Secondary Acute Myelogenous Leukemia Research Articles

Prediction of Sinusoidal Obstructive Syndrome after Allogeneic Stem Cell Transplantation Using Liver Stiffness Measurement By Fibroscan

Background: Sinusoidal Obstructive Syndrome/ Veno-Occlusive Disease (SOS/VOD) is a potentially life-threatening complication post allogeneic transplantation (HSCT) with an incidence of ~ 10% in adults. The sensitivity of SOS symptoms (hyperbilirubinemia ≥2 mg/dl, weight gain>5%, painful hepatomegaly and ascites) is good, but the specificity is relatively low because other conditions such as infections, GvHD, and exacerbation of previous liver disease may cause similar symptoms. Transient elastography (TE) using FibroScan has been implemented as a non-invasive assessment of post-sinusoidal portal hypertension (PHTN) one of the hallmarks of SOS. We aimed to assess TE's applicability in predicting and diagnosis of SOS. Methods: This single-center study was conducted between January 2021 and June 2023. Twenty-seven patients (pts) underwent TE, 11 before HSCT (group 1) due to high risk of developing SOS in order to guide subsequent treatment, and 17 after HSCT (group 2) (1 pt was in both groups) due to an elevation of bilirubin ≥2 mg/dl. SOS was defined using the EBMT criteria. Results: Eleven pts were included in the 1 st group (M 5, F 6). The median age was 43 (22-65) years. 7 pts had acute myelogenous leukemia (AML) -4/7 secondary AML (sAML), and 4 pts had myelofibrosis (MF). 5/7 AML pts received a median of 4 (2-5) lines of chemotherapy before HSCT; 2/4 sAML pts got azacytidine/ venetoclax and all 4 MF pts received Ruxolitinib before HSCT. Two pts had chemotherapy for antecedent malignancy. Donors were HLA-matched siblings (n=5), matched unrelated (n=2), or haploidentical (n=4). Risk factors for developing VOD included: active disease (n=9), multiple lines of chemotherapy (n=7), elevated serum ferritin (n=5), splenomegaly (n=5 including 1 pt with overt PHTN), severe liver toxicity during previous treatment (n=4), age ≥60 (n=3), second transplantation (n=3), pre-existing liver disease including fatty liver (n=3, including 1 pt with liver cirrhosis), severe obesity (n=2), prior treatment with GO (n=2), baseline liver enzymes elevation (n=2), and alcohol abuse(n=1). The conditioning regimen included total body irradiation (n=1), busulphan (BU) alone (n=5), or double alkylating agents (DAC, n=5), respectively. Four patients had myeloablative conditioning (MAC). Most pts had several risk factors for VOD median 5 (3-8). This group had a median liver stiffness measurement (LSM) of 10.1 kPa (range, 3.3-28.3). In 6/11 pts with LSM ≥7.2 kPa, the conditioning was modified; Treosulfan was given instead of BU (n=3), non-DAC instead of DAC protocol (n=3), reduced intensity instead of MAC (n=4), methotrexate was omitted (n=2). One pt received Defibrotide prophylaxis. With these modifications only 2 pts developed SOS (1 died). The second group included 17 pts (M 10, F 7), median age 49 (32-62) years with AML/myelodysplastic syndrome (n=7), acute lymphoblastic leukemia (n=5), MF (n=4), and lymphoma (n=1). Ten had MAC, and 5 had DAC. Five had active disease at HSCT. Three had prior liver disease. All pts had bilirubin elevation ≥2 mg/dl after HSCT but only 10 fulfilled additional criteria for the diagnosis of SOS based on the EBMT criteria. Pts who developed SOS had significantly higher LSM compared to those who did not; 10.7 kPa (IQR, 7.5-25.2) versus 5.9 kPa (IQR, 5.1-7.4), respectively (p=0.007) (Figure 1A). There was a positive correlation between the diagnosis of SOS and LSM levels, with a correlation coefficient of 0.6 (p= 0.04) as determined by the Spearman correlation test. LSM was able to diagnose SOS with an AUC of 0.89 (p=0.008) (Figure 1B). The cut-off value for SOS diagnosis was 7.5 kPa, with a sensitivity of 80% and specificity of 88%. Pts with severe VOD were treated with defibrotide and none of them died .of VOD. Conclusions: Pts with a high risk for VOD may have a high baseline LSM. In these pts, modifying the planned conditioning and GVHD prophylaxis regimens to less hepato-toxic ones may reduce the incidence of subsequent VOD. LSM elevation after HSCT should increase awareness of SOS, while pts with hyperbilirubinemia and low LSM usually suffered from other causes of liver toxicity. High LSM could support the diagnosis of VOD in borderline cases. Therefore, LSM may be an additional diagnostic tool in diagnosing SOS after HSCT, but more studies are needed to confirm these findings.

Myeloablative Fractionated Busulfan Conditioning Regimen with Chidamide in Patients with AML/MDS Less Than Complete Remission

Introduction Pre-transplant leukemic load significantly impacts relapse and long-term survival in patients with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). A prolonged duration of busulfan administration was reported as a safe myeloablative option with less toxicity and allows the addition of epigenetic agents, like chidamide, which may be synergistic with conditioning chemotherapy and may further improve disease control. Meanwhile, Pre-conditioning busulfan may play a priming role in enhancing the sensitivity of tumor cells to the following conditioning therapy. Here we report the safety and preliminary efficacy of chidamide and fractionated busulfan regimen in patients with AML or MDS who could not clear leukemia cells before transplantation. Methods We enrolled AML or MDS patients with residual or active disease after at least one line of standard therapy. Eligible patients received fractionated busulfan at a total dose of 12.8 mg/kg within 2 weeks. The first two doses of busulfan (1.4 mg/kg IV each) were administered on days -14 and -13. The rest of the busulfan was given on days -7 to -4. Fludarabine and cytarabine were given on days -7 to -3. Chidamide 30 mg twice weekly was given from day -14 to + 3. Peripheral stem-cell were used as grafts harvested from HLA-matched sibling donors (MSD), matched unrelated donors (MUD), or haploidentical donors (HID). Post-transplantation acute graft versus host disease (GVHD) prophylaxis consisted of cyclophosphamide on day +3 to +4, and cyclosporine started on day +5. For HID transplant recipients, mycophenolate mofetil was added from day +5 to day +35. Follow-up examinations were scheduled at +1, +2, +3, +4, +6, +9, +12, +18, and +24 months post-transplant. Donor lymphocyte infusion was not administered prophylactically in this trial. Results Twenty-six patients with de novo AML (n=19), secondary AML transformed from MDS (n=4), or MDS-EB2 (n=3) were enrolled with a median age of 48 years (range, 23~65 years). Patient and disease characteristics are summarized in Table 1. Nineteen patients had adverse risk karyotype according to European LeukemiaNet risk stratification. They received MSD (n=7), MUD (n=2), or HID (n=17) HSCT. Pre-transplant tests revealed that 14 of the patients had MRD (n=14, blast cells＜5% in the bone marrow), and 12 had active disease (blast cells ≥5%, including 4 who had blast cells ≥20%). The median pre-transplant blast cells were 7.5%. All patients successfully finished scheduled conditioning. Neutrophils and platelets engrafted at a median of 13 days (range,11-18 days) and 16 days (range, 11-53 days) post-transplant, respectively. All patients reached MRD negative with full donor chimerism at day +30. Cumulated incidence of grade II to IV and grade III to IV acute GvHD were 12.5% and 5.3% respectively. The median follow-up time was 13 months (2-45.5 months). For the whole cohort, the estimated 1-year progression free survival (PFS) and overall survival (OS) were 59.1% and 69.0% (Figure-1A). For patients with MRD+ or active disease, estimated 1-year PFS are 77.1% and 45.5%, respectively (Figure-1B), and estimated 1year OS of these two groups of patients are 87.5% and 63.6%, respectively (Figure-1C). Three patients died from pulmonary infections (2 with COVID-19 and 1 with cytomegalovirus) in CR at 5.8, 6.9, and 11.5 months post-transplant. The incidence of non-relapse mortality at 6 months and 1 year post-transplant was 4.8% and 16.3% respectively (Figure-1D). Conclusion Fractionated-busulfan based myeloablative conditioning regimen with chidamide confers survival advantage and good tolerance in acute leukemia and MDS patients with residual or active disease.

UCHMC 1812: A phase 1b trial of CPX-351 plus gemtuzumab ozogamicin for relapsed/refractory acute myeloid leukemia.

7024 Background: Gemtuzumab ozogamicin (GO) is effective in favorable-risk acute myelogenous leukemia (AML), while its activity is limited in higher-risk AML in part due to multi-drug resistance (MDR) mechanisms, particularly P-glycoprotein efflux pumps. CPX-351 provides a survival benefit in secondary AML, a disease characterized by high MDR activity. The objective of this trial is to utilize CPX-351 as a bulk cytoreduction agent, to first reduce the high MDR leukemia clones, followed by sequential treatment with GO in a more favorable leukemia environment. Methods: This was a multicenter phase Ib trial of CPX-351 plus GO in relapsed/refractory (R/R) AML patients with standard 3+3 dose escalation design (NCT03904251). Cohort A was treated with CPX-351 100 u/m2 on days 1, 3, and 5 plus GO 3 mg/m2 (max 4.5 mg) on day 7. Cohort B was treated with the same regimen plus an additional dose of GO 3 mg/m2 on day 4. The primary endpoint was the maximum tolerated dose (MTD), defined as < 2 dose limiting toxicities (DLTs) in the highest dose cohort. Secondary endpoints were IWG complete remission (CR) rate at day 28-42, liver veno-occlusive disease (VOD) rate diagnosed by the Baltimore criteria, and time of hematologic recovery (defined as ANC > 1000/uL and platelet count > 100,000/uL). Patients were enrolled at 4 University of California Hematologic Malignancies Consortium (UCHMC) centers: UC Los Angeles, UC San Francisco, UC Davis, and UC Irvine. Results: Thirteen participants were enrolled. The median age was 63 years (range 29-75). Eleven had relapsed disease, and two had refractory disease. Most received one prior line of therapy (n = 9). Seven had ELN 2022 adverse-risk disease at initial diagnosis, and two had intermediate-risk disease. The MTD was not reached. DLTs were observed in 1/6 participants in cohort A (grade 3 rash), and 1/6 participants in cohort B (grade 5 intracranial hemorrhage in the setting of severe thrombocytopenia). There were no cases of liver VOD. Of 12 evaluable participants, 4 achieved CR (33%), of whom 3 were negative for measurable residual disease by multiparametric flow cytometry, and 1 one achieved partial remission. The median age of responders was 30 years (range 28-65). The median time to return of normal hematopoiesis in those who achieved remission was 37 days (range 36-43). Three participants received allogeneic hematopoietic cell transplant (alloHCT) following investigational therapy: one remains in remission 34 months post-transplant, one died of infectious complications shortly after alloHCT, and one relapsed at day +60. Conclusions: CPX-351 plus two doses of GO 3 mg/m2 is a feasible treatment with acceptable toxicity and reasonable marrow recovery kinetics. However, only three participants went on to curative alloHCT. Further evaluation for efficacy in a larger patient population is needed to determine the utility of this regimen in R/R AML. Clinical trial information: NCT03904251 .

Abstract 5467: Single-cell analysis of CD34-enriched blood cells reveals early prognostic markers of myelodysplastic syndromes

Abstract Myelodysplastic Syndromes (MDS) are a group of blood malignancies characterized by aberrant differentiation of hematopoietic stem and progenitor cells (HSPC) in the bone marrow that results in inefficient hematopoiesis and high risk of transformation to acute myeloid leukemia. In order to detect aberrant HSC differentiation in blood samples sensitively and accurately, we explored the use of scRNA-seq of CD34-enriched cells from peripheral blood in identifying differentiation trajectories that are abnormal in patient samples versus expected normal development. A total of 685,000 CD34-enriched PBMCs from 93 samples were analyzed using 10X 3’ v3 scRNA-seq library preparation. For increased efficiency, the samples were multiplexed in groups of 5 individuals and were later identified based on individual natural genetic variation using a custom genotyping assay or low-pass WGS. We then sequenced these 24 libraries on a UG100 sequencer to yield an average of 20,000 reads per cell. Six of these libraries were also sequenced on a NovaSeq. Comparison between scRNA profiles generated on the two different sequencers yielded highly similar results, including a similar ability to demultiplex the patient samples using genetic markers, accurately quantify gene modules and determine cell populations.To analyze the scRNA data, we used a novel computational framework, Metacell, to reconstruct metacell modules for both healthy and disease samples allowing us to find variability in the differentiation process between the disease samples and the normal baseline state. Two patients with MDS which had transformed to acute myelogenous leukemia (AML) demonstrated unique and distinct metacell clusters that were significantly separate from normal HSPC differentiation patterns, demonstrating distinct clusters with elevated levels of BCL2 which is an existing therapy target in secondary AML. Our results demonstrate that scRNA-seq analysis of peripheral blood HSPCs samples can be used to detect aberrations in HSC development in MDS patients and serve as a prognostic tool for stratification of patients with aggressive disease and drug response. Given the cost-efficiency of the entire process, we believe this is one of the first examples of the potential practical utility of single-cell analysis in a clinical setting. Citation Format: Eti Meiri, Nili Saar-Furer, Nimrod Rappoport, Sarah Pollock, Gila Lithwick-Yanai, Zohar Shipony, Nika Iremadze, Doron Lipson, Amos Tanay, Liran Shlush. Single-cell analysis of CD34-enriched blood cells reveals early prognostic markers of myelodysplastic syndromes. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5467.

Defining Primary Vs Secondary AML: Correlation between Pathology and NGS/FISH

Introduction: The treatment of acute myelogenous leukemia (AML) is often determined by factors that include an antecedent dysplasia. At presentation it is often unknown whether a patient has had dysplastic bone marrow features or not. We opted to look back at our leukemia patients to determine the frequency of antecedent dysplasia and to determine if next generation sequencing (NGS) or Florescent in situ hybridization (FISH) findings correlate with the pathologic review. Methods: We chart reviewed 43 charts from a period of 9/21/2021 to current from Orlando Health records. We focused on 29 charts that we could gather complete information from. We reviewed initial bone marrow biopsies and NGS/ FISH findings. We determined if a patient had a known history of myelodysplasia from previous records. If there was no known history of myelodysplastic syndrome (MDS) but dysplasia was seen on the bone marrow biopsy, we looked at NGS/FISH. While there can be overlap with AML, findings that suggest MDS are as follows: NGS: TET2, NRAS, U2AF1, RUNX1, TP53, SF3B1 FISH: 5q-, -5 (5p15, 5q31, 5q33), 7q-, -7 (Cen 7, 7q22, 7q31), Trisomy 8 (Cen 8), MLL (11q23), 20q- (20q12, 20qter) We then examined what treatments were used based on these findings. Results: Overall: 11/29 patients had dysplasia mentioned in their initial pathology report. 4/11 had a known preexistent dysplasia. Of the 7 who didn't have known dysplasia, 6/7 had an NGS or FISH suggesting MDS. Age: Of the patient who had dysplastic findings as well as NGS/FISH to support those findings, the patients had an average age of 57. The one patient without MDS/FISH findings has an age of 69. The average age of all patients with dysplastic findings on their bone marrow was 60. Of the patients who did not have any dysplastic findings on the bone marrow, the average age was 58. Treatment: Vyexos (liposomal daunorubicin and cytarabine), a therapy generally used for secondary leukemias was only used in two patients. Age and performance status was cited as a reason to use alternative therapy. Although one patient did receive 7+3 (idarubicin and cytarabine) instead of Vyxeos. One patient also had severe COVID pneumonia at diagnosis as the reason for not getting induction with Vyexos and instead getting venetoclax/azacitidine. Four patients were either treated with hypomethylating agent of either azacitidine or decitabine, again this was normally chosen due to performance status, age, or active COVID pneumonia as above. Conclusion: These results show that pathology findings of underlying dysplastic changes seem to correlate with NGS or FISH findings. Of the 7 patients with these bone marrow changes but no known MDS, 6 of them had NGS or FISH to support an underlying disease. Factors such as age did not help to predict antecedent MDS. Based on this information it may be appropriate to start with induction therapies such as Vyxeos when dysplastic changes are seen on the bone marrow while FISH and NGS are still pending, if their performance status and age allow to do so. Further larger retrospective studies to compare underlying dysplastic findings versus FISH/NGS findings should be done to further support this concept.

Abstract 6259: Molecular biomarker testing and targeted therapy patterns in patients with acute myelogenous leukemia (AML): A real-world data analysis

Abstract Background and Objective: Molecular testing and targeted treatments for patients (pts) diagnosed with AML have evolved in recent years. Real-world testing patterns, including next-generation sequencing (NGS), and clinical management of pts with AML were analyzed in 2 large U.S. community health systems. Methods: Pts >18 years, diagnosed with AML from January 1, 2015 to December 31, 2020, were identified in a database containing clinical and genomic data from integrated community delivery networks. Study end was March 31, 2021, allowing for 3 months minimum follow up. Actionable biomarkers were defined by NCCN guidelines version 3, 2021. Results: The study included 685 pts, median age of 70 and median follow up of 5.4 months; 55% were male, 73% non-Hispanic White (NHW), 10% non-Hispanic Black (NHB). 69% had de novo AML. Cytogenetic prognostic classification was: 4% favorable; 33% intermediate; 30% adverse; and 33% unknown. 541 (79%) pts, median age of 69, received NGS or single gene/small panel tests. 144 (21%) pts with no testing had a median age of 78. Pts with de novo AML were more likely to be tested compared to secondary AML (84% vs. 67%, p<0.001). No significant difference was found in testing receipt between NHW and NHB pts (82% vs. 76%, p=0.3). 80% of pts received NGS testing in upfront setting, 15% in relapse setting (>30 days after diagnosis), 5% were unknown. 77% of pts diagnosed in 2020 received NGS tests (Table 1). 52/100 (52%) of pts with FLT3 (ITD or TKD) mutation, 5/27 (19%) with IDH1 mutation and 11/44 (25%) with IDH2 mutation received targeted therapy. Conclusions: Molecular biomarker testing has increased over time with NGS becoming the dominant modality. Testing uptake did not differ by race. Half of pts with FLT3 mutation received targeted therapy, one fifth with IDH1 and one quarter with IDH2 mutations. Future research should explore targeted therapy receipt over time and address gaps in uptake for pts with AML in the community setting. Table 1. Proportion of patients with molecular biomarker testing by diagnosis year among (n=685) Diagnosis Year 2015(N = 77) 2016(N = 92) 2017(N = 113) 2018(N = 138) 2019(N = 129) 2020(N = 136) Overall(N = 685) NGS testing, n (%) 7 (9%) 17 (18%) 46 (41%) 100 (72%) 100 (78%) 105 (77%) 375 (55%) Other non-NGS molecular biomarker testing only, n (%) 48 (62%) 52 (57%) 38 (34%) 14 (10%) 14 (11%) 0 (0%) 166 (24%) Molecular biomarker testing (NGS and/or other), n (%) 55 (71%) 69 (75%) 84 (74%) 114 (83%) 114 (88%) 105 (77%) 541 (79%) Proportion tested by actionable biomarker, n (%) FLT3-ITD 51 (66%) 64 (70%) 77 (68%) 108 (78%) 106 (82%) 94 (69%) 500 (73%) FLT3-TKD 50 (65%) 63 (68%) 76 (67%) 105 (76%) 106 (82%) 90 (66%) 490 (72%) IDH2 5 (6%) 10 (11%) 34 (30%) 95 (69%) 100 (78%) 102 (75%) 346 (51%) IDH1 5 (6%) 10 (11%) 28 (25%) 91 (66%) 101 (78%) 102 (75%) 337 (49%) Citation Format: Jeanna Wallenta Law, Zartash Gul, Anna Berry, Michael A. Thompson, Christopher Willner, Sowjanya Vuyyala, Haley McCracken, Katherine Geverd, Frank M. Wolf, Thomas D. Brown, Philip Kuriakose. Molecular biomarker testing and targeted therapy patterns in patients with acute myelogenous leukemia (AML): A real-world data analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6259.

Impact of conditioning regimen intensity on outcomes of second allogeneic hematopoietic cell transplantation for secondary acute myelogenous leukemia.

Limited data is available on factors impacting the outcomes of second hematopoietic cell transplantation (HCT2) in patients with secondary acute myeloid leukemia (sAML). This study aimed to assess HCT2 outcome for sAML comparing reduced-intensity (RIC) to myeloablative (MAC) conditioning. Two hundred and fifteen patients were included: RIC (n = 134), MAC (n = 81). The median follow-up was 41.1 (95% CI: 26.7-69.3) and 28.5 (95% CI: 23.9-75.4) months, respectively. At two years, the relapse incidence (RI) was 58.3% versus 51.1% in RIC and MAC, respectively. The 2-year leukemia free survival (LFS) was 26.6% versus 26%, and the graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) was 16.4% versus 12.1%, while OS was 31.4% and 39.7%, for RIC and MAC respectively. MVA showed a significantly lower RI [hazard ratio (HR) = 0.46 (95% CI, 0.26-0.8, p = 0.006)] and improved LFS [HR = 0.62 (95% CI, 0.39-0.98, p = 0.042)] with MAC versus RIC. The choice of conditioning regimen did not impact non-relapse mortality [HR = 1.14 (95% CI, 0.52-2.5, p = 0.74)], overall survival (OS) [HR = 0.72 (95% CI, 0.44-1.17, p = 0.18)] or GRFS [HR = 0.89 (95% CI, 0.59-1.36, p = 0.6)]. In conclusion, MAC was associated with a lower RI and superior LFS. These results support the use of MAC for eligible patients with sAML who are being considered for HCT2.

Outcome of Human Umbilical Cord Blood Stem Cell Transplantation (CBT) for Acute Myeloid Leukemia in Patients Achieving First Complete Remission after One Versus Two Induction Courses: A Study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT)

Background: Achieving a first complete remission (CR1) is an important prognostic factor for transplantation outcome. However, there are no data in the setting of cord blood transplantation (CBT) indicating whether the number of induction courses (1 or 2) needed to achieve CR1, is of prognostic significance. As CBT is advantageous for acute myelogenous leukemia (AML) patients (pts) with positive pre transplant measurable residual disease (MRD) (Milano F, NEJM 2016), it is conceivable that in the CBT setting, no difference in transplantation outcome will be observed between pts achieving CR1 after 1 or 2 inductions.Methods: Using the European Society for Blood and Marrow Transplantation (EBMT)/Acute Leukemia Working Party (ALWP) registry, we compared transplantation outcomes of adult pts aged ≥18 years with AML that underwent CBT in 2005-2020 in CR1, achieved following 1 versus (vs) 2 induction courses. Multivariate analysis (MVA) adjusting for differences between the induction groups was performed using a Cox's proportional-hazards regression model for main outcomes.Results: Three hundred and twenty-five pts were included comprising 243 (75%) with 1 and 82 (25%) with 2 induction chemotherapy courses. Median (range) follow-up was 65.4 (57.4-73.5) and 51.0 (34.8-61.5) months, respectively (p=0.6). Median age was 49.4 (19.0-70.9) and 52.1 (19.2-71.5) years (p=0.8), respectively. For patients with 1 and 2 induction courses, respectively, 49.4% and 57.3% were male, 225 (92.6%) and 78 (95.1%) pts had de novo AML, and 18 (7.4%) and 4 (4.9%) had secondary AML (p=0.6). Pts with 1 and 2 induction courses, respectively, were classified by cytogenetic risk as follows: intermediate, 62.0% and 79.2%, adverse, 33.2% and 19.5%, and favorable, 4.8% and 1.3% (p=0.02) (missing data~25%). The FLT3-ITD mutation was harbored by 33.7% and 32.3% of the pts (p=0.8), respectively (missing data ~6%). Conditioning was myeloablative (MAC) in 43.0% and 36.6% and reduced intensity (RIC) in 57.0% and 63.4%, respectively (p=0.31). Karnofsky performance score (KPS) was > 90 in 74.7% and 71% of the pts, respectively (p=0.5). The most frequent anti-graft-versus-host disease (GVHD) prophylaxis was cyclosporin A (CSA) and mycophenolate mofetil (MMF) in 75.6% and 82.5 %, or CSA with or without steroids in 16.1 % and 11.2%, respectively. Anti-thymocyte globulin (ATG) was administered to 32.9% and 25.6% of the CBT recipients, respectively (p=0.2). Engraftment rates were lower for pts achieving CR1 after 1 vs 2 induction courses (91.3% and 98.8% p=0.02) with corresponding day 60 absolute neutrophil count (ANC) > 0.5 x 10 9/L in 89.6% vs 96.3% of the pts (p=0.03).Day 180 incidence of acute GVHD grades II-IV was similar in both induction groups, 38.3% and 37.2% (p=0.8), as was 2-year total chronic GVHD, 23.4% and 27.5 %, respectively (p=0.6). In univariate analysis, the 2–year non-relapse mortality (NRM), relapse incidence (RI), leukemia-free survival (LFS), overall survival (OS) and GVHD-free, relapse-free survival (GRFS) were similar between patients achieving CR1 with 1 vs 2 induction courses with 22.6% vs 23.6% (p=0.87) 25.1% vs 30.4% (p=0.4), 52.3% vs 46.0% (p=0.3), 58.6% vs 50.0% (p=0.2), and 44% vs 44.1% (p=0.66), respectively. Similarly in MVA, there was no significant association between 2 courses of induction and NRM (hazard ratio (HR) = 1.1; 95% CI, 0.6-1.8, p=0.7), RI (HR = 1.4; 95% CI, 0.9-2.3, p=0.1), LFS (HR = 1.3; 95% CI, 0.9-1.8, p=0.2), OS (HR = 1.3; 95% CI, 0.9-1.9, p=0.1), and GRFS (HR = 1.1; 95% CI, 0.8-1.5, p=0.5).Conclusions: In CBT recipients, we did not find any significant differences in outcomes in patients achieving CR1 after one or two induction courses. Notably, engraftment was better in patients receiving two courses of induction chemotherapy. [Display omitted] DisclosuresLabopin: Jazz Pharmaceuticals: Honoraria. Forcade: Novartis: Other: travel grant. Sierra: Amgen: Other: Educational grant; Roche: Other: Educational grant; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alexion: Other: Educational grant; Jazz Pharmaceuticals: Research Funding; Janssen: Other: Educational grant; Novartis: Honoraria, Research Funding, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria; BMS Celgene: Honoraria, Research Funding. Byrne: Incyte: Honoraria. Blaise: Jazz Pharmaceuticals: Honoraria. Mohty: Sanofi: Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Astellas: Honoraria; Amgen: Honoraria; Adaptive Biotechnologies: Honoraria.

Molecular Biomarker Testing and Targeted Therapy Patterns in Patients with Acute Myelogenous Leukemia (AML) in Community Health Systems in the United States: A Real-World Data Analysis

Molecular Biomarker Testing and Targeted Therapy Patterns in Patients with Acute Myelogenous Leukemia (AML) in Community Health Systems in the United States: A Real-World Data Analysis

Unique Metabolic Vulnerabilities of Myelodysplastic Syndrome Stem Cells

Background: The mechanisms that cause the progression of myelodysplastic syndrome (MDS) are poorly understood. Little is known about major signaling networks and energy metabolism in MDS cells as patients progress from low risk (LR) to high risk (HR) disease and from high risk to secondary acute myelogenous leukemia (sAML). As many as 30% of HR MDS patients progress to sAML and a portion of LR MDS patients progress to HR. The goal of this project is preventing progression by identifying MDS-specific targets for therapy. A deeper understanding of the metabolic properties of leukemia stem cells (LSCs) in AML has shown these cells are uniquely vulnerable to venetoclax and azacitidine (Ven/Aza) (Pollyea et al, Nat. Medicine, 2018) and metabolic changes cause resistance to Ven/Aza (Stevens et al, Nat. Cancer, 2021). Little however is known about the contribution of metabolism to the pathogenesis of MDS. The contributing factors to progression including metabolic properties, transcriptional programs, and immunophenotype are examined in this study.Methods: Bone marrow specimens from MDS patients at various disease stages, including serial samples during progression, were obtained. Single cell techniques including mass cytometry, antibody based single cell RNA sequencing (CITE-Seq) and transcriptional profiling with RNA sequencing were used to elucidate novel mechanisms of progression. Selective targeting of primitive MDS cells was tested using several agents.Results: Our previous work characterizing MDS stem cells (MDSC) showed significant similarities between MDSCs and AML LSCs (Stevens et al, Nat. Communications, 2018). However, little is known about lower risk disease. In order to understand transcriptional changes and their relationship to metabolism across pathogenesis, the transcriptome of blasts from patients with LR, intermediate (INT), or HR IPSS scores was investigated. The first major transcriptional difference identified was enrichment of glycolysis pathway at LR and INT stage. In contrast, HR MDS demonstrated enrichment of oxidative phosphorylation. Furthermore, comparison of intermediate to HR MDS showed increased RNA polymerase and Ribosome pathways at the HR stage. These changes demonstrate the progressive alteration of metabolic properties during MDS pathogenesis with cells first relying on mechanisms associated with normal stem cells (i.e. glycolysis) and later transitioning to a state associated with AML stem cells (i.e. reliance on oxidative phosphorylation).Using serial specimens of patients of who progressed from LR to HR MDS we performed CITE-Seq and mass cytometry. CITE-seq in serial specimens showed up-regulation of protein translation and oxidative phosphorylation in a subset of MDS stem and progenitor cells (CD34+ at transcript and antibody level) present at LR stage and conserved at HR stage (Fig 1A-C). MDSCs also acquired surface antigens including CD99 and CD52 upon progression from LR to HR. Analysis of the mass cytometry data showed significant overlap with CITE-Seq data including increased CD123+ and MCL1 expression in MDS stem cells upon progression.In order to understand therapeutic vulnerabilities as they relate to progression, we investigated ex vivo drug response in LR and HR specimens. MDS samples were challenged with two regimens, Ven/Aza, a regimen known to inhibit OXPHOS; and omacetaxine and azacitidine (Oma/Aza), which inhibits translation. CITE-seq showed that MDSC were selectively sensitive to these agents (Fig 1D). Importantly, addition of either drug regimen caused ablation of MDSC at LR and HR stages and these changes were most profound in cells with LSC properties.Based on preclinical findings, we are investigating MDS patients treated with Ven/Aza or Oma/Aza via CITE-seq and metabolomics for correlation of clinical response with properties of MDSC. Preliminary studies show that patients that respond to Oma/Aza present with a population of MDSC with transcriptional signatures of protein translation and LSCs (Fig. 1E). Studies are underway to investigate overlapping properties of ven/aza resistance in AML to resistance in MDS specifically investigating fatty acid metabolism in MDSC.Conclusions: Analysis of MDS patient bone marrow reveals acquisition of aberrant metabolic properties at both low and high risk stages of disease. These distinct aspects of MDSC biology create unique and targetable features. [Display omitted] DisclosuresPollyea: Genentech: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy; Syndax: Consultancy; Takeda: Consultancy; Daiichi Sankyo: Consultancy; Celgene/BMS: Consultancy; Amgen: Consultancy; AbbVie: Consultancy, Research Funding; Agios: Consultancy; Glycomimetics: Other.

Evaluation of the need for cytoreduction and its potential carcinogenicity in children and young adults with myeloproliferative neoplasms.

Myeloproliferative neoplasms are rare at a young age, and few reports have described the disease characteristics and outcomes in this group. This study aimed to elucidate the clinical course of essential thrombocythemia (ET) and polycythemia vera (PV) in children and young adults aged <39 years focusing on thromboembolic events (TE) and second primary malignancies (SPMs). A total of 990 patients who were diagnosed from 2008 to 2017 were included by analyzing the Health Insurance Review and Assessment Service database in Korea. The incidence was 2.53 per 1,000,000 for ET (643 patients; 276 male patients; median 31 years) and 1.37 per 1,000,000 for PV (347 patients; 309 male patients; median 32 years). Three ET patients developed secondary acute myelogenous leukemia and three developed secondary myelofibrosis. The 5-year cumulative incidence of TE was 14.2% in ET and 21.3% in PV. Thus, the incidence was higher in PV; in particular, arterial TE (ATE) was evidently higher in PV than in ET. The 5-year cumulative incidence of SPMs was 2.5% in ET and 2.6% in PV. While the use of both aspirin and hydroxyurea reduced the incidence of ATE, hydroxyurea significantly increased the incidence of SPMs. The incidence of ET and PV was very low, and ET was more common than PV in children and young adults. The high incidence of TE in young patients suggests the importance of thrombosis prevention. However, hydroxyurea appears to increase the incidence of SPMs; therefore, the risks and benefits should be considered.

Number Of Apheresis Days To Reach Target Stem Cell Dose May Be a Predictor Of Secondary Myelodysplastic Syndrome and Acute Myelogenous Leukemia

Introduction Autologous stem cell transplantation (ASCT) is an effective consolidation therapy for patients with relapsed/refractory Hodgkin's and Non-Hodgkin's lymphoma. Studies have shown that infusion of at least 2 × 106 CD34+ cells/kg recipient body weight is required for reliable neutrophil and platelet engraftment. However there is no published data on the impact of number of apheresis days required to reach the target stem cell dose and incidence of secondary myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML). Methods Consecutive patients who underwent ASCT at M. D. Anderson cancer center from January 2008-July 2011 for Hodgkin's or Non-Hodgkin's lymphoma were evaluated to assess the impact of duration of mobilization on the incidence of secondary MDS/AML. Baseline patient, disease, and transplant characteristics including number of days of mobilization needed to collect target cell dose of 5 × 106 CD34+ cells/kg. The median number of days to reach target was 2 (range 1-5) days. We used the median as cut off to classify patients as slow (> 2 days) or fast (≤ 2 days) mobilizers. The cumulative incidence of secondary MDS/AML was estimated considering death preceding a secondary malignancy as a competing event. Cox's proportional hazards regression analysis was used to evaluate predictors of the rate of secondary MDS/AML. Results A total of 283 patients underwent ASCT during the study period. 153 of these patients were classified as fast mobilizers and 130 patients as slow mobilizers. Indication for transplant, disease status prior to transplant, age and gender distribution are as shown in [Table 1][1]. Twelve patients were diagnosed with secondary MDS/AML after a median follow-up of 39 (range 2-64) months. Only one of these patients had pre-existing pretransplant cytogenetic abnormalities (monosomy 7 in one metaphase). Nine of 12 cases were diagnosed within 3 years post-transplant. On univariate analysis, days to target stem cell dose was the only predictor of the rate of secondary MDS/AML. The rate of secondary MDS/AML within 3 years post-transplant was higher in the slow mobilizer group (n=8, 6% cumulative incidence at 3 yrs) compared with the fast mobilizer group (n=4, 1 % cumulative incidence at 3 yr, HR=0.2, P value 0.05) [Figure 1][2]. None of the remaining factors listed in [Table 1][1] were found to be associated with the rate of secondary MDS/AML on univariate analysis. In patients who did not have active disease at transplant, overall survival tended to be higher in the fast mobilizer group compared with slow mobilizers. However, this effect did not reach statistical significance on multivariate analysis (hazard ratio of 0.6; with P value of 0.1). Absolute neutrophil count of > 500/mm3 was achieved at a median of 10 days in fast mobilizers versus 11 days in slow mobilizers (P value 0.000). Similarly platelet count >20,000 was achieved sooner in fast mobilizers at a median of 11 versus 12.5 days in slow mobilizers (P value 0.000). View this table: Table 1 Conclusions Number of apheresis days required to collect target stem cell may be a predictor of secondary MDS/AML. There is a trend towards better survival among patients who mobilize in two or less than two days. As expected fast mobilizers have quicker neutrophil and platelet engraftment. ![Figure 1][3] Figure 1 Disclosures: Qazilbash: Millennium: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees. [1]: #T1 [2]: #F1 [3]: pending:yes

Serum Lipidome and Glucose Metabolism Uncover Vulnerabilities in Myelodysplasia and Secondary Acute Myelogenous Leukemia

Background Secondary acute myelogenous leukemia (sAML) is highly aggressive and molecularly heterogenous. Previous reports have demonstrated differential serum lipid expression among hemopoietic malignancies (i.e AML, myelodysplastic syndrome (MDS) and acute lymphoblastic leukemia (ALL). Such a distinct serum lipidome among hemopoietic disorders suggest "unique oncogenic metabolic addiction" of leukemia initiating cells (LICs). MDS to AML transition is characterized by clonal evolution [i.e severe aneuploidy, high P53 frequency etc.] and chemorefractoriness. However, mechanism(s) for transformation are not entirely understood. In this study, we investigate serum lipidome and "proxy" of glucose [HbA1C] metabolism among: (1) low risk, (2) high risk MDS and (3) sAML patients (pts) to identify features that may suggest disease specific vulnerabilities. Methods After IRB approval, 214 pts were selected for analysis. ANOVA was used to detect differential expression of total cholesterol (TC), low density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides (TAG) among low risk, high risk and sAML pts. Multivariate linear regression model was performed to evaluate the independent effect of confounders on relevant lipid modifications observed among subtypes of MDS and sAML pts. SAS software was used for data processing. Results 69/214 (32.2%), 26/214 (12.1%), 35/214 (16.3%), 35/214 (16.3%), 28/214 (13.08%), 21/214 (9.8%) were sAML, very low (VLR), low (LR), intermediate (I), high (H) and very high risk (VHR) MDS. Median age (range) was 68 y (42-91), 68 y (22-87), 70 y (55-91), 76 (53-88), 72 y (60-85) and 74 y (54-84), for sAML, VLR, LR, I, H and VHR, p=0.0001. In sAML, VLR, LR, I, HR and VHR MDS TC was 177 mg/dL, 150 mg/dL, 126 mg/dL, 134 mg/dL, 125 mg/dL and 122 mg/dL, p=0.0001; LDL was 113.4 mg/dL, 81.3 mg/dL, 67.8 mg/dL, 72 mg/dL, 63.2 mg/dL and 70.8 mg/dL, p=0.0001; HDL 35.8 mg/dL, 39.2 mg/dL, 36.1 mg/dL, 40 mg/dL, 33.7 mg/dL, 32.05 mg/dL, p=0.40; TAG 134 mg/dL, 140 mg/dL, 109 mg/dL, 120 , mg/dL 134 mg/dL, 98 mg/dL, p=0.1. Given "similarities" among MDS subgroups, "MDS lipid data" was compared vs sAML. Median TC, LDL, HDL and TAG among sAML vs MDS pts was 179.1 mg/dL vs 130.4 mg/dL, p=0.0001; 113 mg/dL vs 70.1 mg/dL, p=0.0001; 38.6 mg/dL vs 36.7 mg/dL, p=0.5; 142 mg/dL vs 116.6 mg/dL, p=0.056, respectively. 20/89 (22.7%) vs 69/89 (77.53%) sAML vs MDS pts, respectively were diabetic, p=0.002, OR =2.62; 95% CI 1.40-4.90. However, data extracted from 82 pts (16 sAML and 66 MDS, each) demonstrated that hemoglobin A1C (HbA1C) was 7.84% vs 6.34%, in sAML vs MDS, respectively, p=0.009. Multivariate linear regression accounting for age, blast count, BMI, DM status and HbA1C showed that higher TC, LDL and HbA1C were independent predictors of sAML. Conclusions While this study is restricted to demonstrate distinct lipid and metabolic profile between sAML and MDS, our results suggest blastic phase dependency on higher serum cholesterol and possibly higher advanced glycosylation. As compared to MDS, our data highlights the possibility that sAML induces serum Lipidome modifications that may "hijack endogenous lipogenesis" to favor TC, LDL and possibly TAG production. Additionally, despite larger number of patients is needed to confirm our results, higher HbA1C potentially initiates advanced glycosylation facilitating blastic conversion in MDS pts. Disclosures Rivero: Incyte: Membership on an entity's Board of Directors or advisory committees; agios: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees.

LSD1 Inhibitor CPI-482 Shows Efficacy and Prolongs Survival in Mouse Models of AML and Post-MPN AML in the Context of Constitutive JAK-STAT Pathway Activation

LSD1 Inhibitor CPI-482 Shows Efficacy and Prolongs Survival in Mouse Models of AML and Post-MPN AML in the Context of Constitutive JAK-STAT Pathway Activation

How to address second and therapy-related acute myelogenous leukaemia.

Secondary acute myelogenous leukaemia (AML), as compared to de novo AML, occurs in the more elderly population, is independently more resistant to cytotoxic chemotherapy, has a higher relapse rate, and a worse prognosis. Secondary AML (sAML) is a heterogeneous disease, both biologically and clinically, even within the World Health Organization subgroups of sAML. Outcomes are the poorest in subgroups with sAML arising from an antecedent haematologic disorder which has been previously treated (ts-AML), and sAML in patients <55years of age. This review describes the suboptimal outcomes of contemporary therapy, to support the notion of an unmet need for innovative treatment strategies in sAML. Despite the recent approval of CPX-351, long-term outcomes for this high-risk disease remain dismal. Resistance mechanisms to intensive chemotherapy contribute to relapse. Targeted immune therapy may avoid multidrug resistance mechanisms, but are unlikely to provide long-term remission due to a complex and rapidly evolving clonal disease profile. Advances for sAML will likely be accomplished by CAR T cell therapy or bispecific antibodies providing a bridge to allogeneic stem cell transplantation. Therefore, focus should be placed on novel strategies that can augment the untargeted effector function of allogeneic grafts.

Differential Induction Among Younger Patients Diagnosed with Secondary Acute Myelogenous Leukemia Is Feasible By Cytogenetic/Molecular Risk Stratification

Background: Secondary acute myeloid leukemia (s-AML) [therapy-related (t-AML) and evolving from antecedent hematologic disorder, i.e. myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN)] are highly aggressive disorders with 20% overall survival [OS] at 1 year. Challenges for initial therapy selection include 1. Difficulty for precise discrimination of pre-existing disorders [MDS vs MPN vs t-AML] and 2. Lack of reliable karyotypic/molecular risk stratification [i.e. European-leukemia-network-2017 [ELN 2017], originally designed for de novo AML]. In s-AML, enrichment for high-risk karyotypic and molecular abnormalities [i.e. complex karyotype (CK), -17p, -7/7p, p53, RUNX1, ASXL1 mutations] suggests that systematic stratification is feasible to adopt tailored therapy for complete remission [CR] success and OS estimation. In this study, our primary aim was to investigate clinical, cytogenetic and molecular predictors for CR and OS outcome among s-AML patient (pt). Methods: After IRB approval, 178 AML pt diagnosed in Baylor College of Medicine institutions [Michael E. DeBakey VA Houston and Baylor St. Luke's Medical Center] were screened. 68/178 [38%] s-AML pt were selected, however, 55/68(81%) had data available for analysis. Variables with known predictive value for AML prognosis were investigated including age, hemoglobin, white blood cell count [WBC], marrow blast percentage, pre-existing disease [MDS v MPN], karyotypic abnormalities and mutations obtained by next generation sequencing [NGS]. To identify cytogenetic subgroups with differential effect on survival, individual karyotypic abnormalities were "aggregated" into groups exhibiting similar OS [inferior v intermediate v superior survival, see Figure 1, group 0 v 1 v 2]. Kaplan Meier method was used to evaluate differential significant OS among cytogenetic groups. Linear regression model examined independent prognostic effect of "proposed cytogenetic stratification" when adjusting for potential confounders selected from our univariate analysis. Statistical analysis was performed with SAS software, NC, USA and Prism 5. Result: Median age of pt was 67 years (range 42-91). S-AML pt was Male 52/55 (96%), and white 36/55 (65%). Baseline characteristic for the 3 cytogenetic groups are depicted in Table 1. Median OS for all s-AML pt was 90.5 days [d] (range: 3-644). Pre-existing disease was available in 51/55 (93%) pt [10/51 (20%) MPN, 36/51 (70%) MDS, and 5/51(10%) t-AML (p=0.69)]. Intense [7+3] v less intense [hypomethylating agents (HMA)] therapy was delivered in 24/43 (56%), and 16/43 (37%), respectively. Karyotypic abnormalities were 5/55 (9%) monosomy 7, 23/55 (42%) CK [typical 14/23 (61%), and atypical 9/23 (39%)], and 27/55 (49%) abnormalities not classifiable as favorable or adverse (NC or &lt;3 abnormalities not including -5q, -7q, and/or -17p). Median OS for group 0 [all -7] was 70 d (5-78). In intermediate cytogenetic, median OS was 122 d (3-405) [typical + atypical CK were aggregated in group 1 given equal OS (140 d vs 102 d, respectively, p= 0.3)]. Group 2 [NC +others] median OS was 160 d (3-644) [ANOVA, 0 v 1 v 2, p= 0.03] (Figure 1). Complete remission/complete remission incomplete [CR/CRi] rate was 0%, 30%, and 39% for 0 v 1 v 2 [0 v 1 p=0.1 and 0 v 2, p=0.08]. Importantly, in group 2, CR/CRi was 66% v 36%, in pt &lt; and &gt;60 y, respectively, p=0.05. Superior CR/CRi in pt &lt;60 y was associated with absence of high-risk mutations [p53, ASLX1, RUNX1], p=0.008. Proposed cytogenetic stratification was the only independent predictor for survival among pt diagnosed with s-AML when controlled for all potential confounders (p= 0.015; 95% CI, 0.05-0.48). Conclusion: In s-AML with heterogeneous pre-existing disease and cytogenetic background, our "proposed cytogenetic stratification" retains ability to discriminate differential OS and odds for CR/CRi success. Our data adds "body of evidence" for selection of "differential" induction in s-AML cytogenetic subgroups predicted to have inferior CR/CRi and OS [i.e. HMA+ Venetoclax vs CPX 351 formulation, instead of standard 7+3]. It is conceivable that in pts with s-AML younger than 60 y who are assigned into cytogenetic subgroup 2 without high-risk mutations, 7+3 is reasonable induction while bridging toward allogeneic stem cell transplant. Disclosures Yellapragada: Novartis: Employment, Other: Spouse Employment ; Celgene: Research Funding; BMS: Research Funding; Takeda: Research Funding.

Outcomes of Total Body Irradiation- Versus Chemotherapy-Based Myeloablative Conditioning Regimen in Haploidentical Hematopoietic Cell Transplantation with Post-Transplant Cyclophosphamide for Acute Myelogenous Leukemia: ALWP of the EBMT Study

Background The use of haploidentical hematopoietic cell transplantation (haplo-HCT) with post-transplant cyclophosphamide (PTCy) is rapidly increasing. The safety and efficacy of myeloablative conditioning (MAC) in haplo-HCT has been reported in patients with acute leukemia. However, optimal MAC in haplo-HCT setting is unknown. We studied the outcomes of total body irradiation (TBI) vs. chemotherapy (CT) based MAC regimens in acute myelogenous leukemia (AML) patients undergoing haplo-HCT and reported to the Acute Leukemia Working Party of the EBMT. Methods The study included 1008 AML patients (secondary AML=149, 15%) who underwent haplo-HCT with PTCy during the years 2010-2018, following TBI (n=89, 9%) or CT (n=919, 91%) based MAC. Regimen intensity was defined by EBMT criteria and cases with busulfan dose &lt;9 mg/kg or TBI dose ≤6 gray were excluded. Baseline AML cytogenetic risk group was good, intermediate and poor in 8%, 65% and 27% of patients respectively. All pre-HCT disease status (CR1=434, 43%; CR2+=216, 21%; advanced=358, 36%) were included in the study. fludarabine- TBI (78%) and thiotepa- busulfan- fludarabine (56%) were the most common MAC regimens in TBI and CT-cohorts, respectively. Patients in the TBI cohort were more likely to be younger (median age, 38 vs. 47 yrs, p&lt;0.01) and receive BM graft (57% vs. 43%, p-0.01) Other patient, disease, and transplant related characteristics were similar in both groups. Median follow up for TBI and CT cohort were 25.4 (IQR-9.5-58.7) and 20.7 (IQR-11.7-40.3) respectively. Results In univariate analysis, day 100 incidence of acute GVHD (aGVHD) II-IV and III-VI was 22% vs. 27% (p-0.44) and 12% vs. 12% (p-0.92) in TBI and CT cohorts respectively. Two-year total and severe chronic GVHD (cGVHD) incidence was 42% vs. 27% (p&lt;0.01) and 9% vs. 12% (p-0.33) in TBI and CT cohorts respectively. More patients achieved neutrophil engraftment by day 30 in the TBI cohort (97% vs. 86%,p-0.05). Graft failure was reported in 2 (2%) and 65 (7%)(p-0.08) patients who received TBI and CT-based MAC respectively. There were 3 (1%) deaths related to graft failure in the CT-group. Death from veno-occlusive disease was reported in 1(3%) TBI pt and 11(3%) CT patients. The proportions of infection related deaths (TBI-29% vs. CT-32%) and GVHD related deaths (TBI-17% vs. CT-15%) were comparable. Death due to interstitial pneumonitis was reported in 1(3%) TBI and 8(2%) CT patients. Death from a second malignancy was reported in one pt in each group. In multivariate analysis, TBI was associated with a higher incidence of overall cGVHD [HR=1.81, 95% CI:1.14-2.87, p-0.01] compared to CT. There was no difference in other outcomes such as extensive cGVHD [HR=0.34, 95% CI:0.11-1.10, p-0.07], relapse incidence(RI) [HR=1.32, 95% CI:0.85-2.03, p-0.22], nonrelapse mortality(NRM) [HR=0.82, 95% CI:0.46-1.49, p-0.52] and leukemia free survival(LFS) [HR=1.09, 95% CI:0.77-1.55, p-0.62], overall survival(OS) [HR=1.07, 95% CI:0.74-1.56, p-0.71] and GVHD free relapse free survival (GRFS) [HR=1.02, 95% CI:0.74-1.40, p-0.92]. Two-year LFS and OS of TBI and CT cohorts were 45% vs. 49% (p-0.98) and 50% vs. 55% (p-0.79) respectively (Figure 1). Factors impacting OS were pt age (per 10yrs, HR=1.1, p-0.02), KPS ≥90 (HR=0.55, p&lt;0.01) and advanced disease status before haplo-HCT (HR=2.35, p&lt;0.01)(Table 1). Interestingly, cytogenetic risk groups had no impact on LFS or OS in this analysis. No interaction was observed between the type of MAC and RI, NRM, LFS, OS and GRFS in a separate subgroup univariate analysis of patients &lt;40 yrs old and patients with pre-HCT disease status CR2 or advance disease. Conclusions In this large cohort of AML patients who received first haplo-HCT with PTCy, TBI based MAC was associated with higher incidence of overall cGVHD without impacting other transplant outcomes compared to CT based MAC. In the absence of a prospective study, these findings may guide clinicians when choosing an optimal MAC in haplo-HCT with PTCy. Disclosures Dholaria: Celgene: Honoraria. Labopin:Jazz Pharmaceuticals: Honoraria. Angelucci:Jazz Pharmaceuticals: Other: Local advisory board; Roche: Other: Local advisory board; Novatis: Honoraria, Other: Chair Steering Committee TELESTO protocol; Celgene: Honoraria, Other: Participation in DMC; BlueBirdBio: Other: Local advisory board; Vertex Pharmaceuticals Incorp., and CRISPR Therapeutics: Other: Participation in DMC. Blaise:Jazz Pharmaceuticals: Honoraria; Molmed: Consultancy, Honoraria; Sanofi: Honoraria; Pierre Fabre medicaments: Honoraria. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding.

Pediatric Intensive Care Resource Utilization Following Hematopoietic Cell Transplantation in Children with Acute Leukemia

Pediatric Intensive Care Resource Utilization following Hematopoietic Cell Transplantation in Children with Acute Leukemia Baldes C1, Wetzel M3, McCraken C3, Saber W4, Arnold SD2. Introduction: Hematopoietic cell transplantation (HCT) is one of the mainstays of treatment of acute leukemia in children. While previous studies have calculated the overall healthcare resource utilization following this treatment, to date there is limited analysis regarding intensive care resource utilization specifically. The goal of this research is to investigate the costs associated with and potential patient drivers of intensive care resource utilization following hematopoietic cell transplantation in children with acute leukemia. Methods: Retrospective study of U.S. patients aged 1-20 years who received HCT for acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML) from 2004-2011 using data merged from the Pediatric Health Information System (PHIS) and the Center for International Blood and Marrow Transplant Research (CIBMTR). We investigated the primary outcome of total intensive care unit (ICU) cost and total ICU cost per day survived from initial HCT through 100-day post-transplant as well as through two-year follow-up using paired comparisons with Wilcoxon rank sums tests for differences in costs between groups. Results: We identified 202 patients with at least one ICU admission in the first 100 days and 292 in the two years following HCT. At day 100, ICU cost per day survived and total ICU cost were lower for secondary AML (P=0.019; P=0.022, respectively) when compared to AML but no significant difference was identified for ALL patients (P=0.186 ;P=0.064, respectively) compared to AML. Cytomegalovirus (CMV) seropositivity compared to seronegativity (P=0.027; P=0.027, respectively) had higher ICU cost per day survived and total ICU cost at day 100 and at 2-years post-HCT (P=0.026; P=0.045, respectively) (Table 1). At 2-years post-HCT, disease status also showed a statistically significant relationship between ICU cost per day survived and total ICU cost for intermediate disease status at transplant (p&amp;lt;0.001; P=0.018) and ICU cost per day survived for advanced disease (P=0.042) compared to early disease status. Females transplant recipients (P=0.042) and, when compared to matched unrelated donor, unrelated cord blood transplants (P=0.029) also had significantly higher ICU cost per day but not total ICU cost (Table 2). Conclusion: Among patients with at least one ICU visit, patients who are CMV negative generate less ICU costs and costs per day survived at both time intervals. While disease status, donor type, and gender become significant at two-years post HCT. This analysis may help identify patient specific risks that could be mitigated by surveillance or supportive care measures. Ultimately, further investigation of pre-transplant diagnosis, donor type, gender, and disease status at transplant is needed to better determine specific factors influencing these cost outcomes. 1. Department of Pediatrics, Emory University, Atlanta, Georgia. 2. Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University, Atlanta, Georgia. 3. Pediatric Biostatistics Core, Emory University, Atlanta, Georgia. 4. CIBMTR (Center for International Blood and Marrow Transplant Research), Department of Medicine, Medical College of Wisconsin, Milwaukee, WI. Disclosures No relevant conflicts of interest to declare.

Outcome of Allogeneic Hematopoietic Stem Cell Transplantation in Patients Age >69 Years with Acute Myelogenous Leukemia: On Behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

Reduced-intensity conditioning (RIC) allows for the use of allogeneic hematopoietic stem cell transplantation (HSCT) in older patients with acute myelogenous leukemia (AML). We compared outcomes between 713 patients age ≥70 years and 16,161 patients age 50 to 69 years who underwent HSCT between 2004 and 2014. A higher proportion of the older patients were male and had secondary AML, active disease, a peripheral blood stem cell graft, a matched unrelated donor, an RIC regimen, and a lower Karnofsky Performance Status (KPS) score (P< .001). In multivariate analysis, the incidences of acute and chronic graft-versus-host disease and relapse were similar in the 2 age groups. Nonrelapse mortality at 2 years was 34% (95% confidence interval [CI], 31% to 38%) in patients age ≥70 years and 24% (95% CI, 25% to 32%) in those age 50 to 69 years (P< .001). Survival at 2 years in the 2 groups was 38% (95% CI, 34% to 42%) and 50% (95% CI, 49% to 50%), respectively (P< .001). In patients with active disease, the corresponding percentages were 35% (95% CI, 29% to 41%) in those age ≥70 years and 33% (95% CI, 31% to 34%) in those age <70 years (P = .36). In patients age ≥70 years, a KPS score of ≥80% was associated with improved survival (hazard ratio, 1.53; 95% CI, 1.14 to 2.06; P = .003). In summary, patients age ≥70 years had worse outcomes, except for those with active AML.

Predictive Factors for Complete Remission and Survival in AML Patients Failing to Achieve Adequate Bone Marrow Day 14 Blast Eradication

Introduction: Complete remission (CR) is an important endpoint after cytarabine plus anthracycline [7+3] induction therapy in Acute Myelogenous Leukemia (AML). Even though CR is observed in about 50-90% of unselected European Leukemia Network 2017 (ELN-2017) patients (pt), factors such as age >65 years, complex karyotype, and adverse mutations (RUNX1, ASLX1, TP53, FLT3 ITD high, KMT2A, secondary AML), leads to inadequate blast eradication. Early response to induction is a predictor of subsequent complete remission (CR). Bone marrow day 14 [D14] inform pt with early inadequate leukemia eradication [blast >10%] who are suitable for re-induction, a strategy that seeks to facilitate conversion to CR or CR with incomplete hematologic recovery (CRi), secure potential allogenic transplantation and reproduce superior outcomes. In this study, we investigated the clinical outcome of an unselected ELN-2017 AML cohort with inadequate D14 marrow response. From the subgroup of patients exhibiting sub-optimal response (SOR), we examined the odds and predictors for subsequent achievement of CR/CRi for those patients who did not receiving immediate re-induction therapy. Additionally, we evaluated the effect of subsequent CR/CRi achievement on survival.Methods: With prior IRB approval, 160 AML pt diagnosed with AML from 1995 to 2017 within Baylor College of Medicine institutions were evaluated. Kaplan-Meier method was used to estimate overall survival (OS) among pt achieving D14 <> 10% blast in an unselected ELN-2017 AML cohort and pt exhibiting >10% blast in D14 marrow with and without CR/CRi. Logistic and cox regression analysis in SOR pt [1] attaining subsequent CR/CRi and [2] OS, respectively, was performed to investigate multiple independent variables with predictive value for the 2 above outcomes.Results: 68/160 (42.5%) of pt had available D14 [early assessment] and sequential day 30 marrow for CR/CRi evaluation. Among 68 unselected ELN-2017 AML pt with D14 marrow for CR/CRi assessment, 42/68 (61.7%) and 26/68 (38.2%) had D14 marrow blasts < and > 10%. Median age was 57 y (range 27-73) and 59 y (range 24-89), respectively, p= 0.74. OS was 459 d vs 169 d in pt with D14 marrow <10% and >10%, at day 14 (p=0.001 95% CI 0.2-0.9) [Fig 1A]. CR/CRi was observed in 36/42 (90%) and 10/26 (38.7%) of pt with D14 marrow <10% vs >10%, respectively, p=0.0005. After controlling for traditional high-risk factors including WBC, age, platelet count, RDW, de novo v secondary AML, only ELN-2017 classification [fav vs unfav and intermediate vs unfav, p= 0.0026 and p=0.01] retained impact on survival. In pt with SOR, we performed second analysis to investigate survival among pt with and without subsequent CR/CRi achievement who did not receive re-induction [Fig 1B]. 16/26 (62.5%) of pt with SOR failed to achieved CR/CRi. OS was 333 d vs 109 d for pt with CR/CRi vs those without CR/CRi [p=0.002, 95% CI 2.6-3.4]. Logistic regression identified in pt with CR/CRi vs those without CR/CRi that: [a] age [63.1 vs 43.6 y-p=0.001]; [b] lower platelet count [47.1 vs 83.1 K/uL-p=0.03]; [c] higher absolute monocyte count (AMC) [3.7 vs 0.41 K/uL-p=0.04]; [d] increased RDW [18.3 vs 14.7-p=0.004] and [e] high BMI [31 vs 24.1-p=0.0003] were significantly associated with failure to achieve CR/CRi. Typical complex karyotype and initial marrow blast % were not associated with subsequent CR/CRi achievement. However, in pt with SOR, lack of high-risk mutations [P53, RUNX, FLT3-ITD, U2AF1] was significant associated with CR/CRi, [40% v 62.5%, p= 0.0004]. Cox proportional regression model showed significant impact on survival for high-risk mutations and higher BMI in survival.Conclusion: In our retrospective study, despite 38.7% of patients with detectable D14 residual leukemia achieved CR/CRi without re-induction, failure to attain CR/CRi was frequently observed after SOR. Advanced age, lower platelet count, higher AMC, RDW and BMI predict failure to achieve CR/CRi status in patients exhibiting initial SOR. Lack of high-risk mutation was a strong predictor for CR/CRi achievement. Our study is novel by suggesting that a combination of pre-induction and “early post-induction” variables facilitate recognition of high-risk AML subgroups requiring re-induction or alternative novel therapy via clinical trials. [Display omitted] DisclosuresYellapragada:Takeda: Research Funding; Novartis: Employment; Celgene: Research Funding.