Cumulative Incidence Of Treatment-related Mortality Research Articles

Intensification of Therapy and Pharmacogenetic Personalization Mitigate Racial Disparities in Pediatric Acute Myeloid Leukemia Outcomes

Introduction Recent reports have highlighted disparities in outcomes for black children, adolescents, and young adults with acute myeloid leukemia (AML) compared to their non-Hispanic white counterparts. An analysis of pediatric AML patients treated from 1996-2013 revealed that black race was associated with inferior event-free survival (EFS) and overall survival (OS) (Conneely 2021). In a study of adolescent and young adult patients with AML, black race was a predictor of poor outcome, particularly among patients 18-29 years old (Larkin 2022). Addressing these outcome disparities and developing treatment strategies to overcome them is crucial. In this study, we evaluated the interactions between outcomes by race and cytarabine pharmacogenomics in pediatric AML patients treated on two multi-institutional clinical trials. Methods Pediatric patients with newly diagnosed AML treated on AML02 (NCT00136084) or AML08 (NCT00703820) were included. Patients received high-dose cytarabine, daunorubicin, and etoposide (HDAC), low-dose cytarabine, daunorubicin, and etoposide (LDAC), or clofarabine and cytarabine (Clo/AraC) as initial therapy. The pharmacogenomics ACS10 scores, derived from combination of 10 single nucleotide polymorphisms, were calculated as reported (Elsayed 2022). Results Overall, 86 patients were black and 359 were white; 68 had other or unknown racial backgrounds and were not included in this analysis. Complete remission rates after two courses of induction therapy did not differ between black and white patients (92.6% vs 95.0%, p=0.63), nor did the rates of MRD negativity after one course of therapy (55.8% vs 55.4%, p=0.85). The EFS rates of black and white patients were nearly identical, with 5-year estimates of 58.3% (95% CI = 48.8%-69.8%) and 58.2% (95% CI = 53.2%-63.6%; p=0.89, Fig 1). Likewise, OS did not differ between black and white patients (63.8%; 95% CI = 54.3%-74.8% vs 69.4%; 95% CI = 64.7%-74.5%; p=0.24). The cumulative incidence (CI) of relapse did not differ by race (26.0% vs 26.1%, p=0.99), nor did the CI of treatment-related mortality (7.0% vs 6.8%, p=0.78). The prevalence of core binding factor (CBF) leukemia was higher in black patients as compared with white patients (30% vs 19%, p=0.04), but we did not find differences in EFS between black and white patients with or without CBF AML. We recently showed that low ACS10 scores were associated with worse outcomes in patients treated with low-dose cytarabine-based induction. In the present study, there was a significant difference in the distribution of ACS10 scores according to race, with low scores occurring in 73% of black patients compared with 30% of white patients (p<0.001). When patients on all treatment regimens were considered, there were no differences in EFS between black and white patients with low (p=0.88) or with high ACS10 scores (p=0.72). However, black patients with low ACS10 scores had significantly better outcomes after treatment with Clo/Ara-C induction compared with LDAC induction (p=0.01 for EFS and p=0.04 for OS, Fig 2). In multivariable model adjusting for age, risk group, and leukocyte count, Clo/Ara-C induction was identified as the best treatment option for black patients with low ACS10 scores (EFS: HR = 0.2, p=0.03). Discussion Our findings contrast with recent reports, as we did not observe significant outcome differences between black and white patients in terms of complete remission rates, EFS, OS, CI of relapse, or CI of treatment-related mortality. The higher prevalence of low ACS10 scores in black patients compared with white patients likely contributes to outcome disparities observed among patients treated with LDAC in the present study and those in the literature, which have included patients who almost exclusively received low-dose cytarabine-based induction therapy. In the present study, black patients with low ACS10 scores had significantly worse outcomes compared to those with high scores when treated with LDAC. However, these differences in outcome were eliminated by the use of HDAC or Clo/Ara-C induction. By contrast, black patients with high ACS10 scores did not appear to benefit from HDAC or Clo/Ara-C induction. Our results suggest that pharmacogenomics differences between black and white patients should be considered when tailoring induction regimens to improve outcomes of black patients and bridge the racial disparity gap in AML treatment.

Excellent leukemia control after second hematopoietic cell transplants with unrelated cord blood grafts for post-transplant relapse in pediatric patients.

Patients with leukemia relapse after allogeneic hematopoietic cell transplant (HCT) have poor survival due to toxicity and disease progression. A second HCT often offers the only curative treatment. We retrospectively reviewed our bi-institutional experience (MSKCC-USA; Utrecht-NL) with unrelated cord blood transplantation (CBT) for treatment of post-transplant relapse. Overall survival (OS) and event-free survival (EFS) were evaluated using the Kaplan-Meier method, treatment-related mortality (TRM) and relapse were evaluated using the competing risk method by Fine-Gray. Twenty-six patients age < 21 years received a second (n=24) or third (n=2) HCT with CB grafts during the period 2009-2021. Median age at first HCT (HCT1) was 11.5 (range: 0.9-17.7) years and all patients received myeloablative cytoreduction. Median time from HCT1 to relapse was 12.8 (range 5.5-189) months. At CBT, median patient age was 13.5 (range 1.4-19.1) years. Diagnoses were AML: 13; ALL: 4, MDS: 5, JMML: 2; CML: 1; mixed phenotype acute leukemia: 1. Sixteen patients (62%) were in advanced stage, either CR>2 or with active disease. Median time from HCT1 to CBT was 22.2 (range 7-63.2) months. All patients engrafted after CBT. Thirteen patients developed acute GvHD; 7 had grade III or IV. With a median survivor follow-up of 46.6 (range 17.4-155) months, 3-year OS was 69.2% (95% CI 53.6-89.5%) and 3-year EFS was 64.9% (95% CI 48.8-86.4%). Eight patients died, 3 of AML relapse and 5 due to toxicity (respiratory failure [n=4], GvHD [n=1]) at a median time of 7.7 (range 5.9-14.4) months after CBT. Cumulative incidence of TRM at 3 years was 19.2% (95% CI 4.1-34.4%). Notably, all TRM events occurred in patients transplanted up to 2015; no toxicity-related deaths were seen in the 16 patients who received CBT after 2015. Cumulative incidence of relapse was 15.9% (95% CI 1.6-30.2%) at 3 years, remarkably low for these very high-risk patients. Survival was very encouraging following CB transplants in pediatric patients with recurrent leukemia after first HCT, and TRM has been low over the last decade. CBT needs to be strongly considered as a relatively safe salvage therapy option for post-transplant relapse.

Anakinra for Refractory Cytokine Release Syndrome or Immune Effector Cell-Associated Neurotoxicity Syndrome after Chimeric Antigen Receptor T Cell Therapy

Chimeric antigen receptor-engineered (CAR)-T cell therapy remains limited by significant toxicities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The optimal management of severe and/or refractory CRS/ICANS remains ill-defined. Anakinra has emerged as a promising agent based on preclinical data, but its safety and efficacy in CAR-T therapy recipients are unknown. The primary objective of this study was to evaluate the safety of anakinra to treat refractory CRS and ICANS after CAR-T therapy. The secondary objective was to evaluate the impact of key treatment-, patient-, and disease-related variables on the time to CRS/ICANS resolution and treatment-related mortality (TRM). We retrospectively analyzed the outcomes of 43 patients with B cell or plasma cell malignancies treated with anakinra for refractory CRS or ICANS at 9 institutions in the United States and Spain between 2019 and 2022. Cause-specific Cox regression was used to account for competing risks. Multivariable cause-specific Cox regression was used to estimate the effect of anakinra dose on outcomes while minimizing treatment allocation bias by including age, CAR-T product, prelymphodepletion (pre-LD) ferritin, and performance status. Indications for anakinra treatment were grade ≥2 ICANS with worsening or lack of symptom improvement despite treatment with high-dose corticosteroids (n=40) and grade ≥2 CRS with worsening symptoms despite treatment with tocilizumab (n=3). Anakinra treatment was feasible and safe; discontinuation of therapy because of anakinra-related side effects was reported in only 3 patients (7%). The overall response rate (ORR) to CAR-T therapy was 77%. The cumulative incidence of TRM in the whole cohort was 7% (95% confidence interval [CI], 2% to 17%) at 28 days and 23% (95% CI, 11% to 38%) at 60 days after CAR-T infusion. The cumulative incidence of TRM at day 28 after initiation of anakinra therapy was 0% in the high-dose (>200 mg/day i.v.) recipient group and 47% (95% CI, 20% to 70%) in the low-dose (100 to 200 mg/day s.c. or i.v.) recipient group. The median cumulative incidence of CRS/ICANS resolution from the time of anakinra initiation was 7 days in the high-dose group and was not reached in the low-dose group, owing to the high TRM in this group. Univariate Cox modeling suggested a shorter time to CRS/ICANS resolution in the high-dose recipients (hazard ratio [HR], 2.19; 95% CI, .94 to 5.12; P=.069). In a multivariable Cox model for TRM including age, CAR-T product, pre-LD ferritin level, and pre-LD Karnofsky Performance Status (KPS), higher anakinra dose remained associated with lower TRM (HR, .41 per 1 mg/kg/day increase; 95% CI, .17 to .96; P=.039. The sole factor independently associated with time to CRS/ICANS resolution in a multivariable Cox model including age, CAR-T product, pre-LD ferritin and anakinra dose was higher pre-LD KPS (HR, 1.05 per 10% increase; 95% CI, 1.01 to 1.09; P=.02). Anakinra treatment for refractory CRS or ICANS was safe at doses up to 12 mg/kg/day i.v. We observed an ORR of 77% after CAR-T therapy despite anakinra treatment, suggesting a limited impact of anakinra on CAR-T efficacy. Higher anakinra dose may be associated with faster CRS/ICANS resolution and was independently associated with lower TRM. Prospective comparative studies are needed to confirm our findings.

Cytomegalovirus infection is associated with rapid NK differentiation and reduced incidence of relapse in HLA matched sibling donor transplant patients.

The effect of cytomegalovirus (CMV) infection on leukemia relapse and the potential mechanism remains controversial. In this retrospective study, we evaluated the association among CMV infection, NK reconstitution and clinical outcomes in consecutive patients with hematologic malignancy who underwent HLA matched sibling donor transplantation (MST). In total, 228 patients were enrolled in the study between January 2010 and December 2011. The cumulative incidence of CMV infection on day 100 post-HSCT was 13.6 ± 4.9%. The probabilities of OS and DFS were 45.4% vs. 71.7% (P = 0.004) and 43.9% vs. 64.2% (P = 0.050) in the patients with CMV infection and without CMV infection, respectively. The cumulative incidence of treatment-related mortality (TRM) and relapse at 5 years was 48.6 ± 9.6% vs. 11.5 ± 2.9% (P < 0.001) and 6.2 ± 4.3% vs. 29.2 ± 3.9% (P = 0.024) in the patients with CMV infection and without CMV infection, respectively. In the multivariate analysis, CMV infection was associated with higher TRM, lower OS, and lower DFS. In addition, we found that CMV infection may promote the recovery of the absolute number of NK cells and promote the differentiation of NK cells post-MST. In conclusion, CMV infection may promote the recovery and differentiation of NK cells and was correlated with a lower relapse rate post-MST.

In Adults with Ph-Negative Acute Lymphoblastic Leukemia (ALL), Age-Adapted Chemotherapy Intensity and MRD-Driven Transplant Indication Significantly Reduces Treatment-Related Mortality (TRM) and Improves Overall Survival - Results from the Graall-2014 Trial

Background During the 2005-2014 period, the GRAALL conducted the GRAALL-2005 trial in patients (pts) with Philadelphia chromosome (Ph)-negative ALL aged 18-59y. In this trial, all pts received a pediatric-inspired chemotherapy, whatever their age. Post-hoc analysis revealed an unacceptable TRM in pts aged 45-59y (Huguet et al. J Clin Oncol 2018; 36:2514-23). Allogeneic hematopoietic stem cell transplantation (HSCT) was offered in first complete remission (CR) to most CR pts, defined at high-risk (HR) by at least one baseline clinical or biological HR factor (CNS involvement, complex karyotype [≥5 abns.], low hypodiploidy/near triploidy, poor early blast clearance, late CR, as well as WBC ≥ 30x109/L, lack of CD10 expression, KMT2A rearrangement or TCF3::PBX1 fusion for B-cell precursor [BCP] ALL). Minimal residual disease (MRD) response was not considered for HSCT indication at that time. In the next GRAALL-2014 trial conducted in a similar population, we introduced two major changes in the treatment strategy. First, chemotherapy intensity (steroids, anthracycline and L-asparaginase) was reduced in pts aged 45-59y to decrease excessive TRM. Secondly, the indication for HSCT was modified, relying on IG/TR MRD response only (post-induction MRD ≥10-3 and/or post-consolidation MRD ≥10-4) while not on any former baseline HR criterion. Here, we compare the outcomes of the two trials, focusing on the impact of these two major evolutions. Patients & Methods A total of 743 pts treated in the GRAALL-2014 trial between 2015 and 2020 were compared to the 787 pts from the historical GRAALL-2005 trial, in terms of CR and induction death rates, rate of HSCT in CR1, cumulative incidence of TRM (CITRM) and relapse (CIR), relapse-free (RFS) and overall (OS) survival. It should be noted that two nested Phase 2 trials were introduced by amendment during the GRAALL-2014 course (in 2017 and 2018, respectively), aiming to evaluate post-remission addition of nelarabine and blinatumomab in 87 T-ALL and 94 BCP-ALL selected pts, respectively. Results Main patient characteristics, including age, gender, BCP/T-ALL, WBC, and historical baseline HR features, did not significantly differ between the two trial cohorts, even if CNS disease at diagnosis was more frequent in the 2014 cohort (12 vs 7%, p= 0.001). Outcome comparisons are shown in Table 1. Overall, the induction death rate was significantly reduced in the GRAALL-2014 (3 vs 6%, p= 0.005). As expected, this was only observed in pts aged 44-59y (3 vs 11%, p= 0.001), in whom dose-intensity reduction also translated into a higher need for second induction course (9 vs 5%, p= 0.05) eventually resulting in a higher CR rate (92 vs 86%, p= 0.05). Due to the newly introduced MRD-based stratification, the rate of pts with HSCT indication was markedly reduced (30 vs 65%, p<0.001), especially in pts aged 18-44y (21 vs 40%, p<0001). Consequently, the rate of pts transplanted in CR1 dropped down from 38 to 23% (p<0.001). The GRAALL-2014 strategy also yielded a significant reduction in CITRM (5 vs 11% at 3 years; p<0.001; Figure 1B) after CR achievement. This reduction was more pronounced in pts aged 45-59y (7 vs 17%, p<0.001 compared to 4 vs 8%, p= 0.02 in 18-44y pts). This was associated with an increased CIR (35% vs 28% at 3 years; p= 0.01), with more late relapses as depicted in Figure 1A. Even if the resulting RFS was similar in both cohorts (59 vs 62% at 3 years; p= 0.77), OS was significantly longer in the GRAALL-2014 (71 vs 64%; p= 0.002) (Figure 1C) likely due to better post-relapse outcomes. When censoring those GRAALL-2014 pts who received nelarabine or blinatumomab in CR1, observations were basically unchanged, even if the difference in CIR was even more marked. Finally, using a 3-month RFS landmark in the 211 GRAALL-2014 pts eligible for HSCT in CR1 based on their poor early MRD response, HSCT significantly prolonged RFS (HR= 0.46 [95% CI, 0.27-0.78]; p= 0.004). Conclusions In adults with Ph-negative ALL enrolled in the GRAALL-2014, age-adapted chemotherapy intensity and MRD-driven indication for HSCT significantly reduced induction and post-remission TRM. This translated into a prolonged OS, indicating that this strategy was safe, despite a higher incidence of late relapses. Newly available salvage options along with HSCT in CR2 might also have played a role. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

An evaluation based on relative treatment intensity in older patients treated with reduced-dose R-THP-COP therapy for diffuse large B-cell lymphoma: A multicenter retrospective cohort study

IntroductionThe number of older patients with diffuse large B-cell lymphoma (DLBCL) is increasing. Although the standard treatment for newly diagnosed younger patients with DLBCL has been established, no consensus has been reached regarding the optimal chemotherapy intensity and regimen for older patients with DLBCL. In addition, no method for evaluating treatment intensity in retrospective studies when different numbers of chemotherapy courses are administered has been elucidated. Materials and MethodsA multicenter retrospective analysis was conducted to evaluate the outcomes of a reduced-dose R-THP-COP regimen, which included 30 mg/m2 of pirarubicin, in 54 patients with DLBCL who were aged ≥75. To assess treatment intensity, we defined the relative treatment intensity (RTI) as the number of courses administered multiplied by the relative dose intensity (RDI). ResultsThe estimated four-year overall survival rates (OS) of the patients aged 75–80 and ≥ 80 were 55.1% and 60.6%, respectively. There was no significant difference in four-year OS between these age groups. In our cohort, there was no significant difference in the estimated four-year OS between the patients who received reduced-dose R-THP-COP at an RDI of ≥61% and those that received it at an RDI of <61% (P = 0.35). On the other hand, the patients who received reduced-dose R-THP-COP at an RTI of ≥2.7 exhibited a significantly higher estimated four-year OS than those treated at an RTI of <2.7 (68.5% vs. 28.7%; P < 0.001). Multivariate analysis revealed that the RTI was a significant independent predictor of OS. The cumulative incidence of treatment-related mortality (TRM) at one year was 4.2% and 3.4% in the 75–80 and ≥ 80 age groups, respectively. The cumulative incidence of TRM was significantly worse among the patients with Charlson Comorbidity Index (CCI) scores of ≥2 than among those with CCI scores of 0 or 1. DiscussionOur study suggests that the reduced-dose R-THP-COP regimen is a suitable treatment option for older patients with DLBCL, especially those with CCI scores of <2. Our study also showed that the RTI may be a valuable tool for assessing treatment intensity in retrospective studies involving older patients.

Downregulation of the vitamin D receptor expression during acute gastrointestinal graft versus host disease is associated with poor outcome after allogeneic stem cell transplantation.

The vitamin D receptor (VDR) is critical in regulating intestinal homeostasis and emerging evidence demonstrates that VDR deficiency is a critical factor in inflammatory bowel disease pathology. However, no clinical data exist regarding the intestinal expression of VDR in patients after allogeneic haematopoietic stem cell transplantation (HSCT). Analyzing intestinal biopsies from 90 patients undergoing HSCT with mortality follow-up, we demonstrated that patients with severe acute gastrointestinal graft versus host disease (GI-GvHD) showed significant downregulation of VDR gene expression compared to mild or no acute GI-GvHD patients (p = 0.007). Reduced VDR expression was already detectable at acute GI-GvHD onset compared to GvHD-free patients (p = 0.01). These results were confirmed by immunohistochemistry (IHC) where patients with severe acute GI-GvHD showed fewer VDR+ cells (p = 0.03) and a reduced VDR staining score (p = 0.02) as compared to mild or no acute GI-GvHD patients. Accordingly, low VDR gene expression was associated with a higher cumulative incidence of treatment-related mortality (TRM) (p = 1.6x10-6) but not with relapse-related mortality (RRM). A multivariate Cox regression analysis identified low VDR as an independent risk factor for TRM (p = 0.001, hazard ratio 4.14, 95% CI 1.78-9.63). Furthermore, VDR gene expression significantly correlated with anti-microbial peptides (AMPs) gene expression (DEFA5: r = 0.637, p = 7x10-5, DEFA6: r 0 0.546, p = 0.001). In conclusion, our findings suggest an essential role of the VDR in the pathogenesis of gut GvHD and the prognosis of patients undergoing HSCT.

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.

The CIBMTR Chronic GVHD Risk Group Predicts Major Outcomes In An Independent Validation Cohort

The beneficial anti-leukemic effect of chronic GVHD (CGVHD) is offset by an increased risk of late treatment-related mortality (TRM). Several clinical risk factors have been identified as predictors of outcomes in patients with CGVHD. We previously identified 10 variables significantly associated with TRM and survival in5343 patients with CGVHD transplanted between 1995 and 2004. We then developed a CGVHD CIBMTR risk score using these variables (Arora, M., et al.: Blood, 2011; 117: 6714-6720). Variables included in the score were age, prior acute GVHD, time from HCT to CGVHD, donor type, disease status at transplant, GVHD prophylaxis, gender match, serum bilirubin and Karnofsky score and platelet count at time of diagnosis of CGVHD. Six risk-groups were identified with powerful discriminative ability to predict TRM and survival. In the current study we sought to validate this risk score in an independent dataset of 1007 patients with CGVHD transplanted between 2005 and 2007 using the same inclusion criteria and risk-score calculations. Patients were divided into 4 risk groups (RGs) according to the sum of the overall risk score: RG1 (0-2), RG2 (3-6), RG3 (7-8) and RG4 (9-10) (Table), and cumulative incidences of TRM and survival were calculated. TRM and survival at 12 and 24 months after CGVHD for each RG are shown in the Table. We found a strong correlation between CGVHD RG with TRM (p<0.0001) and survival (p<0.0001). Also, TRM and survival were significantly different between each RG (Figure and Table). Our study validates the prognostic value of the CIBMTR CGVHD RGs for OS and TRM in a contemporary transplant population. The CIBMTR CGVHD RGs can be used to predict major outcomes and tailor treatment planning. [Display omitted] TableOutcomes by Risk Group, according to CGVHD CIBMTR risk-score (RS)Adjusted Overall Survival, (95% CI) after CGVHDAdjusted Cumulative Incidence, TRM, (95% CI) after CGVHDRisk GroupOverall RSPatients, n (%)12 months24 months12 months24 months10-2213 (21)88 (84-93)80 (75-86)6 (3-10)9 (5-13)23-6684 (68)74 (71-77)64 (60-67)15 (18-33)20 (17-23)37-899 (10)44 (34-54)37 (28 -48)33 (24-42)37 (28-46)49-1011 (1)43 (14-73)43 (14-73)39 (16-63)39 (16-63) Disclosures:No 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.

The Role of Matrix Metalloproteinase-9 in Monocytic Myeloid-Derived Suppressor Cells in Allogeneic Hematopoietic Stem Cell Transplantation

Background: Myeloid-derived suppressor cells (MDSCs) have emerged as a heterogeneic immunoregulatory population that accumulate in large numbers during many pathologic conditions, including cancer, infectious diseases, trauma, and sepsis. Given that MDSCs are an important element of a cellular network regulating immune responses, their recovery early after allogeneic hematopoietic stem cell transplantation (allo-HSCT) seems to be related to regulating graft-versus-host disease (GVHD) and/or immune reconstitution. However, the nature of these cells remains controversial in terms of clinical allo-HSCT. Therefore, we conducted a large prospective analysis of patients undergoing allogeneic HSCT for hematologic malignancies to evaluate MDSC recovery and function in the proinflammatory milieu post-transplant, and its immune suppressive mechanisms.Methods: We examined the expansion of circulating monocytic (M-) MDSCs and granulocytic (G-) MDSCs at the time of engraftment in 130 patients undergoing allo-HSCT. Further, we investigated differentially expressed genes between G-MDSCs and M-MDSCs by transcriptome resequencing and characterized the molecular functions using carboxyfluorescein succinimidyl ester (CFSE) assay.Results: The high M-MDSC group had a higher infection rate within 100 days, worse 1-year cumulative incidence of treatment-related mortality (TRM) and 2-year probability of event-free survival (EFS) compared to those with low M-MDSC group. The frequency of M-MDSCs was associated with preceding severe mucositis. Transcriptome profiling analysis of 2 isolated subtypes of MDSCs showed that matrix metalloproteinase-9 (MMP-9) was expressed much more highly in M-MDSCs than in G-MDSCs. The high expression of MMP-9 (P<0.001)and its upstream genes, including ARRB2 (P = 0.010) and F2RL1 (P = 0.024), in M-MDSC was confirmed using qRT-PCR. Moreover, MMP-9 concentrations in cell lysates (P < 0.001) and in culture supernatants (P = 0.001) were much higher in M-MDSCs than G-MDSCs, as shown by ELISA.Importantly, M-MDSCs isolated from patients post-HSCT had a higher capacity to suppress T cell responses than did G-MDSCs, and MMP-9 blockade more forcefully inhibited the immunosuppressive effect of M-MDSCs than that of G-MDSCs. Ultimately, the patients with high serum levels of MMP-9 had significantly higher infections within 100 days (P = 0.015), TRM by 1 year (P = 0.001) and a trend toward reduced EFS (P = 0.055) compared to those with low MMP-9.Conclusion: Our data demonstrated that early expansion of M-MDSCs was associated with early infections and poorer clinical outcomes than was expansion of G-MDSCs. Post-HSCT M-MDSCs exhibited increased levels of matrix metalloproteinase-9 (MMP-9), which might play a key role in worsening post-transplant infections and, ultimately, survival outcomes. DisclosuresKim:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Il-Yang: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

#45: Reopening a Successful Stem-cell Transplantation Unit in a Public Children’s Hospital in La Plata, Argentina

Abstract Background Hematopoietic stem cell transplantation (HSCT) is challenging because of economic, educational, and organizational reasons. Argentina is a middle-income country. HSML is a public pediatric hospital with an HSCT unit halted its services in July 2014. Among the reasons for suspending the services were healthcare providers(HCP) burn out, miscommunication, and tasks breakdown. The HSCT service resumed in December 2014. Objectives The primary objective was to describe and share the experiences in resuming the HSCT service by using a multicomponent strategic plan and interventions. The secondary objective was to review the outcomes. Methods Our strategic plan consisted of four main components: (1) Use of quality improvement tools for quality assessment and management (Six Sigma quality improvement processes, root-cause analysis, process maps, and brain storming); (2) participate in international collaborative networks (St. Jude Global Alliance and PRINCIPAL networks, the BFM-Forum-SCT, Sick-Kids Hospital, Canada); (3) participate in national and international training programs; and (4) improve healthcare delivery and organization processes, including infection care and prevention (develop and standardize all HSCT care delivery procedures). Results and Outcomes Healthcare facilities and services auditing and accreditation: An infection prevention and control program was started. This program managed: air and ventilation system improvement (air-conditioning, HEPA filters, positive pressure) and the creation of 47 standardized operating procedures. The HSCT wards were audited 3 times, and received accreditation (2018) by a national accreditation agency in Argentina. Human resources: 7 new doctors and 4 nurses were hired, the nurse:patient ratio was 1:2. 4 doctors attended a course for SPSS software®management; 6 doctors attended different American Society of Hematology H-Clinical Research Institute meetings. Personnel felt a reduction in the level of burn-out after the implementation of a plan designed by all stakeholders. Family information: 28 families received training for management of immunosuppressed patients. Scientific production: 4 clinical trials were accepted in indexed journals, 23 abstracts were presented in scientific meetings, and 27 educational national and international meetings were attended by personnel. Data management: Creation of a patient database (n = 310 patients), and registration of infection episodes for monthly assessment and monitoring patterns of infections (n = 776 events). Outcomes: During 2015–2019, 73 children were transplanted: autologous 11 (15%), match sibling donor (MSD) 35 (48%) and match unrelated donors (MUD) 27 (37%) Median age was 6 years of age (IQR 2–9), 53% were male, and 60% were acute leukemias. At a mean median time of 12 months (IQR 5–18), the overall survival by Kaplan–Meier for MSD and MUD was similar (62.3 ± 10.7% and 54.2 ± 15.0%, log-rank P = 0.54). The cumulative incidence of treatment-related mortality (log-rank P = 0.31), cumulative incidence of relapse (LR P = 0.99) were comparable as well. Infection rates were 40.5% and 69.6% in MSD vs. MUD (OR 3.36; 95% CI 1.14–9.98; P = 0.038). Conclusion The strategic plan implemented allowed us to offer optimal care to children in a public hospital without further financial cost and more satisfied HCPs. Results are comparable to published literature. Implementation of quality improvement interventions leads to the success of our program. Education and collaboration with national and international networks assisted improvement of the standard of care.

Possible clinical outcomes using early enteral nutrition in individuals with allogeneic hematopoietic stem cell transplantation: A single-center retrospective study.

Intensive nutritional support during allogeneic hematopoietic stem cell transplantation (allo-HSCT) yields improved clinical outcomes. However, the clinical implications of early enteral nutrition (EN) in allo-HSCT remain unclear. This retrospective study was conducted to determine the significance of early EN in individuals who underwent allo-HSCT, and the association between early nutritional intervention and clinical outcomes, including the status of the intestinal microbiome. Thirty-one participants received EN before conditioning. The intestinal microbiota was examined by meta 16S rRNA gene sequencing of fecal samples. The median body mass variation was only -0.35 kg on day 60. The probability of 2-y overall survival was 61.1%. The cumulative incidence of treatment-related mortality was 17.4%, and those of acute graft-versus-host disease were 32.3% (grades II-IV) and 3.2% (grades III-IV). Chronic graft-versus-host disease was observed in four participants. Dysbiosis of the intestines and acute graft-versus-host disease occurred simultaneously, and Enterococcus species were abundant. Our results suggest that early nutritional support can improve the outcomes for individuals who have undergone allo-HSCT and can maintain homeostasis of their intestinal microbiome. Future prospective clinical trials are required to elucidate the role of EN in allo-HSCT and the association between the intestinal microbiome and EN.

Reduced Toxicity Conditioning for Nonmalignant Hematopoietic Cell Transplants.

Allogeneic hematopoietic cell transplantation (HCT) for children with nonmalignant disorders is challenged by potential drug-related toxicities and poor engraftment. This retrospective analysis expands on our single pediatric medical center experience with targeted busulfan, fludarabine, and intravenous (IV) alemtuzumab as a low-toxicity regimen to achieve sustained donor engraftment. Sixty-two patients received this regimen for their first HCT for a nonmalignant disorder between 2004 and 2018. Donors were matched sibling in 27%, 8/8 HLA allele-matched unrelated in 50%, and 7/8 HLA allele-mismatched in 23% (some of whom received additional immunoablation with thiotepa or clofarabine). Five patients experienced graft failure for a cumulative incidence of 8.4% (95% CI, 1 to 16%). In engrafted patients, the median donor chimerism in whole blood and CD3, CD14/15, and CD19 subsets at 1-year were 96%, 90%, 99%, and 99%, respectively. Only one patient received donor lymphocyte infusions (DLIs) for poor chimerism. Two patients died following disease progression despite 100% donor chimerism. The 3-year cumulative incidence of treatment-related mortality was 10% (95% CI, 2 to 17%). Overall survival and event-free-survival at 3-years were 87% (95% CI, 78 to 95%) and 80% (95% CI, 70 to 90%), respectively. The 6-month cumulative incidence of grade II to IV acute graft-versus-host disease (GVHD) was 7% (95% CI, 3 to 13%), while the 3-year cumulative incidence of chronic GVHD was 5% (95% CI, 0 to 11%). These results suggest that use of targeted busulfan, fludarabine and IV alemtuzumab offers a well-tolerated option for children with nonmalignant disorders to achieve sustained engraftment with a low incidence of GVHD.

Superior Graft-Versus-Leukemia Effect in Haploidentical Transplantation Compared with HLA-Matched Sibling Transplantation for High-Risk Acute Myeloid Leukemia in First Complete Remission: A Prospective Multicentre Cohort Study

This study aimed to investigate graft-versus-leukemia (GVL) of haploidentical donor (HID) compared with HLA-matched sibling donor (MSD) for high-risk acute myeloid leukemia (H-AML) in first complete remission (CR1). One hundred and eighty-nine patients with H-AML in CR1 were enrolled in this multicentre prospective cohort study. Patients were assigned to groups transplanted with HID (n=83) or MSD (n=106) based on donor availability (biological randomization). The primary endpoint was the incidence of MRD positivity post-transplantation (post-MRD+). All post-MRD+ patients received preemptive interventions. The cumulative incidences of post-MRD+ were 18% and 42% in HID and MSD groups, respectively, (p&lt;.001). Fifty-two patients received preemptive DLI, including 13 (16%) in HID and 39 cases (37%) in MSD groups (p=.001). Among HID and MSD groups, the 3-year cumulative incidence of relapse were 14% and 24% (p=0.101); the 3-year cumulative incidence of treatment-related mortality were 15% and 10% (p=0.368); the 3-year overall survival rates were 72% and 68% (p=0.687); the 3-year disease-free-survival were 71% and 66% (p=0.579); the 3-year graft-versus-host disease and relapse free survival were 63% and 43% (p=0.035), respectively. HID has a stronger GVL than MSD in H-AML patients. HID transplantation as post-remission therapy should be recommended as one of the optimal choices for H-AML in CR1. Disclosures No relevant conflicts of interest to declare.

Reduced Toxicity Conditioning for Non-Malignant Hematopoietic Cell Transplants

Background. Reduced-intensity conditioning (RIC) regimens are commonly used for hematopoietic cell transplantation (HCT) in non-malignant disorders to minimize potential drug-related toxicity from myeloablative conditioning (MAC). However, melphalan-based RIC regimens are associated with poor engraftment and need for second HCT or donor lymphocyte infusions (DLIs). This study expands on our previous experience with targeted busulfan, fludarabine, and intravenous (IV) alemtuzumab as a low-toxicity but myeloablative regimen to achieve sustained donor engraftment. Methods. We conducted a retrospective analysis of patients ≤25 years of age with non-malignant disorders who received targeted busulfan, fludarabine and IV alemtuzumab as conditioning for their first HCT between 2004 and 2018. Graft-versus-host disease (GVHD) prophylaxis included calcineurin inhibitors in all patients, plus methotrexate (n=59), methylprednisolone (n=2), or mycophenolate (n=1). The primary end point was 3-year overall survival (OS). Secondary end points included treatment-related mortality (TRM), event-free survival (EFS) defined as alive without second HCT or disease progression, and incidence of acute and chronic GVHD (aGVHD and cGVHD). Other end points included incidence of graft failure (GF) defined as &lt;5% donor chimerism in whole blood, sinusoidal obstruction syndrome (SOS) and CMV viremia. Analysis was stratified by era of HCT (2004-2011 vs. 2012-2018). Results. We identified 62 patients with a median age of 5.5 years and male:female of 46:16. Diagnoses included primary immune deficiencies (60%), hemoglobinopathies (22%), bone marrow failure disorders (8%) and inherited metabolic disorders (10%). The median busulfan cumulative area-under-the-curve (cAUC) was 70 mg*h/L (range, 57-108 mg*h/L). Donors were matched sibling (MSD) in 27%, 8/8 allele-matched unrelated (MUD) in 50% and Class I allele-mismatched (MM) in 23%. All but 2 of the Class I allele-MM donors were unrelated. The source was bone marrow (BM) in 74% and peripheral blood stem cells (PBSC) in 26%. The cumulative incidence (CI) of GF was 8% (95% CI, 1-16%). In engrafted patients, the median donor chimerism in whole blood, CD3, CD14/15, and CD19 at 1-year was 96%, 90%, 99%, and 99%, respectively. Only 1 patient required DLIs for poor chimerism. T-cell reconstitution (CD4 &gt;200 x 109/L and PHA response &gt;50% control) was achieved at a median of 182 days (range, 76-585 days). Two patients died following disease progression despite 100% donor chimerism. The CI of TRM was 10% (95% CI, 2-17%). Causes of TRM included infectious complications (n=2), hemorrhage (n=1), respiratory failure (n=3 with 2 following subsequent transplants after graft rejection). TRM incidence was significantly higher in patients with Class I MM compared to those with MSD or 8/8 allele-MUD (29% vs 6% vs 3%; p=0.024; Figure 1A). SOS occurred in 5% of patients and all resolved with supportive therapy (n=1) or defibrotide (n=2). Post-transplant CMV viremia occurred in 26% of all patients and in 71% of CMV seropositive patients. None developed CMV disease and all infections resolved with anti-viral therapy. OS and EFS at 3-years were 87% (95% CI, 78-95%) and 80% (95% CI, 70-90%), respectively. HCTs performed in the more recent era showed an OS of 97% compared to 79% in HCTs performed earlier (p=0.057; Figure 1B). OS was 97% in patients with 8/8 allele-MUD compared to 79% in those with MSD and 71% in those with Class I allele-MM (p=0.051). The 6-month CI of grade II-IV aGVHD was 7% (95% CI, 3-13%), while the 3-year CI of cGVHD was 5% (95% CI, 0-11%). GVHD incidence was higher in patients receiving PBSC compared to BM (25% vs 0%; p&lt;0.001) and in patients ≥5 years of age compared to those &lt;5 years of age (13% vs 0%; p=0.043). Patients with inherited metabolic disorders showed significantly worse OS (44%, p=0.016), EFS (33%, p=0.001) and aGVHD (33%, p=0.008) than those in other disease groups. Univariate analysis did not show any significant differences in survival or GVHD incidence by race or sex. Conclusions. Use of targeted busulfan, fludarabine and IV alemtuzumab as myeloablative conditioning in pediatric patients with primary immunodeficiencies, hemoglobinopathies, and bone marrow failure syndromes undergoing matched sibling or well-matched unrelated donor HCT provides a well-tolerated option to achieve sustained engraftment with low incidence of GVHD and toxicities such as SOS. Figure 1 Disclosures Shimano: Pfizer: Research Funding; Daiichi Sankyo: Research Funding; Novartis: Research Funding. Huang:Novartis: Research Funding. Cowan:Homology Medicine: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Leadiant: Consultancy; California Institute Of Regenerative Medicine: Research Funding; NIH NIAD: Research Funding; Rocket Pharma: Consultancy; UpToDate: Honoraria; bluebird bio: Consultancy. Dvorak:Alexion Inc: Consultancy; Jazz Pharmaceuticals: Consultancy.

Association of Sarcopenia with Toxicities and Survival after Autologous Hematopoietic Stem Cell Transplantation for Adults with Lymphomas

Introduction: Sarcopenia, defined as low muscle mass and low muscle function and/or reduced physical performance, has been identified as a potential risk factor for adverse outcomes in a variety of conditions like elderly patients and patients with solid tumors. However, fewer studies assessed this association in patients undergoing autologous hematopoietic stem cell transplantation (autoHSCT). With this aim, we performed a retrospective study to evaluate the effect of sarcopenia on complications (such as toxicities, infections and intensive care unit - ICU - admission) and survival after autoHSCT for adults with lymphoma.Methods: We enrolled 135 patients with lymphoma who underwent autoHSCT between January, 2014 and December, 2017, in a single center. Computed tomography (CT) imaging scans were used for muscle mass analysis. Skeletal muscle area (SMA, cm2) was measured on axial CT images at the level of the third lumbar vertebra (L3) using appropriate software (Slice O´Matic, Tomovision, CA). SMA was normalized for height to obtain the skeletal muscle index (SMI, cm2/m2). We set our own cut-off values at lowest specific tertiles of SMI based on sex and body mass index (BMI, Kg/m2) for diagnosing sarcopenia. Sarcopenia was defined in this cohort as SMI <46 cm²/m² if BMI <25 kg/m² or <51 cm²/m² if BMI ≥25 kg/m² in men, and ≤41.5 cm²/m² in women. Toxicities (overall, renal, hepatic and gastrointestinal) after autoHSCT were graded according to the National Cancer Institute Common Toxicity Criteria (version 4.0). In addition, infections and ICU admission were also analyzed. Patients with previous autoHSCT CT scans more than 120 days were excluded. Probabilities of overall survival (OS), event-free survival (EFS) and treatment-related mortality (TRM) were calculated according to the Kaplan-Meier method. Unadjusted and adjusted analyses were conducted by using Logistic Regression models to determine the association of covariates with outcome. The significance level was adopted at p<0.05.Results: A total of 110 patients met the eligibility criteria (39 sarcopenic and 71 non-sarcopenic). Mean age at transplant was similar in both groups (43 years, p=0.96), with 18% of elderly. The majority of patients was male (65%) and had an aggressive disease at diagnosis (77%). Sarcopenics had a higher Charlson comorbidity index (≥3) at transplant than non-sarcopenics (p=0.02). The conditioning regimen used was different between groups, with a higher proportion of bussulfan-based conditioning in the sarcopenic group (p=0.04). Table 1 list characteristics between sarcopenics and non-sarcopenics patients. Neutrophil recovery was achieved at a median time of 11 days after transplant in both groups (p=0.55). We found association between grade 3-4 gastrointestinal toxicity and sarcopenia (44% vs. 24%; OR 2.46, CI95% 1.07-5.66, p=0.03), although, after adjustment by conditioning regimen, no significant difference was detected (OR 2.09, CI95% 0.89-4.97, p=0.10). No statistically differences were detected in ICU admission, occurrence of infection, hepatic, renal or overall toxicities. Median follow-up of survivors was 20 months (range, 1-50). The 2-years OS and EFS were 72% (CI95% 61-81; sarcopenic 70% [50-84] vs. non-sarcopenic 74% [59-84], p=0.99) and 62% (CI95% 51-71; sarcopenic 68% [49-81] vs. non-sarcopenic 59% [46-70], p=0.37), respectively. The cumulative incidence of TRM was 6.5% at day 100 (CI95% 2.5-11.9; sarcopenic 5.1% [1.3-19.0] vs. non-sarcopenic 5.7% [2.2-14.5], p=0.70).Conclusion: In our study, sarcopenia was not statistically associated with severe toxicity and higher mortality. To the best of our knowledge, this is the first study to assess CT images and compare sarcopenia with toxicity in aHSCT for lymphoma. Prospective studies are needed to investigate the real impact of sarcopenia on outcomes after autologous transplantation. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Treatment-related mortality in newly diagnosed pediatric cancer: a population-based analysis.

Using a previously developed reliable and valid treatment‐related mortality (TRM) definition, our objective was to describe the proportion of children newly diagnosed with cancer experiencing TRM and to identify risk factors for TRM in a population‐based cohort. We included children with cancer <19 years diagnosed and treated in Ontario who were diagnosed between 2003 and 2012. Children with cancer were identified using data in a provincial registry. Cumulative incidence of TRM was calculated where progressive disease death was considered a competing event. Among the 5179 children included, 179 had TRM, 478 died of progressive disease, and 4522 were still alive. At 5 years, the cumulative incidence of TRM among the entire cohort was 3.9% (95% confidence interval (CI) 3.3–4.5%). When compared to brain tumor patients, leukemia and lymphoma patients had a significantly higher risk of TRM (hazard ratio (HR) 2.5, 95% CI: 1.6–4.0; P < 0.0001). Infants were at significantly higher risk of TRM across diagnostic groups. Other factors associated with higher risks of TRM were metastatic disease (P < 0.0001), diagnosis prior to 1 January 2008 (P = 0.001), hematopoietic stem cell transplantation (HSCT) (P < 0.0001), and relapse (P < 0.0001). The 5‐year cumulative incidence of TRM was 3.9% among newly diagnosed children with cancer. Infants were at higher risk of TRM across diagnostic groups. Other risk factors for TRM were leukemia or lymphoma, metastatic disease, earlier diagnosis year, HSCT, and relapse. Future work should further refine prognostic factors by specific cancer diagnosis to best understand when and how to intervene to improve outcomes.

474 - High Calculated Glomerular Filtration Rate is Associated with Treatment-Related Mortality in Older Adults Undergoing Allogeneic Hematopoietic Cell Transplantation

Background: Older adults are undergoing allogeneic hematopoietic cell transplant (allo-HCT) at historically unprecedented rates. However, identifying older adults at high risk for adverse outcomes remains a challenge. Hypothesis: High calculated glomerular filtration rate (GFR) at the time of transplant admission (TxA) is a surrogate marker for low muscle mass and predicts treatment-related mortality (TRM). Methods: All patients age 65 who underwent allo-HCT at Washington University School of Medicine between October 2012 and June 2017 were retrospectively screened for inclusion. Patients with previous allo-HCT, HLA mismatched unrelated donors and donor-specific antibodies were excluded. GFR was calculated using the Modified of Diet in Renal Disease formula. Patients were stratified into four groups: Low (GFR < 60), Intermediate (60-90), High (90-120) and Very High (>120). The primary outcome was the cumulative incidence of TRM, which was defined as any death prior to day +28 and any death following day +28 without relapse. Relapse was treated as a competing risk. The secondary outcome was overall survival (OS). Results: 127 patients were identified. Median follow up was 6.4 and 15.2 months in all patients and surviving patients, respectively. 23, 68, 29 and 7 patients were in the Low, Intermediate, High and Very High GFR groups at TxA. GFR group was not associated with any baseline demographic or clinical characteristic with the exception of KarnofksyPerformance Score (KPS) (P = .02) (Table 1). TRM at 2 years was significantly different between Low (38%, 95% C.I. 16%-59%), Intermediate (31%, 95% C.I. 19%-43%), High (48%, 95% C.I. 27%-70%) and Very High (71%, 95% C.I. 28%-100%) GFR groups (P = .02) (Figure 1). Similarly, OS was significantly different among the groups (P = .02). On pairwise analysis, Very High GFR was associated with inferior survival compared to all other groups (all P < .01). High GFR was associated with inferior survival compared to Intermediate GFR (P = .046). After adjusting for KPS, Very High GFR continued to be associated with inferior OS (aHR: 4.58, 95% C.I. 1.9-10.9) compared to Intermediate GFR.Table 1Demographics and Clinical Characteristics.GFR CategoryLowIntermediateHighVery HighTotal2368297Age*68 (65-75)68 (65-75)68 (65-76)67 (65-73)Male Gender13 (57)43 (63)20 (69)3 (43)Caucasian22 (96)64 (94)28 (97)7 (100)HCT CI 02 (9)9 (13)3 (10)0 (0) 1 to 25 (22)12 (18)6 (21)3 (43) ≥316 (70)47 (69)20 (69)4 (57)KPS < 9011 (48)31 (46)21 (72)6 (86)*Median (range). Open table in a new tab *Median (range). Conclusion: High GFR was associated with inferior outcomes following allo-HCT. Consequently, GFR at TxA may provide novel information to identify older adults at high risk for TRM during allo-HCT. Larger studies are needed to evaluate this association and prospective studies are needed to evaluate possible interventions to decrease TRM in at-risk patients.

Matrix Metalloproteinase-9 in Monocytic Myeloid-Derived Suppressor Cells Correlate with Early Infections and Clinical Outcomes in Allogeneic Hematopoietic Stem Cell Transplantation

The recovery of myeloid-derived suppressor cells (MDSCs) and its relevance in clinical acute graft-versus-host disease (GVHD) and post-hematopoietic stem cell transplantation (HSCT) infections remain to be fully characterized. We examined the expansion of circulating monocytic (M-) MDSCs and granulocytic (G-) MDSCs at the time of engraftment in 130 patients undergoing allogeneic HSCT (allo-HSCT). Compared with the G-MDSC group, the high M-MDSC group had a higher infection rate within 100 days, along with worse 1-year cumulative incidence of treatment-related mortality (TRM) and 2-year probability of event-free survival (EFS). The frequency of M-MDSCs was associated with preceding severe mucositis. Transcriptome profiling analysis of 2 isolated MDSC subtype showed significantly greater matrix metalloproteinase-9 (MMP-9) expression in M-MDSCs than in G-MDSCs. M-MDSCs produced abundantly more MMP-9. Importantly, compared with G-MDSCs, M-MDSCs isolated from patients post-HSCT had a greater capacity to suppress T cell responses, and MMP-9 blockade more forcefully inhibited their immunosuppressive effect. MMP-9 levels also were associated with the occurrence of infections and with transplantation outcomes. Based on these findings, we identify M-MDSCs as a major contributor to infections early after allo-HSCT and worse clinical outcomes via MMP-9.