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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]

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]

Gut dysbiosis has been associated with worse allogeneic hematopoietic cell transplantation (allo-HCT) outcomes. We reported an association between intrinsically vancomycin-resistant enterococci (iVRE: E. gallinarum and E. casseliflavus) gut colonization and lower post-transplant mortality. In this study, using an expanded cohort, we evaluated whether our previously observed association is species-specific. We included allo-HCT recipients with ≥1 positive rectal swab or stool culture for iVRE between days -14 and +14 of transplant. To investigate whether iVRE modulate the gut microbiota, we performed agar diffusion assays. To investigate whether iVRE differ in their ability to activate the aryl hydrocarbon receptor, we analyzed iVRE genomes for enzymes in the shikimate and tryptophan pathways. Sixty six (23 E. casseliflavus and 43 E. gallinarum) of the 908 allograft recipients (2011–2017) met our inclusion criteria. Overall survival was significantly higher in patients with E. casseliflavus (91% vs. 62% at 3 years, P = 0.04). In multivariable analysis, E. casseliflavus gut colonization was significantly associated with reduced all-cause mortality (hazard ratio 0.20, 95% confidence interval 0.04–0.91, P = 0.04). While agar assays were largely unremarkable, genome mining predicted that E. casseliflavus encodes a larger number of enzymes in the tryptophan metabolism pathway. In conclusion, E. casseliflavus gut colonization is associated with reduced post-HCT morality. Further research is needed to understand the mechanisms for this association. [ABSTRACT FROM AUTHOR]

• Allogeneic hematopoietic cell transplantation (alloHCT) is the sole curative therapy for chronic lymphocytic leukemia (CLL). • Allogeneic donor killer immunoglobulin-like receptor (KIR) genotype does not impact CLL patient outcomes. • KIR genotype should not be used as donor selection criteria in alloHCT for CLL. Allogeneic hematopoietic cell transplantation (alloHCT) remains the sole curative therapy for patients with chronic lymphocytic leukemia (CLL), leading to 40% to 45% long-term survival. The impact of donor killer immunoglobulin-like receptor (KIR) genotype on outcomes of unrelated donor (URD) alloHCT for CLL is unknown. We examined 573 adult URD CLL recipient pairs. KIR genotype (presence/absence) was determined for each donor, and comprehensive modeling of interactions with recipient HLA class I loci (KIR ligands) was used to evaluate their effect on relapse and survival. Recipients had a median age of 56 years, and most were not in remission (65%). Both 8/8 HLA-matched (81%) or 7/8 HLA matched grafts (19%) were studied. Factors associated with improved overall survival (OS) were reduced-intensity conditioning (hazard ratio [HR] of death,.76) and good performance status (HR,.46), whereas alloHCT in nonremission (HR, 1.96) and mismatched donors (HR, 2.01) increased mortality. No models demonstrated a relationship between donor KIR genotype and transplant outcomes. Cox regression models comparing donors with A/A versus B/x KIR haplotypes and those with KIR gene content scores of 0 versus 1 versus ≥2 yielded similar rates of nonrelapse mortality, relapse, acute graft-versus-host disease (GVHD), and chronic GVHD and the same progression-free survival and OS. Relapse risk was not different for grafts from donors with KIR3DL1 transplanted into HLA C1/1 versus C2 recipients. This large analysis failed to demonstrate an association between URD KIR genotype and transplant outcome for patients with CLL, and thus KIR genotyping should not be used as a donor selection criterion in this setting. [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]

Infection is one of the most common complications after hematopoietic cell transplantation. Many patients experience infectious complications repeatedly after transplant. Existing statistical methods for recurrent gap time data typically assume that patients are enrolled due to the occurrence of an event of interest, and subsequently experience recurrent events of the same type; moreover, for one-sample estimation, the gap times between consecutive events are usually assumed to be identically distributed. Applying these methods to analyze the post-transplant infection data will inevitably lead to incorrect inferential results because the time from transplant to the first infection has a different biological meaning than the gap times between consecutive recurrent infections. Some unbiased yet inefficient methods include univariate survival analysis methods based on data from the first infection or bivariate serial event data methods based on the first and second infections. In this article, we propose a nonparametric estimator of the joint distribution of time from transplant to the first infection and the gap times between consecutive infections. The proposed estimator takes into account the potentially different distributions of the two types of gap times and better uses the recurrent infection data. Asymptotic properties of the proposed estimators are established. [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]

Killer cell Ig-like receptors (KIRs) interact with HLA class I ligands to regulate NK cell development and function. These interactions affect the outcome of unrelated donor hematopoietic cell transplantation (HCT).We have shown previously that donors with KIR B versus KIR A haplotypes improve the clinical outcome for patients with acute myelogenous leukemia by reducing the incidence of leukemic relapse and improving leukemia-free survival (LFS). Both centromeric and telomeric KIR B genes contribute to the effect, but the centromeric genes are dominant. They include the genes encoding inhibitory KIRs that are specific for the C1 and C2 epitopes of HLA-C. We used an expanded cohort of 1532 T cell-replete transplants to examine the interaction between donor KIR B genes and recipient class I HLA KIR ligands. The relapse protection associated with donor KIR B is enhanced in recipients who have one or two C1-bearing HLA-C allotypes, compared with C2 homozygous recipients, with no effect due to donor HLA. The protective interaction between donors with two or more, versus none or one, KIR B motifs and recipient C1 was specific to transplants with class I mismatch at HLA-C (RR of leukemia-free survival, 0.57 [0.40-0.79]; p = 0.001) irrespective of the KIR ligand mismatch status of the transplant. The survival advantage and relapse protection in C1/x recipients compared with C2/C2 recipients was similar irrespective of the particular donor KIR B genes. Understanding the interactions between donor KIR and recipient HLA class I can be used to inform donor selection to improve outcome of unrelated donor hematopoietic cell transplantation for acute myelogenous leukemia. [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.

In this issue of Blood, Pulsipher et al identify key differences in adverse events related to donation for hematopoietic cell transplantation (HCT) from a prospective cohort of nearly 9500 unrelated allogeneic donors recruited through the National Marrow Donor Program. Although the rates of life-threatening complications were very low overall (<0.3%) for donors of both peripheral blood and bone marrow, those donating bone marrow had a 4-fold increased risk of experiencing a serious adverse event. Most adverse events were acute in nature, resolving within a matter of days to weeks, and importantly, no deaths as a result of donation procedures occurred. This prospective study, with more than 20 000 donor-years of follow-up after granulocyte colony-stimulating factor administration, also showed no increased risk for hematologic or other cancers, autoimmune diseases, or thrombosis associated with growth factor mobilization. In fact, donors in this cohort had a significantly lower incidence of cancer compared with the general population, regardless of granulocyte colony-stimulating factor exposure. [ABSTRACT FROM AUTHOR]

• The rate of potentially inappropriate medication (PIM) use was similar in older and younger recipients of allogeneic hematopoietic cell transplantation (HCT). • Females, high-risk Hematopoietic Cell Transplantation Comorbidity Index, and umbilical cord blood recipients had higher use of PIMs. • In recipients age ≥65 years, PIM use was associated with higher toxicity and mortality. The use of potentially inappropriate medications (PIMs) using Beers criteria and its impact on older allogeneic hematopoietic cell transplantation (HCT) recipients is not known. Here the use of any PIMs and their therapeutic classes in reduced-intensity conditioning allogeneic HCT recipients were compared between older (≥65 years; n = 114) and younger (40 to 64 years; n = 240) patients during their initial HCT admission, defined as the number of days that a patient received 1 or more PIMs between day -14 and day +28. Poisson regression was used to determine rate ratios (RRs) in the 2 groups. In the ≥65 years group, we evaluated the impact of PIMs on Common Terminology Criteria for Adverse Events (CTCAE) grade 3-4 toxicities within 100 days and on overall mortality within 1 year post-HCT. The rate of any PIM use was similar in the older and younger groups (RR,.98; 95% confidence interval [CI],.90 to 1.06; P =.65). In terms of PIM classes, the older group had a 48% higher rate of gastrointestinal (GI) medication use (RR, 1.48; 95% CI, 1.32 to 1.65; P <.01) and a 25% higher rate of genitourinary (GU) medication use (RR, 1.25; 95% CI, 1.02 to 1.53; P =.03). Compared with males, females had a 19% higher rate of central nervous system (CNS) medication use (RR, 1.19; 95% CI, 1.03 to 1.37; P =.02) and a 30% higher rate of benzodiazepine use (RR, 1.30; 95% CI. 1.09 to 1.54; P <.01). A high-risk HCT-CI was associated with a higher rate of use of any PIMs (RR, 1.13; 95% CI, 1.01 to 1.26; P =.02), CNS medications (RR, 1.26; 95% CI, 1.04 to 1.53; P =.02) and GU medications (RR, 1.46; 95% CI, 1.09 to 1.94; P =.01). Compared with matched sibling donor HCT recipients, umbilical cord blood transplantation recipients had higher rates of GI medication use (RR, 1.32; 95% CI, 1.14 to 1.53; P <.01) and anticholinergic medication use (RR, 1.30; 95% CI, 1.06 to 1.61; P =.01). In the ≥65 years group, increasing duration of narcotic use was associated with a 1.3-fold (95% CI, 1.0 to 1.7; P =.05) higher risk of overall mortality and a 1.6-fold (95% CI, 1.02 to 2.69) greater odds of CTCAE grade 3-4 toxicities (P =.04). Our data show that older recipients (≥65 years) were as likely as their younger counterparts to receive PIMs. Among older recipients, the use of PIMs, particularly narcotics, was associated with higher mortality and higher incidence of grade 3-4 toxicities. Identifying and reducing the use of PIMs in older HCT recipients may help decrease the burden of adverse events and associated health care costs. [ABSTRACT FROM AUTHOR]

• BMT CTN 1703 compares graft-versus-host disease prophylaxis regimens in reduced-intensity allogeneic hematopoietic cell transplantation. • We highlight this study's importance and explore the possible implications on clinical practice. Effective immunosuppressive regimens to prevent the development of graft-versus-host disease (GVHD) are essential to the success of allogeneic hematopoietic cell transplantation (HCT). After revolutionizing haploidentical transplantation, post-transplantation cyclophosphamide (PTCy) is now being evaluated for HCT performed from related and unrelated donors. In this setting, 2 recent randomized studies have demonstrated lower rates of GVHD and superior GVHD-free, relapse-free survival with PTCy compared with conventional GVHD prophylaxis. The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) is currently conducting a large, randomized phase III, multicenter trial (BMT CTN 1703) comparing PTCy/tacrolimus/mycophenolate mofetil to tacrolimus/methotrexate as GVHD prophylaxis regimens in reduced-intensity allogeneic HCT. Here we review the ongoing study, highlight its importance to the field, and explore the possible implications of its results on clinical practice. [ABSTRACT FROM AUTHOR]

• We summarize hematopoietic cell transplantation activity in the United States in 2018. • Key findings include fewer autologous transplantations performed for non-Hodgkin lymphoma and increasing numbers of haploidentical transplantations. • There is a continuing increase in transplantation activity in adults age >70 years. Hematopoietic cell transplantation (HCT) is a well-established treatment to control and/or cure many malignant and nonmalignant diseases involving the hematopoietic system and some solid tumors. We report information about HCT procedures performed in the United States in 2018 and analyze trends and outcomes of HCT as reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Overall, compared with 2017, the number of allogeneic HCTs performed in the United States increased by 1%, and the number of autologous HCTs decreased by 5%. Key findings are fewer autologous HCTs performed for non-Hodgkin lymphoma and increasing numbers of haploidentical HCTs, nearly all of which use post-transplantation cyclophosphamide for graft-versus-host disease prophylaxis. There is a continuing increase in HCT in adults age >70 years, particularly for acute myelogenous leukemia and myelodysplastic syndromes. Survival rates by disease, disease stage, donor type, and age are presented. This report, prepared annually by the CIBMTR, provides a snapshot of current transplant activity in the United States. [ABSTRACT FROM AUTHOR]

With the COVID-19 pandemic and the ensuing barriers to the collection and transport of donor cells, it is often necessary to collect and cryopreserve grafts before initiation of transplantation conditioning. The effect on transplantation outcomes in nonmalignant disease is unknown. This analysis examined the effect of cryopreservation of related and unrelated donor grafts for transplantation for severe aplastic anemia in the United States during 2013 to 2019. Included are 52 recipients of cryopreserved grafts who were matched for age, donor type, and graft type to 194 recipients who received noncryopreserved grafts. Marginal Cox regression models were built to study the effect of cryopreservation and other risk factors associated with outcomes. We recorded higher 1-year rates of graft failure (hazard ratio [HR], 2.26; 95% confidence interval, 1.17 to 4.35; P =.01) and of 1-year overall mortality (HR, 3.13; 95% CI, 1.60 to 6.11; P =.0008) after transplantation of cryopreserved compared with noncryopreserved grafts, with adjustment for sex, performance score, comorbidity, cytomegalovirus serostatus, and ABO blood group match. The incidence of acute and chronic graft-versus-host disease did not differ between the 2 groups. Adjusted probabilities of 1-year survival were 73% (95% CI, 60% to 84%) in the cryopreserved graft group and 91% (95% CI, 86% to 94%) in the noncryopreserved graft group. These data support the use of noncryopreserved grafts whenever possible in patients with severe aplastic anemia. [ABSTRACT FROM AUTHOR]

• The evidence for MAC versus RIC in allografted patients with MDS is poor. • We found no significant differences between RIC and MAC in pooled analysis. In a systematic review and meta-analysis, we compared allogeneic transplant outcomes after myeloablative conditioning (MAC) versus reduced-intensity conditioning (RIC) in patients with myelodysplastic syndromes. Only 2 published randomized clinical trials were found, with a pooled sample size of 183 (RIC, 92; MAC, 91). Both studies suggested an overall survival advantage after RIC, with a pooled hazard ratio (HR) of.67 (95% confidence interval [CI],.41 to 1.09) for RIC versus MAC. Relapse results were also concordant, with a pooled HR of 1.55 (95% CI,.74 to 3.25) for RIC versus MAC. Neither result was statistically significant. Comparisons for other outcomes were unremarkable. In conclusion, the evidence for the optimal conditioning intensity in myelodysplastic syndromes is weak. Post-transplant maintenance strategies and incorporation of genomic information into decision-making may improve post-transplant outcomes. [ABSTRACT FROM AUTHOR]

• Prophylactic levofloxacin (LEVO) during intensive therapy did not reduce gut microbiota diversity. • LEVO exposure was associated with a relative reduction of Parabacteroides. • LEVO exposure was associated with a relative expansion of Blautia. Antibiotic-induced gut dysbiosis has been associated with poor outcomes after intensive therapy. We evaluated the effect of levofloxacin (LEVO), the most commonly used prophylactic antibacterial antibiotic during intensive chemotherapy and allogeneic hematopoietic cell transplantation (allo-HCT), on the gut microbiota in 2 cohorts of patients, 1 cohort comprising 20 patients with acute leukemia receiving intensive chemotherapy and the other cohort comprising 20 allo-HCT recipients. 16S rRNA gene sequencing of thrice-weekly collected stool samples permitted a comparison between intervals with no antibacterial antibiotic exposure and those with only LEVO exposure. In mixed-effects modeling, the only variables influenced by LEVO were the relative abundances of Parabacteroides (regression coefficient, -.063; 99% confidence interval [CI], -.102 to -.024) and Blautia (regression coefficient,.050; 99% CI,.004 to.095). Other taxa and microbiota diversity were unaffected. Overall, the effect of LEVO on the gut microbiota in these cohorts was mild. [ABSTRACT FROM AUTHOR]

Damage-associated angiogenic factors (AFs), including follistatin (FS) and soluble endoglin (sEng), are elevated in circulation at the onset of acute graft-versus-host disease (GVHD). We hypothesized that regimen-related tissue injury also might be associated with aberrant AF levels and sought to determine the relevance of these AF on nonrelapse mortality (NRM) in patients with acute GVHD and those without acute GVHD. To test our hypothesis, we analyzed circulating levels of FS, sEng, angiopoietin-2 (Ang2), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF) A and B, placental growth factor (PlGF), and soluble VEGF receptor (sVEGFR)-1 and -2, in plasma samples from patients enrolled on Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0402 (n = 221), which tested GVHD prophylaxis after myeloablative hematopoietic stem cell transplantation (HCT). We found that the interaction between FS and sEng had an additive effect in their association with 1-year NRM. In multivariate analysis, patients with the highest levels of day +28 FS and sEng had a 14.9-fold greater hazard ratio (HR) of NRM (95% confidence interval, 3.2 to 69.4; P <.01) when compared with low levels of FS and sEng. We validated these findings using an external cohort of patients (n = 106). Pre-HCT measurements of FS and sEng were not associated with NRM, suggesting that elevations in these factors early post-HCT may be consequences of early regimen-related toxicity. Determining the mechanisms responsible for patient-specific vulnerability to treatment toxicities and endothelial damage associated with specific AF elevation may guide interventions to reduce NRM post-HCT. [ABSTRACT FROM AUTHOR]

• Routine PET imaging at day +100 post autologous HCT detects asymptomatic relapse in about 30% of patients with DLBCL and portents worse survival. • High SUV max at day+100 PET is associated with survival of less than 1 year post -transplant • Identifying this high-risk cohort in autologous HCT recipients highlights the opportunity to develop preemptive interventions to improve survival in DLBCL. The utility of surveillance imaging after autologous hematopoietic cell transplantation (AHCT) in relapsed/refractory diffuse large B cell lymphoma (DLBCL) remains unclear. The purpose of this study was to determine whether surveillance imaging predicts survival after AHCT. At the University of Minnesota, serial imaging for early relapse detection has been used prospectively for all consecutive AHCT recipients treated since 2010. The present analysis included 91 AHCT recipients with DLBCL who underwent 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) scan at day +100 post-AHCT. 18F-FDG-PET parameters included the Deauville (D) 5-point scale, peak standardized uptake values (SUV max), total legion glycolysis (TLG), and total metabolic tumor volume (TMTV). Survival of patients with clinically symptomatic versus asymptomatic radiographically detected relapsed DLBCL after AHCT was compared. Sixty patients experienced relapse; 35% was detected on day +100 surveillance PET scan. 5-year overall survival (OS) by 18F-FDG-PET scan at day +100 post-AHCT was significantly lower in D4 and D5 patients (37%; 95% confidence interval [CI], 14% to 100% versus 25%; 95% CI, 43% to 89%) compared with patients with D1 and D2 (62%; 95% CI, 43% to 89% versus 62%; 95% CI, 46% to 84%). TLG and TMTV were not prognostic. SUV max at day +100 varied from 1.5 (D1) to 17.9 (D5). In multivariate analysis, only SUV max was predictive of relapse and OS; mortality increased 1.8-fold with each SUV max doubling (hazard ratio [HR], 1.8; 95% CI, 1.3 to 2.3; P <.01). At a median follow-up of 3.3 years (range, 1 to 12 years), lymphoma-related mortality was 1.8-fold higher among patients whose relapse was detected clinically (symptomatic) versus radiographically on surveillance scan (HR, 1.8; 95% CI,.9 to 3.4; P =.08). In patients with relapsed/refractory DLBCL, a routine PET imaging at day +100 post-AHCT detects asymptomatic relapse and high SUV max identifies patients with poor expected survival of less than 1 year. Identifying this high-risk cohort can potentially highlight patients who might benefit from preemptive interventions to prevent or delay relapse. [ABSTRACT FROM AUTHOR]

Image, graphical abstract Graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) represents complete, ideal recovery after allogeneic hematopoietic cell transplantation (HCT). However, as originally proposed, this composite endpoint does not account for the possibility that HCT complications may improve after treatment. To more accurately estimate survival with response to GVHD and relapse after HCT, we developed a dynamic multistate GRFS (dGRFS) model with outcomes data from 949 patients undergoing their first allogeneic HCT for hematologic malignancy at the University of Minnesota. Because some patients were successfully treated for GVHD and relapse, dGRFS was higher than the originally defined time-to-event GRFS at 1 year (37.0 versus 27.6%) through 4 years (37.4% versus 22.2%). Mean survival without failure events was.52 years (95% confidence interval,.45 to.58 year) greater in dGRFS compared with the originally defined GRFS. Patient age (P <.001), disease risk (P <.001), conditioning intensity (P =.007), and donor type (P =.003) all significantly influenced dGRFS. The multistate model of dGRFS closely estimates the continuing and prevalent severe morbidity and mortality of allogeneic HCT. To serve the greater HCT community in more accurately modeling recovery from transplantation, we provide our R code for determination of dGRFS with annotations in Supplementary Materials. • Because some patients were successfully treated for graft-versus-host disease (GVHD) and relapse, dynamic GVHD-free, relapse-free survival (dGRFS) was approximately 10% higher than the originally defined time-to-event GRFS at 1 year (37.0% versus 27.6%). • Patient age (P <.001), disease risk (P <.001), conditioning intensity (P =.007), and donor type (P =.003) all significantly influenced dGRFS. • To serve the hematopoietic stem cell transplantation community in more accurately modeling recovery from transplantation, we provide our R code for determination of dGRFS with annotations in Supplementary Materials. [ABSTRACT FROM AUTHOR]

• Robust monocyte subpopulation recovery was seen in UCB recipients at days 60 and 100. • OS and DFS were superior when AMC and classic monocyte recovery were above optimal cutpoints. • Relapse was reduced when AMC and classic monocyte counts were above optimal cutpoints. • TRM was reduced when classic monocyte counts exceeded optimal cutpoint. Monocyte recovery after hematopoietic cell transplantation (HCT) has been correlated with overall survival (OS). However, monocytes are heterogeneous and consist of classic (CD14++CD16-), intermediate (CD14+CD16+), and nonclassic (CD14+CD16++) subpopulations, with unique functional properties. We hypothesized that monocyte subpopulation reconstitution would vary based on allogeneic stem cell source and would be associated with outcomes. We studied monocyte subpopulation recovery at days 28, 60, 100, 180, and 365 post-HCT among 202 patients with hematologic malignancy. Significant differences in absolute monocyte count (AMC) and monocyte subpopulation counts at days 60 and 100 were identified based on stem cell source (all P <.01), with more robust recovery in umbilical cord blood (UCB) recipients. Using 2-fold cross-validation, optimal cutpoints were calculated for day 28 AMC and monocyte subpopulations based on OS. These were used to calculate hazard ratios for OS, disease-free survival (DFS), relapse, transplant-related mortality (TRM), and acute and chronic graft-versus-host disease. OS and DFS were superior when AMC and classic monocyte recovery were above optimal cutpoints (all P <.03). Relapse was reduced for those with AMC (P <.01) and classic (P =.05) monocyte counts above optimal cutpoints. TRM was also reduced when classic (P =.02) monocyte count exceeded optimal cutpoints. Intermediate and nonclassic monocyte recovery were not associated with outcomes. In summary, hematopoietic cell source is associated with monocyte subpopulation recovery, with the early robust recovery in UCB recipients. Recovery of AMC and classic monocytes were prognostic for survival, relapse, and TRM. These indicators may identify patients at increased risk for post-HCT failure and guide therapeutic interventions. [ABSTRACT FROM AUTHOR]

The treatment of elderly patients with advanced hematological malignancies has expanded to include reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (alloHCT) as a potentially curative option. We studied the association between Disease Risk Index (DRI) and clinical outcomes of 196 elderly patients (median age, 64.8; range, 60 to 75 years) with hematological malignancies receiving RIC alloHCT (2000 to 2014). Donors were related and unrelated adults (n = 100, 51.1%) or umbilical cord blood (n = 96, 48.9%). DRI classified 12 patients (6.1%) as low risk (LR), 146 patients (74.5%) as intermediate risk (IR), and 38 patients (19.4%) as high risk (HR). Two-year overall survival (OS) was 47% (52% for LR/IR versus 29% for HR, P  < .01) and 2-year disease-free survival was 39% (44% for LR/IR versus 21% for HR, P  < .01). Relapse incidence was 30% (26% for LR/IR versus 44% for HR, P  < .01). Treatment-related mortality was 29% at 2 years; this was similar for all DRI groups. In multiple regression analysis, HR DRI was associated with increased risk of relapse (hazard ratio, 2.07; 95% confidence interval [CI], 1.34 to 3.33; P  = .02) and treatment failure (hazard ratio, 2.07; 95% CI, 1.35 to 3.18; P  < .01) and decreased OS (hazard ratio, 2.11; 95% CI, 1.34 to 3.33; P  < .01). In elderly patients, DRI is a significant prognostic factor for post-transplantation relapse, treatment failure, and mortality. Because of increased risk of relapse leading to poor survival in HR DRI, participation in clinical trials offering relapse prevention strategies after RIC alloHCT should be encouraged when available. [ABSTRACT FROM AUTHOR]

Risk factors for acute GVHD (AGVHD), overall survival, and transplant-related mortality were evaluated in adults receiving allogeneic hematopoietic cell transplants (1999-2005) from HLA-identical sibling donors (SDs; n = 3191) or unrelated donors (URDs; n = 2370) and reported to the Center for International Blood and Marrow Transplant Research, Minneapolis, MN. To understand the impact of transplant regimen on AGVHD risk, 6 treatment categories were evaluated: (1) myeloablative conditioning (MA) with total body irradiation (TBI) + PBSCs, (2) MA + TBI + BM, (3) MA + nonTBI + PBSCs, (4) MA + nonTBI + BM, (5) reduced intensity conditioning (RIC) + PBSCs, and (6) RIC + BM. The cumulative incidences of grades B-D AGVHD were 39% (95% confidence interval [CI], 37%-41%) in the SD cohort and 59% (95% CI, 57%-61%) in the URD cohort. Patients receiving SD transplants with MA + nonTBI + BM and RIC + PBSCs had significantly lower risks of grades B-D AGVHD than patients in other treatment categories. Those receiving URD transplants with MA + TBI + BM, MA + nonTBI + BM, RIC + BM, or RIC + PBSCs had lower risks of grades B-D AGVHD than those in other treatment categories. The 5-year probabilities of survival were 46% (95% CI, 44%-49%) with SD transplants and 33% (95% CI, 31%-35%) with URD transplants. Conditioning intensity, TBI and graft source have a combined effect on risk of AGVHD that must be considered in deciding on a treatment strategy for individual patients. [ABSTRACT FROM AUTHOR]

Little information exists regarding long-term psychological health of hematopoietic cell transplantation (HCT) survivors. Using resources offered by the Bone Marrow Transplant Survivor Study (BMTSS), we evaluated adverse psychological outcomes in 1065 long-term HCT survivors and a healthy comparison group composed of siblings. Psychological health status was evaluated using the Brief Symptom Inventory-18. Twenty-two percent of the HCT survivors reported adverse psychological outcomes, compared with 8% of the siblings. Exposure to prednisone was associated with psychological distress across all domains (anxiety, depression, and somatic distress). Fifteen percent of the HCT survivors reported somatic distress, representing an almost 3-fold higher risk comparing to siblings. Among survivors, in addition to low annual household income and self-reported poor health, having severe/life-threatening conditions and presence of active chronic GVHD were associated with a 2-fold increased risk for somatic distress. Seven percent of the HCT survivors expressed suicidal ideation; patients with higher scores on depression subscale were most vulnerable. This study demonstrates that somatic distress is the biggest challenge faced by survivors long after HCT. These results identify vulnerable subpopulations and provide patients, families, and healthcare providers with necessary information to plan for post-HCT needs many years after HCT. [ABSTRACT FROM AUTHOR]

Natural killer (NK) cells mediate GVL effects after allogeneic hematopoietic cell transplantation (allo-HCT) by the production of inflammatory cytokines and by direct target lysis. The acquisition of both functions was presumed to be developmentally linked, but this linkage remained unstudied after allo-HCT. We tested the cytokine production and degranulation of reconstituting NK cells after adult unrelated donor or umbilical cord blood grafting. Recipients of T cell-depleted transplants, receiving no immune suppression, showed diminished NK cell degranulation. In contrast, degranulation was normal or increased after T-cell replete transplants given with immune suppression. Strikingly, target cell-induced IFNγ production was markedly diminished in all transplant settings, especially with T cell-depleted or naive T cell-containing umbilical cord blood grafts, suggesting a role for T cells in NK education. Although degranulation was similar in the KIR+ and KIR- populations that coexpressed NKG2A, target cell-induced IFNγ production was limited to the subset of NK cells expressing KIR inhibited by self-ligands. Thus, cytokine production and cytotoxic function do not consistently coexist in NK cells reconstituting after allo-HCT. Exposure to IL-15 rapidly increased target-inducible IFNγ production, indicative of IL-15's potential as a therapeutic tool to enhance NK cell function to protect against infection and relapse after allo-HCT. [ABSTRACT FROM AUTHOR]

Abstract: The hematopoietic cell transplantation specific comorbidity index (HCT-CI) has been recently proposed to predict the probability of nonrelapse mortality (NRM) and overall survival (OS) in allogeneic HCT recipients while taking into account any pretransplant comorbidity. We tested the validity of the HCT-CI in a cohort of 373 adult HCT recipients (184 matched-related donor and 189 unrelated umbilical cord blood) who received a myeloablative (N = 150) or nonmyeloablative (N = 223) conditioning regimen. HCT-CI scores of 0, 1, 2, and ≥3 were present in 58 (16%), 56 (15%), 64 (17%), and 195 (52%) patients, respectively. Pulmonary conditions were the most common comorbidity. Cumulative incidence of NRM at 2 years was 10%, 20%, 24%, and 28% for HCT-CI scores of 0, 1, 2, and ≥3, respectively (P = .01). The corresponding probability of OS at 2 years was 72%, 67%, 51%, and 48%, respectively (P < .01). On multivariate analyses adjusted for recipient age, disease risk, donor source, and conditioning regimen intensity, the relative risks for NRM for HCT-CI scores of 1, 2, and ≥3 (compared to a score of 0) were 2.0 (95% confidence intervals, 0.8–5.3), 2.6 (1.0–6.7), and 3.2 (1.4-7.4), respectively. The risks for overall mortality were 1.2 (0.6-2.1), 2.0 (1.1-3.4), and 2.1 (1.3-3.3), respectively. In subgroup analyses, the HCT-CI score did not consistently predict NRM and OS among different donor sources and conditioning regimens. The HCT-CI, although a useful tool for capturing pretransplant comorbidity and risk-assessment, needs to be further validated prior to adopting it for routine clinical use. [Copyright &y& Elsevier]

Abstract: Chronic kidney disease (CKD) in recipients of myeloablative (MA) allogeneic hematopoietic cell transplantation (HCT) has been well characterized. However, the risk of CKD after HCT using reduced-intensity conditioning (RIC) is not well known. We compared the incidence of CKD by conditioning regimen in 221 allogeneic HCT recipients (MA = 117, RIC = 104) who had survived for ≥1 year post-HCT and had no history of CKD pretransplant. CKD was defined as glomerular filtration rate (GFR) <60 mL/min/1.73 m2 for ≥3 months anytime after 180 days post-HCT. The median follow-up was 28 months (range: 12-75) for MA and 25 months (range: 12-67) for the RIC group. The 3-year cumulative incidence rate of CKD was 28% (95% confidence intervals [CI], 19%-36%) in MA and 29% (95% CI, 20%-38%) in the RIC group (P = .44). In multivariate analysis, conditioning regimen intensity had no impact on the risk of developing CKD (relative risk [RR] for MA 1.50 [95% CI, 0.78-2.89] versus the RIC regimen). Factors independently associated with an increased risk of CKD were older age at transplant, acute graft-versus-host disease, cyclosporine use for >6 months, and acute kidney injury in the early posttransplant period. CKD is frequent in long-term adult allogeneic HCT survivors, but RIC is associated with similar risks as MA conditioning. Continuous monitoring of renal function is necessary in allogeneic HCT survivors, and studies exploring prevention strategies are needed. [Copyright &y& Elsevier]

Abstract: Cytomegalovirus (CMV) infection is an important complication following allogeneic hematopoietic stem cell transplant (HSCT), but the natural history in the cord blood setting has not been well studied. We assessed CMV infection episodes in 753 consecutive allogeneic HSCT recipients at the University of Minnesota between January 1, 1998 and December 31, 2003. The 6-month cumulative incidence of viremia/antigenemia was 22% by day +182: 21% (95% confidence interval 16%-26%) in cord blood recipients (UCB), 24% (20%-28%) in marrow (BM), and 22% (16%-28%) using peripheral blood grafts (PBSC). CMV disease incidence was 6% (2%-10%) in UCB, 8% (5%-11%) in BM, and 9% (6%-12%) in PBSC. In multivariate analysis, CMV infection (viremia/antigenemia and disease) was significantly more likely in patients who were seropositive to CMV, in those with acute graft versus host disease, and in those receiving T cell-depleted grafts. Graft source did not independently contribute to the risk of CMV infection and did not impact survival after CMV infection. These data confirm that recipient CMV serostatus remains the dominant risk factor for CMV infection. Recipients of UCB have similar risks of CMV infection, responses to antiviral therapy, and survival following CMV infection as recipients of either marrow or PBSC. [Copyright &y& Elsevier]

Abstract: To investigate the impact of exercise on adult allogeneic hematopoietic cell transplant recipients, we randomized 100 patients to either a structured walking regimen or to a control group with no formal exercise program. Starting on the day of admission for transplant, patients in the exercise arm were asked to walk on a treadmill twice a day for 15 minutes while in the hospital. After discharge, they were asked to walk once a day for 30 minutes. The effect of the exercise program was primarily measured by the change in the Karnofsky score (KPS) from transplant admission to day 100 posttransplant, which was scored by the attending physician who was blinded to the assigned exercise regimen. The decline in KPS was smaller in the exercise group than in the control group: 10 points versus 20 points. This difference was not statistically significant in the total study population (P = .21) but was statistically significant among the subset of older and less fit patients receiving nonmyeloablative pretransplant conditioning (P = .04). Sixty-four percent of patients on the exercise arm who had a baseline KPS <90 had a score ≥90 by day 100 compared to 18% of the control arm (P = .03). Thirty-two percent of patients with a baseline score ≥90 had a score ≥90 by day 100 in both groups (P = .99). Analyses of patients’ self reported scores at the time of discharge for physical and emotional well-being showed that the exercise arm had better scores for physical well-being (P < .01). Among the subset of nonmyeloablative patients, scores for physical and emotional well-being were both higher in the exercise arm (P = .02). Length of hospitalization and survival were not different between the 2 study arms. We conclude that assignment of a structured walking regimen to patients can lead to better physical performance during the recovery period and by patient assessment, a better perceived physical and emotional state. In addition, exercise has a greater impact among patients who are less fit coming into transplant. Structured exercise may have a positive impact on physical and emotional recovery following transplant therapy and may accelerate patients’ return to health and function. [Copyright &y& Elsevier]