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Background: Autologous peripheral blood stem cell transplantation (aPBSCT) is the standard of care for adults with relapsed lymphoma, yet recipients remain at risk of developing chronic health conditions (CHCs). It was hypothesized that body composition measurements of skeletal muscle and fat are associated with late‐onset CHCs and nonrelapse mortality after aPBSCT. Methods: Leveraging the Blood or Marrow Transplant Survivor Study, we examined association between pre‐aPBSCT body composition and new‐onset grade 3–5 CHCs among 187 adults with lymphoma treated with aPBSCT (2011–2014) surviving ≥2 years after aPBSCT. Using computed tomography scans at the L3 level, skeletal muscle mass (skeletal muscle area and skeletal muscle density [SMD]) and body fat (subcutaneous adipose tissue and visceral adipose tissue) were measured and quantified as sex‐specific z‐scores. Competing risk models were built to study the impact of body composition on incident grade 3 through 5 CHCs and nonrelapse mortality (NRM) adjusting for confounders. Results: The study cohort had a median age at aPBSCT of 57 years with 63% males, 77% non‐Hispanic Whites and 81% with non‐Hodgkin lymphoma. The 5‐year cumulative incidence of grade 3 through 5 CHCs was 47% (95% Confidence Interval, CI, 38%–56%). Each SD increase in SMD was associated with 30% reduced risk of grade 3 through 5 CHCs (95% CI, 0.50–0.96). The 10‐year cumulative incidence of NRM was 16% (95% CI, 10–22). No body composition measure was associated with NRM. Conclusions: The association between SMD and grade 3 through 5 CHCs following aPBSCT could inform development of prognostic models to identify adults with lymphoma at greatest risk of morbidity following aPBSCT. [ABSTRACT FROM AUTHOR]

Background: Blood or marrow transplantation (BMT) survivors carry a high burden of morbidity, yet health care utilization by this vulnerable population remains understudied. Patterns and predictors of various domains of health care utilization in long‐term BMT survivors were evaluated. Methods: Study participants were drawn from the Bone Marrow Transplant Survivor Study (BMTSS). Patients transplanted between 1974 and 2014 at one of three transplant centers who had survived ≥2 years after BMT and were aged ≥18 years at the time of the study were included. A BMTSS survey served as the source of data for health care utilization, sociodemographics, and chronic health conditions. Domains of health care utilization in the 2 years preceding study participation included routine checkups, BMT‐related visits, transplant/cancer center visits, emergency room (ER) visits, hospitalizations, and high health care utilization (≥7 physician visits during the 2 years before the study). Clinical characteristics and therapeutic exposures were abstracted from medical records. Results: In this cohort of 3342 BMT survivors (52% allogeneic), the prevalence of health care utilization declined over time since BMT for both allogeneic and autologous BMT survivors, such that among those who had survived ≥20 years, only 49%–53% had undergone routine checkups, 37%–38% reported BMT‐related visits, and 28%–29% reported transplant/cancer center visits. The presence of severe/life‐threatening conditions and chronic graft‐vs‐host disease increased the odds of health care utilization across all domains. Lower education, lack of insurance, and Hispanic ethnicity were associated with a lower prevalence of routine checkups and/or transplant/cancer center visits. Lower income increased the odds of ER visits but reduced the odds of hospitalizations or high health care utilization. Conclusions: This study identified vulnerable populations of long‐term BMT survivors who would benefit from specialized risk‐based anticipatory care to reduce high health care utilization, ER visits, and hospitalizations. Health care utilization (including routine medical checkups) declines with increasing time since blood or marrow transplantation, except among survivors with severe/life‐threatening chronic health conditions as well as those with chronic graft‐vs‐host disease. Lower education and lack of insurance are associated with lower health care utilization. [ABSTRACT FROM AUTHOR]

Summary: The role of the gastrointestinal microbiome in predisposing to chronic graft‐versus‐host disease (cGVHD), an immune‐mediated haematopoietic cell transplant (HCT) complication, is not well defined. We examined the relationship of the host faecal microbiome with subsequent cGVHD development by analysing baseline stool samples as well as post‐HCT changes in microbiome composition and metabolite pathway analyses. We analysed pre‐transplant baseline samples from 11 patients who subsequently developed cGVHD compared to 13 controls who did not develop acute GVHD or cGVHD at any time. We found a significant differential abundance of multiple taxa at baseline between cGVHD versus controls, including the Actinobacteria phylum and Clostridium genus. A subgroup analysis of longitudinal samples within each patient revealed a greater loss of alpha diversity from baseline to post‐engraftment in patients who subsequently developed cGVHD. Metabolic pathways analysis revealed that two pathways associated with short‐chain fatty acid metabolism were enriched in cGVHD patient microbiomes: β‐oxidation and acyl‐CoA synthesis, and γ‐aminobutyrate shunt. In contrast, a tryptophan catabolism pathway was enriched in controls. Our findings show a distinct pattern of baseline microbiome and metabolic capacity that may play a role in modulating alloreactivity in patients developing cGVHD. These findings support the therapeutic potential of microbiome manipulation for cGVHD prevention. [ABSTRACT FROM AUTHOR]

Background: A comprehensive assessment of morbidity after allogeneic bone marrow transplantation (BMT) performed in childhood remains understudied. Methods: Seven hundred eighty‐nine allogeneic BMT recipients who had survived ≥2 years after BMT performed between 1974 and 2014 at age <22 years and 690 siblings completed a 255‐item survey self‐reporting sociodemographics and chronic health conditions. A severity score (grade 3 [severe], 4 [life‐threatening], or 5 [fatal]) was assigned to the conditions using Common Terminology Criteria for Adverse Events, version 5.0. For the BMT cohort, the cumulative incidence of chronic health conditions was calculated as a function of time from BMT. Proportional subdistribution hazards models were used to determine predictors of grade 3–5 conditions. Logistic regression was used to estimate the risk of grade 3–4 conditions in BMT recipients who were alive at the time of this study compared with siblings. Results: The median age at transplantation was 11.3 years (range, 0.4–22.0 years), and the median length of follow‐up was 11.7 years (range, 2.0–45.3 years). The most prevalent primary diagnoses were acute lymphoblastic leukemia (30.7%), and acute myeloid leukemia/myelodysplastic syndrome (26.9%). At age 35 years, the cumulative incidence of a grade 3–4 condition was 53.8% (95% CI, 46.7%–60.3%). The adjusted odds ratio of a grade 3–4 condition was 15.1 in survivors (95% CI, 9.5–24.0) compared with siblings. The risk of a grade 3–5 condition increased with age at BMT (hazard ratio [HR], 1.03; 95% CI, 1.01–1.05) and was higher among females (HR, 1.27; 95% CI, 1.02–1.59), patients who received total body irradiation (HR, 1.71; 95% CI, 1.27–2.31), and those reporting chronic graft‐versus‐host disease (HR, 1.38; 95% CI, 1.09–1.74). Conclusions: Two‐year survivors of allogeneic BMT in childhood have an increased risk of grade 3–4 chronic health conditions compared with siblings, suggesting the need for long‐term follow‐up. Two‐year survivors of allogeneic bone marrow transplantation in childhood have a substantially increased risk of chronic health conditions compared with siblings. By age 35 years, more than one half of bone marrow transplantation recipients had a severe or life‐threatening chronic health condition. [ABSTRACT FROM AUTHOR]

Background: Blood or marrow transplantation (BMT) is increasingly offered to older individuals with hematologic malignancies. The high prevalence of chronic health conditions in such individuals necessitates use of multiple medications. Beers Criteria represent a list of potentially inappropriate medications (PIMs) shown to increase the risk of health problems in the elderly. We sought to determine the prevalence and predictors of PIM use in older BMT survivors and identify associations with health problems. Methods: Study participants were drawn from the BMT Survivor Study, a cohort study of patients transplanted at three US transplant centers between 1974 and 2014 and surviving ≥2 years. For this report, the survivors were aged ≥65 years. Siblings served as a comparison group. Participants self‐reported sociodemographics, chronic health conditions, and medication use. Logistic regression analyses identified predictors of PIM use and associations with health problems. Results: Overall, PIM use was comparable between BMT survivors (49.4%) and siblings (49.3%) (odds ratio [OR] = 0.9; 95% CI, 0.7–1.2); however, BMT survivors were more likely to use >1 PIM (17.4% vs. 12.4%; OR = 1.5; 95% CI, 1.01–2.4) and central nervous system–related PIMs (8.3% vs. 4.3%; OR = 2.18; 95% CI, 1.17–4.09). Predictors of PIM use included presence of severe/life‐threatening chronic health conditions (OR = 1.5; 95% CI, 1.1–2.0), and chronic graft versus host disease (OR = 1.7; 95% CI, 1.1–2.7). Survivors taking >1 PIM reported more issues with vertigo (OR = 2.3; 95% CI, 1.1–4.7), balance (OR = 2.6; 95% CI, 1.7–4.1), faintness/dizziness (OR = 2.8; 95% CI, 1.8–4.6), and personal care (OR = 4.5; 95% CI, 1.4–14.8). Conclusions: This study shows the health problems associated with PIM use and identifies vulnerable populations at higher risk for PIM use, providing evidence for caution in using PIMs in high‐risk populations. Older blood or marrow transplantation survivors were more likely to use multiple potentially inappropriate medications than a sibling comparison group. Survivors with multimorbidity and/or chronic graft versus host disease were more likely to use these medications; survivors taking multiple potentially inappropriate medications reported several health problems. [ABSTRACT FROM AUTHOR]

Background: Amphiregulin (AREG) is increased in circulation in acute graft‐versus‐host disease (aGVHD) and is associated with poor steroid response and lower survival. The expression of AREG in aGVHD target organs and its association with clinical outcomes are unknown. Methods: We performed AREG immunohistochemical staining on skin specimens from 67 patients with aGVHD between the years 2010 and 2015. Two blinded reviewers assessed AREG expression and scored specimens with a semiquantitative scale ranging from 0 (absent) to 4 (most intense). Results: Median AREG score of aGVHD cases was 3. Sixteen of 67 (23.9%) aGVHD cases had an AREG >3. High skin AREG expression (>3 vs. ≤3) was associated with increased overall clinical grade of aGVHD (52.9% vs. 33.4% clinical grade III‐IV, p = 0.02), reduced 3‐year overall survival (OS; 13% vs. 61%, p < 0.01), and increased 3‐year non‐relapse mortality (NRM; 56% vs. 20%, p = 0.05). Conclusion: High skin AREG immunohistochemical expression is associated with high clinical grade aGVHD, poor OS, and increased NRM. [ABSTRACT FROM AUTHOR]

Background: Clostridioides difficile infection (CDI) frequently complicates allogeneic hematopoietic stem cell (allo‐HCT) and solid organ transplantation (SOT). Methods: We retrospectively analyzed risk factors and outcomes of CDI occurring within 30 days of transplant. Results: Between March 2010 and June 2015, 466 allo‐HCT and 1454 SOT were performed. The CDI cumulative incidence (95% CI) was 10% (8–13) and 4% (3–5), following allo‐HCT and SOT, respectively (p <.01), occurring at a median (range) 7.5 days (1–30) and 11 (1–30), respectively (p =.18). In multivariate analysis, fluoroquinolones use within 14 days pre‐transplantation was a risk factor for CDI following allo‐HCT (HR 4.06 [95% CI 1.31–12.63], p =.02), and thoracic organ(s) transplantation was a risk factor for CDI following SOT (HR 3.03 [95% CI 1.31–6.98]) for lung and 3.90 (1.58–9.63) for heart and heart/kidney transplant, p =.02. Compared with no‐CDI patients, the length of stay (LOS) was prolonged in both allo‐HCT (35 days [19–141] vs. 29 [13–164], p <.01) and SOT with CDI (16.5 [4–101] vs. 7 [0–159], p <.01), though not directly attributed to CDI. In allo‐HCT, severe acute graft‐versus‐host disease (aGVHD) occurred more frequently in patients with CDI (33.3% vs. 15.8% without CDI, p =.01) and most aGVHD (87.5%) followed CDI. Non‐relapse mortality or overall survival, not attributed to CDI, were also similar in both allo‐HCT and SOT. Conclusions: Early post‐transplant CDI is frequent, associated with fluoroquinolones use in allo‐HCT and the transplanted organ in SOT, and is associated with longer LOS in both the groups without difference in survival but with increased aGVHD in allo‐HCT. [ABSTRACT FROM AUTHOR]

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. In bone marrow transplantation survivors who were followed for a median of 13 years, the prevalence of frailty increased from 4.8% to 9.6%. Exposure to vincristine before bone marrow transplantation was associated with 2.1 times greater odds (95% CI, 1.3‐3.39 greater odds) of a worsening frailty state. [ABSTRACT FROM AUTHOR]

Objectives: Higher MMF dose can reduce acute GVHD risk after allogeneic hematopoietic cell transplantation (HCT). We examined the effect of MMF dose, relative to patient actual body weight (mg/kg/day), on outcomes of 680 adults after HCT. Methods: MMF was combined with cyclosporine (n = 599) or sirolimus (n = 81). We divided MMF dose/kg/day in quartiles. Results: The median time to grade II‐IV acute GVHD was 32 days. The incidence of grade II‐IV acute GVHD at day 30 was 30% in 1st (<29), 20% in 2nd (29‐34), 16% in 3rd (35‐41), and 19% in 4th (≥42) quartile (P <.01). Corresponding relapse incidence at 1 year was 16%, 25%, 27%, and 31%, respectively (P =.01). In multivariate analysis, as compared to 1st quartile, higher dose of weight‐based MMF reduced grade II‐IV acute GVHD (HR = 0.64 for 2nd, HR = 0.48 for 3rd, and HR = 0.55 for 4th quartile), but increased the risk of relapse (HR = 1.63 for 2nd, HR = 1.75 for 3rd, and HR = 2.31 for 4th quartile). Conclusions: Weight‐based MMF dose had no significant impact on engraftment, chronic GVHD, or survival. These data suggest that higher weight‐based MMF dose reduces the risk of acute GVHD at the expense of increased relapse and supports conducting prospective studies to optimize MMF dosing after HCT. [ABSTRACT FROM AUTHOR]

Shotgun sequencing of the faecal microbiome to predict response to steroids in patients with lower gastrointestinal acute graft-versus-host disease: An exploratory analysis Keywords: GVHD; microbiome; transplantation EN GVHD microbiome transplantation e69 e73 5 02/02/21 20210201 NES 210201 Acute graft- I versus i -host disease (aGVHD) is a major cause of morbidity and mortality in allogeneic haematopoietic cell transplantation (HCT) recipients.1 High-dose steroids are the conventional front-line treatment for aGVHD.2 Because steroid-refractory aGVHD, esp. lower gastrointestinal (LGI) aGVHD, has a dismal prognosis,3 early identification of patients unlikely to respond to front-line treatment is of critical importance and highlights a target population for novel therapeutics. The patient shown at the top had steroid-responsive lower gastrointestinal (LGI) acute graft-versus-host disease (aGVHD), whereas the patient at the bottom had steroid-refractory disease. Patient numbers are shown. gl This is the first exploratory analysis of gut microbiome predictors of LGI aGVHD steroid response using shotgun sequencing. [Extracted from the article]

Background: Autologous blood or bone marrow transplantation (aBMT) is considered the standard of care for patients with multiple myeloma (MM). Significantly improved survival necessitates an understanding of the morbidity burden borne by the growing survivor population.Methods: The authors evaluated severe and/or life-threatening chronic health conditions (CHCs) and subsequent neoplasms (SNs) in patients with MM who were treated with aBMT using the Bone Marrow Transplant Survivor Study. A total of 630 study participants had undergone aBMT for MM at 1 of 3 BMT centers, had survived ≥2 years after aBMT, and were aged ≥18 years at the time of survey completion. Survivors of aBMT identified 289 nearest-age siblings to constitute an unaffected comparison group. Scoring of CHCs was based on version 5 of the National Cancer Institute Common Terminology Criteria for Adverse Events to determine severity (with grade 3 indicating serious and grade 4 indicating life-threatening).Results: The 10-year cumulative incidence of any grade 3 to 4 CHC among survivors of aBMT was 57.6 ± 3.2%. Survivors of MM were found to be at 40% higher odds of developing grade 3 to 4 CHCs when compared with siblings (95% confidence interval [95% CI], 1.0-1.9). Among SNs, 96% were solid tumors, yielding a 10-year cumulative incidence of 13.6% ± 2.5%. Pre-aBMT exposure to cyclophosphamide (hazard ratio [HR], 3.5; 95% CI, 1.5-8.1) and immunomodulatory drugs (HR, 3.9; 95% CI, 1.5-10.1) were associated with an increased risk of solid tumors. Melanoma (10-year cumulative incidence: 3.3% ± 1.2%) and squamous cell carcinoma (10-year cumulative incidence: 5.1% ± 1.8%), were the most common SNs. Pre-aBMT exposure to cyclophosphamide (HR, 6.02; 95% CI, 1.4-26.1) and immunomodulatory drugs (HR, 7.9; 95% CI, 0.9-68.5) was associated with an increased risk of melanoma.Conclusions: The 10-year cumulative incidence of severe and/or life-threatening CHCs was found to approach 60% in long-term survivors of MM, with solid SNs constituting a large morbidity burden. The current study has provided evidence supporting the close monitoring of survivors to manage morbidity. [ABSTRACT FROM AUTHOR]

Summary: We previously reported a protective association between single nucleotide polymorphisms (SNPs; rs4415345G and rs4610776A alleles) of Paneth cell α‐defensin‐5 against acute graft‐versus‐host disease (aGVHD). Because dysbiosis has been associated with aGVHD, we hypothesized that these SNPs may have a gut microbiota signature. In Lasso regression analysis of 248 healthy individuals, rs4415345G was associated with a higher abundance of Odoribacter splanchnicus, an anaerobic butyrogenic commensal. In multivariable analysis of data from 613 allogeneic haematopoietic cell transplant recipients, peri‐engraftment presence of O. splanchnicus was associated with ~50% lower risk for grade II–IV aGVHD (hazard ratio 0·53, 95% confidence interval 0·28–1·00, P = 0·05). O. splanchnicus may protect rs4415345G individuals against aGVHD. [ABSTRACT FROM AUTHOR]

Background: In the field of malignant hematology, most microbiome studies have focused on recipients of allogeneic hematopoietic cell transplantation (allo-HCT). As a result, this population has remained the primary target for novel microbiota therapeutics. Because the types of insults to the microbiome are similar during hematopoietic cell transplantation and intensive antileukemia therapy, this study evaluated whether the dysbiosis states are similar in the 2 settings.Methods: This study compared gut microbiota assemblages and community domination states in 2 cohorts of patients: patients with intensively treated acute leukemia (AL) and allo-HCT recipients. 16S ribosomal RNA gene profiling of thrice weekly stool samples was performed. Linear discriminant analysis effect size was used to determine differentially abundant taxa in groups of interest, and mixed modes were used to determine the predictors of microbiome states.Results: Microbiome changes in both cohorts were characterized by a marked loss of diversity and domination of low-diversity communities by Enterococcus. In the AL cohort, the relative abundance of Lactobacillus was also inversely correlated with diversity. Communities dominated by these genera were compositionally different.Conclusions: Similarities in microbiota assemblages between the 2 cohorts support a broader scope for microbiota-directed therapeutics than previously considered, whereas specific differences suggest a personalized aspect to such therapeutics with the possibility of a differential response. [ABSTRACT FROM AUTHOR]

Background: Patients with non-Hodgkin lymphoma (NHL) have an increased risk of venous thromboembolism (VTE), particularly when they are receiving treatment. Blood or marrow transplantation (BMT) is recommended for relapsed/refractory NHL, and the risk of VTE after these patients undergo BMT is uncertain.Methods: Patients with NHL who survived 2 years or longer after BMT were surveyed for long-term health outcomes, including VTE. The median follow-up was 8.1 years (interquartile range, 5.6-12.9 years). The risk of VTE in 734 patients with NHL versus 897 siblings without a history of cancer and the risk factors associated with VTE were analyzed.Results: BMT survivors of NHL were at increased risk for VTE in comparison with siblings (odds ratio for allogeneic BMT survivors, 4.61; P < .0001; odds ratio for autologous BMT survivors, 1.75; P = .035). The cumulative incidence of VTE was 6.3% ± 0.9% at 5 years after BMT and 8.1% ± 1.1% at 10 years after BMT. In allogeneic BMT recipients, an increased body mass index (BMI; hazard ratio [HR] for BMI of 25-30 kg/m2 , 3.52; 95% confidence interval [CI], 1.43-8.64; P = .006; HR for BMI > 30 kg/m2 , 3.44; 95% CI, 1.15-10.23; P = .027) and a history of chronic graft-versus-host disease (HR, 3.33; 95% CI, 1.59-6.97; P = .001) were associated with an increased risk of VTE. Among autologous BMT recipients, a diagnosis of coronary artery disease (HR, 5.94; 95% CI, 1.7-20.71; P = .005) and prior treatment with carmustine (HR, 4.91; 95% CI, 1.66-14.51; P = .004) were associated with increased VTE risk.Conclusions: Patients with NHL who survive BMT are at risk for developing late occurring VTE, and ongoing vigilance for this complication is required. Future studies assessing the role of thromboprophylaxis in high-risk patients with NHL are needed. [ABSTRACT FROM AUTHOR]

Background: Late mortality was investigated in patients with chronic myelogenous leukemia (CML) who underwent blood or bone marrow transplant (BMT) with or without prior tyrosine kinase inhibitor (TKI) therapy.Methods: By using data from the Blood or Marrow Transplant Survivor Study, the authors examined late mortality in 447 patients with CML who underwent BMT between 1974 and 2010, conditional on surviving ≥2 years post-BMT. For vital status information, the medical records, the National Death Index, and the Accurint database were used. Standardized mortality ratios (SMRs) were calculated using general population age-specific, sex-specific, and calendar-specific mortality rates. Kaplan-Meier techniques and Cox regression were used for all-cause mortality analyses. Cumulative incidence and proportional subdistribution hazards models for competing risks were used for cause-specific mortality analyses.Results: The 10-year overall survival rate was 65.7% and 73% for those who underwent transplant with and without pre-BMT exposure to TKI therapy, respectively. Patients who underwent transplant with and without pre-BMT TKI experienced SMRs of 6.4 and 6.4, respectively (P = .8); and the SMRs were 11.6 and 8.1, respectively, for those with high-risk disease (P = .2). Independent predictors of non-CML-related mortality included chronic graft-versus-host disease (hazard ratio [HR], 2.8; 95% CI, 1.8-4.4) and busulfan/cyclophosphamide conditioning (HR, 0.5; 95% CI, 0.3-0.9; reference, total body irradiation/cyclophosphamide conditioning). The 20-year cumulative incidence of CML-related and non-CML-related mortality was 6% and 36%, respectively, for the entire cohort. Both CML-related mortality (HR, 1.0; 95% CI, 0.1-12.6) and non-CML-related mortality (HR, 1.3; 95% CI, 0.6-3.1) were comparable for those with and without pre-BMT TKI therapy.Conclusions: The similar late mortality experienced by patients with CML who undergo transplantation with or without pre-BMT TKIs suggests that allogeneic BMT can be considered in the context of TKI intolerance or nonadherence. The prevention of post-BMT non-CML-related mortality could favorably affect long-term survival. [ABSTRACT FROM AUTHOR]

Up to a quarter of patients with acute lymphoblastic leukaemia (ALL) have central nervous system (CNS) involvement at the time of diagnosis (Lazarus et al, [8]) and approximately 10% at relapse (Fielding et al, [4]). The rationale for co-culture with meningeal cells was to more accurately model ex vivo the primary site of CNS leukaemia in our patient in order to provide a biological rationale for why ruxolitinib may have synergized with IT therapy. In these co-culture experiments, ruxolitinib alone had no effect on leukaemia cell apoptosis, but its addition to methotrexate or cytarabine significantly (>2-fold) increased their cytotoxicity, resulting in increased leukaemia cell apoptosis (Fig B). [Extracted from the article]

The article discusses late mortality in blood or marrow transplant survivors with venous thromboembolism. Topics include how Haemostatic complications are commonly observed in patients undergoing blood or marrow transplantation (BMT), and are related to thrombocytopenia and immunological complications.

Keywords: acute leukaemia; chemotherapy; dysbiosis; microbiota; transplantation EN acute leukaemia chemotherapy dysbiosis microbiota transplantation e94 e96 3 04/30/20 20200501 NES 200501 Cure from acute leukaemia (AL) often requires multiple rounds of intensive therapy including chemotherapy and haematopoietic cell transplantation (HCT). This provided a unique opportunity to study the microbiome trajectory through three phases of intensive therapy in the same patient: AL1 (first induction chemotherapy), HCT, and AL2 (second induction chemotherapy). [Extracted from the article]

Summary: Host genetics shape the gut microbiota, and gut dysbiosis increases the risk of acute graft‐versus‐host disease (aGVHD). Paneth cells and microbiota have interactions that contribute to immune regulation. α‐defensin‐5 (HD5) and regenerating islet‐derived protein 3 alpha (Reg3A) are the most abundant Paneth cell antimicrobial peptides (AMPs). We hypothesized that single nucleotide polymorphisms (SNPs) in the genes for HD5 (DEFA5) and Reg3A (REG3A) predict aGVHD risk. We analysed pre‐transplant recipient peripheral blood mononuclear cell samples from randomized Blood and Marrow Transplant Clinical Trials Network (BMT CTN) studies 0201 (94 patients with bone marrow and 93 with peripheral blood grafts) and 0901 (86 patients with myeloablative and 77 with reduced‐intensity conditioning; all using peripheral blood grafts). In multivariable analysis (with a SNP × graft source interaction term in CTN‐0201 and a SNP × conditioning intensity term in CTN‐0901), DEFA5 rs4415345 and rs4610776 were associated with altered incidence of aGVHD grade II–IV [rs4415345 G vs. C: hazard ratio (HR) 0·58, 95% confidence interval (95% CI) 0·37–0·92, P = 0·02; rs4610776 T vs. A: HR 1·53, 95% CI 1·01–2·32, P = 0·05] in CTN‐0201, but not CTN‐0901, suggesting a stronger effect in bone marrow allografts. REG3A SNP was not associated with aGVHD. Host genetics may influence aGVHD risk by modulating Paneth cell function. [ABSTRACT FROM AUTHOR]

Summary: The prognosis of relapsed acute myeloid leukaemia (AML) is poor and treatment is challenging. While the most potent treatment modality for patients who achieve a complete remission after relapse is still allogeneic haematopoietic cell transplantation (allo‐HCT), both transplant‐related mortality and relapse rates are high and many patients are not candidates for this approach. After a few decades of relative stasis in this field, a large number of novel approaches have become available to tackle this highly fatal disease. This is mostly due to our improved understanding of disease pathogenesis (including targetable mutations) and the anti‐leukaemia potential of the immune system. Several small‐molecule inhibitors and immunotherapeutic options are being explored in clinical trials and many more are in pre‐clinical phase. Future studies will focus on novel and mechanistically driven combinations, sequential treatments, and low‐toxicity maintenance strategies. While cure of relapsed/refractory AML without allo‐HCT is currently unlikely, treatments are becoming less toxic and remissions are lasting longer. [ABSTRACT FROM AUTHOR]

Abstract: Chromosomally integrated human herpesvirus‐6 (ciHHV‐6) can be transmitted from parent to child or via allogeneic hematopoietic cell transplantation (HCT). We report a case of ciHHV‐6 transmitted via syngeneic HCT, and vertically across 3 generations. ciHHV‐6 was transmitted from a parent to the patient and her identical twin, and from the patient to her son. The patient underwent syngeneic HCT as rescue from chemotherapy‐induced aplasia during which ciHHV‐6 was re‐transmitted to her, this time from her identical twin. This is the first report, to our knowledge, of a patient acquiring ciHHV‐6 once via germline from a parent and again via syngeneic HCT from an identical twin. [ABSTRACT FROM AUTHOR]

Background: Patients with acute myeloid leukemia (AML) without complete remission (CR) or in first relapse (Rel1) can have extended leukemia control and survival after allogeneic hematopoietic cell transplantation (HCT). For patients in Rel1 or primary induction failure (PIF), transplantation versus treatment to achieve a second CR (CR2) and subsequent HCT might yield similar outcomes, but available comparative data are scarce.Methods: Survival was analyzed in 4682 HCT recipients according to disease status: PIF (N = 1440), Rel1 (failing ≥1 reinduction; N = 1256), and CR2 (N = 1986).Results: Patient, disease, and transplantation characteristics were similar, except that patients in CR2 more often had performance scores of 90% to 100%, de novo AML, and longer CR1 duration. Adverse cytogenetics were more common in patients who experienced PIF. The 5-year survival rate adjusted for performance score, cytogenetic risk, and donor type for CR2 was 39% (95% confidence interval [CI], 37%-41%) compared with 18% (95% CI, 16%-20%) for HCT in Rel1 and 21% (95% CI, 19%-23%) in PIF (P < .0001).Conclusions: Although survival is superior for patients who undergo HCT in CR2, transplantation for selected patients in Rel1 or PIF may still be valuable. These data can guide decision making about additional salvage therapy versus prompt HCT for patients not in CR, but they also highlight that AML is intrinsically more treatable in patients who have favorable-risk cytogenetics, those with longer CR1 duration, and younger patients with better performance status. Cancer 2017;123:2025-2034. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

Glucocorticoids are central to effective therapy of acute graft-versus-host disease ( GVHD). However, only about half of the patients respond to steroids in initial therapy. Based on postulated mechanisms for anti-inflammatory effectiveness, we explored genetic variations in glucocorticoid receptor, co-chaperone proteins, membrane transporters, inflammatory mediators, and variants in the T-cell receptor complex in hematopoietic cell transplant recipients with acute GVHD requiring treatment with steroids and their donors toward response at day 28 after initiation of therapy. A total of 300 recipient and donor samples were analyzed. Twenty-three SNPs in 17 genes affecting glucocorticoid pathways were included in the analysis. In multiple regression analysis, donor SNP rs3192177 in the ZAP70 gene (O.R. 2.8, 95% CI: 1.3-6.0, P=.008) and donor SNP rs34471628 in the DUSPI gene (O.R. 0.3, 95% CI: 0.1-1.0, P=.048) were significantly associated with complete or partial response. However, after adjustment for multiple testing, these SNPs did not remain statistically significant. Our results, on this small, exploratory, hypothesis generating analysis suggest that common genetic variation in glucocorticoid pathways may help identify subjects with differential response to glucocorticoids. This needs further assessment in larger datasets and if validated could help identify subjects for alternative treatments and design targeted treatments to overcome steroid resistance. [ABSTRACT FROM AUTHOR]

Background: Transfusion of blood products is an essential component of the hematopoietic cell transplantation (HCT) process. Blood transfusion carries several risks including, but not limited to, lung injury. The effect of transfusions on lung complications after HCT has not been previously investigated.Study Design and Methods: We retrospectively studied 215 adult allogeneic HCT recipients at the University of Minnesota and examined the association between transfusion of blood components and development of lung complications after HCT. Patients without lung complications were used as the control group.Results: A total of 113 (58%) of the patients developed lung injury events before Day 180 after HCT. Six-month survival was significantly lower in the lung event group (52%) versus the controls (78%; p = 0.01). Patients who eventually developed lung events received more transfusion episodes per week in the first month after HCT (median, 4.3 vs. 2.7 for controls), platelet units per week (3.5 vs. 2.0), and RBC units per week (1.8 vs. 1.4; p < 0.01) for all. In a multivariable analysis, each additional transfusion before Day +30 was associated with a 2.7% higher risk of lung complication (95% confidence interval, 0.8-4.8; p = 0.01), adjusting for time to engraftment, conditioning intensity, and donor type. Blood utilization increased after the lung event and remained high for several months relative to controls.Conclusion: Our data suggest that transfusion of blood products is associated with and may further complicate lung complications after HCT. Cautious use of blood components in the post HCT period is recommended. [ABSTRACT FROM AUTHOR]

Quantitative serum PCR argues against long-term persistence of HHV-6 viremia after umbilical cord blood transplantation Cord blood transplantation, HHV-6, PCR, viremia Keywords: cord blood transplantation; HHV-6; PCR; viremia EN cord blood transplantation HHV-6 PCR viremia 1 2 2 06/26/21 20210601 NES 210601 To the Editor, Human herpes virus-6 (HHV-6) reactivates in ~75% of cord blood transplant (CBT) recipients at a median of 2-3 weeks post-transplant.1-3 This contrasts with peripheral blood or bone marrow allografts where HHV-6 reactivation is uncommon.4 In a previous study of 23 CBT recipients, 52% of patients had detectable HHV-6 by whole blood qPCR at a median of 3.9 years (range 1.3-7.1) post-transplant.5 Because whole blood qPCR can be positive with both latent virus and viremia, these results do not distinguish between the two scenarios. [Extracted from the article]

To define high-risk acute graft- versus-host disease ( GVHD) at onset, we examined the initial GVHD stage and grade of 864 patients at the University of Minnesota who received uniform therapy with prednisone 60 mg/m2 per d. We compared the prognostic utility of the Minnesota ( MN; modified from Consensus) versus Center for International Blood and Marrow Transplant Research ( CIBMTR) GVHD organ stage-derived grading systems. As neither GVHD grading system optimally predicted outcomes, a novel acute GVHD risk score was devised by combining the MN and CIBMTR systems. Using multiple regression analysis, we could dichotomize patients into high risk ( HR, n = 86) acute GVHD with initial grade IIIC, IIID or IVD who were less likely to respond to steroid therapy by day 28 [relative risk ( RR), 0·3, P < 0·001] and had a higher risk for transplant-related mortality ( RR, 2·0, P < 0·001) than patients with standard risk ( SR, initial grade IA- IIIB, n = 778) GVHD. Using this novel acute GVHD Risk Score, HR GVHD is either skin stage 4, lower gastrointestinal ( GI) stage 3+, liver stage 3+, or skin stage 3 and lower GI or liver stage 2+ GVHD. Patients with HR acute GVHD have a poor prognosis, require alternative initial therapy and should be the focus of novel therapeutic trials. [ABSTRACT FROM AUTHOR]

The article offers information on the risks for veno-occlusive disease (VOD) in allogeneic hematopoietic cell transplantation (alloHCT) in systemic mastocytosis. Topics discussed include Advanced systemic mastocytosis (AdvSM) is associated with shortened survival, alloHCT with durable disease-free has reported survial of majority of patients; and Veno-occlusive disease (VOD) being a potential complication of alloHCT.

Interleukin-1 alpha (IL-1 α) is a pro-inflammatory cytokine that is implicated in the initiation/maintenance of graft-versus-host disease (GVHD) and the immune response to infection. A cytosine (C) to thymine (T) transition at position −889 is believed to influence gene transcription. A previous single institution study showed that the presence of at least one IL1A T allele in the donor was associated with improved survival after unrelated donor haematopoietic stem cell transplant and lower transplant-related mortality if the donor and recipient each possessed the IL1A T allele. The present study sought to confirm these results in a larger homogeneous population. Thus the study population included 426 patients older than 18 years with chronic myeloid leukaemia (CML), transplanted in first chronic phase and receiving a total body irradiation and cyclophosphamide preparative regimen. Donor recipient pairs were categorised into four groups according to the presence or absence of an IL1A T allele in the donor and recipient. There were no significant differences in patient, donor and transplant characteristics between the groups. We did not observe an association with IL-1 α genotype in donor and/or recipient and transplant-outcome. These data suggest that the outcome of unrelated donor transplant for CML is not influenced by IL-1 α genotype. [ABSTRACT FROM AUTHOR]

BACKGROUND: Natural killer (NK) cells, a subset of lymphocytes and part of the innate immune system, play a crucial role in defense against cancer and viral infection. Herein is a report on the experience of clinical-scale, good manufacturing practices (GMPs) production of NK cells to treat advanced cancer. STUDY DESIGN AND METHODS: Two types of NK cell enrichments were performed on nonmobilized peripheral blood mononuclear cell apheresis collections with a cell selection system (CliniMACS, Miltenyi): CD3 cell depletion to enrich for NK cells and CD3 cell depletion followed by CD56 cell selection to obtain a more pure NK cell product. After overnight incubation with interleukin-2 (IL-2), cells were washed, resuspended in 5 percent human serum albumin, and then released for infusion. RESULTS: A total of 70 NK cell therapy products have been manufactured for patient infusion since 2000. For the CD3 cell–depleted NK cell products, the mean purity, recovery, and viability were 38, 79, and 86 percent, respectively. For the CD3 cell–depleted/CD56 cell–enriched NK cell products, the mean purity, recovery, and viability were 90, 19, and 85 percent, respectively. Gram stain, sterility, and endotoxin testing were all within acceptable limits for established lot release. Compared to the resting processed cells, IL-2 activation significantly increased the function of cells in cytotoxicity assays. CONCLUSION: Clinical-scale production of NK cells is efficient and can be performed under GMPs. The purified NK cell product results in high NK cell purity with minimal contamination by T cells, monocytes, and B cells, but it requires more time for processing and results in a lower NK cell recovery when compared to NK cell enrichment with CD3 cell depletion alone. Additional laboratory studies and results from clinical trials will identify the best source and type of NK cell product. [ABSTRACT FROM AUTHOR]

Most acute myeloid leukaemia (AML) patients lack human leucocyte antigen-identical sibling donors for transplantation. Autotransplants and unrelated donor (URD) transplants are therapeutic options. To compare autologous versus URD transplantation for AML in first (CR1) or second complete remission (CR2), we studied the outcomes of 668 autotransplants were compared with 476 URD transplants reported to the Center for International Blood and Marrow Transplant Research. Proportional hazards regression adjusted for differences in prognostic variables. In multivariate analyses transplant-related mortality (TRM) was significantly higher and relapse lower with URD transplantation. Adjusted 3-year survival probabilities were: in CR1 57 (53–61)% with autotransplants and 44 (37–51)% URD ( P = 0·002), in CR2 46 (39–53)% and 33 (28–38)% respectively ( P = 0·006). Adjusted 3-year leukaemia-free survival (LFS) probabilities were: CR1 53 (48–57)% with autotransplants and 43 (36–50)% with URD ( P = 0·021), CR2 39 (32–46)% and 33 (27–38)% respectively ( P = 0·169). Both autologous and URD transplantation produced prolonged LFS. High TRM offsets the superior antileukaemia effect of URD transplantation. This retrospective, observational database study showed that autotransplantation, in general, offered higher 3-year survival for AML patients in CR1 and CR2. Cytogenetics, however, were known in only two-thirds of patients and treatment bias cannot be eliminated. [ABSTRACT FROM AUTHOR]

Interleukin-18 (IL-18), a proinflammatory cytokine, is elevated in patients with acute graft- versus-host disease (aGVHD). IL-18 induces Th1 differentiation and cytotoxic T-lymphocyte function, both of which have been implicated in the pathogenesis of aGVHD. However, recent studies have shown that neutralization of IL-18 by antibodies leads to an increased risk of aGVHD-related mortality while administration of IL-18 significantly improved survival. We have genotyped a cohort of 157 patient/donor pairs undergoing unrelated donor bone marrow transplantation (BMT) for three polymorphisms recently identified in the promoter of the IL-18 gene: G-137C, C-607A and G-656T. Using phase software, three main haplotypes were reconstructed: GCG, CAT and GAT. We found no association between the occurrence of aGVHD and patient/donor haplotypes. The presence of the GCG haplotype in patients was associated with significantly decreased risk of transplant-related mortality at 100 d (23% in patients with GCG vs. 48% in patients without GCG, P < 0·01) and at 1 year (36% vs. 65%, P < 0·01). The presence of the GCG haplotype in patients was also associated with improved survival (57% vs. 32%, P < 0·01). Cox regression analysis showed that the presence of the GCG haplotype was associated with a twofold increased probability of survival. These data suggest that the IL-18 promoter GCG haplotype may influence survival after unrelated donor BMT without altering the risk of aGVHD. [ABSTRACT FROM AUTHOR]

Discusses scales that have been used to assess bleeding and the contexts in which they have been used. Focus on major diseases such as neoplastic disorders and idiopathic thrombocytopenic purpura; Ideal scale for measuring bleeding; Bleeding scales used in cancer settings; Bleeding scales used in the assessment of bleeding complications of anticoagulant therapies; Bleeding scales used in congenital disorders of secondary hemostasis such as hemophilia.

Summary. The interleukin 1 (IL-1) gene family includes three members (IL-1-α, IL-1-β and IL-1Ra) that mediate immune and inflammatory responses through two specific cell surface receptors. Cytosine to thymine transitions at codons -889 and -511 in the IL-1-α and IL-1-β genes, respectively, and an 86-base pair repeat in the IL-1Ra are believed to influence gene transcription. We have genotyped these three polymorphisms in 90 donor/recipient pairs undergoing unrelated donor bone marrow transplantation (BMT) at the University of Minnesota. We found no association between the occurrence of acute GVHD and donor and/or recipient polymorphisms of any of the three IL-1 genes. The presence of at least one IL-1α- 889 T allele in the donor was associated with significantly improved survival in univariate analysis (survival at 1 year 40% C/C donor, 68% T/C donor, 75% T/T donor, P < 0·01). Multiple regression analysis showed that if the donor and recipient each possessed the IL-1α T allele there was significantly improved survival [relative risk (RR) 0·2, P < 0·01] and decreased treatment-related mortality (TRM; RR 0·2, P = 0·01). The presence of the IL-1β T allele in donor and recipient was also associated with improved survival (RR 0·2, P < 0·01) and decreased TRM (RR 0·1, P < 0·01). These data suggest that donor polymorphism in IL-1α and IL-1β might influence survival after unrelated donor BMT, but does not alter risk of GVHD. [ABSTRACT FROM AUTHOR]

Summary. We evaluated transplant-related mortality (TRM), leukaemia relapse, leukaemia-free survival (LFS) and overall survival (OS) in patients receiving busulphan and cyclophosphamide (BuCy) or cyclophosphamide and total body irradiation (CyTBI) prior to allogeneic bone marrow transplantation (BMT) for acute myelogenous leukaemia (AML) in first remission. Outcomes of 381 human leucocyte antigen (HLA)-matched sibling transplants using BuCy were compared with 200 transplants using CyTBI performed between 1988 and 1996. The incidence of hepatic veno-occlusive disease was higher with BuCy (13%) than with CyTBI (6%) (P = 0·009). Risks of acute and chronic GVHD were similar. In multivariate analysis, relapse risk was higher in the BuCy group [relative risk (RR) = 1·72; 95% confidence interval (CI), 1·05–2·81; P = 0·031]. Eleven of 373 evaluable patients in the BuCy group had a central nervous system relapse in contrast to none of 194 evaluable patients in the CyTBI group (P = 0·016). There were no differences in TRM, LFS and OS. CyTBI conditioning may lower relapse risk but produces comparable TRM, LFS and OS to BuCy for HLA-matched sibling transplantation in first remission AML. [ABSTRACT FROM AUTHOR]

Summary. Unrelated donor (URD) bone marrow transplantation (BMT) in adults can be associated with high non-relapse mortality (NRM). Therefore, factors determining survival in 136 human leucocyte antigen (HLA)-A, B, DRB1-matched adult BMT recipients were reviewed. Fifty-four per cent of patients had chronic myelogenous leukaemia (CML) and 36% had acute leukaemia or myelodysplasia. Graft-versus-host disease (GvHD) prophylaxis was either cyclosporin A (CSA)/methotrexate (64%) or T-cell depletion and CSA/corticosteroids (34%). The probability of donor engraftment by d 45 was 97% (95% CI: 94–100). Incidence of grades III–IV acute GvHD was 18% (95% CI: 12–24) at 100 d, and chronic GvHD was 42% (95% CI: 32–52) at 2 years. At 2 years, 14% (95% CI: 8–20) had relapsed. Multiple regression analysis showed that adverse risk factors for survival were non-CML diagnosis, age > 35 years, diagnosis to transplant time of > 18 months [chronic-phase CML (CML-CP) only]; and grades III–IV acute GvHD. Patients ≤ 35 years with early CML-CP had a 2 year survival of 77% (95% CI: 54–100), which compared with a survival in advanced CML patients ≤35 years of 67% (95% CI: 37–97) and 37% (95% CI: 20–54) in non-CML patients. Two year survival for patients > 35 years with early CML-CP was 55% (95% CI: 33–77), 40% (95% CI: 19–61) in advanced CML and 14% (95% CI:1–27) in non-CML. Future efforts should focus on improving the outcome for older BMT recipients, especially those with diagnoses other than CML. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions The prevalence of suboptimal self‐rated health (SRH) and its association with subsequent all‐cause and cause‐specific mortality after blood or marrow transplantation (BMT) were examined.Study participants were drawn from the multicenter Blood or Marrow Transplant Survivor Study, and included patients who were transplanted between 1974 and 2014 and had survived ≥2 years after BMT. Participants (aged ≥18 years) completed a survey at a median of 9 years from BMT, and were followed for a median of 5.6 years after survey completion. Survivors provided information on sociodemographic factors, chronic health conditions, health behaviors, and SRH (a single‐item measure rated as excellent, very good, good, fair, or poor; excellent, very good, and good SRH were classified as good SRH, and fair and poor were classified as suboptimal SRH). The National Death Index Plus and Accurint databases and medical records provided vital status through December 2021.Of 3739 participants, 784 died after survey completion (21%). Overall, 879 BMT survivors (23.5%) reported suboptimal SRH. Pain, low socioeconomic status, psychological distress, lack of exercise, severe/life‐threatening chronic health conditions, post‐BMT relapse, obesity, smoking, and male sex were associated with suboptimal SRH. BMT survivors who reported suboptimal SRH had a 1.9‐fold increased risk of all‐cause mortality (95% confidence interval [CI], 1.6–2.3), 1.8‐fold increased risk of recurrence‐related mortality (95% CI, 1.4–2.5), and 1.9‐fold increased risk of non–recurrence‐related mortality (95% CI, 1.4–2.4) compared to those who reported good SRH.This single‐item measure could help identify vulnerable subpopulations who could benefit from interventions to mitigate the risk for subsequent mortality. [ABSTRACT FROM AUTHOR]