: a CIBMTR analysis.

Single-center studies have reported an association between early (before day 100) cytomegalovirus (CMV) reactivation and decreased incidence of relapse for acute myeloid leukemia (AML) following allogeneic hematopoietic cell transplantation. To substantiate these preliminary findings, the Center for International Blood and Marrow Transplant Research (CIBMTR) Database was interrogated to analyze the impact of CMV reactivation on hematologic disease relapse in the current era. Data from 9469 patients transplanted with bone marrow or peripheral blood between 2003 and 2010 were analyzed according to 4 disease categories: AML (n = 5310); acute lymphoblastic leukemia (ALL, n = 1883); chronic myeloid leukemia (CML, n = 1079); and myelodysplastic syndrome (MDS, n = 1197). Median time to initial CMV reactivation was 41 days (range, 1-362 days). CMV reactivation had no preventive effect on hematologic disease relapse irrespective of diagnosis. Moreover, CMV reactivation was associated with higher nonrelapse mortality [relative risk [RR] among disease categories ranged from 1.61 to 1.95 and P values from .0002 to <.0001; 95% confidence interval [CI], 1.14-2.61). As a result, CMV reactivation was associated with lower overall survival for AML (RR = 1.27; 95% CI, 1.17-1.38; P <.0001), ALL (RR = 1.46; 95% CI, 1.25-1.71; P <.0001), CML (RR = 1.49; 95% CI, 1.19-1.88; P = .0005), and MDS (RR = 1.31; 95% CI, 1.09-1.57; P = .003). In conclusion, CMV reactivation continues to remain a risk factor for poor posttransplant outcomes and does not seem to confer protection against hematologic disease relapse.

Bone marrow-derived mononuclear cell therapy for nonischaemic dilated cardiomyopathy-A meta-analysis.

OBJECTIVE: The therapeutic effects of bone marrow-derived mononuclear cells (BMMNCs) transplantation in patients with nonischaemic dilated cardiomyopathy (DCM) are still under debate. Current randomized controlled trials (RCTs) reported conflicting results. The aim of this study was to assess the effects of BMMNCs transplantation on left ventricular ejection fraction (LVEF) in patients with nonischaemic DCM. METHODS: A comprehensive search of PubMed, EMBASE and Cochrane Controlled Trials Register was performed. We included RCTs reporting data on LVEF in patients with nonischaemic DCM after BMMNCs transplantation. RESULTS: Seven RCTs including 463 patients were included. BMMNCs transplantation significantly improved LVEF by 3.79% (95% CI: 0.56%-7.03%; P = .007) and LVESV by -24.36 mL (95% CI: -46.36 to -2.36 mL; P = .03), while had no impact on the risk of all-cause death (OR 0.92; 95% CI: 0.41 to 2.08%; P = .84). Subgroup analysis demonstrated a more significant improvement of LVEF in patients with longer follow-up (~15 months to 5 years) than shorter ones (12 months). Moreover, using bone marrow mononuclear cells was more effective than using G-CSF-stimulated bone marrow/peripheral blood stem cells in the improvement of LVEF in patients with nonischaemic DCM. CONCLUSIONS: Bone marrow-derived mononuclear cells transplantation is associated with a moderate, but significant, improvement in LVEF in patients with nonischaemic DCM. This meta-analysis supports further RCT conductions using BMMNCs transplantation with larger patient's population and longer term follow-up.

Influenza vaccines in immunosuppressed adults with cancer.

BACKGROUND: This is an update of the Cochrane review published in 2013, Issue 10.Immunosuppressed cancer patients are at increased risk of serious influenza-related complications. Guidelines, therefore, recommend influenza vaccination for these patients. However, data on vaccine effectiveness in this population are lacking, and the value of vaccination in this population remains unclear. OBJECTIVES: To assess the effectiveness of influenza vaccine in immunosuppressed adults with malignancies. The primary review outcome is all-cause mortality, preferably at the end of the influenza season. Influenza-like illness (ILI, a clinical definition), confirmed influenza, pneumonia, any hospitalisations, influenza-related mortality and immunogenicity were defined as secondary outcomes. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and LILACS databases up to May 2017. We searched the following conference proceedings: ICAAC, ECCMID, IDSA (infectious disease conferences), ASH, ASBMT, EBMT (haematological), and ASCO (oncological) between the years 2006 to 2017. In addition, we scanned the references of all identified studies and pertinent reviews. We searched the websites of the manufacturers of influenza vaccine. Finally, we searched for ongoing or unpublished trials in clinical trial registry databases. SELECTION CRITERIA: Randomised controlled trials (RCTs), prospective and retrospective cohort studies and case-control studies were considered, comparing inactivated influenza vaccines versus placebo, no vaccination or a different vaccine, in adults (16 years and over) with cancer. We considered solid malignancies treated with chemotherapy, haematological cancer patients treated or not treated with chemotherapy, cancer patients post-autologous (up to six months after transplantation) or allogeneic (at any time) haematopoietic stem cell transplantation (HSCT). DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the risk of bias and extracted data from included studies adhering to Cochrane methodology. Meta-analysis could not be performed because of different outcome and denominator definitions in the included studies. MAIN RESULTS: We identified six studies with a total of 2275 participants: five studies comparing vaccination with no vaccination, and one comparing adjuvanted vaccine with non-adjuvanted vaccine. Three studies were RCTs, one was a prospective observational cohort study and two were retrospective cohort studies.For the comparison of vaccination with no vaccination we included two RCTs and three observational studies, including 2202 participants. One study reported results in person-years while the others reported results per person. The five studies were performed between 1993 and 2015 and included adults with haematological diseases (three studies), patients following bone marrow transplantation (BMT) (two studies) and solid malignancies (three studies).One RCT and two observational studies reported all-cause mortality; the RCT showed similar mortality rates in both arms (odds ratio (OR) 1.25 (95% CI 0.43 to 3.62; 1 study, 78 participants, low-certainty evidence)); and the observational studies demonstrated a significant association between vaccine receipt and lower risk of death, adjusted hazard ratio 0.88 (95% CI 0.78 to 1; 1 study, 1577 participants, very low-certainty evidence) in one study and OR 0.42 (95% CI 0.24 to 0.75; 1 study, 806 participants, very low-certainty evidence) in the other. One RCT reported a reduction in ILI with vaccination, while no difference was observed in one observational study. Confirmed influenza rates were lower with vaccination in one RCT and the three observational studies, the difference reaching statistical significance in one. Pneumonia was observed significantly less frequently with vaccination in one observational study, but no difference was detected in another or in the RCT. One RCT showed a reduction in hospitalisations following vaccination, while an observational study found no difference. No life-threatening or persistent adverse effects from vaccination were reported. The strength of evidence was limited by the low number of included studies and by their low methodological quality and the certainty of the evidence for the mortality outcome according to GRADE was low to very low.For the comparison of adjuvanted vaccine with non-adjuvanted vaccine, we identified one RCT, including 73 patients. No differences were found for the primary and all secondary outcomes assessed. Mortality risk ratio was 0.54 (95% CI 0.05 to 5.73; low-certainty evidence) in the adjuvanted vaccine group. The quality of evidence was low due to the small sample size and the large confidence intervals for all outcomes. AUTHORS' CONCLUSIONS: Observational data suggest lower mortality and infection-related outcomes with influenza vaccination. The strength of evidence is limited by the small number of studies and low grade of evidence. It seems that the evidence, although weak, shows that the benefits overweigh the potential risks when vaccinating adults with cancer against influenza. However, additional placebo or no-treatment controlled RCTs of influenza vaccination among adults with cancer is ethically questionable.There is no conclusive evidence regarding the use of adjuvanted versus non-adjuvanted influenza vaccine in this population.