Risk Of Treatment-related Mortality Research Articles

The Efficacy and Safety of Tandem Transplant Versus Single Stem Cell Transplant for Multiple Myeloma Patients: A Systematic Review and Meta-Analysis.

While high-dose therapy and autologous stem cell transplant (ASCT) remain integral to the primary treatment of newly diagnosed transplant-elble multiple myeloma (MM) patients, the challenge of disease progression persists. The primary objective of this meta-analysis is to evaluate the efficacy and safety of tandem ASCT compared to single ASCT. We conducted a systematic review and meta-analysis of randomized controlled trials and observational studies comparing tandem ASCT with single ASCT in patients with newly diagnosed MM. We searched PubMed, EMBASE, Cochrane Library, and Clinical Trials databases for studies published up to January 2024. The primary outcomes were progression-free survival (PFS), overall survival (OS), overall response rate (ORR), complete response rate (CRR), and treatment-related mortality (TRM). We used a random-effects model to calculate pooled hazard ratios (HRs) and relative risks (RRs) with 95% confidence intervals (CIs). Study quality was assessed using the Cochrane risk of bias tool and Newcastle-Ottawa Scale. Twelve studies involving 5057 patients met the inclusion criteria. Tandem ASCT was associated with a significantly higher CRR compared to single ASCT (HR 1.33, 95% CI 1.03-1.71, I2 = 15%), but no significant differences were observed in PFS (HR 0.75, 95% CI 0.42-1.34, I2 = 14%), OS (HR 0.60, 95% CI 0.33-1.10, I2 = 27%), or the ORR (RR 0.80, 95% CI 0.59-1.08, I2 = 33%). However, tandem ASCT was associated with a significantly higher risk of TRM (RR 1.78, 95% CI 1.00-3.18, I2 = 0%). Tandem ASCT improves the CRR but does not provide significant benefits in terms of PFS, OS, or ORR compared to single ASCT in patients with newly diagnosed MM. Moreover, tandem ASCT is associated with a higher risk of TRM. The decision to pursue tandem ASCT should be made on an individual basis, carefully weighing the potential benefits and risks in light of each patient's unique clinical situation. Future research should focus on identifying patient subgroups most likely to benefit from tandem ASCT and exploring strategies to optimize the efficacy and safety of this approach in the context of novel agent-based therapies.

A Novel Transgenic Mouse Model of Down Syndrome Acute Lymphoblastic Leukemia Identifies Targetable Vulnerabilities

Background: Children with Down syndrome (DS) have a 10-fold increased risk of developing B-cell acute lymphoblastic leukemia (B-ALL), and they have poorer survival due to increased relapses and treatment-related mortality (TRM). Targeted therapies for DS-ALL are needed to improve anti-leukemic efficacy and reduce the risk of TRM. Mouse models and cell lines recapitulating DS-ALL are lacking, and may aid in identifying new targets for DS-ALL. Methods: We used the Dp(16)1Yey (Dp16) mouse model of DS, which has a triplication of ~115 human chromosome 21 (Hsa21) orthologues. We introduced Kras G12D and Pax5 heterozygosity, both driven in B cells by CD19-Cre, in Dp16 and non-DS wild-type (WT) mice. We performed RNA-Sequencing (RNA-Seq) and gene set enrichment analysis (GSEA) to identify differentially regulated signaling pathways in Dp16 and WT B-ALL blasts. We cultured B-ALL blasts from mice to generate immortal cell lines. We tested the chemosensitivity of Dp16 and WT B-ALL cell lines with 35 agents with known efficacy in hematologic malignancies, and with 481 anti-cancer compounds used in the Cancer Therapeutics Response Portal project, to screen for drugs effective in DS-ALL. We screened top candidate drugs in DS-ALL and non-DS ALL patient samples in vitro, and tested FK866 and cucurbitacin I in vivo in mice xenografted with a DS-ALL patient sample. Results: Kras G12D.Pax5 +/- mice developed B-ALL with complete penetrance, with significantly shorter median survival in the Dp16 versus WT background (Figure 1A; 80 versus 114 days, p<0.0001). GSEA demonstrated upregulation of DNA repair signaling pathways in Dp16 B-ALL, recapitulating a signature observed in human DS-ALL. Growth of Dp16 and WT B-ALL cell lines, and DS-ALL and non-DS ALL patient samples, was inhibited at low nanomolar concentrations by novel therapies targeting NAMPT, DNA damage responses, autophagy, and JAK and PI3K/mTOR signaling. In mice xenografted with a DS-ALL patient sample, the NAMPT inhibitor FK866 significantly reduced the leukemic burden compared to vehicle (Figure 1B; 14.6% vs 22.4% after 4 weeks of treatment, p<0.005). The effect of FK866 was also significant after weeks 2 and 3 of treatment. Conclusions: We have generated the first de novo mouse model and cell lines recapitulating DS-ALL, which we have employed in drug screens to identify novel therapeutic approaches. These studies suggest promising candidates for further study in DS-ALL and other high-risk ALL subtypes to reduce toxicity and improve outcomes.

Autologous Transplant (auto-HCT) Is Associated with Improved Clinical Outcomes Compared to CAR-T Therapy in Patients (pts) with Large B-Cell Lymphoma (LBCL) Achieving a Complete Remission

Introduction: CAR-T therapy is the standard of care for pts with relapsed LBCL as early as in the second line in those with early relapse or with primary refractory disease. In practice, pts who are intended to receive CAR-T, commonly require interim therapy before leukapheresis, wherein a small fraction may achieve a complete remission (CR). Having chemosensitive disease, these pts can be considered for auto-HCT. Also, there are reports indicating the efficacy of CAR-T therapy in CR pts (Strati et al., Haematologica, 2023; Wudhikarn et al., Blood Adv, 2022). We compared the outcome of pts with LBCL who received CAR-T vs. auto-HCT while in a CR. Methods: Pts aged 18-75 years with DLBCL or primary mediastinal lymphoma who received CAR-T (between 2018-2021) or auto-HCT (between 2015-2021) while in a CR by PET or CT were included in this analysis using the data from the Center for International Blood & Marrow Transplant Research (CIBMTR) registry. Primary endpoints included progression-free survival (PFS) and overall survival (OS). Treatment-related mortality (TRM) and relapse rate were among the secondary endpoints. Results: We identified 360 pts with LBCL who were in a CR before receiving CAR-T (n=79, tisa-cel 53%, axi-cel 46%, and liso-cel 1%) or auto-HCT (n=281). Median follow-up was 24.7 months (range 3.3-49.4) for the CAR-T cohort and 49.7 months (range 3.0-95.4) for the auto-HCT cohort. Selected baseline characteristics are shown in Table 1. CRs were confirmed by PET scan in 90% of CAR-T pts and 99.6% of auto-CAR-T pts (p < 0.01). The most common lymphodepletion regimen for CAR-T was Cy/Flu (82.3%) and the most common conditioning regimen for auto-HCT was BEAM (77.6%). Thirty-seven (13.2%) of auto-HCT pts had a later CAR-T but no pts from the CAR-T cohort had subsequent auto-HCT. In univariate analysis, treatment with CAR-T was associated with a higher rate of relapse at 2 years (48% vs. 27.8%; p < 0.001), a lower rate of 2-year PFS (47.8% vs. 66.2%; p < 0.001) and lower 2-year OS (65.6% vs. 78.9%; p=0.037). There was no difference in rates of 2-year TRM (4.1% vs. 5.9%; p=0.673). Similarly, focusing on patients with early (12 months) treatment failure (CAR-T =57 and auto-HCT=163), treatment with CAR-T was associated with a higher 2-year relapse rate (45.9% vs. 22.8%; p <0.001) and an inferior 2-year PFS (48.3% vs.70.9%.; p <0.001) compared to auto-HCT (figure-2) while there was no difference in 2-year OS or TRM. In the multivariable analysis of outcomes, treatment with CAR-T was associated with higher risk of relapse (HR 2.18; p < 0.0001) and an inferior PFS (HR 1.83; p=0.0011) compared to auto-HCT. There was no difference in the risk of TRM (HR 0.59; p=0.36) or OS (HR 1.44; p=0.12). Conclusions: In pts with relapsed LBCL who achieve a CR, treatment with auto-HCT is associated with a lower relapse rate and an improved PFS compared to CAR-T, including in pts with early treatment failure (within 12 months). These results are in line with previously reported improved clinical outcomes with auto-HCT compared to CAR-T in pts in partial remission (Shadman et al. Blood, 2022). The data support utilization of auto-HCT in pts with relapsed LBCL achieving a CR.

Utility of the frailty score for predicting prognosis and individualizing treatment intensity in elderly patients with diffuse large B cell lymphoma.

The optimal dose intensity of chemotherapy for elderly patients with diffuse large B cell lymphoma (DLBCL) remains controversial because of concerns about adverse events and comorbidities related to the patients' frailty. This single-center study retrospectively analyzed patients aged ≥ 70 years who were newly diagnosed with DLBCL and received chemotherapy between 2004 and 2022. Survival outcomes and treatment-related mortality (TRM) were stratified according to geriatric assessment variables, and the influence of chemotherapy dose intensity on outcomes was assessed using the frailty score with a Cox hazards model with restricted cubic spline (RCS) in patients aged 70-79 years. In total, 337 patients were included. The frailty score accurately predicted prognosis (5-year overall survival [OS]: 73.1%, 60.2%, and 29.7% in fit, unfit, and frail patients, respectively; P < 0.001) and TRM (5-year TRM: 0%, 5.4%, and 16.8 in fit, unfit, and frail patients, respectively; P < 0.001). Cox regression with RCS demonstrated a linear association between dose intensity and survival outcomes. Initial dose intensity (IDI) and relative dose intensity (RDI) had a significant impact on OS in fit patients. However, IDI and RDI had no significant effect on survival in non-fit (unfit and frail) patients. The frailty score identified non-fit patients with poorer survival and a higher risk of TRM. While fit patients were likely to benefit from full-dose R-CHOP, unfit and frail patients would likely benefit more from attenuated R-CHOP. This study suggested a potential role for the frailty score in individualizing treatment intensity in elderly patients with DLBCL.

Predicting In-Hospital Mortality After Acute Myeloid Leukemia Therapy: Through Supervised Machine Learning Algorithms

Despite careful patient selection, induction chemotherapy for acute myeloid leukemia (AML) is associated with a considerable risk for treatment-related mortality (5%-20%). We evaluated machine learning (ML) algorithms trained using factors available at the time of admission for AML therapy to predict death during the hospitalization. We included AML discharges with age > 17 years who received inpatient chemotherapy from State Inpatient Database from Arizona, Florida, New York, Maryland, Washington, and New Jersey for years 2008-2014. The primary objective was to predict inpatient mortality in patients undergoing chemotherapy using covariates present before initiation of chemotherapy. ML algorithms logistic regression (LR), decision tree, and random forest were compared. 29,613 hospitalizations for patients with AML were included in the analysis each with 4,177 features. The median age was 58.9 (18-101) years, 13,689 (53.7%) were male, and 20,203 (69%) were White. The mean time from admission to chemotherapy was 3 days (95% CI, 2.9 to 3.1), and 2,682 (9.1%) died during the hospitalization. Both LR and random forest models achieved an area under the curve (AUC) score of 0.78, whereas decision tree achieved an AUC of 0.70. The baseline LR model with age yielded an AUC of 0.62. To clinically balance and minimize false positives, we selected a decision threshold of 0.7 and at this threshold, 51 of our test set of 5,923 could have potentially averted treatment-related mortality. Using readily accessible variables, inpatient mortality of patients on track for chemotherapy to treat AML can be predicted through ML algorithms. The model also predicted inpatient mortality when tested on different data representations and paves the way for future research.

Associations of Minor Histocompatibility Antigens with Clinical Outcomes Following Allogeneic Hematopoietic Cell Transplantation

Introduction Donor T-cell recognition of tumor-presented minor histocompatibility antigens (mHAs) is thought to be a central mediator of the therapeutic graft versus leukemia (GvL) effect following allogeneic hematopoietic cell transplantation (alloHCT). In contrast, graft versus host disease (GvHD) develops when donor T-cells react to mHAs presented by normal recipient cells. While the role of mHAs in outcomes following alloHCT is recognized, it has not been well-characterized. It remains unclear whether GvL and GvHD are mediated by the cumulative effect of total mHAs in a donor-recipient pair (DRP) or individual immunodominant mHAs. We hypothesized that an increased mHA count and individual mHAs would be associated with lower relapse and disease-related mortality (DRM) and/or increased GvHD mortality. To this end, we predicted genome-wide mHA peptides in a large patient population and analyzed the associations between clinical outcomes and 1) the total number of predicted class I and class II mHAs, and (2) individual and groups of mHAs. Methods The study population consisted of 2249 European American DRPs in the DISCOVeRY-BMT dataset treated for Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) with alloHCT. To predict mHAs in a DRP, we translated nonsynonymous SNP alleles present in alloHCT recipients, but absent in their donor, into all possible peptides of varying lengths that would encompass the altered amino acid. To identify mHAs most likely to be immunogenic, peptides were filtered based on (1) source protein gene expression data in GvL and GvHD target tissues, including AML, liver, skin, and colon, from UCSC's Xena Dataset repository and (2) recipient HLA binding affinity from netMHCpan. To test the association of mHA count and individual mHAs with all-cause mortality (OS) and leukemia-free survival (LFS) we used cox proportional hazard models and competing risk models for DRM, treatment-related mortality (TRM), and GvHD mortality. Individual mHA analyses were stratified by HLA type to recognize that T-cell responses depend on HLA-mHA complexes. Models were adjusted for clinical covariates. Bonferroni correction for multiple testing was based on the number of independent SNPs. Results Patients with a class I mHA count greater than the population median had a 39% (HR=1.39, 95%CI 1.005,1.772, P=0.046) increase in hazard of GvHD mortality compared to those with a count less than the median. Patients with a class II mHA count greater than the population median had a decreased overall survival compared to those with a count less than the median (Fig. 1, P=0.029). In recipients with HLA-B*08:01, the class I mHA DLRCKYISL was associated with increased risk of GVHD mortality (HR=2.84, 95%CI 1.52,5.31, P=0.01). Within HLA-B*40:01, WEHGPTSLL was associated with decreased LFS (HR=1.94, 95%CI 1.27,2.95, P=0.044). Within HLA-C*03:04, STSPTTNVL was associated with increased risk of DRM (HR=2.32, 95%CI 1.5,3.6, P=0.008). In recipients with HLA-DRB1*15:01, the class II mHA YQEIAAIPSAGRERQ was associated with increased risk of TRM (HR=3.05, 95%CI 1.75,5.31, P=0.02). Two mHAs, WEHGPTSLL and STSPTTNVL, were found within the HLA haplotype B*40:01-C*03:04. Recipients with both mHAs (versus neither) had a greater hazard of 1-year all-cause mortality (HR=3.58, P=7.9×10-5) and DRM (HR=3.65, P=0.003) (Fig. 2). Patients with either mHA (versus neither) had greater 1-year all-cause mortality (HR=1.69, P=0.008) and increased DRM (HR=2.05, P=0.008) Conclusions The number of class I mHAs in a DRP was associated with increased GvHD mortality, which is consistent with our hypothesis. We also found two mHAs correlated with GvHD mortality and DRM which may represent increased GvH effects driven by these peptides. However, contrary to our hypothesis, an increased number of class II mHAs was correlated with greater risk of all-cause mortality that may be due to decreased LFS. Similarly, we found two mHAs correlated with increased DRM and decreased LFS. These two mHAs are found in an HLA haplotype where they exhibit a dose effect relationship with the risk of DRM and decreased OS. These findings may reflect an unexpectedly attenuated GvL effect that requires further investigation. Our study reports the first large scale investigation of the role of predicted mHA peptides in clinical outcomes following alloHCT. If validated, these results may be used to help guide clinical decision making. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Intensive chemotherapy followed by autologous stem cell transplantation in primary central nervous system lymphomas (PCNSLs). Therapeutic outcomes in real life-experience of the French Network.

We analysed the therapeutic outcomes of all consecutive patients with primary central nervous system lymphoma (PCNSL) registered in the prospective French database for PCNSL and treated with intensive chemotherapy (IC) followed by autologous stem cell transplantation (IC-ASCT) between 2011 and November 2019 (271 patients recruited, 266 analysed). In addition, treatment-related complications of thiotepa-based IC-ASCT were analysed from the source files of 85 patients from 3 centers. Patients had received IC-ASCT either in first-line treatment (n = 147) or at relapse (n = 119). The median age at IC-ASCT was 57 years (range: 22-74). IC consisted of thiotepa-BCNU (n = 64), thiotepa-busulfan (n = 24), BCNU-etoposide-cytarabine-melphalan (BEAM, n = 36) and thiotepa-busulfan-cyclophosphamide (n = 142). In multivariate analysis, BEAM and ASCT beyond the first relapse were adverse prognostic factors for relapse risk. The risk of treatment-related mortality was higher for ASCT performed beyond the first relapse and seemed higher for thiotepa-busulfan-cyclophosphamide. Thiotepa-BCNU tends to result in a higher relapse rate than thiotepa-busulfan-cyclophosphamide and thiotepa-busulfan. This study confirms the role of IC-ASCT in first-line treatment and at first-relapse PCNSL (5-year overall survival rates of 80 and 50%, respectively). The benefit/risk ratio of thiotepa-busulfan/thiotepa-busulfan-cyclophosphamide-ASCT could be improved by considering ASCT earlier in the course of the disease and dose adjustment of the IC.

Hematopoietic Cell Transplantation-Comorbidity Index Score Is Correlated with Treatment-Related Mortality and Overall Survival following Second Allogeneic Hematopoietic Cell Transplantation in Children

Allogeneic hematopoietic cell transplantation (HCT) can lead to considerable complications and treatment-related mortality (TRM); therefore, a detailed assessment of risks is essential. The Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI) can predict both TRM and overall survival (OS). Although the HCT-CI has been validated as a useful tool for first HCT, its potential utility for second HCT has not yet been investigated. Here we aimed to evaluate the utility of the HCT-CI score in assessing the risk of TRM and OS in the setting of a second allogeneic HCT. This was a retrospective analysis of all pediatric patients (age <21 years) who underwent a second allogeneic HCT at UCSF Benioff Children's Hospital San Francisco between 2008 and 2019. According to their HCT-CI, patients were classified as "low risk" with an HCT-CI of 0 or "intermediate-high risk" with an HCT-CI ≥1. A total of 59 patients were included in the study. Our primary endpoint was TRM, observed at 100 days, 180 days, 1 year, and last follow-up following HCT, and our secondary endpoint was OS at 1 year and at 5 years or last follow-up. We also evaluated outcomes of patients admitted to the pediatric intensive care unit based on the HCT-CI score. Seventy-six percent of patients had an HCT-CI of 0. The most frequent comorbidities were pulmonary, seen in 7 patients (12%; 95% CI, 5% to 23%), including 5 (71%) with moderate and 2 (29%) with severe comorbidities. The OS and the cumulative incidence of TRM at 1 year for the entire cohort were 81% (95% CI, 69% to 90%) and 12% (95% CI, 5% to 22%), respectively. The cumulative incidence of TRM and OS at 1 year showed a significant correlation with HCT-CI score; TRM was 4% (95% CI, 1% to 13%) for an HCT-CI of 0 versus 36% (95% CI, 13% to 60%) for an HCT-CI ≥1 (P < .001), and OS was 89% (95% CI, 75% to 99%) for an HCT-CI of 0 versus 57% (95% CI, 28% to 78%) for an HCT-CI ≥1 (P=.003). After adjusting for covariates, HCT-CI continued to be associated with both TRM (P=.004) and OS (P=.003). In addition, comparing patients with malignancies and nonmalignant disorders, disease-free-survival at last follow-up was higher in the nonmalignant disorder group and also was influenced by the HCT-CI score in each group (P=.0035). There also was a significant difference in outcomes of patients admitted to the pediatric intensive care unit; 15 patients (68%) with an HCT-CI of 0 were alive at last follow-up, compared with only two (22%) with an HCT-CI ≥1 (P=.016). HCT-CI has an impact on TRM and OS and may serve as a predictor of outcomes of second allogeneic transplantation. Although this study was conducted in a relatively small sample, it is the first to investigate the utility of the HCT-CI score in predicting outcomes after a second allogeneic HCT in pediatric recipients. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Development and validation of a mortality predicting scoring system for severe aplastic anaemia patients receiving haploidentical allogeneic transplantation.

Haploidentical allogeneic haematopoietic stem cell transplantation (haplo-HSCT) is a significant alternative treatment for severe aplastic anaemia (SAA). To improve this process by modifying the risk stratification system, we conducted a retrospective study using our database. 432 SAA patients who received haplo-HSCT between 2006 and 2020 were enrolled. These patients were divided into a training (n=288) and a validation (n=144) subset randomly. In the training cohort, longer time from diagnosis to transplantation, poorer Eastern Cooperative Oncology Group (ECOG) status and higher haematopoietic cell transplantation-specific comorbidity index (HCT-CI) score were independent risk factors for worse treatment-related mortality (TRM) in the final multivariable model. The haplo-HSCT scoring system was developed by these three parameters. Three-year TRM after haplo-HSCT were 6% [95% confidence interval (CI), 1-21%], 21% (95% CI, 7-40%), and 47% (95% CI, 20-70%) for the low-, intermediate-, and high-risk group, respectively (P<0·0001). In the validation cohort, the haplo-HSCT scoring system also separated patients into three risk groups with increasing risk of TRM: intermediate-risk [hazard ratio (HR) 2·45, 95% CI, 0·92-6·53] and high-risk (HR 11·74, 95% CI, 3·07-44·89) compared with the low-risk group (P=0·001). In conclusion, the haplo-HSCT scoring system could effectively predict TRM after transplantation.

A Refined Model of HLA-DP Permissiveness Improves Stratification of Acute Graft-Versus-Host Disease Risks after Unrelated Hematopoietic Cell Transplantation: A Retrospective Study from the CIBMTR

Introduction: Permissive HLA-DPB1 mismatches defined by the T-cell epitope (TCE) model are an established selection criterion for unrelated donors in allogeneic hematopoietic cell transplantation (alloHCT) (Dehn et al. Blood 2019). Based on biological evidence, the TCE model has classified HLA-DPB1 alleles into at least three functional groups, one of which (TCE group 3; TCE3) houses a large number of alleles with different structural and functional characteristics. We have recently shown that structurally close HLA-DP allotypes have similar peptide-binding motifs and share a significant proportion of their immunopeptidomes, the latter being fundamental for permissiveness (Meurer & Crivello et al. Blood 2021). Hence, we hypothesized that HLA-DPB1 mismatches involving alleles that encode structurally distant allotypes within TCE3 could be less permissive than those involving alleles that encode structurally closer allotypes, and thus have a differential impact on clinical outcomes.Methods: Multidimensional scaling techniques were used to compare 28 polymorphic positions (amino acids 8-215) among 51 alleles present in a cohort of 5,140 10/10 matched patient-donor pairs who received a first alloHCT for AML, ALL, or MDS between 2008-2017. Based on these analyses, TCE3-permissive mismatches (N=2,216) were further stratified into those involving structurally close or more distant combinations and compared with HLA-DPB1-matched (N=785) and non-permissively mismatched (N=2,023) pairs. These models were tested in parallel to the “classical” TCE model considering permissive mismatches (N=2,332) as a whole, to determine their association with overall survival (OS), disease-free survival (DFS), treatment-related mortality (TRM), primary disease relapse, and acute (a) and chronic (c)GVHD. Kaplan-Meier analysis and log-rank testing were used to compare the median OS and DFS. The incidences of GVHD, relapse and TRM were compared using competing risks and Gray's test. The effect of HLA-DPB1 mismatch on time-to-event outcomes was modelled by Cox regression after adjusting for confounders and testing for the proportional hazards assumption.Results: Within TCE3, we identified a subgroup of 4 frequent and structurally as well as functionally closely related alleles (i.e. DPB1*02:01, 04:01, 04:02, 23:01) that form a separate cluster (Figure 1A). These “core” alleles have similar bound-peptide motifs (van Balen et al. J Immunol 2020) and can be distinguished from other alleles in TCE3 in terms of the strength of in vitro alloreactive responses elicited from permissive responders (Meurer et al. Front Immunol 2018). Moreover, principal component analysis identified the HLA-DP 84-87 DEAV/GGMP motif as a major factor driving structural variability among TCE3 alleles (not shown). We used these observations to stratify TCE3 permissive mismatches in the allo-HCT cohort into “core” (N=930) and “non-core” (N=1,286) or into DEAV/GGPM-matched (N=1,209) and mismatched (N=1,007) pairs (Figure 1B).Multivariable analysis confirmed the association of aGVHD2-4 for the classical TCE model of non-permissive mismatching (p<.0001) and revealed a trend in DEAV/GGPM and “core”/“non-core” TCE3-permissive models. When compared to HLA-DPB1 allele matched pairs the risks of aGVHD2-4 increased progressively with “core” TCE3-permissive (HR 1.12 [0.98-1.28]; p=0.1012), “non-core” TCE3-permissive (HR 1.24 [1.06-1.46]; p= 0.0082), and non-permissive mismatches (HR 1.32 [1.16-1.50]; p<.0001) (Figure 1C, “core” vs. “non-core” HR 0.90 [0.80-1.01]; p=0.062). Similar albeit less significant results were obtained with the DEAV/GGPM model. The “core”/“non-core” TCE3 model was also associated with TRM with alloHCT from “core” TCE3-permissive donors showing lower risks of TRM than “non-core” TCE3-permissive (HR 0.82 [0.70-0.96]; p=0.0118) and non-permissive donors (HR 0.78 [0.68-0.88]; p=0.0002).Conclusion: Our results suggest that structural differences within TCE3 that reflect functional divergence and differential immunogenicity of alleles in this group associate with the risks of aGVHD and TRM after alloHCT. Hence, within the population of 10/10 matched donors, selection of “core” TCE3-permissive donors might reduce patient morbidity after transplantation. [Display omitted] DisclosuresPaczesny: Medical University of South Carolina: Patents & Royalties: inventor on the ST2 bispecific antibody patent application. Lee: AstraZeneca: Research Funding; Incyte: Research Funding; Janssen: Other; Kadmon: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Syndax: Research Funding; Takeda: Research Funding; National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding.

Comparative Outcomes of Central and Ultracentral Lung Tumors Managed With Five-Fraction Stereotactic Body Radiation Therapy

Central (CLT) and ultracentral (UCLT) lung tumors can be at higher risk for treatment related mortality following stereotactic body radiation therapy (SBRT) and the preferred dose and fractionation is unclear. We assessed the toxicity and outcomes of patients with CLT and UCLT who underwent definitive five-fraction SBRT.We reviewed the charts of patients with either CLT or UCLT managed with SBRT from June 2010-April 2019. CLT were defined as gross tumor volume within 2 cm of either the proximal bronchial tree, trachea, mediastinum, aorta, or spinal cord. UCLT were defined as GTV abutting any of these structures. Toxicity was graded by the Common Terminology Criteria for Adverse Events version 5.0. Propensity score matching was performed for gender, performance status, and history of prior lung cancer. Survival outcomes evaluated by Cox regression and Kaplan-Meier estimation.Within this cohort of 83 patients, the median age was 73.1 years with a median follow up of 29.9 months. All patients underwent 5 fraction SBRT, with dose range of 50-60 Gy. Most patients had T1 tumors (68.7%) and 43 (51.8%) were considered UCLT. In 20 (50%) patients with CLT, the proximal bronchial tree was the closest central structure while the aorta was the closest structure in 16 (37.2%) of UCLT patients. Grade 2+ toxicity was similar between the two groups, 11 (27.5%) for CLT and 13 (30.2%) (P = 0.78) for UCLT patients. Furthermore, there was no difference in grade 3 toxicity with 3 (7.5%) CLT and 4 (9.3%) UCLT patients (P = 0.77) and no observed grade 4+ events. There was no difference in crude local failure (5% vs 7.0%) (P = 0.34) or recurrence rates (22.5% vs 9.3) (P = 0.09). Multivariate analysis adjusting for gender, performance status, prior lung cancer, history of diabetes, history of heart disease, and prescription volume revealed UCLT to be associated with worse overall survival (OS) (P = 0.02) but not freedom from progression (FFP). Using propensity score match pairing, 29 match pairs were generated finding UCLT to correlate with reduced non-cancer related survival (NC-OS) and OS, but not FFP.Definitive 5 fraction SBRT yielded similar toxicity profiles for CLT and UCLT. Despite no difference in FFP, UCLT were associated with worse (NC-OS) and OS.

Abdominal Complications During Treatment for Pediatric Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) accounts for 15% to 20% of childhood leukemias. Because of high-intensive therapy, up to 5% of patients suffer from treatment-related mortality (TRM). Abdominal complications are frequent, however, literature on this subject is sparse. We aimed to characterize severe abdominal pain (AP) and hyperbilirubinemia experienced by pediatric AML patients treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO)-AML 2004 protocol (n=313). Patients were censored at hematopoietic stem cell transplantation and relapse. Toxicity information was collected prospectively. Additional information was requested retrospectively from the treating centers. Sixteen episodes of hyperbilirubinemia and 107 episodes of AP were reported. The treating centers deemed infection (30%) and typhlitis (18%) as the most frequent causes of AP. Six patients developed appendicitis (2%). Patients experiencing concurrent AP and sepsis had a high risk of TRM (36%, n=4). Eighty percent of episodes with hyperbilirubinemia fulfilled the European Society for Bone and Marrow Transplantation criteria for sinusoidal obstruction syndrome. In conclusion, abdominal complications were frequent with infection considered the predominate cause. Most patients with hyperbilirubinemia fulfilled the criteria for sinusoidal obstruction syndrome. AML treatment might be associated with appendicitis. Patients suffering from concurrent AP and sepsis had a high risk of TRM indicating that high awareness of abdominal complications is essential to reduce mortality, especially during sepsis.

Autologous Hematopoietic Cell Transplantation (HCT) Is Superior To Allogeneic Transplantation For Acute Promyelocytic Leukemia In Second Complete Remission (CR2)

Acute promyelocytic leukemia (APL) is often curable in adults. However, in 10-20% of patients with initial remission, leukemic relapse occurs. For these patients extended disease free survival is possible following stem cell infusion during second complete remission (CR2). The choice between allogeneic and autologous transplantion is dependent on the availability of suitable donors, the presence of minimal residual disease (MRD) and comorbid illnesses. The risks of treatment related mortality (TRM) associated with allografts must be balanced against a possible higher recurrence rate when autografts are used. To compare the utility of allogeneic and autologous transplantation in the arsenic era, we reviewed 294 patients with APL undergoing HCT in CR2 reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) from 1995 to 2006. Outcomes included overall survival (OS), disease free survival (DFS), relapse incidence, and TRM following either allogeneic or autologous HCT. The influence of pre-HCT molecular MRD status on outcome was examined in 114/232 allogeneic grafts and 41/62 autologous grafts. As summarized in Table 1, OS significantly favored autologous transplant, largely related to differences in TRM. Multivariate analysis confirmed that treatment failure was increased with age >40 years (HR=2.30, 95% CI 1.44-3.67, p= 0.0005), and after allogeneic HCT (HR=1.88, 95% CI=1.16-3.06, p=0.011). OS was significantly worse with allogeneic vs. autologous HCT (HR= 2.66, 95%CI 1.52-4.65, p=0.0006; age >40 (HR=3.29, 95% CI 1.95-5.54, p<0.001) and short CR1 (HR=1.56 95% CI 1.07-2.26, p=0.021). Relapse rates (RR) at 5 years were similar after autologous 30% (95% CI 19-42%) vs. allogeneic HCT (18% (95% CI 14-24%); adjusted HR=0.71, 95%CI 0.4-1.28, p=0.26). As expected, TRM in allogeneic was significantly higher at 31% (25-37) compared to autologous 7 % (2-17) with a HR of 7.07(2.56-19.57) P=0.0002. These results are summarized in Table 1. In patients with pre-HCT positive molecular or cytogenetic MRD, the allogeneic group (n=17) had a 5 year relapse rate of 27%, DFS 60%, and OS 65%. Notably, in MRD+ autologous group (n=6), only 1 relapsed at 6 months and died; 5 remain alive and disease-free at 47, 60, 61, 72, and 129 months after HCT. Surprisingly, pre-HCT molecular status did not influence relapse, treatment failure or OS in either group. Although the mechanism is not clear, this observation suggests effective eradication of residual disease in vivo. In this diverse cohort of patients, this retrospective study identifies that autologous transplantation offers superior overall survival when compared to allogeneic transplantation. The finding of long term survival in autologous transplanted patients with MRD+ grafting remains an important subject for further study.Table 1Outcome of Patients with APL Undergoing HCT in C2OutcomeAutoAlloP-valueOS54%(48-61)75%(68-85)0.02TRM31%(25-37)7%(2-17)<0.0001DFS50%(44-57)63%(49-75)0.10RR18%(14-24)30%(19-42)0.40 [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Abnormal Coagulation Function in CD19-Targeted CAR-T Therapy

Cytokine release syndrome (CRS), central nervous system (CNS) abnormalities and B-cell aplasia have been widely reported in recent clinical trials for chimeric antigen receptor T-cell (CAR-T) therapy. In our study, we also note that patients who received CAR-T therapy were easily to develop coagulopathy, even disseminated intravascular coagulation (DIC), which increased the risk of treatment related mortality (TRM) and required timely intervention. Therefore, it is important to pay attention to the symptom and find out the way to improve it.In our phase-1 clinical trial (NCT02965092) for B-cell acute lymphoblastic leukemia (B-ALL), we dynamically monitored the coagulation indicators and treated coagulopathy. Twenty-five patients (median age 28, [10-61]) were recruited into the trial and they underwent leukapheresis on day -11. Then they were subjected to the lymphodepleting regimens (fludarabine + cyclophosphamide, n=22; fludarabine, n=2; cyclophosphamide, n=1) on day -7~-5. Finally, they received the infusions of anti-CD19 CAR-T cells at a median dose of 4.5×106/kg (3.2-8.3×106/kg) on day 0~2. Excluding 3 patients who quitted from the trial for rapid progression of disease, and 3 patients who have not reached one-month follow-up time point yet, the overall one-month response rate for the evaluable 22 patients was 86.36%. Up to date, the longest leukemia free survival (LFS) was 16 months (median 5 months, [1-16]). As for side effects, 12 patients developed grade 2-3 CRS, 2 patients suffered from CNS symptoms, and no patients experienced serious infections. Besides, the obvious coagulopathy caught our attention. Eleven patients (11/22, 50%) developed coagulation dysfunction, manifested as petechiae and abnormal laboratory indicators (Table 1), such as deceased platelet count and fibrinogen, increased D-Dimer and fibrin degradation products, prolongations of activated partial thromboplastin time, prothrombin time and thrombin time. According to Chinese DIC Scoring System (CDSS), 5 of these 11 patients should be diagnosed as DIC (Table 2).Furthermore, we collected patients' plasma to measure the concentrations of tissue factor (TF) and platelet endothelial cell adhesion molecular-1 (PECAM-1), which are 2 vascular endothelial molecules that may play important roles in inflammation and coagulation. It was observed that coagulation disorders were more common in patients who developed severe CRS. Here we present the experiment results of 3 patients who experienced severe CRS and DIC at the same time. As shown in Figure 1, when the concentration of interleukin 6 rose and indicated CRS, the coagulopathy happened. At the same time, the TF concentration rose and PECAM-1 concentration dropped. Taken together, these data indicate that there is a relationship between CRS and DIC. We hypothesize that the cytokines released from inflammatory cells during CRS could cause dysfunction of endothelial cells and destroy the integrity of endothelial barrier, thus resulting in coagulopathy. However, the mechanism remains poorly understood, more in vivo experiments should be conducted to identify the mechanism, which may suggest novel therapeutic targets for coagulopathy.In conclusion, our data demonstrate that coagulation disorders are common side effects in CAR-T therapy, and suggest that TF and PECAM-1 are critical parameters in the pathogenesis of CRS-related coagulopathy. Investigators should pay more attention to coagulopathy and take preventive measures to avoid DIC. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

A Multicenter Nonrandom Clinical Study of Induction Regimen of FLAG-ID and Dae in the Treatment of Childhood De Novo Acute Myeloid Leukemia in South of China:the Early Report of Efficacy and Safety

Objective: Complete remission (CR) after induction chemotherapy was one of the important prognostic factors in the treatment of acute myeloid leukemia(AML). Intensive induction regimen have potential of increasing the CR rate, but also followed high risk of treatment related mortality (TRM). This multicenter nonrandom clinical study is to evaluate the early efficacy and safety of induction regimen of FLAG-IDA and DAE in the treatment of childhood de novo acute myeloid leukemia in south of China.Methods: Total of 135 newly diagnosed childhood AML patients come from 8 centers of south of China involved in the clinical study from November 2014 to January 2017.Eighty-three boys and 52 girls, median age 6 (1-14) year old were included. Patients with Down syndrome and acute promyelocytic leukemia were excluded. The median follow-up period was 12 (4 to 33) months till to June 2017.Thirty-seven patients (27.4%)had favorable cytogenetic karyotypes including t(8;21) and inv(16) but without FLT3-ITD, and c-KIT mutations. Sixty-one patients had unfavorable cytogenetic karyotypes including 11q23/MLL(non MLL-MLLT3) , FLT3-ITD, ASXL1 and c-KIT. Double FLAG-IDA courses(n=77) or DAE(3+5+10) followed DAE(3+5+8) course(n=58) by non random scheme admitted to patients for induction chemotherapy. The similarity of clinical data between two groups was analyzed by the chi square test. Complete remission (CR) rate, serious adverse event(SAE) and treatment related mortality (TRM) were studied by Log-Rank chi square test.Results:The FLAG-IDA and DAE group in gender, age, initial WBC count, morphological classification, risk classification,cytogenetics and molecular genes(favorable and unfavorable ) had no significant difference.The overall CR rates was 80.0% and 91.1% after 1st course and 2nd course respectively. CR rates of FLAG-IDA group is 83.1% and 96.1% after 1st and 2nd course.CR rates of DAE group is 75.8% and 84.5% after 1st course of DAE(3+5+10) and 2nd course of DAE(3+5+8).The remission rates of FLAG-IDA group was significantly superior than that of DAE group after 2 courses of induction treatment(P=0.03).The CR rates of patients with favorable cytogenetic karyotypes was significantly higher than patients with unfavorable cytogenetic karyotypes (100% vs 84.3%,P=0.012) after the first course. The SAE during induction chemotherapy included : 44 cases of sepsis (32.59%), 34 cases of invasive fungal disease (25.18%), 32 cases of abdominal infection (23.70%), 22 cases of severe pneumonia (16.30%),4 cases of heart failure (2.96%). Nine cases died (6.67% ) during induction chemotherapy.Moreover, the TRM in FLAG-IDA group were not different from DAE group in induction treatment.FLAG-IDA is an effective induction regimen with high CR rates after 2 courses of treatment and can be used as first line induction chemotherapy in childhood de novo acute myeloid leukemia in south of China. Severe infection and drug toxicity will be needed more strategies of prophylaxis and treatment. DisclosuresNo relevant conflicts of interest to declare.

Is the Outcome of Patients with High Risk T-Cell Acute Lymphoblastic Leukemia Improving in the Era of Pediatric—Inspired Protocols? a Comparison of 2 Consecutive Pethema Trials

BACKGROUND: Pediatric-inspired regimens have been adopted by several groups as the treatment strategy for adult patients with acute lymphoblastic leukemia (ALL). Whether subsequent modifications of these protocols have led to an improvement in the outcome of patients is uncertain. This is especially relevant in T-cell ALL, where barely no new drugs have been approved in recent years. The aim of the study was to compare the outcome of patients with high risk T-cell ALL included in 2 consecutive trials of the Spanish PETHEMA Group (ALL-HR03 [NCT00853008] and the more contemporary ALL-HR11 [NCT NCT01540812]).METHODS: Both ALL-HR03 and ALL-HR11 trials included pediatric-inspired regimens and have been published. Modifications in the ALL-HR11 protocol included a lower dose of daunorubicin in the induction phase, lower intensity of chemotherapy in the consolidation phase (except for a higher dose of MTX: 3g/m2 vs. 5g/m2) and a centralized review of minimal residual disease (MRD) by flow cytometry according to EuroFlow recommendations. In both trials, patients with poor clearance of MRD after induction or consolidation were assigned to receive allogeneic hematopoietic stem cell transplantation (allo-HSCT) in CR1 while patients with good clearance of MRD underwent subsequent delayed consolidation and maintenance with reinductions phases without allo-HSCT.RESULTS: One-hundred and sixty-nine patients with T-cell ALL were included (104 in the HR03 and 65 in the HR11). Patient- and disease-characteristics were balanced between both groups except for a longer follow-up time in patients included in the HR03 than in the HR11 (5.2 years [range 0.1-9.1] vs. 1.8 years [0.2-4.7], p<0.001).In terms of efficacy, the results are summarized in table 1. We observed a similar risk of slow cytologic response on day +14 of induction, complete remission (CR) rate and relapse in both protocols. Disease-free survival (DFS) in patients achieving CR was also similar in both groups. Patients included in the HR11 protocol had better 4-yr overall survival (OS) compared with the HR03 protocol (61% [95% CI 46%-76%] vs. 40% [95% CI 30%-50%], p = 0.026) (Figure 1).Regarding toxicity and after censoring the follow-up at the time of transplantation, the cumulative incidence of treatment-related mortality (TRM) at 5 years for all patients was 7% (95% CI 3%-12%). More patients died of TRM during induction (7% vs. 3%) and consolidation (6% vs. 0%) in the HR03 protocol than in the HR11, respectively (p = 0.05).Of the 152 patients achieving CR1 in both trials, 109 reached the time point for allocation to allo-HSCT in CR1 or chemotherapy (35 were assigned to allo-HSCT and 74 to chemotherapy). Patients assigned to allo-HSCT showed lower risk of relapse at 4-yrs (20% [95% CI 8%-37%] vs. 50% [95% CI 37%-62%], p = 0.005) but higher risk of TRM at 4-yrs (28% [95% CI 14%-45%] vs. 1% [95% CI 0%-7%], p < 0.001) than patients treated with chemotherapy alone. DFS at 4 years (52% [95% CI 34%-70%] vs. 49% [95% CI 36%-62%], p = 0.97) and OS at 4 years (51% [95% CI 31%-71%] vs. 67% [95% CI 55%-79%], p = 0.14) were similar in patients undergoing transplantation and chemotherapy (Figure 2).CONCLUSIONS: Patients with T-ALL included in the HR-11 trial showed better OS than patients in the HR-03 mainly due to lower treatment-related deaths. CR rate and DFS were similar in both protocols. Promising long-term survival can be achieved in patients with T-cell ALL and good MRD clearance throughout the treatment without the need of allo-HSCT in CR1. [Display omitted] DisclosuresMontesinos:Celgene Corporation: Honoraria, Research Funding. Ribera:Celgene: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Pfizer: Research Funding, Speakers Bureau; Incyte: Research Funding, Speakers Bureau; ARIAD: Research Funding, Speakers Bureau; Roche: Honoraria; Amgen Inc.: Research Funding, Speakers Bureau.

Adolescents and young adult acute myeloid leukemia outcomes at pediatric versus adult centers: A population-based study.

Adolescents and young adult (AYA) acute myeloid leukemia (AML) outcomes remain poor. The impact of locus of care (LOC; adult vs pediatric) in this population is unknown. The IMPACT cohort comprises detailed data for all Ontario, Canada, AYA aged 15-21 years diagnosed with AML between 1992 and 2012, linked to population-based health administrative data. We determined the impact of LOC on event-free survival (EFS) and overall survival (OS), treatment-related mortality (TRM), and relapse/progression. Among 140 AYA, 51 (36.4%) received therapy at pediatric centers. The five-year EFS and OS for the whole cohort were 35.0% ± 4.0% and 53.6% ± 4.2%. Cumulative doses of anthracycline were higher among pediatric center AYA [median 355mg/m2 , interquartile range (IQR) 135-492vs 202mg/m2 , IQR 140-364; P=0.003]. In multivariable analyses, LOC was not predictive of either EFS [adult vs pediatric center hazard ratio (HR) 1.3, 95% confidence interval (CI) 0.8-2.2, P=0.27] or OS (HR 1.0, CI 0.6-1.6, P=0.97). However, patterns of treatment failure varied; higher two-year incidence of TRM in pediatric centers (23.5% ± 6.0%vs.10.1% ± 3.2%; P=0.046) was balanced by lower five-year incidence of relapse/progression (33.3% ± 6.7%vs 56.2% ± 5.3%; P=0.002). AYA AML survival outcomes did not vary between pediatric and adult settings. Causes of treatment failure were different, with higher intensity pediatric protocols associated with higher TRM but lower relapse/progression. Careful risk stratification and enhanced supportive care may be of substantial benefit to AYA with AML by allocating maximal treatment intensity to patients who most benefit while minimizing the risk of TRM.

Comparative study on allogeneic with autologous hematopoietic stem cell transplantation in adult patients with Philadelphia chromosome–positive acute lymphoblastic leukemia in the era of TKIs: a systematic review and meta-analysis

In the era of tyrosine kinase inhibitors (TKIs), allogeneic hematopoietic stem cell transplantation (allo-HSCT) is recommended as a standard approach for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) achieving complete remission (CR). However, the role of autologous hematopoietic stem cell transplantation (auto-HSCT) in adult patients achieving complete molecular remission (CMR) is an alternative, less toxic treatment options, especially for the patients who lack suitable donors and are unfit for allo-HSCT. Thus, we conducted a systematic review and meta-analysis to compare the efficacy of allo-HSCT and auto-HSCT for the treatment of adult patients with Ph+ ALL. We searched the PubMed, Embase, Scopus, and Cochrane Library for studies published before June 2019 without language restriction. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for overall survival (OS) and relapse-free survival (RFS) and odds ratios (ORs) and 95% CIs for relapse rate (RR) and treatment-related mortality (TRM). Four prospective studies and one retrospective study were included with a total of 810 patients. We found auto-HSCT was superior to allo-HSCT in OS (HR = 1.42, 95% CI: 1.06-1.91, P = 0.02), and there was no difference between allo-HSCT and auto-HSCT for RFS (HR = 1.10, 95% CI: 0.86-1.40, P = 0.44) and RR (OR = 0.53, 95% CI: 0.22-1.26, P = 0.15). The risk of TRM for patients undergoing allo-HSCT was significantly higher than that of the patients who received auto-HSCT (OR = 5.06, 95% CI: 1.03-24.75, P = 0.05). Our meta-analysis shows that auto-HSCT may be an attractive and alternative treatment option for adult Ph+ ALL patients achieving CMR, with similar or better outcomes than allo-HSCT in the era of TKIs.

Intensive Care Outcomes of Patients after High Dose Chemotherapy and Subsequent Autologous Stem Cell Transplantation: A Retrospective, Single Centre Analysis.

High dose chemotherapy (HDT) followed by autologous peripheral blood stem cell transplantation (ASCT) is standard of care including a curative treatment option for several cancers. While much is known about the management of patients with allogenic SCT at the intensive care unit (ICU), data regarding incidence, clinical impact, and outcome of critical illness following ASCT are less reported. This study included 256 patients with different cancer entities. Median age was 56 years (interquartile ranges (IQR): 45–64), and 67% were male. One-year survival was 89%; 15 patients (6%) required treatment at the ICU following HDT. The main reason for ICU admission was septic shock (80%) with the predominant focus being the respiratory tract (53%). Three patients died, twelve recovered, and six (40%) were alive at one-year, resulting in an immediate treatment-related mortality of 1.2%. Independent risk factors for ICU admission were age (odds ratio (OR) 1.05; 95% confidence interval (CI) 1.00–1.09; p = 0.043), duration of aplasia (OR: 1.37; CI: 1.07–1.75; p = 0.013), and Charlson comorbidity score (OR: 1.64; CI: 1.20–2.23; p = 0.002). HDT followed by ASCT performed at an experienced centre is generally associated with a low risk for treatment related mortality. ICU treatment is warranted mainly due to infectious complications and has a strong positive impact on intermediate-term survival.

Modified Reduced Intensity Conditioning (RIC) of HLA-Haploidentical Related Hematopoietic Cell Transplantation (HAPLO-HCT) for Patients with Hematological Malignancies: Interim Analysis of an Age- and Risk-Adapted Phase II Trial

Use of full intensity conditioning regimens with haplo-HCT in younger patients lowered the risk of relapse; however, this is often not an option especially for older patients and for those with higher comorbidities due to high risk of treatment related mortality (TRM). Novel RIC regimens to reduce the risk of relapse and improve survival are in great demand. We hypothesize that intensification of the widely used PT-Cy RIC regimen (Flu150/Cy29/TBI 200) by adding intermediate dose melphalan and increasing the TBI to 400 cGy would reduce the risk of relapse and improve DFS without increasing TRM. We report an interim analysis of our age- and risk-adapted phase II trial. We treated 27 Haplo-HCT patients on one of 2 arms based on age and HCT-CI. Arm A (n=10) included patients The 12 month estimated DFS and OS were 80% vs 25 % and 90% vs 23% in Arms A and B, respectively. There was a significant correlation between advanced age and both DFS and OS. The 12-month TRM was significantly lower in Arm A vs Arm B; 10% and 69% respectively. Only 1 of 6 patients over age 65 survived. Grade II-IV acute GVHD occurred in 20% and 26% of patients in each arm. Neutrophil and platelet engraftment were prompt in both arms. Although follow-up is still short, the estimated 1-year relapse rates were low at 10% in Arm A and 6% in Arms B. This planned interim analysis demonstrated that patients