Early Treatment-related Mortality Research Articles

The Outcome of Outpatient Intermediate and High Dose Cytarabine Consolidation Chemotherapy in Patients with Acute Myeloid Leukemia. The Experience of King Fahad Specialist Hospital in Dammam, Saudi Arabia

Background: Adult patients with Acute Myeloid Leukemia (AML) have traditionally been hospitalized for the duration of intensive consolidation chemotherapy until blood count recovery to avoid complications. Recently, there has been a trend to shift the care of AML patients treated with intensive chemotherapy from inpatient to outpatient settings to reduce treatment costs and save beds. Methods and materials: A retrospective study of AML patients who received cytarabine consolidation chemotherapy between the 1st of August 2016 and the 31st of December 2023 at King Fahad Specialist Hospital in Dammam, Saudi Arabia was performed. Results: Over a period of 7 years and 4 months, 62 patients received a total of 127 cycles of intensive consolidation chemotherapy at outpatient setting. At diagnosis: 12 patients had extramedullary disease, and 17 patients had adverse cytogenetic abnormalities. Following the 127 cycles of chemotherapy, 38 episodes of febrile neutropenia were encountered, and 46 hospital admissions were required. No complications were encountered following 62.2% of the cycles of consolidation therapy and no early mortality due to intensive consolidation therapy was reported. Out of 62 patients studied, 36 patients underwent various forms of hematopoietic stem cell transplantation. Disease relapses were encountered in 24 patients and the 5-year incidence of relapse for the entire group of patients was 42%. The 5-year leukemia-free survival for the: entire study patients, transplanted patients, and non-transplanted patients were: 43%, 38%, and 50% respectively. The 5-year overall survival for the: entire study patients, transplanted patients, and non-transplanted patients were: 44%, 34%, and 65% respectively. At the end of follow-up: 37 patients (59.68%) were alive, 24 patients (38.71%) were dead, and the fate of 1 patient (1.61%) was unknown as the patient moved to another hospital. Conclusion: Administration of intensive consolidation chemotherapy for patients with AML at outpatient setting is safe, feasible, and cost-effective. The incidence of infectious complications was relatively low. No early treatment-related mortality due to intensive consolidation therapy was encountered. Outpatient administration of intensive consolidation therapy can save beds, reduce hospital costs, and is associated with short-term and long-term outcomes that are comparable to inpatient administration of consolidation therapy.

Comparable Survival of Treatment Naïve TP53 Mutated Acute Myeloid Leukemia Treated with Hypomethylating Agent Compared to Hypomethylating Agent Plus Venetoclax Based Therapy

Background TP53-mutated (m) acute myeloid leukemia (AML) is an adverse risk disease, which continues to have dismal outcome in the contemporary era of novel therapies. Venetoclax (VEN) in combination with hypomethylating agents (HMA; azacitidine or decitabine) have shown to improve complete remission (CR) rates compared to HMA alone, however no significant differences in overall survival (OS) have been observed. Methods We conducted a retrospective study through the COMMAND consortium (a collaboration of acute leukemia experts from 10 US academic institutions) to analyze the impact on survival outcomes of HMA plus (+) VEN compared to HMA-based therapies in adult (≥18 years) pts with TP53m AML. The AML Database of 381 pts with TP53m AML diagnosed between 2012-2022 was queried and 154 (40%) (HMA [n=50] and HMA +VEN [n=104]) pts were identified eligible for this analysis. Continuous variables were summarized as median (range) while categorical variables were reported as frequency (percentage). The Kaplan-Meier method was used to estimate OS, defined as time from diagnosis to death or last follow-up. Logistic regression models were used to determine the univariate and multivariate of OS. Multivariable models included all significant univariate predictors. All tests were two-sided with a p value <0.05 considered statistically significant. Results Baseline characteristics and responses The median age (years [yrs]) was 74 (range [R], 38-87) and 71 (R,29-88) yrs in the HMAand HMA + VEN groups (gps) (p= 0.23), respectively ( Table 1). Thirty-four (68%) and 57 (55%) patients (pts) were ≥ 70 yrs in the HMA and HMA + VEN gps, respectively (p= 0.16). Twenty-six percent vs 31% ( p=0.57), 86% vs 90% ( p=0.58) and 68% vs 73% ( p=0.56) of pts had secondary AML, had complex cytogenetics (CG), and had multi-hit TP53m in the HMA and HMA + VEN gps, respectively. The proportion of pts with most frequently occurring (> 5%) myeloid co-mutations ( RUNX1, ASXL1, TET2, DNMT3A, RAS, PTPN11 and JAK2) were not significantly (NS) different between the HMA and HMA + VEN gps, as shown in Table 1. The early treatment related mortality in first 30 days of induction was higher in the HMA+VEN gp (25%) when compared with the HMA gp (6%), p=0.004. The complete remission rates (CR/CRi) were higher in the HMA + VEN gp compared to the HMA gp (35% vs 18%, p=0.05). Similarly, the proportion of pts receiving allogeneic stem cell transplant (allo-HCT) after induction was higher in the HMA + VEN gp when compared with the HMA gp (13% vs 4%; p=0.14). Duration of response and overall survival The median follow up was 9.8 months (mo) (R, 1-56) and 5.80 mo (R, 1-30.4) in the HMA and HMA + VEN gps, respectively ( p=0.12). The median duration of response (DOR) was higher in the HMA +VEN gp (15.6 mo) when compared with the HMA gp (7.93 mo), but NS ( p=0.26). The median OS was NS different when comparing the HMA and HMA + VEN gps (9.23 vs 7.3 mo, p=0.80 [ Figure 1]). Multivariable analysis for duration of response and overall survival We did multivariable analysis (MVA) for DOR and OS using baseline variables ( Table 1) that showed significance/trend towards significance in univariate analysis ( p<0.1). Allo-HCT (HR; 0.11, 95% CI: 0.02-0.52, p=0.005) retained significance for better DOR, whereas age ≥ 70 yrs (HR; 1.7, 95% CI: 0.63-4.65, p=0.28) and complex CG (HR; 3.05, 95% CI: 0.79-11.73, p=0.10) did not retain significance in MVA. In MVA for OS, achievement of CR/CRi (HR; 0.35, 95% CI; 0.20-0.59, p=<0.001) and allo-HCT after induction (HR; 0.06, 95% CI; 0.09-0.46, p=0.007) retained favorable significance for OS, whereas complex CG (HR; 2.36, 95% CI: 1.11-4.99, p=0.02) retained significance for shorter OS. PTPN11m (HR; 1.57, 95%CI: 0.75-3.28, p=0.23) and TET2m (HR; 1.02, 95% CI: 0.56-1.87, p= 0.92) did not retain significance in MVA. Conclusion In this multi-center real-world study, while HMA+VEN led to improvement in CR rates and a higher proportion of pts were bridged to allo-HCT, it did not associate with an improvement in OS when compared with HMA monotherapy. More effective treatment strategies are warranted to improve outcome of pts with TP53m AML.

Efficacy and Safety Analysis of Venetoclax Combined with Azacitidine in Real-World Treatment of Patients with AML

Objective: To evaluate overall survival (OS), response rate, time to first response, duration of response, depth of response, and safety in real-world treatment with Venetoclax (Ven) combined with Azacitidine (AZA) in patients with Acute Myeloid Leukemia (AML). Methods: From January 2019 to December 2021, 31 patients with AML who completed at least 2 courses of Ven (100-400mg, 28 days), the Ven dose was adjusted based on drug interactions particularly with azole antifungal prophylaxis, and AZA (75mg/m 2,7 days). Baseline characteristics: Median age 65 years (30-82 years), including 5 patients ≥75 years. ECOG score: 19 patients (61.3%) scored 0-1, 12 patients (38.7%) scored 2-3. Type of AML: 20 De novo cases (64.5%), 8 MDS or MPN conversion cases (25.8%), 3 primary AML-MRC cases (9.7%). Previous treatment: 22 patients (71%) were initially treated, 8 patients (25.8%) were relapsed/refractory, and 1 patient (3.2%) was maintained after remission with standard therapy. At baseline, grade 3 or greater cytopenia was associated: 3 cases were anemia (9.7%), 13 cases were neutropenia (41.9%), and 14 cases were thrombocytopenia (45.2%). Bone marrow original cell count: < 30% (10 cases), 30-50%(9 cases), ≥50% (12 cases). Cytogenetic risk: 1 case was low risk (3.2%), 19 cases were medium risk (61.3%), 10 cases were high risk (32.3%), and 1 case was no dividing phase (3.2%). Molecular mutations included: NRAS/KRAS mutation in 12 cases, DNMT3A mutation in 11 cases, NPM1 mutation in 9 cases, IDH1/2 mutation in 6 cases, FLT3-ITD mutation in 5 cases each, HOX11 positive, ASXL1, RUNX1 and NPM1+FLT3-ITD mutation in 3 cases each. Results: After a median of 3 courses of treatment (C2-C15), 3 of the patients underwent bridge hematopoietic stem cell transplantation after remission. The best efficacy was evaluated in CR+CRi: 22 patients (71%), PR: 5 patients (3 of whom were refractory to recurrence), SD: 3 patients (1 of whom was refractory to recurrence), and NR: 1 patient (refractory to recurrence). First-line efficacy was better than second-line or multi-line. Median time to start treatment to reach CR/CRi: 45 days, DOR: 314 days. The negative response rate of flow MRD in CR/CRi patients was 81.8%, including 11 cases of C1 conversion, 3 cases of C2 conversion, 3 cases of C3 conversion and 1 case of C4 conversion. Flow minimal residual disease (MRD) persisted in AML1-ETO subgroup. The early combined response rate of patients with important gene mutations: ASXL1 and RUNX1 mutation subgroup 100%, NPM1 mutation subgroup 77.78%, IDH1/2 mutation subgroup 83.33%, FLT3-ITD mutation subgroup 80%, HOX11 positive subgroup 80%, 66.67% in the NPM1+FLT3-ITD and NRAS/KRAS mutation subgroups, 53.55% in the DNMT3A mutation subgroup, and 1 patient with TP53 mutation was not in remission. The median OS of the first-line/ maintenance treatment group was 19 months, which was better than the median OS of the second-line or multi-line treatment group was 7 months. Safety: The incidence of tumolysis syndrome and early treatment-related mortality was 0; The incidence of early reduction or treatment interruption was higher (25.8%). Severe adverse reactions included sepsis in 2 cases, severe pneumonia in 2 cases and septic shock in 1 case. Conclusions: In the real world first-line treatment of high-risk AML patients with Ven combined with AZA, the disease control and survival were initially improved, and the early combined response rate (CR+CRi) of molecular subgroups IDH1/2, NPM1, RUNX1, ASXL1, FLT3-ITD and HOX11 were higher. The higher incidence of adverse events in early treatment and delayed treatment may be related to 41.9% of patients with grade 3 neutropenia at baseline, partly AML-MRC. So, based on Ven-28d/AZA, We still need to explore new therapeutic modalities which should balance the efficacy and safety.

PHASE II/III STUDY OF R‐MINICHOP ± ORAL AZACITIDINE IN PARTICIPANTS AGE 75 YEARS OR OLDER WITH DIFFUSE LARGE B CELL AND RELATED LYMPHOMAS

Introduction: Diffuse large B cell lymphoma (DLBCL) is an aggressive but potentially curable malignancy. Nearly one-third of patients are >75 y, and advanced age is an adverse prognostic variable. R-miniCHOP, a dose attenuated version of standard R-CHOP, offers a 2-year progression-free survival (PFS) of 47% based on phase II data (Peyrade F et al, 2011). For comparison, patients age 60-80 have about a 75% 2-year overall survival (OS) with R-CHOP chemotherapy (Coiffier B et al., 2002). A key dilemma is identifying which older patients with DLBCL should be considered for curative intent chemoimmunotherapy. The FIL (Fondazione Italiana Linfomi; Italian Lymphoma Foundation) has developed a tool accounting for age, comorbidities, and ability to perform daily and instrumental activities to classify patients as fit, unfit, or frail (Tucci A et al, 2015), with a key observation being improved survival when curative intent chemoimmunotherapy was delivered to fit and unfit patients. (Merli F et al., 2021). However, there is no prospective validation of frailty assessment and treatment outcomes. Epigenetic deregulation is a feature of DLBCL in older patients. Pre-clinical models show that pre-treatment with hypomethylating agents improves the anti-tumor effect of the agents contained in R-CHOP (Clozel T et al., 2013). Early studies of azacitidine with R-CHOP showed promising efficacy and acceptable toxicity (Martin P et al., 2022). The availability of oral azacitidine is appealing, reduces the infusion burden of treatment, and is agnostic to cell-of-origin. Methods: S1918 is a randomized trial of R-miniCHOP ± oral azacitidine in patients >75 y with newly diagnosed aggressive B-cell non Hodgkin lymphomas (NCT04799275). This is the first randomized study in this population conducted in North America by the National Clinical Trials Network (NCTN) and will enroll 384 patients. Patients receive prephase therapy with prednisone 60–100 mg × 4–7 days to improve performance status and decrease early treatment-related mortality (Owens CN et al., 2015; Pfreundschuh M et al., 2008). A safety run-in has been completed. The phase II objective is to determine if oral azacitidine + R-miniCHOP should be tested further against R-miniCHOP based on estimates of 1-year PFS. The phase III objective is to compare OS at 2 years between arms. S1918 incorporates the FIL Tool for baseline frailty assessment and a serial comprehensive geriatric assessment to evaluate effects of therapy on quality of life and functional status. Key correlative tests include circulating tumor DNA (ctDNA) assays to explore if ctDNA quantity and methylation patterns correlate with response. S1918 has potential to impact future trial design and change the standard of care for patients > 75 y with aggressive lymphoma with its randomized design, incorporation of baseline frailty and geriatric assessments, and utilization of ctDNA correlatives. The research was funded by: NIH/NCI grants U10CA180888, U10CA180819, U10CA180820, and U10CA180821; and in part by Celgene Corporation (now part of Bristol-Myers Squibb). Keywords: aggressive B-cell non-Hodgkin lymphoma, combination therapies, ongoing trials Conflicts of interests pertinent to the abstract. E. A. Brem Consultant or advisory role Bayer, TG Therapeutics, Astra Zeneca, BeiGene Honoraria: Astra Zeneca, BeiGene, SeaGen, Morphosys/Incyte, Pharmacyclics/Janssen P. Caimi Research funding: Abbvie, ADC Therapeutics, Genentech, Consultancy: Abbvie, ADC Therapeutics, Beigene, BMS, Genentech, Incyte, Kite, Lilly, MEI Pharma, Novartis, Takeda R. L. Olin Consultant or advisory role Actinium, Servier Research funding: Cellectis B. Kahl Consultant or advisory role Genentech, BMS J. P. Leonard Consultant or advisory role Roche/Genentech, BMS/Celgene

Venetoclax with decitabine or azacitidine in the first-line treatment of acute myeloid leukemia.

Treatment paradigms for acute myeloid leukemia (AML) have evolved at a rapid pace in recent years. The combination of venetoclax with a hypomethylating agent prolonged survival in clinical trials when compared to hypomethylating agent monotherapy. However, little is known about the performance of venetoclax-based regimens outside of clinical trials, given conflicting safety and efficacy data. Even less is known about the impact of the hypomethylating agent backbone. In this study, we demonstrate that decitabine-venetoclax is associated with a significantly higher rate of grade three or higher thrombocytopenia, but lower rates of lymphocytopenia compared to azacitidine-venetoclax. There was no difference in response or survival across ELN 2017 cytogenetic risk categories in the overall cohort. Significantly more patients succumb to relapsed or refractory disease than death from any other cause. We demonstrated that a Charlson comorbidity index score threshold of seven identifies exceptionally high-risk patients, providing evidence for clinical use to reduce the risk of early treatment-related mortality. Lastly, we provide evidence that measurable residual disease negativity and an IDH mutation predict a significant survival benefit outside clinical trials. Taken together, these data illuminate the real-world performance of venetoclax and decitabine or azacitidine in the treatment of AML.

Stem cell transplantation for systemic sclerosis.

Stem cell transplantation for systemic sclerosis.

Favorable outcomes with durable chimerism after hematopoietic cell transplantation using busulfan and fludarabine-based reduced-intensity conditioning for pediatric patients with hemophagocytic lymphohistiocytosis

BackgroundThe incorporation of a reduced-intensity conditioning (RIC) regimen in hematopoietic cell transplantation (HCT) for patients with hemophagocytic lymphohistiocytosis (HLH) has decreased early mortality but is associated with a high rate of mixed chimerism and graft failure. Here, we present a successful single-center experience using busulfan and a fludarabine-based RIC regimen for the treatment of HLH.MethodsThe medical records of pediatric patients with HLH who underwent HCT using a busulfan/fludarabine-based RIC regimen between January 2008 and December 2017 were reviewed retrospectively.ResultsNine patients received HCT with a busulfan/fludarabine-based RIC regimen. Three patients had primary HLH, and the other six patients had secondary HLH with multiple reactivations. All three patients with primary HLH had UNC13D mutations. All patients achieved neutrophil and platelet engraftment at a median of 11 days (range, 10‒21) and 19 days (range, 13‒32), and all eight evaluable patients had sustained complete donor chimerism at the last follow-up. Two patients (22%) experienced grade 2 acute graft-versus-host disease (GVHD). Two patients (22%) developed chronic GVHD, and one died from chronic GVHD. One patient (11%) experienced reactivation 4 months after HCT from a syngeneic donor and died of the disease. The 8-year overall survival and event-free survival rates were 78%. No early treatment-related mortality within 100 days after HCT was observed.ConclusionOur experience suggests that a busulfan/fludarabine-based RIC regimen is a viable option for pediatric patients with HLH who require HCT.

Guideline for the treatment of chronic lymphocytic leukaemia

Guideline for the treatment of chronic lymphocytic leukaemia

S1918: A Phase II/III Randomized Study of R-Minichop with or without Oral Azacitidine (CC-486) in Participants Age 75 Years or Older with Newly Diagnosed Diffuse Large B Cell Lymphoma, Grade IIIb Follicular Lymphoma, Transformed Lymphoma, and High-Grade B-Cell Lymphomas with MYC and BCL2 and/or BCL6 Rearrangements

S1918: A Phase II/III Randomized Study of R-Minichop with or without Oral Azacitidine (CC-486) in Participants Age 75 Years or Older with Newly Diagnosed Diffuse Large B Cell Lymphoma, Grade IIIb Follicular Lymphoma, Transformed Lymphoma, and High-Grade B-Cell Lymphomas with MYC and BCL2 and/or BCL6 Rearrangements

Sequential intensive chemotherapy followed by autologous or allogeneic transplantation for refractory lymphoma

We evaluate the safety of bendamustine as a bridge to stem cell transplantation (SCT) in patients with relapsed/refractory lymphoma and residual disease after salvage therapy. Thirty-four subjects without complete responses (CR) received bendamustine 200 mg/m2/day for 2 days followed 14 days later by SCT. Sixteen subjects in partial remission (PR) with maximal FDG-PET SUVs ≤8 prior to bendamustine received autologous SCT, while 13 with suboptimal responses were allografted. Five subjects did not proceed to transplant. No bendamustine toxicities precluded transplantation and no detrimental effect on engraftment or early treatment-related mortality (TRM) was attributable to bendamustine. At 1 year, 75% of auto-recipients and 31% of allo-recipients were alive with CR. Two subjects in the autologous arm developed therapy-related myeloid neoplasia (t-MN). In conclusion, a bendamustine bridge to SCT can be administered without early toxicity to patients with suboptimal responses to salvage chemotherapy. However this approach may increase the risk of t-MN. (NCT02059239). Supplemental data for this article is available online at here.

Venetoclax-containing regimens in acute myeloid leukemia.

Venetoclax in combination with hypomethylating agents (HMAs) or low-dose cytarabine (LDAC) has demonstrated exceptional activity in elderly and unfit patients with newly diagnosed acute myeloid leukemia (AML). Notably, the safety profile of venetoclax-based induction regimens was favorable, with a low rate of early treatment-related mortality, even in frail study participants. Thus, the introduction of venetoclax has transformed the landscape of AML therapy in elderly patients. Given these promising results, venetoclax in combination with other agents is now being studied as a frontline therapy in younger patients with AML, as well as in relapsed/refractory AML patients. Here, we review clinical data for venetoclax-based therapy in AML, both from prospective as well as retrospective studies, and highlight ongoing novel studies of venetoclax-containing regimens and discuss future research directions.

The risk factors for treatment-related mortality within first three months after kidney transplantation.

Mortality at an early stage after kidney transplantation is a disastrous event. Treatment-related mortality (TRM) within 1 or 3 months after kidney transplantation has been rarely reported. We designed a cohort study using the national Korean Network for Organ Sharing database that includes information about kidney recipients between 2002 and 2016. Their demographic, and laboratory data were collected to analyze risk factors of TRM. A total of 19,815 patients who underwent kidney transplantation in any of 40 medical centers were included. The mortality rates 1 month (early TRM) and 3 months (TRM) after transplantation were 1.7% (n = 330) and 4.1% (n = 803), respectively. Based on a multivariate analysis, older age (hazard ratio [HR] = 1.044), deceased donor (HR = 2.210), re-transplantation (HR = 1.675), ABO incompatibility (HR = 1.811), higher glucose (HR = 1.002), and lower albumin (HR = 0.678) were the risk factors for early TRM. Older age (HR = 1.014), deceased donor (HR = 1.642), and hyperglycemia (HR = 1.003) were the common independent risk factors for TRM. In contrast, higher serum glutamic oxaloacetic transaminase (HR = 1.010) was associated with TRM only. The identified risk factors should be considered in patient counselling, and management to prevent TRM. The recipients assigned as the high-risk group require intensive management including glycemic control at the initial stage after transplant.

Distinct Clinical and Genetic Factors Predict Early Versus Late Mortality in AML Patients Undergoing Induction Chemotherapy

Background: Long-term survival after intensive induction chemotherapy in acute myeloid leukemia (AML) is limited by both early mortality and disease resistance. A central clinical challenge is predicting which patients will experience early toxicity during induction or resistant disease. Limitations of prior analyses include a specific focus on either early treatment-related mortality or overall survival (OS), an absence of genetic annotation in early mortality studies, and reliance on clinical trial cohorts which may not be broadly representative. Here, we perform a detailed analysis of pretreatment clinical and disease characteristics in a cohort of real-world AML patients to elucidate factors associated with early mortality and with OS after induction. Methods: We identified 290 consecutive adult patients treated with standard induction chemotherapy ("7+3" with cytarabine and an anthracycline, or CPX-351) for newly diagnosed AML (2014-2019). We collected pretreatment clinical, pathology, and laboratory data, and annotated clinical outcomes. Gene mutations were determined at the time of diagnosis using targeted next-generation sequencing of recurrently mutated genes. The median age at diagnosis was 61 years (range 19-76), with 56% of patients aged 60 or older. Most patients (71%) had de novo AML; 15% had clinically defined secondary AML and 14% had therapy-related AML. Median follow-up for survivors landmarked at 60 days was 26.1 months, with a minimum follow up of at least 60 days for all patients. Median OS and relapse-free survival (RFS), both landmarked at day 60, were 33.9 months and 28.0 months, respectively. Results: In total, 24 of 290 (8%) patients died within the first 60 days of receiving induction chemotherapy, with shock being the most common cause of death (42%), followed by respiratory failure (21%) (Figure 1A). In a multivariable logistic regression model, we found that pretreatment albumin < 3 mg/dL, pretreatment LDH >= 600 U/L, and mutations in TET2 or RUNX1 were independently associated with death within 60 days (Figure 1B). Factors not independently associated with early mortality included older age (<60 versus 60 or older), clinical ontogeny (secondary or treatment-related AML), complex karyotype, and pretreatment blood counts. To identify factors associated with outcomes among patients surviving past 60 days, we generated a multivariable model with allogeneic stem cell transplantation as a time-varying covariate. In this model, age >= 60, secondary AML, pretreatment LDH >= 600 U/L, and the presence of TP53 mutation, U2AF1 mutation, or 11q23 rearrangement were independently associated with inferior OS after day 60, whereas the presence of CBF rearrangement was independently associated with superior OS after day 60 (Figure 1C). To determine the contribution of resistant disease to OS landmarked at day 60, we developed multivariable models for failure to achieve remission by day 60 and for RFS landmarked at day 60, and then applied them to the OS model. All variables remained significant, indicating that disease resistance is a main driver of OS after 60 days. Conclusions: Early treatment-related mortality is most commonly the result of shock and respiratory failure, irrespective of disease status, and is associated with specific pretreatment lab values (elevated LDH, low albumin) and disease-specific mutations (TET2 and RUNX1). Among patients surviving induction, survival is driven primarily by resistant disease (primary refractoriness and disease relapse) and is associated with factors previously correlated with outcome in AML, including age, clinical ontogeny, and disease genetics. Overall, we show that early and late outcomes in AML are associated with distinct sets of pretreatment clinical, genetic, and laboratory characteristics and for the first time show that disease-specific mutations are associated specifically with induction toxicity. Improved ability to identify patients likely to experience toxicity after receiving anthracycline-based AML induction may help develop mitigation strategies for these patients. Figure 1: Predictors of early mortality and overall survival in AML patients undergoing induction. A. Clinical and genetic characteristics of early mortality patients. B-C. Forest plots of multivariate analysis of pretreatment risk factors associated with early mortality (B) and with OS landmarked at 60 days (C). Disclosures Lindsley: Jazz Pharmaceuticals: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; MedImmune: Research Funding; Bluebird Bio: Consultancy.

The risk factors associated with treatment-related mortality in 16,073 kidney transplantation-A nationwide cohort study.

Mortality at an early stage after kidney transplantation is a catastrophic event. Treatment-related mortality (TRM) within 1 or 3 months after kidney transplantation has been seldom reported. We designed a retrospective observational cohort study using a national population-based database, which included information about all kidney recipients between 2003 and 2016. A total of 16,073 patients who underwent kidney transplantation were included. The mortality rates 1 month (early TRM) and 3 months (TRM) after transplantation were 0.5% (n = 74) and 1.0% (n = 160), respectively. Based on a multivariate analysis, older age (hazard ratio [HR] = 1.06; P < 0.001), coronary artery disease (HR = 3.02; P = 0.002), and hemodialysis compared with pre-emptive kidney transplantation (HR = 2.53; P = 0.046) were the risk factors for early TRM. Older age (HR = 1.07; P < 0.001), coronary artery disease (HR = 2.88; P < 0.001), and hemodialysis (HR = 2.35; P = 0.004) were the common independent risk factors for TRM. In contrast, cardiac arrhythmia (HR = 1.98; P = 0.027) was associated only with early TRM, and fungal infection (HR = 2.61; P < 0.001), and epoch of transplantation (HR = 0.34; P < 0.001) were the factors associated with only TRM. The identified risk factors should be considered in patient counselling, selection, and management to prevent TRM.

The Efficacy and Safety of Decitabine in Combination with ATRA, G-CSF and Low Dose Cytarabine(Dlaag Regimen)in Relapsed/Refractory Acute Myeloid Leukemia Not Suitable for Strong Chemotherapy : A Phase 2, Prospective, Single-Arm, Multicenter Study

Background. Patients with relapsed or refractory acute myeloid leukemia (R/R AML)who are intolerant of strong regimen chemotherapy have poor responsibility to chemotherapy and clinic remission is lower. The DNMT is depleted to reactivate the silencing tumor suppressor gene to exert anti-tumor effects. Vitro experiments confirmed that ATRA has an anti-leukemia effect on non-M3-AML cell lines. We perform the 2 phase, single-arm, multicenter study of Decitabine in Combination with ATRA, G-CSF and low dose cytarabine(DLAAG Regimen)in R/R AML not suitable for strong chemotherapy (NCT03356080). Methods. R/R AML patients aged more than 18 years not suitable for strong chemotherapy were eligible to enroll on this study. The objective was to assess the responses and safety of this therapy. All patients received subcutaneous decitabine injection 0.1-0.2mg/kg on days 1-3 ,8-10,15-17 .ATRA was taken orally at 45mg/m2 on day 4-6 and 15mg/m2on days 7-20. Subcutaneous injection cytarabine 15mg/m2 every 12 hours on days 1-10 and G-CSF 300ug/d on day 0 until disease remission or absolute neutrophils count ≥ 0.5×109/L were administered. The FLT3 inhibitor, arsenious acid, and the JAK-2 inhibitor, rotectinib, were allowed to be combined.All patients received one or two courses of induction treatments. Results. During the period from December 1, 2017 to July 2019, a total of 33 patients were recruited, including 17 women and 16 men. The median age is 64 years (range 46-82). In 33 patients, the overall response rate (ORR = CR + PR) was 36.3%, and the complete response rate (CRR = CR + CRi) was 33.3%. The early treatment-related mortality rate was 6.0%. One died of infection and one died of organ bleeding. Of the 26 patients with karyotype data, 11 received CR. Seven patients (63.6%) in CR showed normal karyotype, 2 patients (18.1%) in CR, and 1 patient (9.0%) in PR showed other moderate karyotypes. One case (9.0%) of the CR group had a poor karyotype. Statistical analysis showed that there was a statistically significant difference between the different karyotype groups (P &lt; 0.05). Only 2 of the 10 FLT3 mutant patients achieved CR (20%). Two patients with abnormal MLL gene did not receive CR. Conclusions DLAAG regimen is effective and tolerated in patients with R/R AML who are not suitable for intensive therapy and could be as a bridging therapy regimen followed by HSCT. Disclosures No relevant conflicts of interest to declare.

Updated Analysis: Novel Machine-Learning-Based Sepsis Prediction Model for Patients Undergoing Hematopoietic Stem Cell Transplantation (Early Sepsis Prediction/Identification for Transplant Recipients: ESPRIT)

Updated Analysis: Novel Machine-Learning-Based Sepsis Prediction Model for Patients Undergoing Hematopoietic Stem Cell Transplantation (Early Sepsis Prediction/Identification for Transplant Recipients: ESPRIT)

Sequential Therapy for Remission Induction in Severe Antineutrophil Cytoplasmic Autoantibody-Associated Glomerulonephritis

Background: The introduction of combination therapy with glucocorticoids (GC) and cyclophosphamide (CYC) or rituximab (RTX) has resulted in remission rates exceeding 90% in patients with antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV). However, early treatment-related mortality remains a major concern and has driven the search for safer induction regimens exploring minimization or avoidance of GC and CYC. Most trials have excluded patients with severe renal disease. We report the outcomes of AAV patients with severe renal disease treated with sequential therapy (ST) starting with (GC) and oral (CYC) followed by transition to (RTX). Methods: Patients with new or relapsing severe AAV who presented with severe renal disease and/or rapidly progressive glomerulonephritis (RPGN) were identified. RPGN was defined as at least a 20% decrease in estimated glomerular filtration rate (eGFR) over a 2-week period along with hematuria and proteinuria. Induction treatment included pulse (GC) for 3 days followed by oral prednisone tapered to 5 mg by month 6, oral (CYC) adjusted for GFR until improvement in Birmingham Vasculitis Activity Score (BVAS), and serum creatinine at which point (CYC) was stopped and induction dose of (RTX) was given. Use of plasmapheresis (PLEX) was allowed. The primary outcome was complete remission defined as BVAS of zero by 6 months. Descriptive data are presented as median with range and mean with SD. Results: Nine patients met the inclusion criteria. Median age at diagnosis was 63 years. The majority were females, myeloperoxidase ANCA positive, and had a new diagnosis. The mean nadir (SD) eGFR was 12 (5) with 3 requiring dialysis. The median BVAS at the time of diagnosis was 15. All patients received ST and 3 received PLEX. The median exposure to oral CYC was 35 days. The mean (SD) eGFR and median BVAS were 26 (12) and 3, respectively, at the time of switching to RTX. The median prednisone dose at 6M was 5 mg. The median follow-up was 44 months. All patients achieved remission. One patient with relapsing disease reached ESRD. The mean (SD) eGFR in the remaining 8 patients at last FU was 37 (27), and the mean (SD) eGFR rise at 1 year was 26 (25). Adverse events included 2 patients with pneumonia and 3 with bone marrow suppression. There were no deaths. Conclusion: ST with GC and CYC followed by RTX is effective for in AAV patients with severe renal disease. Therapy-related adverse events are comparable to other studies, and further modification in ST with decrease in GC dosage should be explored.

Allogeneic Hematopoietic Cell Transplantation (HCT) Vs. Non-HCT Consolidation Therapies in Acute Myeloid Leukemia (AML) Patients 60-75 Years of Age in First Complete Remission (CR1): An Alliance (A151509), SWOG, ECOG-ACRIN and CIBMTR Study

Introduction: The preferred post-remission therapy for older patients (pts) with AML remains uncertain. We compared outcomes for older AML pts in CR1 receiving HCT reported to the CIBMTR to older AML pts achieving CR1 on National Clinical Trials Network induction and non-HCT consolidation therapy (CT) trials.Methods: This study focused on pts 60-75 years of age treated between 2004 to 2013. CT pts (n=211) underwent induction and consolidation on Alliance for Clinical Trials in Oncology, ECOG-ACRIN or SWOG clinical trials for initial therapy for newly diagnosed AML; the CIBMTR provided data for HCT pts (n=431). CT patients received at least one cycle of CT on study and were excluded if HCT occurred at any time. Time to event started at CR1 and pts entered at CT or HCT, respectively, using left-truncation to account for differential entry times.Results: For the CT cohort, first consolidation included standard therapy (e.g., cytarabine or a hypomethylating agent) and additional study drug (e.g., bortezomib, dasatinib, sorafenib, and Zosuquidar, gemtuzumab) or tipifarnib alone. Among HCT pts, the donor was a HLA-matched sibling or unrelated donor (URD) in 66% and the others were partially HLA-matched/mismatched URD (10%) or cord blood (24%). HCT pts were younger and more frequently had high-risk AML (high WBC, secondary AML and unfavorable cytogenetics) (Table). The median time from CR1 to HCT and CT was 3.2 and 0.5 months, respectively.Allogeneic HCT showed worse overall survival (OS) (HR=1.52, p=0.02) prior to 9 months and better OS thereafter (HR= 0.53, p <0.0001) relative to CT (figure 1A). Treatment-related mortality (TRM) was worse after HCT in the first 9 months (HR=2.8, CI: 1.5 -5.2, p=.0009), while relapse was less frequent beyond 9 months after treatment (HR = 0.42, CI: 0.29 to 0.61, p<.0001). Despite higher early TRM, HCT recipients went on to manifest superior OS [5 year OS: HCT 29% (24-34%), CT 13.8% (9 -22%)] (Figure 1A). The benefit of HCT for survival after 9 months was more prominent in those with unfavorable cytogenetics (Figure 1B). Multivariate analysis for OS showed no statistically significant effect of age or performance status, while unfavorable cytogenetics were detrimental (HR=1.74, p<.0001).Conclusions. Allogeneic HCT led to heightened early risks from TRM, but resulted in superior long-term survival in older AML pts receiving HCT relative to CT by reducing relapse. Efforts to attenuate early TRM after allogeneic HCT may further improve HCT outcomes for older pts. [Display omitted] DisclosuresUstun:novartis: Speakers Bureau. Attar:Agios: Employment, Equity Ownership. Larson:Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BristolMyers Squibb: Consultancy, Research Funding; Ariad/Takeda: Consultancy, Research Funding. Roboz:Roche/Genentech: Consultancy; Eisai: Consultancy; Cellectis: Research Funding; Aphivena Therapeutics: Consultancy; Sandoz: Consultancy; Janssen Pharmaceuticals: Consultancy; Otsuka: Consultancy; Jazz Pharmaceuticals: Consultancy; Sandoz: Consultancy; AbbVie: Consultancy; Celltrion: Consultancy; Cellectis: Research Funding; Eisai: Consultancy; Astex Pharmaceuticals: Consultancy; Argenx: Consultancy; Pfizer: Consultancy; Celgene Corporation: Consultancy; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy; Bayer: Consultancy; Bayer: Consultancy; Roche/Genentech: Consultancy; Orsenix: Consultancy; Astex Pharmaceuticals: Consultancy; Celgene Corporation: Consultancy; Daiichi Sankyo: Consultancy; Pfizer: Consultancy; Janssen Pharmaceuticals: Consultancy; Otsuka: Consultancy; Orsenix: Consultancy; Daiichi Sankyo: Consultancy; Celltrion: Consultancy; Novartis: Consultancy; Aphivena Therapeutics: Consultancy; Argenx: Consultancy; AbbVie: Consultancy. Uy:GlycoMimetics: Consultancy; Curis: Consultancy. Stone:Fujifilm: Consultancy; Ono: Consultancy; Orsenix: Consultancy; Otsuka: Consultancy; Agios: Consultancy, Research Funding; AbbVie: Consultancy; Argenx: Other: Data and Safety Monitoring Board; Celgene: Consultancy, Other: Data and Safety Monitoring Board, Steering Committee; Arog: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Jazz: Consultancy; Astellas: Consultancy; Merck: Consultancy; Pfizer: Consultancy; Sumitomo: Consultancy; Amgen: Consultancy; Cornerstone: Consultancy. Foran:Agios: Research Funding; Xencor, Inc.: Research Funding. Weisdorf:Seattle Genetics: Consultancy; Equillium: Consultancy; FATE: Consultancy; SL Behring: Consultancy; Pharmacyclics: Consultancy.

A Machine-Learning Sepsis Prediction Model for Patients Undergoing Hematopoietic Cell Transplantation

▪Sepsis and severe sepsis contribute significantly to early treatment-related mortality after hematopoietic cell transplantation (HCT), with reported mortality rates of 30 and 55% due to severe sepsis, during engraftment admission, for autologous and allogeneic HCT, respectively. Since the clinical presentation and characteristics of sepsis immediately after HCT can be different from that seen in general population or those who are receiving non-HCT chemotherapy, detecting early signs of sepsis in HCT recipients becomes critical. Herein, we developed and validated a machine-learning based sepsis prediction model for patients who underwent HCT at City of Hope, using variables within the Electronic Health Record (EHR) data.We evaluated a consecutive case series of 1046 HCTs (autologous: n=491, allogeneic: n=555) at our center between 2014 and 2017. The median age at the time of HCT was 56 years (range: 18-78). For this analysis, the primary clinical event was sepsis diagnosis within 100 days post-HCT, identified based on - use of the institutional sepsis management order set and mention of “sepsis” in the progress notes. The time of sepsis order set was considered as time of sepsis for analyses. To train the model, 829 visits (104 septic and 725 non-septic) and their data were used, while 217 visits (31 septic and 186 non-septic) were used as a validation cohort. At each hour after HCT, when a new data point was available, 47 variables were calculated from each patient's data and a risk score was assigned to each time point. These variables consisted of patient demographics, transplant type, regimen intensity, disease status, Hematopoietic cell transplantation - specific comorbidity index, lab values, vital signs, medication orders, and comorbidities. For the 829 visits in the training dataset, the 47 variables were calculated at 220,889 different time points, resulting in a total of 10,381,783 data points. Lab values and vital signs were considered as changes from individual patient's baselines at each time point. The baseline for each lab value and vital sign were the last measured values before HCT.An ensemble of 20 random forest binary classification models were trained to identify and learn patterns of data for HCT patients at high risk for sepsis and differentiate them from patients at lower sepsis risk. To help the model learning patterns of data prior to sepsis, available data from septic patients' within 24 hours preceding diagnosis of sepsis was used. For 829 septic visits in the training data set, there were 5048 time points, each having 47 variables.Variable importance for the 20 models was assessed using Gini mean decrease accuracy method. The sum of importance values from each model was calculated for each variable as the final importance value. Figure 1a shows the importance of variables using this method. Testing the model on the validation cohort results in an AUC of 0.85 on the test dataset (Figure 1b). At a threshold of 0.6, our model was 0.32 sensitive and 0.96 specific. At this threshold, this model identified 10 out of 31 patients with a median lead time of 119.5 hours, of which 2 patients were flagged as high risk at the time of transplant and developed sepsis at 17 and 60 days post-HCT. The lead time is what truly sets this predictive model apart from detective models with organ failure or dysfunction or other deterioration metrics as their detection criteria. At a threshold of 0.4, our model has 0.9 sensitivity and 0.65 specificity.In summary, a machine-learning sepsis prediction model can be tailored towards HCT recipients to improve the quality of care, prevent sepsis associated-organ damage and decrease mortality post-HCT. Our model significantly outperforms widely used Modified Early Warning Score (MEWS), with AUC of 0.73 in general population. Possible application of our model include showing a “red flag” at a threshold of 0.6 (0.32 true positive rate and 0.04 false positive rate) for antibiotic initiation/modification, and a “yellow flag” at a threshold of 0.4 (0.9 true positive rate and 0.35 false positive rate) suggesting closer monitoring or less aggressive treatments for the patient. DisclosuresDadwal:MERK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Research Funding; AiCuris: Research Funding; Shire: Research Funding.

Early achievement of full donor chimerism after allogeneic hematopoietic stem cell transplantation predicts lower relapse risk in patients with acute lymphoblastic leukemia

BackgroundAcute lymphoblastic leukemia (ALL) remains one of the most difficult-to-cure hematological malignancies. Allogeneic hematopoietic stem cell transplantation (HSCT) provides curative potential but a substantial proportion of patients eventually will relapse. It is unknown if there are any modifiable factors exists that could improve survival or predict relapse immediately after HSCT is unknown. The aim of this study was to explore whether achieving early (<30 days) full donor chimerism (FDC) could predict disease relapse after allogeneic HSCT in ALL patients. A second objective is to examine the impact of achieving early donor chimerism on survival. MethodsThis study retrospectively enrolled 55 ALL patients undergoing allogeneic HSCT during the 10-year period from 1999 to 2008. Analysis of short tandem repeats (STR) was used to determine donor chimerism, and was prospectively followed at the time of engraftment and on days 30. Patients with early treatment-related mortality (<30 days), without STR analysis, or who were lost to follow-up before FDC were excluded. Survival analyses were performed using Kaplan–Meier Methods. Cox proportional hazard analyses were performed for poor prognostic factors associated with overall survival (OS) and relapse-free survival (RFS). ResultsThe general characteristics were comparable between patients with early donor chimerism (n = 31) and those with late donor chimerism (n = 24). Survival analyses showed patients with early FDC had both lower probability of relapse (χ2 = 5.770, p = 0.022) and longer RFS than those with late chimerism. The OS was not different according to the chimerism status on days 30. In the Cox proportional hazard analyses, early FDC is a significant factor predictive for longer RFS (HR = 0.264, p = 0.010). ConclusionOur results indicate that the achievement of early FDC within 30 days after allogenic HSCT can be used as a significant predictor of RFS. The results underscored the need to improve outcome in ALL patients with late FDC.