Aplenc, Richard

AbstractSomatic mutations in isocitrate dehydrogenase (IDH) genes occur frequently in adult acute myeloid leukemia (AML) and less commonly in pediatric AML. The objective of this study was to describe the prevalence, mutational profile, and prognostic significance of IDH mutations in AML across age. Our cohort included 3141 patients aged between <1 month and 88 years treated on Children’s Cancer Group/Children’s Oncology Group (n = 1872), Southwest Oncology Group (n = 359), Eastern Cooperative Oncology Group (n = 397) trials, and in Beat AML (n = 333) and The Cancer Genome Atlas (n = 180) genomic characterization cohorts. We retrospectively analyzed patients in 4 age groups (age range, n): pediatric (0-17, 1744), adolescent/young adult (18-39, 444), intermediate-age (40-59, 640), older (≥60, 309). IDH mutations (IDHmut) were identified in 9.2% of the total cohort (n = 288; IDH1 [n = 123, 42.7%]; IDH2 [n = 165, 57.3%]) and were strongly correlated with increased age: 3.4% pediatric vs 21% older, P < .001. Outcomes were similar in IDHmut and IDH-wildtype (IDHWT) AML (event-free survival [EFS]: 35.6% vs 40.0%, P = .368; overall survival [OS]: 50.3% vs 55.4%, P = .196). IDH mutations frequently occurred with NPM1 (47.2%), DNMT3A (29.3%), and FLT3-internal tandem duplication (ITD) (22.4%) mutations. Patients with IDHmut AML with NPM1 mutation (IDHmut/NPM1mut) had significantly improved survival compared with the poor outcomes experienced by patients without (IDHmut/NPM1WT) (EFS: 55.1% vs 17.0%, P < .001; OS: 66.5% vs 35.2%, P < .001). DNTM3A or FLT3-ITD mutations in otherwise favorable IDHmut/NPM1mut AML led to inferior outcomes. Age group analysis demonstrated that IDH mutations did not abrogate the favorable prognostic impact of NPM1mut in patients aged <60 years; older patients had poor outcomes regardless of NPM1 status. These trials were registered at www.clinicaltrials.gov as #NCT00070174, #NCT00372593, #NCT01371981, #NCT00049517, and #NCT00085709.

Background: Somatic mutations in the IDH genes are common in acute myeloid leukemia (AML). Mutations occur at active site arginine residues in IDH1 (R132) and IDH2 (R140, R172). IDH inhibitors, ivosidenib (IDH1) and enasidenib (IDH2), have shown improved clinical outcomes in patients with relapsed/refractory IDH-mutant AML and are approved for use in this setting, while investigations in combination with chemotherapy are underway in de novo AML. The prognostic significance of IDH mutations remains controversial. We hypothesize that refining our understanding of IDH-mutated AML will contribute to risk-adapted treatment strategies, including optimal use of IDH-targeted agents. The objective of our study was to identify characteristics that affect outcome in de novo IDH-mutated AML across the age spectrum utilizing a large cohort of patients enrolled on several pediatric and adult trials. Methods: The total cohort (N=3588) included patients age <1 month - 88 years. Pediatric and young adult (YA) patients were treated on recent CCG/COG AML trials (CCG2961, COG 03P1, 0531, 1031, N=2231) and YA/adult patients were treated on SWOG S0106 (N=396), ECOG E1900 AML trials (N=398), Beat AML (N=363), or included in the TCGA biology study (N=200; outcomes not evaluated for this group). Patients were analyzed according to three defined age groups: "younger" 0-29 years of age (N=2401), "intermediate" 30-59 years of age (N=819) and "older" 60 years of age and above (N=319). Data regarding clinical characteristics and treatment outcomes were collected and evaluated according to the standard practices of each cooperative or research groups for the respective studies. Mutational profiling was performed by targeted sequencing for patient samples from COG trials, Beat-AML, ECOG, and SWOG; whole-genome or whole-exome sequencing for the TCGA cohort. Prevalence of IDH mutations, co-occurring mutations, and outcomes (5-year event-free survival [EFS]) were analyzed across the defined age groups. Results: The prevalence of IDH mutations among the entire cohort was 8.6% (N=276). Analysis according to mutation type demonstrated that IDH2 mutations comprised 57% (N=158) and IDH1 mutations 43% (N=118). The prevalence of IDH mutations was strongly correlated with increased age (Fig 1A); according to the age-defined cohorts was 4.0% (N=82) in younger, 15.2% (N=126) in intermediate, and 20.3% (N=65) in older patients (p<0.001). The co-occurring mutational profile demonstrated that IDH mutations commonly co-occurred with NPM1,DNMT3A, and FLT3-ITD mutations (Fig 1B). Among IDH-mutant patients, 48% (N=132) harbored dual mutations (IDHmut/NPM1mut); 11.6% (N=32) triple mutations (IDHmut/NPM1mut/DNMT3Amut), the latter particularly prevalent in intermediate-aged adults (N=27/32, 85%). Analysis of the cohort with outcome data (N=2824) demonstrated that IDHmut and IDH-WT patients experienced similar EFS of 39% vs. 40%, respectively (p=0.723). Given the favorable prognostic significance of NPM1, we subsequently analyzed outcomes of this dual mutant group and found that NPM1 mutations retained favorable prognostic impact in the context of IDH mutant patients (Fig 2A). Notably, this effect was age-dependent, as those with IDHmut/NPM1mut had a favorable EFS compared to IDHmut/NPM1-WT for younger (76% vs. 24%, p<0.001) and intermediate patients (43% vs. 15%, p=0.001, Fig 2B) but this favorable effect was lost in older patients (29% vs. 34%, p=0.456, Fig 2C). Among intermediate age patients, outcome was further stratified by DNMT3A status, and IDHmut/NPM1mut/DNMT3Amut patients experienced an inferior EFS of 25% vs. 57% in IDHmut/NPMmut (p=0.003, Fig 2D). Conclusion: Analysis of this large patient cohort provides the most comprehensive description of IDH mutations in AML across the age spectrum. We confirm age-associated prevalence of IDH mutations and frequent co-occurrence with NPM1 mutation in all ages and in further combination with DNMT3A mutation in intermediate-aged adults. We definitively demonstrate that IDH mutation status is not an independent prognostic determinant of outcome in any age group. Co-occurrence of NPM1 and IDH mutations favorably impacts outcome in patients < 60 years of age with AML, particularly in the absence of DNMT3A mutation. Our data support that IDH inhibitors may be of particular interest in older adults and in patients <60 according to co-occurring NPM1 and DNMT3A mutations. Disclosures Othus: Marck: Consultancy; Daiichi Sankyo: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Glycomimetics: Membership on an entity's Board of Directors or advisory committees. Radich:Jazz: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Amgen: Consultancy; Bristol-Myers Squibb: Consultancy. Abdel-Wahab:Merck: Consultancy; Janssen: Consultancy; Envisagenics Inc.: Current equity holder in private company; H3 Biomedicine Inc.: Consultancy, Research Funding. Tallman:UpToDate: Patents & Royalties; ADC Therapeutics: Research Funding; BioSight: Membership on an entity's Board of Directors or advisory committees, Research Funding; Glycomimetics: Research Funding; Rafael: Research Funding; Amgen: Research Funding; Bioline rx: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; KAHR: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Membership on an entity's Board of Directors or advisory committees; Oncolyze: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; Cellerant: Research Funding; Orsenix: Research Funding. Atallah:Jazz: Consultancy; Genentech: Consultancy; Abbvie: Consultancy; Takeda: Consultancy, Research Funding; Pfizer: Consultancy; Novartis Pharmaceutical Corporation: Consultancy. Luger:Daiichi-Sankyo: Honoraria; Pfizer: Honoraria; Bristol-Myers Squibb: Honoraria; Acceleron: Honoraria; Agios: Honoraria; Loxo Oncology: Honoraria; Onconova: Research Funding; Kura: Research Funding; Biosight: Research Funding; Ariad: Research Funding; Hoffman La Roche: Research Funding. Levine:Novartis: Consultancy; Loxo: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy; Astellas: Consultancy; Janssen: Consultancy; Prelude Therapeutics: Research Funding; Amgen: Honoraria; Gilead: Honoraria; Lilly: Consultancy, Honoraria; Qiagen: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Imago: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Isoplexis: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding. Cooper:Celgene: Other: Spouse was an employee of Celgene (through August 2019).

Abstract Acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML) are the two most common childhood leukemias. Novel drug therapies and allogeneic hematopoietic cell transplant (alloHCT) have improved ALL and AML treatment outcomes over the past two decades. However, alloHCT may be associated with significant morbidity and mortality that results in increased healthcare utilization. To date, no multi-center comparative effectiveness studies have been performed specifically evaluating alloHCT in children with ALL or AML. This study uses a novel methodology to investigate the hypothesis that matched sibling donor (MSD) alloHCT has significantly lower healthcare utilization compared to unrelated donor (URD) and that among URD, umbilical cord blood transplants (CBT) will have higher initial utilization but lower long-term utilization. Clinical and transplant outcomes data from the Center for International Blood and Marrow Transplant Research (CIBMTR) database were merged with inpatient resource utilization and standardized cost data from the Pediatric Health Information System (PHIS) database using a probabilistic merge methodology. This merged dataset contained U.S. patients age 1-21 years who received alloHCT for ALL or AML from 2004-2013 with comprehensive CIBMTR data at a PHIS reporting hospital. The primary outcomes of overall survival (OS), leukemia free survival (LFS), and inpatient resource utilization were evaluated using Kaplan-Meier analysis, Cox proportional hazards, and unadjusted Poisson regression analysis. Cost and resource comparisons for all donor types were made through day+100 and focused on URD only comparisons up to 2-year follow-up. Donor procurement costs were not directly included in this analysis. A total of 797 patients (54% of CIBMTR eligible patients and 89% of CIBMTR patients at PHIS centers) were successfully identified in both CIBMTR and PHIS; 433 had ALL and had 364 AML. LFS for ALL at 3 years was 68% for MSD, 53% for MUD, and 53% for CBT. The LFS in ALL was significantly impacted by donor type, age, disease status, and CMV (Table). The associated total costs were significantly higher for well-matched unrelated bone marrow (MUD) vs MSD at 100d ($246,149 vs $147,547, p<0.01), but CBT costs were not significantly higher compared to MUD at 100d ($275,673 vs $246,149, p=0.09). When median total costs per day were compared across donor source, findings were similar with well- MUD was significantly higher than MSD at 100d ($3,388/d vs $2,511/d, p=0.012), and no significant difference between CBT and MUD ($3,881/d vs $3,388/d, p=0.53). The corresponding average length of stay (ALOS) was 35 days for MUD, 34 days MSD, and 53 days CBT. Among URD alloHCT, median CBT costs per day were not significantly higher compared to MUD at 2yrs ($2,472/d vs $2,294/d, p=0.49). AlloHCT for AML had a 3-yr LFS of 56% for MSD, 46% for MUD, and 41% for CBT. LFS were significantly different by disease status and performance status (Table). The associated total costs were significantly higher for MUD at 100d than MSD ($259,293 vs $143,870, p<0.001), but CBT costs were not significantly higher compared to MUD at 100d ($301,160 vs $259,293, p=0.055). Comparisons of median total costs per day were similar, MUD vs MSD at 100d was significantly higher ($3,627/d vs $2,478/d, p<0.01), but CBT costs were not significantly higher compared to MUD at 100d ($3,891/d vs $3,627/d, p=0.95). The corresponding ALOS was 38 days for MUD, 35 days MSD, and 66 days CBT. Among URD alloHCT, median CBT costs per day were not significantly higher compared to MUD at 2yrs ($3,232/d vs $3,102/d, p=0.49). This study recapitulates previously published outcomes of alloHCT for acute leukemia AND adds key findings on the impact of alloHCT on inpatient resource utilization and costs. Specifically, MSD and MUD alloHCT provide similar survival outcomes; however, MSD alloHCT has a significant advantage in cost and resource utilization for both ALL and AML. Among URD transplants, CBT does not show any substantial survival or resource utilization advantage over MUD. Ongoing research will need to be performed to determine if the difference among URD alloHCT becomes significant with a larger sample size and/or beyond the 2 years following alloHCT. Table Table. Disclosures Pulsipher: Novartis: Consultancy, Other: Study Steering Committee; Jazz Pharmaceutical: Consultancy; Medac: Other: Housing support for conference; Chimerix: Consultancy. Hahn:Novartis: Equity Ownership; NIH: Research Funding.

Abstract Introduction: Current advances in allogeneic hematopoietic cell transplant (alloHCT) may warrant a paradigm shift in managing children with sickle cell disease (SCD). This study characterizes the clinical outcomes and health care utilization (HCU) of alloHCT for pediatric SCD. We hypothesize that early alloHCT will have improved clinical outcomes, and decreased HCU. Methods: The Center for International Blood and Marrow Transplant Research database was used to identify children 21 years or less with alloHCT for SCD in the United States. Patient data included comprehensive research forms (CRF) from 2000-13 and transplant essential data (TED) forms from 2000-11. CRFs provided clinical risk factors associated with overall survival, graft failure, grade III-IV acute GVHD, and GVHD related event free survival (GREFS) - the survival free of graft failure, chronic GVHD, or death. Risk factors included age, gender, performance status, year of alloHCT, prior SCD complications and therapy, CMV status, donor type, conditioning regimen, and GVHD prophylaxis. Due to low event rates and sample size, only univariate analysis of risk factors was performed. TED data was merged with Pediatric Health Information System (PHIS) inpatient data using a probabilistic merging algorithm to determine risk factors and clinical outcomes associated with HCU. Available PHIS adjusted cost data was used to determine the total adjusted cost for all inpatient admissions per patient per hospital day. To standardize these costs, the total adjusted cost per 30 hospital days was calculated for each patient and used as the primary HCU outcome. HCU outcomes were analyzed for the alloHCT year, day 0 to day +365. Results: CRF data for 161 patients showed an overall survival at 2 years of 90% (95% confidence intervals [CI] 85-95%): 96% (95% CI 89-100%) for related and unrelated cord blood transplant (CBT), 94% (95% CI 86-98%) matched siblings (MSD), and 74% (95% CI 54-90%) matched unrelated donors (MUD, p=0.002). All deaths occurred among children with pre-alloHCT complications of SCD, and deaths were due to organ failure (37.5%), infections (25%), GVHD (6.25%). Risk of death was significantly higher for children ≥10 years old (HR 21, p=0.003) and MUD compared to MSD (HR 5.88, p=0.005) but lower with cyclosporine A (CSA) GVHD prophylaxis versus FK506 (HR 0.33, p=0.031). 75% of deaths occurred before day +42. Cumulative acute GVHD incidence at day 100 was 14% (95% CI 9-20%)and was associated with age ≥10yrs (HR 2.63, p=0.035). Chronic GVHD incidence was 31% (95% CI 23-38%) at 2yrs, and factors associated were age ≥10yrs (HR 1.92, p=0.034), MUD vs MSD (HR 2.53, p=0.017), and CSA vs FK506 prophylaxis (HR 0.48, p=0.018). Chronic GVHD risk increased significantly after 2006 (HR 2.81, p=0.018). The 2yr GREFS was 64% (95% CI 56-71%). Age ≥10yrs (HR 2.2, p=0.005), MUD (vs MSD, HR 3.00, p=0.002) and CSA prophylaxis (vs FK506, HR 0.49, p=0.011) were significantly associated with this outcome. Among the 175 patients with combined TED and PHIS data, the median total adjusted cost was $117,393 per 30 hospital days per patient (range: $36,244-$515,640) during the alloHCT year with a median of 53 hospital days per patient (range: 16-304). Age ≥10yrs and HCU were not significantly associated (p=0.775). MSD had the lowest HCU compared to CBT and unrelated transplants (p<0.001). CBT and peripheral blood stem cells were associated with higher HCU compared to bone marrow (p=0.004). Increased HCU was associated with prior stroke (p=0.0004) and pain crises (p=0.0094) but not acute chest syndrome (p=0.2913). Overall SCD complication and severity indices correlated with increased HCU (p=0.052, p=0.0219, respectively). Conclusions: AlloHCT outcomes in children with SCD were linked to age and donor type suggesting that early alloHCT before age 10 years is preferred. Specifically, SCD severity and MUD alloHCT are associated with poorer outcomes and increased HCU. This supports the recommendation of early alloHCT, prior to onset of SCD complications, for children with SCD and an available MSD. Donor source and type had a significant impact on both outcomes and HCU. CBT outcomes were similar to MSD bone marrow; yet CBT had higher HCU suggesting additional analysis is needed to determine if the clinical benefit outweighs the cost. Further analysis is also needed to better understand and mitigate risk factors associated with poor outcomes and increased HCU following MUD alloHCT. Disclosures Arnold: Robert Wood Johnson Foundation Harold Amos Medical Faculty Development Program: Other: award. Hahn:NIH/NHLBI: Research Funding; Novartis: Equity Ownership.

Abstract Background. Many children and adults with acute myeloid leukemia (AML) relapse or are incurable with current treatment modalities, highlighting a need for alternative therapies. Chimeric antigen receptor (CAR) T cells targeting CD123 have demonstrated potent anti-leukemia activity in murine xenograft models of human AML. However, CD123-redirected T cell treatment of mice engrafted with normal human hematopoietic cells resulted in profound myeloablation, raising concerns for hematologic toxicity in patients with AML who may be treated with such therapies. We hypothesized that T cell deletion after CD123-redirected T cell-induced eradication of AML could minimize this bystander toxicity without impairing leukemia control, thereby increasing the therapeutic window of anti-AML CAR T cell immunotherapy. Methods. To test this hypothesis, we compared three termination strategies in human AML xenograft models: (1) T cell ablation with the anti-CD52 antibody alemtuzumab after treatment with T cells lentivirally-transduced with anti-CD123-41BB-CD3ζ (CART123), (2) T cell ablation with the anti-CD20 antibody rituximab after treatment with CART123 engineered to co-express CD20 (CART123/CD20), and (3) treatment with "biodegradable" anti-CD123 mRNA-electroporated CAR T cells (RNA-CART123). Mice engrafted with luciferase-expressing human AML cell lines (MOLM14, MOLM13, U937) or primary AML specimens (n=3) were treated with CD123-redirected CAR T cells as above. For T cell depletion studies, alemtuzumab 1 or 5 mg/kg was injected intraperitoneally (IP) at 1-4 weeks after 1x105-106 CART123 to determine optimal dosing and timing of T cell ablation. In subsequent studies, rituximab 10 mg/kg was injected IP 4 weeks after 1x105 -106 CART123/CD20, or 1x107 RNA-CART123 were injected intravenously at 5, 9, and 16 days after AML engraftment. Mice were followed by weekly bioluminescent imaging and/or quantitative flow cytometry analyses of blood, spleen, and/or bone marrow. Results. CART123 treatment of CD123+ AML xenografts induced marked T cell expansion and leukemia eradication in vivo, resulting in long-term animal survival (p<0.0001 vs untransduced T cell-treated controls). Minimal xenogeneic graft-versus-host effects were observed. One dose of alemtuzumab rapidly eliminated T cells in all tested models with best efficacy of 5 mg/kg dosing at 4 weeks post-CART123. CART123/CD20 inhibited AML proliferation with similar kinetics to those of CART123, and 1 dose of rituximab at 4 weeks post-CART123/CD20 infusion rapidly eliminated T cells while preserving leukemia remission. Alemtuzumab or rituximab alone did not inhibit AML proliferation in non-CART123-treated xenograft models vs AML-only controls (p=1.00). Mice with CART123- or CART123/CD20-induced AML remission at time of T cell ablation remained leukemia-free for ≥12 weeks, and animal survival did not differ from that of CD123-redirected CAR T cell-treated mice that did not undergo T cell depletion (p=1.00). In contrast, early depletion of T cells with alemtuzumab at 1, 2, or 3 weeks post-CART123 resulted in failure to eliminate AML with subsequent leukemia progression and animal death. Furthermore, AML rechallenge of animals with alemtuzumab- or rituximab-ablated T cells resulted in rapid leukemia proliferation without T cell re-expansion, confirming completeness of T cell depletion. Non-ablated mice demonstrated CAR T cell re-expansion with rejection of CD123+ leukemia rechallenge (p<0.0001). RNA-CART123 rapidly eliminated AML and facilitated long-term animal survival, although RNA-CART123 had expectedly shorter persistence in vivo than did CART123 or CART123/CD20. Conclusions. Alemtuzumab and rituximab completely eliminated CD123-redirected CAR T cells in human AML xenograft models. Sustained leukemia remission required CART123 or CART123/CD20 persistence for 4 weeks prior to T cell termination via alemtuzumab or rituximab post-CART123 or CART123/CD20, respectively. Ongoing studies are investigating efficacy of T cell elimination in additional xenograft models and against other anti-AML CAR T cell immunotherapies. Results from these studies may help to identify promising T cell termination strategies that will augment efficacy of CAR T cell therapy in patients with AML, particularly prior to stem cell transplantation. RNA-CART123 trials in patients with relapsed/refractory AML will open soon. Disclosures Off Label Use: depletion of CAR T cells with alemtuzumab or rituximab. Kenderian:Novartis: Patents & Royalties, Research Funding. Ruella:Novartis: Patents & Royalties, Research Funding. Aplenc:Sigma Tau: Consultancy. June:Novartis: Patents & Royalties, Research Funding. Grupp:Novartis: Consultancy, Research Funding. Gill:Novartis: Patents & Royalties, Research Funding.

Purpose Randomized comparisons of idarubicin (IDA) with daunorubicin (DNR) show that in adults with acute myeloid leukemia (AML), IDA achieves higher remission rates and longer remission durations. In Children's Cancer Group Pilot Study CCG-2941, we assessed toxicity and feasibility of substituting 4 mg of DNR with 1 mg of IDA in intensive-timing daunorubicin-based induction therapy (DNR/DNR) used in CCG-2891. Patients and Methods On days 1 through 3 and 10 through 14, patients received two courses of dexamethasone, cytarabine, 6-thioguanine, etoposide, and IDA (IDA/IDA). After enrollment of 65 patients, toxicity prompted replacement of IDA with DNR (IDA/DNR) on days 10 through 14 for the remaining 28 patients. Outcomes were compared with those of intensive timing in CCG-2891. Results Treatment-related mortality after two courses of induction was not significantly different among the three regimens: 14% with IDA/IDA, 7% with IDA/DNR, and 9% with DNR/DNR. In course 1 of CCG-2941 IDA/IDA, 11% of patients withdrew compared with 1.5% in CCG-2891 (P < .001) and 5% in CCG-2941 IDA/DNR (P = not significant). Compared with CCG-2891 DNR/DRN, CCG-2941 IDA/IDA increased days in hospital (43 v 36 days; P = .007), mean duration of course 1 by a week (P = .002), and risk of grade 3 or 4 hyperbilirubinemia (18% v 5%; P = .02). Toxicity of IDA/DNR was not different from that of DNR/DNR in CCG-2891. The mean day 7 marrow blast percentage was 11.4% in CCG-2941 versus 21.1% in CCG-2891 (P = .004). Remission induction, survival, and event-free survival rates were not significantly different from those of CCG-2891. Conclusion In CCG-2941, excessive toxicity and withdrawals outweighed potential benefits of early response with IDA.