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Objective/background: Cytomegalovirus (CMV) infection and disease are common infectious complications after allogeneic hematopoietic cell transplantation (alloHCT). Major histocompatibility complex (MHC) class I chain-related gene A (MICA) is a ligand of the natural killer (NKG2D) receptor on immune effector cells that helps mediate NK cell alloreactivity. We hypothesized that MICA polymorphisms may influence CMV infection and disease incidence after alloHCT., Methods: We conducted a retrospective analysis of 423 adults at the Cleveland Clinic with hematologic malignancies treated with a matched related or unrelated donor alloHCT. CMV cases analyzed included a compositive of instances of viral copy replication above detection limits as well as any biopsy-proven tissue invasive disease episodes. Genotypes at the MICA-129 position have been categorized as weak (valine/valine; V/V), intermediate (methionine/valine; M/V), or strong (methionine/methionine; M/M) receptor affinity., Results: In multivariable analysis, V/V donor MICA-129 genotype was associated with CMV infection and disease (hazard ratio [HR] = 1.40; 95% confidence interval [CI], 1.00-1.96; p = .05), but not MICA mismatch (HR = 1.38; 95% CI, 0.83-2.29; p = .22). There was no association of acute or chronic GVHD with MICA donor-recipient mismatch (HR = 1.05; 95% 95% CI, 0.66-1.68; p = .83 and HR = 0.94; 95% CI, 0.51-1.76; p = .85, respectively) or V/V donor MICA-129 genotypes (HR = 1.02; 95% CI, 0.79-1.31; p = .89 and HR = 0.89; 95% CI, 0.65-1.22; p = .47, respectively)., Conclusion: These findings suggest that the donor MICA-129 V/V genotype with weak NKG2D receptor binding affinity is associated with an increased risk of CMV infection and disease after alloHCT., Competing Interests: Declaration of Competing Interest There are no conflicts of interest to report., (Copyright © 2019 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. All rights reserved.)

Optimal administration of busulfan (Bu) is hampered by variable and unpredictable drug metabolism in individual patients. At our institution, Bu was previously administered with fixed weight-based dosing (WBD) in combination with cyclophosphamide (Cy) and etoposide (E) for patients with non-Hodgkin lymphoma (NHL) undergoing autologous stem cell transplantation (ASCT). In 2014, we adopted real-time pharmacokinetic (PK)-guided therapeutic drug monitoring (TDM) of Bu for all NHL patients undergoing Bu-containing ASCT. Here we compare outcomes of NHL patients who underwent ASCT with Bu/Cy/E using WBD and those who did so using TDM of Bu. We studied 336 consecutive adult NHL patients who underwent ASCT with Bu/Cy/E using WBD from January 2007 to December 2013 (n = 258) or TDM from May 2014 to December 2017 (n = 78), excluding patients with mantle cell lymphoma. Clinical outcomes, including relapse, nonrelapse mortality (NRM), progression-free survival (PFS), and overall survival (OS), hepatotoxicity and pulmonary toxicity were compared in the 2 groups. To adjust for differences in baseline characteristics between the groups, propensity-matched cohorts of WBD and TDM patients were also studied. After the first dose of Bu, the dose was increased in 36% of the patients and decreased in 41%. Changes in pulmonary and liver function from baseline to transplantation were not different between the 2 groups, although these changes showed significantly less variability with TDM than with WBD. Relapse was significantly lower and PFS was improved with TDM; 2-year estimates were 19% for TDM and 38% for WBD for relapse (P = .004) and 69% and 55%, respectively, for PFS (P = .038). No significant between-group differences in NRM or OS were seen. In multivariable analysis, TDM remained prognostic for lower risk of relapse (hazard ratio [HR], .52; 95% confidence interval [CI], .30 to .89; P = .018), but did not remain prognostic for PFS (HR, .74; 95% CI, .48 to 1.16; P = .19). Propensity-matched cohorts displayed similar patterns of outcomes. In subset analysis based on disease status at ASCT, TDM was associated with less relapse and better PFS than WBD for patients who underwent transplantation in less than complete remission (CR) compared with those who underwent transplantation in CR. Compared with WBD, PK-directed TDM of Bu reduces the incidence of relapse when used in combination with Cy and E for patients with NHL undergoing ASCT, particularly for patients in less than CR. These data support the continued use of personalized PK-guided dosing for all NHL patients undergoing ASCT with Bu-containing preparative regimens., (Copyright © 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Volatile organic compounds (VOCs) are generated during pathologic processes, and their assessment can be used to diagnose and monitor a variety of diseases. Given the role of the microbiome in graft-versus-host disease (GVHD), we hypothesized that microorganisms producing volatile metabolites may alter VOCs expelled in breath in patients with gastrointestinal (GI) GVHD. In this pilot study, exhaled breath samples were obtained from 19 patients with grade 2 to 4 acute GI GVHD, 10 patients with no GVHD at day 100, and 10 healthy control subjects; the samples were analyzed by using mass spectrometry. Overall, nine (47%) patients had grade 2 GVHD, eight (42%) patients had grade 3 GVHD, and two (11%) patients had grade 4 GVHD; 26% had upper GI, 21% had lower GI, and 53% had both upper and lower GI manifestations. Stepwise canonical discriminant analysis identified 5 VOCs distinguishing patients with and without GI GVHD: 2-propanol, acetaldehyde, dimethyl sulfide, isoprene, and 1-decene (Wilks' Λ, 0.43; F statistic, 6.08; P = .001). The model correctly classified 89% (17 of 19) and 90% (9 of 10) of patients with and without GI GVHD, respectively. Breath analysis is a feasible and promising noninvasive method to detect acute GI GVHD. Further study of serial breath analysis and the gut microbiome in a larger cohort are ongoing to validate these findings., (© 2019 by The American Society of Hematology.)

Donor-derived T-cells mediate graft-versus-leukemia effect, immune reconstitution, and graft-versus-host-disease (GvHD) after allogeneic hematopoietic cell transplantation (HCT). We examined the association of donor cell subsets with outcomes in recipients of myeloablative allogeneic HCT using bone marrow (BM, N = 359) grafts from 2002 to 2014 with related or unrelated donors. Analysis considered pre-infusion graft total nucleated cell (TNC), CD34+ CD3+, CD4+, CD8+ doses. Most patients received busulfan-cyclophosphamide or etoposide-total body irradiation conditioning for acute leukemia or myelodysplastic syndrome. Calcineurin inhibitor-mycophenolate mofetil (CNI-MMF) (49%) or calcineurin inhibitor-methotrexate (CNI-MTX) (47%) were used for GvHD prophylaxis. In multivariable analysis, higher CD34+ dose was associated with platelet engraftment (P < 0.001) and lymphocyte recovery (P = 0.006). There was no association of donor cell subsets with donor chimerism or overall survival. In conclusion, BM graft composition is associated with myeloablative allogeneic HCT outcomes and future studies to evaluate optimal graft composition are needed.

Although day +100 survival among allogeneic hematopoietic cell transplantation (HCT) recipients has improved over time, longer-term survival remains a challenge. The aim of this study was to identify prognostic factors for survival among patients surviving longer than 100 days using baseline characteristics and factors identified within the first 100 days after transplantation. Of 413 patients undergoing a first allogeneic HCT between 2006 and 2014, 335 survived >100 days post-transplantation. The majority underwent a myeloablative transplantation (75%) with a bone marrow (BM) (52%) graft source. One-year all-cause mortality (ACM) was 29%, with 16% relapse mortality (RM) and 12% nonrelapse mortality. In multivariable analysis, high-risk disease (hazard ratio [HR], 1.55; P = .003), non-cytomegalovirus infection (HR, 1.79; P = .003), more days hospitalized (HR, 1.16; P < .001), and relapse (HR, 4.38; P < .001) within the first 100 days were associated with increased risk of ACM. Patients with higher income (HR, .89; P = .024) and those who received BM (HR, .52; P < .001) or umbilical cord blood (HR, .40; P = .002) relative to peripheral blood stem cells had lower risk of ACM. Our study identifies risk factors for adverse long-term survival in 100-day survivors, a time point when patients frequently are discharged from transplantation centers. In addition to disease- and transplantation-related factors, low socioeconomic status was associated with worse long-term survival, highlighting the need for focused efforts to improve outcomes in vulnerable patient populations., (Copyright © 2018 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

There is a critical need for tools to comprehensively describe disparities in hematopoietic cell transplant (HCT) recipients. We conducted a retrospective cohort study to evaluate a Community Risk Score (CRS) tool for this purpose. CRS included 10 community health indicators based on county or state of residence obtained from several secondary data sources and a composite score was assigned to each county (range 0 to 40), that was further categorized into six tiers (I to VI) with higher tiers indicating poor community health. CRS was assessed for 509 allogeneic and 1033 autologous HCT recipients from 2003 to 2013. Our cohort represented allogeneic and autologous HCT recipients from 300 and 431 unique ZIP codes from 99 and 125 counties in 15 and 16 states, although 86% and 90% patients were from Ohio, respectively. A greater proportion of patients had adverse individual community risk indicators in higher-risk tiers (P < .001 for trend for all). In multivariable analysis, clear trends toward association of CRS with outcomes were not observed. For autologous HCTs, Tier III has higher risks of relapse mortality (hazard ratio [HR] 2.2, P = .02) and all-cause mortality (HR 1.8, P = 0.03). In conclusion, CRS was able to categorize patients into groups representing greater levels of health care disparities. We did not see a clear association between CRS and transplant outcomes, although our cohort was limited to a relatively small group of counties. Community-based risk score model may serve as a tool for evaluating disparities in HCT recipients, but its validation in a nationally representative cohort of patients is needed., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Young fit patients with mantle cell lymphoma (MCL) are commonly treated with induction chemotherapy followed by high-dose chemotherapy and autologous hematopoietic cell transplantation (AHCT). Induction regimens with modifications of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) and/or incorporation of high-dose cytarabine (HDAC) appear more effective than R-CHOP alone., Patients and Methods: We adopted a modification of the Nordic protocol using standard, rather than higher dose R-CHOP, alternating with HDAC (rituximab plus HDAC), for 3 cycles each or, for patients already treated with R-CHOP alone before referral for AHCT, an additional 2 cycles of rituximab plus HDAC. We herein report our experience with 28 patients treated with this regimen who proceeded to AHCT, and compare their outcomes with patients treated with either standard-dose R-CHOP (n = 38) or R-HCVAD/MA (cyclophosphamide, vincristine, doxorubicin, dexamethasone alternating with methotrexate, and cytarabine; n = 21), before AHCT., Results: With a median follow-up duration of 26 months, our data show that this modification of the Nordic regimen is a highly effective pre-AHCT first-line therapy for MCL (3-year progression-free and overall survival rates of 69% and 75%, respectively)., Conclusion: By using a less intense induction, this regimen can serve as a platform for combined use of novel agents, with less risk of additive toxicity., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Autologous stem cell transplantation (ASCT) with cyclophosphamide, etoposide and oral busulfan (BuCyVP) is an effective therapy for relapsed or refractory non-Hodgkin lymphoma (NHL). Substituting intravenous for oral busulfan reduces variability in drug exposure, potentially improving the safety and efficacy of the BuCyVP regimen. We retrospectively compared the outcomes of 604 consecutively treated patients who underwent ASCT for NHL with BuCyVP using oral (n = 468) or IV (n = 136) busulfan, without measurement of busulfan levels for pharmacokinetic (PK) analysis. Patients who received oral busulfan experienced more severe oral mucositis and a higher incidence of nonrelapse mortality. Median overall survival (OS) after ASCT was 72 months with oral busulfan but was not reached for the IV busulfan group. IV busulfan was associated with a lower rate of relapse, and superior relapse-free survival (RFS) and OS. In multivariate models, the route of busulfan administration was an independent prognostic factor for relapse (P = 0.01), RFS (P = 0.002) and OS (P = 0.001). IV busulfan appears to provide better efficacy and lower toxicity than oral busulfan in ASCT with BuCyVP for NHL. Whether PK-based busulfan dosing can achieve further improvements in this setting is worthy of study.

Background: Infections are the most common cause of non‐relapse mortality in adult allogeneic hematopoietic stem cell transplant (allo HSCT) recipients. Acute gastrointestinal graft‐vs‐host disease (GI GVHD) often leads to friable mucosa as well as treatment interventions which can increase risk of infection. Our primary objective was to describe the relationship between increasing grades of acute GI GVHD and incidence of bloodstream infections (BSI). Methods: We reviewed 441 adults who underwent allo HSCT from 2011 to 2017 and were clinically diagnosed with GI GVHD, non‐GI GVHD, or no GVHD based on the modified Glucksberg scale within the first 100 days of transplantation. The maximum grades of acute GI GVHD and non‐GI GVHD were used in the analysis. BSI was defined based on the presence of a blood culture positive for bacteria or fungi and treatment with antibiotics. The incidence of BSI within the first 180 days of transplantation was estimated with the cumulative incidence method. Fine and Gray regression was used to assess association between clinical grade of acute GI GVHD and BSI risk, adjusting for grade of non‐GI GVHD and for other significant baseline patient risk factors for BSI identified by multivariable analysis. Results are shown as hazard ratio (HR) and 95% confidence interval (CI). A similar analysis was conducted in 130 patients with histologic grade of acute GI GVHD. Results: Overall BSI incidence by day 180 was 32%; gram‐negative bacilli were the predominant organisms, followed by gram‐positive cocci and fungi. Patients with grade 4 acute GI GVHD had higher risk of BSI as compared to patients with no GI GVHD (HR 2.98, CI 1.65‐5.37, P <.001), while those with grade 3 acute GI GVHD had similar BSI risk (HR 0.89, CI 0.36‐2.21, P =.81). Grade of GI GVHD had no association with risk of non‐BSI. Results were similar in patients with histologic grade acute GI GVHD. Patients who developed BSI or non‐BSI had significantly higher overall mortality risk compared to those without infectious complications (HR 2.52, CI 1.92‐3.31, P <.001 for BSI; HR 1.60, CI 1.20‐2.13, P =.001 for non‐BSI). Conclusions: Grade 4 acute GI GVHD is associated with a higher risk of BSI, which is in turn associated with a higher risk of overall mortality in this population. Understanding the relationships between acute GI GVHD, BSI, and overall mortality can guide future treatment strategies for adult allo HSCT recipients. [ABSTRACT FROM AUTHOR]

Chronic graft-versus host disease (GVHD) is a chronic and disabling complication after hematopoietic cell transplantation (HCT). It is important to understand the association of socioeconomic status (SES) with health outcomes in patients with chronic GVHD because of the impaired physical health and dependence on intensive and prolonged health care utilization needs in these patients. We evaluated the association of SES with survival and quality of life (QOL) in a cohort of 421 patients with chronic GVHD enrolled on the Chronic GVHD Consortium Improving Outcomes Assessment study. Income, education, marital status, and work status were analyzed to determine the associations with patient-reported outcomes at the time of enrollment, nonrelapse mortality (NRM), and overall mortality. Higher income ( P  = .004), ability to work ( P  < .001), and having a partner ( P  = .021) were associated with better mean Lee chronic GVHD symptom scores. Higher income ( P  = .048), educational level ( P  = .044), and ability to work ( P  < .001) also were significantly associated with better QOL and improved activity. In multivariable models, higher income and ability to return to work were both significantly associated with better chronic GVHD Lee symptom scores, but income was not associated with activity level, QOL, or physical/mental functioning. The inability to return to work (hazard ratio, 1.82; P  = .019) was associated with worse overall mortality, whereas none of the SES indicators were associated with NRM. Income, race, and education did not have statistically significant associations with survival. In summary, we did not observe an association between SES variables and survival or NRM in patients with chronic GVHD, although we found some association with patient-reported outcomes, such as symptom burden. Higher income status was associated with less severe chronic GVHD symptoms. More research is needed to understand the psychosocial, biological, and environmental factors that mediate this association of SES with major HCT outcomes. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic cell transplantation (HCT) is recommended for patients with T cell acute lymphoblastic leukemia (T-ALL) in second or later complete remission (CR) and high-risk patients in first CR. Given its relative rarity, data on outcomes of HCT for T-ALL are limited. We conducted a multicenter retrospective cohort study using data from 208 adult patients who underwent HCT between 2000 and 2014 to describe outcomes of allogeneic HCT for T-ALL in the contemporary era. The median age at HCT was 37 years, and the majority of patients underwent HCT in CR, using total body irradiation (TBI)-based myeloablative conditioning regimens. One-quarter of the patients underwent alternative donor HCT using a mismatched, umbilical cord blood, or haploidentical donor. With a median follow up of 38 months, overall survival at 5 years was 34%. The corresponding cumulative incidence of non-relapse mortality and relapse was 26% and 41%, respectively. In multivariable analysis, factors significantly associated with overall survival were the use of TBI (HR, 0.57; P  = .021), age >35 years (HR, 1.55; P  = .025), and disease status at HCT (HR, 1.98; P  = .005 for relapsed/refractory disease compared with CR). Relapse was the most common cause of death (58% of patients). Allogeneic HCT remains a potentially curative option in selected patients with adult T-ALL, although relapse is a major cause of treatment failure. [ABSTRACT FROM AUTHOR]

Autologous hematopoietic cell transplantation (AHCT) is standard therapy for eligible patients with multiple myeloma. Health care disparities can influence transplantation outcomes. However, the association of socioeconomic status (SES), a major indicator of health care disparities, with outcomes in patients with myeloma after AHCT has not been previously described. We analyzed 346 consecutive AHCT recipients with myeloma who underwent transplantation between 2003 and 2013 in this retrospective cohort study. Zip code of residence at the time of AHCT was obtained to assess annual household income based on 2010 US census data (median, $49,054; range, $16,546 to $127,313). SES groups were divided into < $45,000 (low; n = 120), $45,000 to $60,000 (middle; n = 116), and > $60,000 (high; n = 110). The low-income cohort had smallest portion of Caucasians (69% versus 89% versus 91%); otherwise, patient, disease, and transplantation characteristics were comparable among cohorts or different without significant patterns found. Median follow-up was 49 months. There was no difference among SES groups in overall survival, progression-free survival, nonrelapse mortality, or relapse in univariate and multivariable analysis. Similarly, SES was not associated with survival in a subset analysis of 303 patients who had survived for 1 year after transplantation. [ABSTRACT FROM AUTHOR]

Abstract: Central line-associated blood stream infections (CLABSI) commonly complicate the care of patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) after allogeneic stem cell transplantation (HCT). We developed a modified CLABSI (MCLABSI) definition that attempts to exclude pathogens usually acquired because of disruption of mucosal barriers during the vulnerable neutropenic period following HCT that are generally included under the original definition (OCLABSI). We conducted a retrospective study of all AML and MDS patients undergoing HCT between August 2009 and December 2011 at the Cleveland Clinic (N = 73), identifying both OCLABSI and MCLABSI incidence. The median age at transplantation was 52 years (range, 16 to 70); 34 had a high (≥3) HCT comorbidity index (HCT-CI); 34 received bone marrow (BM), 24 received peripheral stem cells (PSC), and 15 received umbilical cord blood cells (UCB). Among these 73 patients, 23 (31.5%) developed OCLABSI, of whom 16 (69.6%) died, and 8 (11%) developed MCLABSI, of whom 7 (87.5%) died. OCLABSI was diagnosed a median of 9 days from HCT: 5 days (range, 2 to 12) for UCB and 78 days (range, 7 to 211) for BM/PSC (P < .001). MCLABSI occurred a median of 12 days from HCT, with similar earlier UCB and later BM/PSC diagnosis (P = .030). Risk factors for OCLABSI in univariate analysis included CBC (P < .001), human leukocyte antigen (HLA)-mismatch (P = .005), low CD34+ count (P = .007), low total nucleated cell dose (P = .016), and non-Caucasian race (P = .017). Risk factors for OCLABSI in multivariable analysis were UCB (P < .001) and high HCT-CI (P = .002). There was a significant increase in mortality for both OCLABSI (hazard ratio, 7.14; CI, 3.31 to 15.37; P < .001) and MCLABSI (hazard ratio, 6.44; CI, 2.28 to 18.18; P < .001). CLABSI is common and associated with high mortality in AML and MDS patients undergoing HCT, especially in UCB recipients and those with high HCT-CI. We propose the MCLABSI definition to replace the OCLABSI definition, given its greater precision for identifying preventable infection in HCT patients. [Copyright &y& Elsevier]

Patients with acute myeloid leukemia (AML) with intermediate or high risk cytogenetics are often considered for allogeneic hematopoietic stem cell transplant (AHSCT) in first remission. Between attainment of remission and AHSCT, post-remission chemotherapy is frequently administered, though there is no evidence for its effectiveness. This study was performed to determine the impact of post-remission chemotherapy on outcome after AHSCT. A subset analysis was performed to determine whether the influence of post-remission chemotherapy might be different in those with intermediate compared to high risk cytogenetics. There was no significant difference in relapse mortality (RM) ( p = 0.70), non-relapse mortality (NRM) ( p = 0.12), or survival (OS) ( p = 0.15) between post-remission chemotherapy groups. There was no difference in RM, NRM, or OS between cytogenetic groups according to whether they received post-remission chemotherapy. No differential effect between intermediate and high risk cytogenetics was detected (RM, p = 0.80; NRM, p = 0.23; OS, p = 0.26). These data do not show a benefit of post-remission chemotherapy before AHSCT. [ABSTRACT FROM AUTHOR]

Background: The spectrum of infectious complications in autologous hematopoietic cell transplant recipients (AHCT) with multiple myeloma has not been well described in the recent era of novel agent induction and improved supportive care. Methods: We conducted a retrospective cohort study of 413 adult myeloma AHCT recipients at our institution from 2007‐2016 to describe the cumulative incidence and risk factors for various infections and FN occurring within the first 100 days after AHCT. Additionally, landmark analysis was done among 404 patients who survived at least 100 days after transplant admission to estimate the association of infections with subsequent non‐relapse mortality (NRM), overall survival (OS), and relapse‐free survival (RFS). Results: Cumulative incidences (95% CI) of infection events by day 100 were: FN 43% (38‐48), any infection 21% (17‐25), bacterial 17% (14‐21), viral 4% (3‐7) and fungal 1% (0.5‐3), central line‐associated blood stream infection 3% (2‐6), and Clostridium difficile colitis 6% (4‐8). Patients with infection had a longer initial transplant hospitalization (median 17 vs 16 days, P < 0.01), more readmissions (31% vs 8%, P < 0.01), and spent more days in hospital in first 100 days (median 18 vs 16 days, P < 0.01). A 100‐day mortality was low and similar between groups (2% vs 1%, P = 0.28). In landmark analysis of 404 100‐day survivors, OS was worse among patients with early infections (hazard ratio 1.54 [1.03‐2.30], P = 0.03), although there was no difference in NRM and RFS. Conclusions: Notwithstanding advances in supportive care, early infectious complications remain a relevant source of morbidity and require attention in myeloma AHCT recipients. [ABSTRACT FROM AUTHOR]

Background Conditional survival (CS) is defined as the probability of surviving an additional x years given a patient has already survived y years since diagnosis or a time-point of interest. Although there are readily available overall survival (OS) estimates in multiple myeloma (MM) from the time of diagnosis or autologous stem cell transplantation (ASCT), data on CS in those who had already survived a landmark time since ASCT are lacking. Our objective was to investigate 5-year CS rate and standardized mortality ratio (SMR) in 1-, 3- and 5-year survivors after front-line ASCT in MM. Method We reviewed the institutional transplant database at Cleveland Clinic to identify 340 patients who underwent frontline ASCT (≤18 months from diagnosis) for MM between 1996 and 2013. OS was estimated by the Kaplan-Meier method. Relapse mortality (RM) and non-relapse mortality (NRM) were estimated with cumulative incidence. SMR was defined as the ratio of number of deaths in the study patients to that in an age, sex and race-matched healthy population. Estimates of outcomes and SMR are presented with 95% confidence intervals (CI). Results We identified 309 survivors at 1 year, 246 at 3 years, and 178 at 5 years from ASCT. The median age at ASCT was 56 years (range, 22-76) in all 3 cohorts. The median time from diagnosis to ASCT was 7.9 months in 1- and 3-year and 8.2 months in 5-year survivors. Approximately 40%, 35%, and 25% of patients had ISS stage I, II and III disease respectively at diagnosis in all cohorts. Median follow-up from ASCT in surviving patients was 88 months, 90 months and 100 months in 1-, 3- and 5-year survivors respectively. Estimated 5-year CS was 59% (53-64) in 1-year survivors, 60% (53-67) in 3-year survivors and 62% (53-70) in 5-year survivors. The respective cumulative incidence of 5-year conditional RM was 34% (28-39), 29% (23-35) and 25% (18-33) and that of NRM was 7% (5-11), 11% (7-16) and 13% (8-19). The SMR of 1-year, 3-year and 5-year survivors was 6.9 (5.8-8.2), 6.1 (5.0-7.5) and 5.6 (4.3-7.3) respectively, indicating significantly worse survival compared to demographically-matched healthy population irrespective of the duration of survival after ASCT. Survival curves for the 3 cohorts are shown in Figure I. Conclusion The probability of surviving an additional 5 years in patients with MM undergoing front-line ASCT does not improve with time, as shown in 1-, 3- and 5-year survivors, with estimated 5-year CS staying constant at around 60%. However, a decrease in the magnitude of SMR was observed with increase in the number of years already survived after ASCT. Information on CS and SMR is a pragmatic resource for long-term survivorship and beneficial at an individual level for counselling patients. [ABSTRACT FROM AUTHOR]

The clinical relevance of mismatches at the MHC class I–related chain A (MICA) in hematopoietic stem cell transplantation (HSCT) remains unclear. We investigated the association of MICA donor/recipient mismatch and whether there is an interaction between these and HLA-DPB1 mismatch on clinical outcomes after unrelated donor HSCT. Our study included 227 patients who underwent unrelated donor allogeneic HSCT at our institution between 2000 and 2010. Among these, 177 (78%) received HSCT from a 10/10 HLA-matched donor. MICA genotyping was performed using commercially available kits. In univariable analysis, the risk of grade II to IV acute graft-versus-host disease (GVHD) was greater for patients with MICA mismatch (hazard ratio [HR], 1.73; P = .02) than for those with HLA-DPB1 mismatch (HR, 1.62; P = .07). When MICA and HLA-DPB1 were assessed simultaneously, patients mismatched at both loci had the greatest risk (HR, 2.51; P < .01) and those mismatched at only 1 locus had somewhat greater risk (HR, 1.53; P = .12) than patients matched at both loci; this remained significant in multivariable analysis. The 100-day incidence was 66%, 45%, and 31%, respectively ( P = .03) . Results were similar for grade III and IV acute GVHD, with 100-day incidence 34%, 16%, and 8% ( P = .01). These results are clinically pertinent to donor selection strategies and indicate that patients with mismatch at both MICA and HLA-DPB1 are at increased risk for acute GVHD. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic stem cell transplantation (SCT) for patients who have previously undergone allogeneic or autologous SCT is potentially curative, but dangerous. To identify patient, disease, and treatment characteristics associated with outcome, we analyzed prognostic factors in 98 consecutive patients who underwent second transplants using allogeneic donors at the Cleveland Clinic between May 1987 and October 2008. Inclusion criteria included age ≥18 years, first SCT either autologous or allogeneic, and second SCT allogeneic. Patients whose second transplant was myeloablative (MA) had shorter survival (median 3.2 versus 14.7 months, P < .001) than patients whose second transplant was nonmyeloablative (NMA). In multivariable analysis, MA second transplant was associated with a higher risk of NRM (hazard ratio [HR] 2.01, P = 0.022) and death (HR 2.13, P = 0.002). Improved survival after NMA second transplant occurred primarily in patients without acute leukemia and when the first transplant was allogeneic. Among 17 patients transplanted within 3 months of first transplant, mortality was 100% and median survival was 2.3 months. MA transplantation within 3 months of prior SCT carries an unacceptably high rate of NRM. NMA second transplants were associated with substantially less NRM and despite a higher incidence of relapse, significantly improved survival compared to MA second transplants. [Copyright &y& Elsevier]

Advances in allogeneic hematopoietic cell transplantation (HCT) have led to significantly improved day 100 survival over time. Longer-term (≥1 year) survival, however, has not changed significantly. In an effort to improve outcomes and identify patients (pts) at higher risk for 1-year mortality, we created a day 100 risk assessment tool. The Day 100 Risk Assessment tool includes 11 items: HCT-co-morbidity index, distance from transplant center, performance status (PS) at day 100, GVHD requiring systemic corticosteroids, infection requiring intravenous antimicrobials, caregiver support, poor coping skills/motivation, substance abuse, poor health literacy/access, medication compliance, and "other" concerns from the care team. Pts were given a point for each identified factor and categorized as low risk (score 0-2) or high risk (score≥3). High risk pts were targeted for closer follow up beyond 100 days. Cox regression was used to identify risk factors for overall survival (OS) within the first year after HCT. Between 11/2015-6/2018, 208 pts underwent allogeneic HCT and 161 pts survived without relapse at day 100 (Table). Median follow up is 12 months (range 3-33). 1-year OS for low-risk pts was significantly better than for high-risk pts (82% vs 68%, P=0.006; Figure). Multivariable analysis accounting for both pre-transplant and Day 100 risk factors identified older age (≥55), (HR 2.92, 95% CI 1.21-7.08, P=0.017); high disease risk (HR 2.93, 95% CI 1.34-6.39, P=0.007), and day 100 high-risk score (HR 2.29, 95% CI 1.17-4.48, P=0.015) as significant factors for poor OS. Univariate analysis of individual components of the day 100 risk score identified poor PS at day 100, infection, and caregiving concerns as significant variables, P<0.004. A second multivariable model including individual factors demonstrated that poor PS (HR 2.68, P=0.013), infection (HR 2.57, P=0.009) and older age (HR 2.55, P=0.041) remained significantly associated with poor OS. In sum, we developed a Day 100 Risk Assessment tool and identified factors occurring within the first 100 days beyond traditional pre-transplant variables which significantly impact longer-term outcome. Targeted close follow up of these higher risk pts may help to improve survival of this at-risk population. [ABSTRACT FROM AUTHOR]

Background Relapse is a challenge after allogeneic hematopoietic cell transplantation (alloHCT) in MDS. MHC class I chain-related gene A (MICA) is a ligand of the natural killer (NKG2D) receptor on immune effector cells. There have been conflicting reports in regards to MICA mismatch and relapse after alloHCT in hematologic malignancies (Carapito Blood 2016, Askar BBMT 2017). However, these studies did not assess somatic mutations, which have shown to impact relapse (Coleman NEJM 2017). We first assessed risk factors for relapse within 6 and 12 months after alloHCT. We then assessed for an effect of somatic mutations and MICA dimorphisms on relapse. Methods We conducted a single center, retrospective analysis of adults with MDS who underwent 1st alloHCT with T-cell replete HLA-8/8 matched related (MRD) or unrelated donor (MUD). In addition to cytogenetic risk stratification, a subset of patients had a 36-gene somatic mutation panel assessed prior to alloHCT by next-generation sequencing. Dimorphisms of MICA-129 were categorized as weak (valine/valine; V/V), intermediate (methionine/valine; M/V), or strong (methionine/methionine; M/M) receptor affinity. Results From 2000 - 2017, 128 adult MDS patients met inclusion criteria. Median age at alloHCT was 56 years (range, 20-76). IPSS-R scores at diagnosis included 2% very good, 42% good, 23% intermediate, 19% poor, and 14% very poor risk. 62% had MUDs and 87% had a myeloablative regimen. Among 78 patients with data, donor/recipient MICA mismatch was present in 8% while donor MICA-129 dimorphisms were 49% V/V, 42% M/V, and 9% M/M In multivariable analysis, the presence of at least 1 of these less favorable mutations (ASXL1, DNMT3A, FLT3, KRAS, NRAS , and TP53) was a risk factor for relapse within 6 mos (HR 4.30, CI 1.40-13.3, P=0.011; Figure 1); 6-mo relapse incidence (CI) was 45% (22-65) for those with at least 1 of the above mutations vs. 15% (9-22) for all others. A MRD graft was a risk factor for relapse within 12 mos (HR 2.27, CI 1.12-4.59, P=0.023); 12-mo relapse incidence was 36% (23-50) for those with a MRD vs. 19% (11-28) for MUDs. In a 41-patient subset with both MICA and mutation data, although not significant, patients with both donor V/V dimorphism and at least 1 of these less favorable somatic mutations had higher relapse incidence (40% at 12 mos) than those with only 1 of these adverse factors (28%) or neither factor (9%) (P=0.12; Figure 2). Conclusion The presence of at least 1 of the 6 less favorable somatic mutations in our cohort was associated with a risk of relapse within 6 mos after alloHCT for MDS. Our data suggest an additive effect of both weak NK cell activation and less favorable somatic mutations in increasing the risk of relapse, but was not statistically significant. Future investigation of larger cohorts and mechanistic studies are needed to better assess potential interactions between these two elements and the risk of relapse. [ABSTRACT FROM AUTHOR]

Background AYA patients have a myriad of specific psychosocial and other challenges which may influence their ability to obtain appropriate treatment. Healthcare disparities regarding access to healthcare have been well described in this population. We hypothesized that hurdles faced by the AYA patient population also apply to patients with AML requiring allogeneic hematopoietic cell transplantation (HCT), resulting in AYAs having a longer TTT compared to older adults. Objectives In this study we aimed to compare TTT, defined as time from diagnosis to transplant for AML in CR1 between AYAs and older adults. Additionally, we aimed to determine if TTT has changed over time for this cohort and to identify factors associated with TTT. Methods BMT Program database was used to identify allogeneic HCT recipients with AML in CR1 from January 2007 to June 2018 for AYAs (age 18-39 years) and older adults (age 40-60 years). All the identified patients underwent allogeneic stem cell transplant in complete remission 1 (CR1). Patients receiving cord blood graft source were excluded. AYA and older adults were compared with Wilcoxon, Chi-square, or Fisher's exact test. Change in TTT over time was assessed with Spearman correlation (r). Factors associated with TTT were assessed with Wilcoxon or Jonckheere-Terpstra test. Results A total of 105 patients were identified: 24 AYAs and 81 older adults. Baseline characteristics were similar between AYAs and older adults aside from Karnofsky performance status; AYAs had better performance status than older adults (p=0.012). Time to Transplant did not differ from between AYA and older adults (median 4.1 vs 4.0 months, p=0.61). There was no evidence of a change in TTT in more recent years in AYA (r=0.15, p=0.48) or older adults (r=-0.02, p=0.85). The only variable associated with TTT, as expected, was donor type (unrelated donors median 4.3 vs related donors 3.8 months, p=0.022) (Table 1). Conclusion Time to transplant for AYAs in AML is comparable to older adults and has not changed over time. Our analysis is limited to experience from a single center and a larger multicenter effort that takes into account other sociodemographic mediators of healthcare disparities is needed to better describe the association of age and time to allogeneic HCT in AML CR1. Our next step is to explore various psychosocial factors in this cohort and determine if they play a role in the TTT and also determine if TTT has an impact on outcomes. [ABSTRACT FROM AUTHOR]

Patient readmission within 30 days from discharge has been perceived by the Centers for Medicare and Medical Services as an indicator of poor healthcare quality for specific high-cost medical conditions. Patients who undergo allogeneic hematopoietic cell transplantation (allo-HCT) are often being readmitted. Our study identified the risk factors for 30-day readmission among 618 adult recipients of myeloablative allo-HCT from 1990 to 2009. Two hundred forty-two (39%) of 618 patients (median age = 42 years [range: 18-66]) were readmitted a median of 10 days (range: 1-30) from their hospital discharge. Median duration of readmission was 8 days (range: 0-103). Infections (n = 68), fever with or without identified source of infection (n = 63), gastrointestinal complications (n = 44), graft-versus-host disease (GVHD) (n = 38), and other reasons (n = 29) accounted for 28%, 26%, 18%, 16%, and 12% of readmissions, respectively. During their index admission, patients who were subsequently readmitted had more documented infections (P < .001), higher hematopoietic cell transplantation comorbidity index (HCT-CI) (P < .01), total body irridiation (TBI)-based conditioning (P < .001), unrelated donor (P < .001), and peripheral stem cell (P = .014) transplantation. In multivariable analysis, HCT-CI (odds ratio [OR] = 1.78; 95% confidence interval [CI], 1.25-2.52), TBI-based preparative regimen (OR = 2.63; 95% CI, 1.67-4.13), and infection during admission for allo-HSCT (OR = 2.00; 95% CI, 1.37-2.92) predicted 30-day readmission. Thirty-day readmission itself was an independent predictor of all-cause mortality (hazard ratio [HR]Adj = 1.66; 95% CI, 1.36-2.10). Our data emphasize the importance of a risk-standardized approach to 30-day hospital readmission if it is used as a quality-of-care metric for bone marrow transplantation. [ABSTRACT FROM AUTHOR]

Busulfan (Bu) based conditioning regimens are associated with serious toxicities including myelosuppression, hepatotoxicity, and sinusoidal obstructive syndrome (SOS). Previous literature reports increased risk of toxicities when the daily AUC concentrations exceed 6000 uM-minute. Bu TDM has also been associated with improved overall and progression free survival in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. We implemented real time pharmacokinetic (PK)-guided therapeutic dose monitoring (TDM) of Bu for myeloablative conditioning (MAC) regimens. Compare toxicity of IV Bu before and after implementation of TDM. The primary endpoint was incidence of hepatotoxicity, defined as days of elevation of AST or ALT > 3 times the upper limit of normal (ULN) or total bilirubin >1.5 times ULN. Secondary outcomes included time to neutrophil and platelet engraftment, duration of IV opioid administration, breakthrough antiemetic use, incidence of SOS, hospital length of stay (LOS), incidence of Bu dose adjustment, and repeat Bu PK. A Bu PK-guided TDM program was implemented in April 2018 for patients receiving busulfan/ cyclophosphamide (BuCy) MAC regimens for allo-HSCT. Medical records were retrospectively reviewed with weight-based dose (WBD) BuCy conditioning from August 2017 through March 2018 (N=14) and TDM from April 2018 through December 2018 (N=22). Bu was given at a fixed dose of 0.8 mg/kg/dose every 6 hours for 16 doses on days -8 to -4 for WBD patients. For TDM patients, after a WBD of 3.2 mg/kg/dose on day -7 (Bu 1), serial plasma Bu concentrations were used to calculate Bu area under the curve (AUC) for subsequent dose adjustment on days -6 to -4 to target a daily AUC of 5000 μM-minute. If the AUC actual /AUC target exceeded 1.2 or was less than 0.8, the second dose of Bu (Bu 2) was changed by no more than ± 20%, repeat PK samples were drawn, and the process was repeated for TDM for the third dose of Bu. Recipients of Bu TDM were younger than those receiving WBD (median 45 vs. 58 years, p=0.008). No other baseline differences were observed. There was no difference in hepatotoxicity between TDM and WBD (median 1 vs. 0 days, p=0.40), time to neutrophil (median 17 vs. 17 days, P=0.18) or platelet engraftment (median 29 vs. 25 days, p=0.75), IV opioid administration (median 4 vs. 4 days, p=0.83), breakthrough antiemetic use (median 59 vs. 58 doses, p=0.99), SOS (4.5 vs. 7.1%, p=1.0), or LOS (median 28 vs. 27 days, p=0.95). In the TDM group, 45% of patients had increases and 41% had decreases in Bu dose after Bu 1. 32% of patients required repeat PK after Bu 2. A PK dose monitoring program for MAC IV Bu regimens may be considered a safe practice in allo-HSCT recipients. The majority of patients receiving PK-guided TDM required dose changes, and TDM patients had no significant difference in toxicity compared to those receiving WBD. [ABSTRACT FROM AUTHOR]

Background BuCyVP and BEAM are two commonly used conditioning regimens for AHCT. Previous literature has reported improved outcomes with BEAM compared to BuCyVP in Hodgkin lymphoma (HL) patients, although results in non-Hodgkin lymphoma (NHL) patients are scarce but similar. Our institution switched from using BuCyVP to BEAM as AHCT conditioning for HL in 2016. We conducted a retrospective study to evaluate tolerability and resource utilization with the two regimens. Given limited data and comparable outcomes, this may influence decisions to use one regimen over the other in patients with NHL. Objectives Assess resource utilization and toxicity of BEAM vs. BuCyVP in patients undergoing AHCT for HL. The primary endpoint was hospital length of stay (LOS). Secondary outcomes were 30-day readmission rates, incidence of fever, time to neutrophil and platelet engraftment, incidence of transfer to intensive care unit (ICU), time on intravenous (IV) opioids, and incidence of diuretic and breakthrough antiemetic use. Methods Beginning March 2016, BEAM replaced BuCyVP as the standard conditioning regimen for AHCT for HL at our institution. We retrospectively reviewed medical records of HL patients receiving BuCyVP with pharmacokinetic (PK)-guided therapeutic dose monitoring (TDM) of busulfan from October 2014 through March 2016 (N = 19) and BEAM from April 2016 through September 2017 (N = 18). Results BuCyVP recipients had significantly longer average hospital LOS, relative to both admission date (21 vs. 19 days, p < 0.001) and transplant date (12 vs. 11 days, p = 0.028), increased incidence of fever (89.5% vs. 33.3%, p < 0.001), increased average days of IV opioid administration (8 vs. 1, p < 0.001), and increased average number of doses of furosemide (3 vs. 0, p < 0.001). BuCyVP resulted in shorter average days to platelet engraftment compared to BEAM (17 vs. 20, p = 0.021). No patients were re-admitted to the hospital within 30 days of discharge in either group. There was no difference in average time to neutrophil engraftment (10 vs. 10 days, p = 0.22), average number of breakthrough antiemetic doses (89 vs. 102, p = 0.17), or incidence of transfer to an ICU (10.5% vs. 0%, p = 0.49) between groups. Conclusions Compared to BuCyVP, patients receiving BEAM as conditioning for AHCT for HL had significantly shorter hospital LOS, fewer episodes of fevers and required less IV opioids and furosemide. However, there was no difference in other endpoints evaluated (e.g., neutrophil engraftment, ICU transfer and breakthrough antiemetic use). Our study provides the background information on expected resource utilization and toxicities for the two regimens and will assist in decisions regarding use of these regimens in NHL patients where outcomes between the two are comparable [ABSTRACT FROM AUTHOR]

Background ES is a potential complication following AHCT. First-line treatment typically involves corticosteroids (CS). In 2002, due to historically high ES incidence resulting in prolonged hospitalizations requiring CS treatment, our institution adopted the practice of administering prophylactic CS in patients undergoing AHCT. Due to lack of contemporary evidence supporting ES prophylaxis as well as potential intolerance of prophylactic CS noted in our patient population, a pilot was instituted to remove prophylactic CS from MEL conditioning regimen for multiple myeloma (MM) or amyloidosis. Objectives The primary objective was to evaluate the impact of prophylactic CS on the incidence of ES. Secondary objectives included hospital length of stay (LOS), duration of intravenous (IV) opioid administration during hospitalization, and incidence of infection, fever, or 30-day readmission due to any cause. Methods Beginning December 2016, CS for ES prophylaxis were removed from our standard of care in patients receiving MEL. Prior to this pilot, patients received methylprednisolone 40 mg IV daily from day +5 to day +15 or hospital discharge (whichever occurred sooner). We retrospectively reviewed the charts of patients receiving MEL from June 1 to December 15 of 2016 (CS group) and December 16, 2016 to June 30, 2017 (CS-free group). ES was defined as noninfectious fever >38°C and new documented rash at the time of engraftment (between day +7 to +11). Results A total of 76 patients were reviewed (CS group, n = 40; CS-free group, n = 36). Baseline characteristics were similar between groups in terms of median age (63 vs. 63 years, p =.65), sex (62.5% vs. 56% male, p =.54), and median CD34+ cell dose (6.36 vs. 6.43 × 106 cells/kg, p =.75). There was no difference in the incidence of documented ES between the CS and CS-free groups (2.5% vs. 0%, p = 1.00). There were no significant differences in median hospital LOS (14 vs. 14 days, p =.67), incidence of infection (17.5% vs. 22.2%, p =.61), incidence of fever (25% vs. 25%, p =.81), and 30-day readmission rate (17.5% vs. 11.1%, p =.43) in CS vs. CS-free groups, respectively. Patients in the CS group received significantly more days of IV opioid administration (median 4.5 vs. 4.0, p =.01). A greater proportion of patients received treatment with CS for suspected ES in the CS-free group compared to the CS group (8.3% vs. 2.5%, p =.34), possibly due to the strict conditions required for our definition of ES or the preemptive use of CS. Conclusions These results suggest a low overall incidence of ES in MM or amyloidosis patients undergoing AHCT using MEL. The use of prophylactic CS did not have a significant impact on incidence of ES which could be attributed to the pre-specified definition of ES. A preemptive strategy of using CS in patients with suspected ES may be sufficient in ameliorating symptoms associated with this syndrome. [ABSTRACT FROM AUTHOR]