The PRIME Trial: PARP Inhibition in IDH Mutant Effectiveness Trial. a Phase II Study of Olaparib in Isocitrate Dehydrogenase (IDH) Mutant Relapsed/Refractory Acute Myeloid Leukemia and Myelodysplastic Syndrome

Background: Recurring mutations have been identified in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) which translate to therapeutic targets. Isocitrate dehydrogenase-1 and -2 (IDH1/2) mutations occur in ~20% of AML, and up to 12% of patients with MDS. Three conserved mutational hotspots in the IDH enzymes alter their function and lead to the production of (R)-2-hydroxyglutarate (2HG), an oncometabolite with numerous downstream effects, including impaired DNA damage repair. Specifically, homologous recombination (HR) is impaired by inhibiting the function of histone demethylases that are critical for HR and recruitment of the HR machinery to sites of DNA damage. In HR deficient tumors poly-ADP ribose polymerase (PARP) enzymes mediate a key salvage pathway. PARP inhibition in HR deficient tumors leads to synthetic lethality via simultaneous inhibition of HR and SSB mediated DNA repair. Our group previously demonstrated synthetic lethality with PARP inhibition in IDH mutant cells lines, and other IDH mutant models including primary patient-derived cell lines and genetically-matched tumor xenografts. Study Design and Methods: The PRIME trial (NCI10264) is a proof of concept, biomarker-driven, multi-institution, phase II open label clinical trial to assess the overall response of IDH1/2 mutant relapsed/refractory AML and MDS to PARP inhibitor monotherapy with olaparib. The clinical trial is executed by the Experimental Therapeutics Clinical Trials Network of the NCI. The Cancer Therapy Evaluation Program will provide olaparib. Eligibility criteria include documented IDH1 or IDH2 mutation in blood or bone marrow within 30 days of enrollment based on mutational testing by PCR or sequencing in a CLIA certified laboratory and willingness to undergo a bone marrow biopsy. Patients will be treated with olaparib 300 mg q12hrs each day of a 28-day cycle, using a tablet formulation, until disease progression, unacceptable toxicity, withdrawal of consent or death. Blood and bone marrow samples for 2-HG analysis will be collected prior to starting therapy and after 1 cycle (28 days), cycle 2, 3, 6, 9, 12 or when there is concern for disease progression (Figure 1). A Simon two-stage optimal design will be used to test the null (ORR=10%) versus the alternative hypothesis (ORR=40%) in each arm. In the first stage, 9 patients will be accrued in each arm. If one or fewer responses are observed in these 9 patients, that arm will be stopped early for futility. Otherwise, 11 additional patients will be accrued for a total of 18 in each arm. We reject the null hypothesis if at least 5 responses are observed in these 20 patients. In each arm, we have approximately 90% power to detect a 30% increase in ORR at a one-sided type I error rate of 0.05. Primary endpoint: Overall response rate (ORR) of 40%, i.e., a 30% ORR improvement (40% vs. historical control ORR = 10%) based on MDS International Working Group 2006 criteria and AML MDS International Working Group 2003 criteria after 6 cycles of treatment. Cumulative ORR will include complete remission, complete remission with incomplete blood count recovery, partial response, and bone marrow complete remission. Secondary endpoints: Progression-free survival (the interval between the time of initiation of olaparib to the time of documentation of olaparib failure or last follow-up) and overall survival (the interval between the time of initiation of olaparib to the time of death or last follow-up) for the trial. Exploratory studies: The PRIME trial will also test the utility of 2-HG and DNA damage markers such as γ-H2AX as potential biomarkers of response to olaparib. Using multiple viability assays on leukemia cell lines and bone marrow cultures we will assess synergistic therapeutic combinations to further improve outcomes in this patient population. To confirm efficacy in vivo without undue toxicity, promising combination therapies will be confirmed in cytokine-humanized immunodeficient "MISTRG" mice. We will also examine the impact of PARP inhibitors on the genomic, proteomic, metabolomic and immunologic landscape of IDH 1/2-mutant hematologic malignancies using DNA whole exome sequencing (WES), RNA-Seq, and liquid chromatography-mass spectrometry assessment of oncometabolites. Disclosures Bindra: Cybrexa: Consultancy, Equity Ownership. Prebet:pfizer: Honoraria; pfizer: Honoraria; pfizer: Honoraria; Boehringer Ingelheim: Research Funding; pfizer: Honoraria; Tetraphase: Consultancy; novartis: Honoraria; novartis: Honoraria; Genentech: Consultancy; Boehringer Ingelheim: Research Funding; novartis: Honoraria; Boehringer Ingelheim: Research Funding; Agios: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; pfizer: Honoraria; novartis: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; novartis: Honoraria. OffLabel Disclosure: We will be using PARP inhibitors as a novel therapy for patients with relapsed or refractory AML and high risk MDS based on preclinical data.

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Clinical Outcomes Following Treatment with Gilteritinib or Quizartinib in Patients with Relapsed/Refractory FLT3-ITD+ Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2020-136118 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 42-43

Author(s):

Alexander E. Perl ◽

Qiaoyang Lu ◽

Alan Fan ◽

Nahla Hasabou ◽

Erhan Berrak ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Complete Remission ◽

Myeloid Leukemia ◽

Research Funding ◽

Phase 3 ◽

Hematopoietic Stem ◽

Travel Costs ◽

Baseline Characteristics ◽

Acute Myeloid

Background: Gilteritinib is approved for patients (pts) with relapsed/refractory (R/R) FLT3-mutated acute myeloid leukemia (AML), based on findings from the phase 3 ADMIRAL trial (Perl AE, et al. N Engl J Med. 2019). A phase 3 trial, QuANTUM-R, demonstrated the benefit of quizartinib in pts with R/R AML with FLT3 internal tandem duplication (FLT3-ITD) mutations (Cortes JE, et al. Lancet Oncol. 2019). Although eligibility criteria across both studies were similar, QuANTUM-R was more stringent as to prior therapy intensity and remission duration, which potentially enriched for higher-risk pts. We sought to describe outcomes from ADMIRAL among pts who otherwise met eligibility for QuANTUM-R. Methods: In this post-hoc analysis, a subset of pts from ADMIRAL were matched with R/R FLT3-ITD+ AML pts from QuANTUM-R on the basis of baseline characteristics and prior treatment criteria. Matched pts were either refractory to initial anthracycline-based chemotherapy or had relapsed ≤6 mos after achieving composite complete remission (CRc) with an anthracycline-based regimen. Results: Overall, 218 pts with R/R FLT3-ITD+ AML in the ADMIRAL trial (gilteritinib, n=140; salvage chemotherapy [SC], n=78) were matched with the QuANTUM-R intention-to treat (ITT) population (N=367; quizartinib, n=245; SC, n=122). Proportions of pts preselected for high-intensity SC were 66% (n=143/218) in the matched ADMIRAL ITT population and 77% (n=281/367) in the QuANTUM-R ITT populations. Demographic and baseline characteristics of the matched ADMIRAL ITT population and QuANTUM-R ITT population were similar. Median durations of exposure to gilteritinib and quizartinib were 3.8 mos and 3.2 mos, respectively, and median number of treatment cycles received were five and four, respectively. Rates of hematopoietic stem cell transplantation (HSCT) were similar in pts treated with gilteritinib (35%; n=49/140) or quizartinib (32%; n=78/245), as were the proportions of pts who resumed gilteritinib (23%; n=32/140) or quizartinib (20%; n=48/245) therapy post-HSCT. Median overall survival (OS) in pts treated with gilteritinib or quizartinib was longer than that observed with SC. After a median follow-up of 17.4 mos, median OS was 10.2 mos with gilteritinib versus 5.6 mos with SC (hazard ratio [HR]=0.573 [95% CI: 0.403, 0.814]; one-sided nominal P=0.0008). After a median follow-up of 23.5 mos, median OS with quizartinib was 6.2 mos versus 4.7 mos with SC (HR=0.76 [95% CI: 0.58-0.98]; one-sided P=0.02). After censoring for HSCT, median OS was 9.3 mos with gilteritinib versus 5.5 mos with SC (HR=0.525 [95% CI: 0.356-0.775]; nominal one-sided P=0.0005), and 5.7 mos versus 4.6 mos with quizartinib versus SC, respectively (HR=0.79 [95% CI: 0.59, 1.05]; one-sided P=0.05). In both QuANTUM-R and matched ADMIRAL populations, the survival benefits of quizartinib and gilteritinib compared with SC were maintained across multiple subgroups, including high FLT3-ITD allelic ratio subsets. Compared with SC, high CRc rates were observed in pts treated with either gilteritinib (57%; n=80/140) or quizartinib (48%; n=118/245). The complete remission (CR) rate with gilteritinib was 23% (n=32/140), whereas the CR rate with quizartinib was 4% (n=10/245) (Table). Median time to achieve CRc was 1.8 mos with gilteritinib and 1.1 mos with quizartinib, median duration of CRc was 5.5 mos with gilteritinib and 2.8 mos with quizartinib. The safety profiles of gilteritinib and quizartinib were generally similar, though aspartate or alanine aminotransferase elevations (any grade) were more frequent with gilteritinib (41-44%) than quizartinib (≤13%), whereas neutropenia (14% vs 34%, respectively), fatigue (24% vs 39%, respectively), and prolonged QT intervals (9% vs 27%, respectively) were more frequent with quizartinib. Conclusions: In pts with R/R FLT3-ITD+ AML and similar baseline characteristics, both gilteritinib and quizartinib were generally well tolerated and associated with improved survival and treatment response compared with SC. Responses to gilteritinib and quizartinib, as measured by CRc, were similar; blood count recovery varied between the two FLT3 inhibitors. Although cross-study comparisons have substantial limitations, the findings suggest that while remission is achieved faster with quizartinib, response may be more durable and survival potentially longer with gilteritinib. Disclosures Perl: Syndax: Consultancy, Honoraria; Leukemia & Lymphoma Society, Beat AML: Consultancy; Novartis: Honoraria, Other, Research Funding; Agios: Consultancy, Honoraria, Other; Jazz: Honoraria, Other; FORMA Therapeutics: Consultancy, Honoraria, Other; Daiichi Sankyo: Consultancy, Honoraria, Other: Writing/editorial support, travel costs for meetings, Research Funding; FUJIFILM Pharmaceuticals USA, Inc: Research Funding; New Link Genetics: Honoraria, Other; Arog Pharmaceuticals Inc: Other: uncompensated consulting, travel costs for meetings; Actinium Pharmaceuticals Inc: Consultancy, Honoraria, Research Funding; Biomed Valley Discoveries: Research Funding; Astellas: Consultancy, Honoraria, Other: writing/editorial support, travel costs for meeting presentations related to study, Research Funding; Bayer HealthCare Pharmaceuticals: Research Funding; AbbVie Inc: Consultancy, Honoraria, Other, Research Funding; Takeda: Honoraria, Other: Travel costs for meeting; Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company: Consultancy, Honoraria, Other. Lu:Astellas: Current Employment. Fan:Astellas Pharma: Current Employment. Hasabou:Astellas Pharma: Current Employment. Berrak:Astellas: Current Employment. Tiu:Eli Lilly & Company: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Astellas Pharma Global Development: Current Employment.

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Hypomethylating Agent and Venetoclax Combination Yields Comparable Outcomes to CPX-351 in Newly Diagnosed Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2019-130379 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3895-3895

Author(s):

Hannah Asghari ◽

Dasom Lee ◽

Yehuda E. Deutsch ◽

Onyee Chan ◽

Najla Al Ali ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Complete Remission ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Risk Group ◽

Newly Diagnosed ◽

Advisory Committees ◽

Acute Myeloid

Background The therapeutic landscape for acute myeloid leukemia (AML) has become complex with recent drug approvals. CPX-351 has become standard-of-care for patients (pts) with therapy-related AML and AML with myelodysplasia-related changes. Moreover, earlier phase studies combining hypomethylating agents (HMA) and Venetoclax (HMA+Ven) in the frontline setting for elderly patients have demonstrated high response rates and improved survival. Given the overlapping indications, yet lack of comparative outcome data between these therapeutic regimens, treatment decisions have become challenging in the frontline setting. Therefore, we compared the outcomes of newly diagnosed AML pts receiving HMA+Ven vs. CPX-351. Methods We retrospectively annotated 119 pts that received frontline treatment with HMA+Ven and CPX-351 at Moffitt Cancer Center and Memorial Healthcare System between 2013 and 2019. Pts were divided in two cohorts: HMA+Ven (Cohort A) or CPX-351(Cohort B). Via comprehensive chart review of each patient that received HMA+Ven, we further classified a subgroup of pts meeting criteria to receive CPX-351 as CPX-351eligible. Clinical and molecular data were abstracted for each patient in accordance with IRB requirements. Overall response rate (ORR) was the combined total of complete remission (CR), complete remission with incomplete count recovery (CRi), and morphologic leukemia free state (MLFS). Fisher's Exact method was used to determine significance. Kaplan-Meier analysis was performed to estimate median overall survival (mOS) with log-rank test to determine significance. All p-values are two-sided. Results Out of 119 total pts, 41 pts received HMA+Ven (Cohort A) and 78 pts received CPX-351 (Cohort B) with baseline characteristics outlined in Table 1. Among 111 response evaluable pts, ORR was 64.1% in Cohort A, including 28.2% with CR and 28.2% with CRi (Table 2). ORR was 50.0% in Cohort B, comprised of CR in 29.2% and CRi in 18.1%. There was no difference in ORR between Cohort A and Cohort B (64.1% vs. 50%, p 0.17). A significantly greater fraction of pts in Cohort B underwent allogeneic stem cell transplant (allo-SCT) (24.4% vs. 2.4%, p=0.004). ORR was higher in pts with European LeukemiaNet (ELN)-defined favorable/intermediate (fav/int) risk compared to adverse risk group in Cohort A (100% vs. 58.3%, p=0.03), however there was no difference in Cohort B (52.6% vs. 49.1%, p=1.0). ORR was similar among adverse risk groups in both cohorts (58.3% in Cohort A vs. 49.1% in Cohort B, p=0.47). Among responders, median time to best response was significantly longer in Cohort A (61.0 days vs. 40.5 days, p<0.0001). Median duration of response was not reached (NR) in both cohorts. Impact of somatic mutations on ORR is represented in Figure 3. Median follow-up was 6.5 months (mo) in Cohort A and 13.0mo in Cohort B. Median OS was similar in both cohorts (A vs. B, 13.8mo vs. 11.1mo, p=0.82) (Figure 1). Among responders, mOS was NR in Cohort A and 18.2mo in Cohort B (p=0.88) (Figure 2). Compared to Cohort B, mOS was superior for pts with fav/int risk disease in Cohort A (14.2mo (B) vs. NR (A), p=0.045) and not different for adverse risk group (11.1mo (B) vs. 7.3mo (A), p=0.2). Prior HMA exposure was 26.8% in Cohort A and 29.5% in Cohort B for an antecedent hematologic malignancy, however it did not impact mOS (p=0.86) or ORR (p=0.7). Early mortality rates for Cohort A and B were similar at day 30 (2.4% vs. 0%) and day 60 (4.9% vs. 3.8%). Rate of relapse was similar between cohorts A and B (16.0% vs. 30.6%, p=0.24). We then compared the outcomes of pts in Cohort B to CPX-351eligible arm from Cohort A (n=14). ORR and mOS were similar in Cohort B and CPX-351 eligible arm (ORR: 50% vs. 50%, p=1.0; mOS 11.1mo vs. 13.8mo, p=0.43). Only 1 patient (7.1%) of the CPX-351eligible arm underwent allo-SCT. Conclusion Our study demonstrates that HMA+Ven results in comparable response rates and survival outcomes to patients receiving CPX-351 when used as an initial remission therapy for patients with newly diagnosed AML, however the median follow up for patients receiving HMA+Ven was short. Survival did not appear to be impacted by a significantly greater proportion of patients proceeding to allo-SCT in the CPX-351 arm. Overall, HMA+Ven may represent a reasonable frontline remission therapeutic choice in patients with AML and a randomized trial would seem justified. Disclosures Kuykendall: Abbvie: Honoraria; Janssen: Consultancy; Incyte: Honoraria, Speakers Bureau; Celgene: Honoraria. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lancet:Pfizer: Consultancy, Research Funding; Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy; Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services . Sallman:Celyad: Membership on an entity's Board of Directors or advisory committees. Komrokji:celgene: Consultancy; Agios: Consultancy; pfizer: Consultancy; DSI: Consultancy; JAZZ: Speakers Bureau; JAZZ: Consultancy; Novartis: Speakers Bureau; Incyte: Consultancy. Sweet:Abbvie: Membership on an entity's Board of Directors or advisory committees; Stemline: Consultancy; Agios: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy; Celgene: Speakers Bureau; Jazz: Speakers Bureau. Talati:Agios: Honoraria; Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Celgene: Honoraria; Daiichi-Sankyo: Honoraria; Astellas: Honoraria, Speakers Bureau; Pfizer: Honoraria.

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Long-Term Subgroup Analyses from Azacitidine Vs. Decitabine in Unfit Newly Diagnosed Acute Myeloid Leukemia Patients: Results from the Pethema Registry

Blood ◽

10.1182/blood-2021-150649 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1256-1256

Author(s):

Jorge Labrador ◽

Adolfo de la Fuente ◽

David Martínez-Cuadrón ◽

Rebeca Rodríguez-Veiga ◽

Josefina Serrano ◽

...

Keyword(s):

Bone Marrow ◽

Board Of Directors ◽

Subgroup Analysis ◽

Myeloid Leukemia ◽

Research Funding ◽

Real Life ◽

Advisory Committees ◽

Baseline Characteristics

Abstract INTRODUCTION The hypomethylating agents (HMAs), decitabine (DEC) and azacitidine (AZA), have made it possible to treat more elderly patients with acute myeloid leukemia (AML). Both HMAs have demonstrated efficacy in monotherapy and in combination with targeted therapies. However, there is little direct comparative data on AZA and DEC in first-line treatment, and we do not know which group of patients might benefit from each drug. Results of the full analysis set (FAS) were presented previously (Labrador J, et al. ASH 2020). Here, we report long-term clinical efficacy from prespecified patient subgroup analyses. METHODS We conducted a retrospective study to compare real-life clinical outcomes between AZA and DEC in patients with AML ineligible for intensive chemotherapy included in the PETHEMA registry, and analyzed clinical variables associated with response and overall survival (OS) between AZA and DEC. RESULTS A total of 626 patients were included for the FAS between 2006 and 2019. 487 (78%) received AZA and 139 (22%) received DEC. Baseline characteristics were comparable in both groups, except for the percentage of bone marrow blasts (44% vs. 34% in the DEC group compared to AZA, p=0.010). In the FAS, there was no difference in the CR, CR/CRi or ORR (CR/RCi + PR) rate: 18%, 20.5% and 32% with AZA vs. 23%, 25% and 39.5% with DEC (p=0.20, p=0.27 and p=0.12). In the subgroup analysis, DEC was associated with higher CR/CRi rate than AZA in patients with ECOG ≥ 2 (95% CI: 0.088 - 0.801), bone marrow blast count < 50% (95% CI: 0.293 - 0.965), secondary AML (95% CI: 0.223 - 0.918) and adverse cytogenetics (95% CI: 0.171 - 0.857) (Figure 1A). DEC was associated with higher ORR rate than AZA in patients with ECOG ≥ 2 (95% CI: 0.116 - 0.782), leukocytes < 10 x10 9/L (95% CI: 0.321 - 0.920) and bone marrow blasts < 50% (95% CI: 0.321 - 0.920) (Figure 1B) 120 days-mortality was 25.4% after AZA and 27.1% after DEC, p=0.70. Patients who did not achieve at least a PR had significantly higher 120-day mortality with both HMAs (OR 8.85 and 8.22 for AZA and DEC, respectively). In the subgroup analysis, patients with leukocytes ≥ 10 x10 9/L (95% CI: 1.069 - 4.157) and those with estimated glomerular filtration rate (eGFR) ≥ 45 mL/min/1.73m 2 (95% CI: 1.249 - 4.664) had higher 120-day mortality with DEC than with AZA (Figure 1C) With a median follow-up of 12 months, median OS was 10.4 months (95% CI: 9.2 - 11.7) for AZA vs. 8.8 months (95% CI: 6.7 - 11.0) for DEC (p = 0.455). The subgroup analysis revealed that patients ≥ 80 years (95%: CI 1.005 - 2.341), with leukocytes ≥ 10 x10 9/L (95% CI 1.039 - 2.062), platelet count <20 x10 9/L (95% CI: 1.150 - 3.422) and those with eGFR ≥ 45 mL/min/1.73m 2 (95% CI: 1.040 - 2.059) did benefit for treatment with AZA compared to DEC (Figure 1D). CONCLUSIONS Our study provides real-life data on the outcomes of AML patients treated with AZA compared to DEC in a large retrospective cohort with long-term follow-up. In addition, we identify for the first time some baseline characteristics that could benefit from AZA or DEC in terms of responses, 120-day mortality and OS. These findings could help us to choose the most appropriate HMA in monotherapy or for the development of new combinations. Figure 1 Figure 1. Disclosures de la Fuente: Novartis: Research Funding; Abbie: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Tormo: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Pérez-Simón: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Montesinos: Forma Therapeutics: Consultancy; Tolero Pharmaceutical: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Glycomimetics: Consultancy; Agios: Consultancy; Stemline/Menarini: Consultancy; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau.

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Myeloid Sarcoma: The Mayo Clinic Experience of Ninety Six Case Series

Blood ◽

10.1182/blood.v128.22.2798.2798 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2798-2798

Author(s):

Jennifer Yui ◽

Mythri Mudireddy ◽

Mrinal M Patnaik ◽

Naseema Gangat ◽

Aref Al-Kali ◽

...

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Mayo Clinic ◽

Myeloid Leukemia ◽

Research Funding ◽

Bone Marrow Involvement ◽

Myeloid Sarcoma ◽

Secondary Acute Myeloid Leukemia ◽

Acute Myeloid

Abstract Background: Myeloid sarcoma is a tumor mass consisting of myeloid blasts occurring at anatomical site other than the bone marrow (Arber et al. Blood 2016;127(20):2391-2405). It is a subgroup of acute myeloid leukemia, which can be localized or disseminated and may involve multiple organs. It can present with or without a positive bone marrow. It may precede or follow bone marrow involvement. It may be identified at diagnosis or relapse, and is not uncommon after stem cell transplantation (Koc et al. Cancer 1999;85(3):608-615; Yoshihara et al. Biol. Blood Marrow Transplant 2012;18(12):1800-1807). Objective: To describe the clinical characteristics, cytogenetics, prognosis and outcome of patients with myeloid sarcoma with or without bone marrow involvement. Methods: The Mayo Clinic database was interrogated using the ICD-9 codes 205.0, 205.2, 205.3, as well as terms "myeloid sarcoma," "chloroma," and "extramedullary sarcoma" in clinical notes and pathology reports. Patients' follow up information was collected until July 2016. Results: Ninety six patients with a diagnosis myeloid sarcoma were identified. The diagnosis was based on biopsy results and in some cases imaging studies in addition to bone marrow biopsy. The median age was 53 (range 17-83) years, and 64 (67%) patients were males. Myeloid sarcoma with de novo (primary) and secondary acute myeloid leukemia (with antecedent hematologic malignancy and therapy related) accounted for 64% (61) and 36% of the cases respectively. The sites involved based on their frequency of occurrence included integumentary system (skin and soft tissues) in 37 (38%), lymphatic system in 17 (18%), the gastrointestinal and genitourinary system in 14 (15%), the nervous system in 9 (9%), the breast in 3 (3%) and multiple and other single sites in 16 (17 %). Bone marrow cytogenetics findings were documented in 74 (77%) patients; favorable, intermediate, and poor cytogenetic abnormalities account for 7 (9%), 45 (61%), and 22 (30%) cases respectively. After a median follow up of 135 weeks, 57 (59%) patients died. The median survival of primary and secondary acute myeloid leukemia with myeloid sarcoma was 52 and 11.5 months (P<0.0001); and that of favorable, intermediate and unfavorable cytogenetics abnormalities was 169, 52 and 17.5 months (P=0.04) respectively. Twenty six (27%) patients had no bone marrow involvement; and 18 (69%) of them were primary myeloid sarcoma (without antecedent malignancy or therapy). The median (range) age of those with and without bone marrow involvement was 53 (17-83) and 56 (17-81) years (P=0.6). At diagnosis patients with and without bone marrow involvement have a median (range) hemoglobin (gm/dL) (10.3 (6.2-15.4) vs 13.1 (9.9-15.2) P=0.0002), white blood cell count (X109/L) (21.4 (1.1-182.5) vs 5.8 (2.4-23.2) P<0.0001), and platelet count (X109/L) (71 (8-437) vs 250 (17-561) respectively. Aggressive chemotherapy therapy was given to 58 (83%) and 20 (77%) of patients with and without bone marrow involvement (P=0.6). The median survival was 17 and 20 months with and without bone marrow involvement (P=0.4). Of those with bone marrow involvement, 49 (70%) achieved complete remission, and 26 (53%) of those individuals subsequently relapsed. Conclusion: The treatment outcome of patients with myeloid sarcoma with or without bone marrow involvement seems the same. The conventional risk factors, antecedent hematological neoplasms and cytogenetic findings, have significant impact on survival. Disclosures Al-Kali: Celgene: Research Funding; Onconova Therapeutics, Inc.: Research Funding.

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Importance of Complete Remission on Predicting Overall Survival in Patients with Lower-Risk Myelodysplastic Syndromes (MDS)

Blood ◽

10.1182/blood.v128.22.4332.4332 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4332-4332

Author(s):

Aziz Nazha ◽

Rami S. Komrokji ◽

John Barnard ◽

Najla H Al Ali ◽

Gail J. Roboz ◽

...

Keyword(s):

Bone Marrow ◽

Overall Survival ◽

Complete Remission ◽

Board Of Directors ◽

Lower Risk ◽

Research Funding ◽

Advisory Committees ◽

Best Response ◽

Bone Marrow Blasts

Abstract Background Lower-risk (LR) MDS (Low/Int-1 per International Prognostic Scoring System (IPSS)) are a heterogeneous group of disorders characterized mainly by refractory anemia and transfusion dependency. As survival of this patient (pt) population is measured in years. Goals of therapy focus on decreasing blood transfusions, improving quality of life, while minimizing treatment toxicities. While achieving complete remission (CR) in higher-risk MDS correlates with improved overall survival (OS), its relationship to OS in LR MDS is not well defined. We evaluated the impact of achieving CR on OS in LR MDS and defined the clinical characteristics that may predict for this response in this pt population. Method Included pts were diagnosed with MDS (per 2008 WHO criteria) and had LR disease with clinical and pathologic data collected from MDS Clinical Research Consortium institutions. Only pts with bone marrow blasts of 5-9% who would thus qualify both as having LR MDS and for being eligible to assess CR were included. Responses (including CR, PR, HI, stable disease and progressive disease) were defined per International Working Group 2006 criteria. OS was calculated from the time of achievement of best response to time of death or last follow-up. Cox proportional hazard analysis that included all clinical variables and treatment characteristics was used to identify independent prognostic factors. Results Of 1470 pts included in the database, 999 identified with LR disease, and 174 had bone marrow blasts of 5-9%. The median age was 60 years (range, 22-87), and 37% were female. Median neutrophil count was 1.25 X 109\L (range, .10-51.0), hemoglobin was 9.8 g/dl, platelets were 109 k/ml (range, 18-562), and bone marrow blasts were 6% (range, 5-9%). Best responses to therapy included: 26 pts (15%) with CR, 10 pts (6%) with PR, and 13 pts (7%) with HI. Among pts who achieved CR/PR/HI, 27 received HMA (25 with azacidtine +/- combination and 2 with single agent decitabine), 16 intensive chemotherapy, 2 lenalidomide, and 4 received other therapies. With a median follow up from diagnosis of 31.2 months, the median time from diagnosis to best response was 11.9 months (range, .69-81.0) and was similar in pts who achieved CR compared to PR/HI (11.5 vs. 12.4 months, respectively, p = .74). The median OS from time of CR/PR/HI for the entire cohort was 21.3 months. The median OS for pts who achieved a CR was longer compared to pts with PR/HI (46.5 vs. 18.5 months, respectively, p = .03). In multivariate analyses that included clinical variables and treatment history, achieving CR remained an independent prognostic factor for longer OS (HR .32, p = .03) but no individual demographic, clinical or treatment variables were predictive of CR. Conclusions Similar to pts with higher-risk MDS, LR MDS pts who achieve CR to therapy have improved OS compared to those with PR or HI. CR is thus an important endpoint in LR MDS, though is difficult to predict. As OS is measured in years in LR MDS, CR may be used as a surrogate endpoint for OS in clinical trials in this pt population. Disclosures Komrokji: Novartis: Consultancy, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Roboz:Cellectis: Research Funding; Agios, Amgen, Amphivena, Astex, AstraZeneca, Boehringer Ingelheim, Celator, Celgene, Genoptix, Janssen, Juno, MEI Pharma, MedImmune, Novartis, Onconova, Pfizer, Roche/Genentech, Sunesis, Teva: Consultancy. Sekeres:Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

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Synthetic lethality between BRCA1 deficiency and poly(ADP-ribose) polymerase inhibition is modulated by processing of endogenous oxidative DNA damage

Nucleic Acids Research ◽

10.1093/nar/gkz624 ◽

2019 ◽

Vol 47 (17) ◽

pp. 9132-9143 ◽

Cited By ~ 9

Author(s):

Sara Giovannini ◽

Marie-Christine Weller ◽

Simone Repmann ◽

Holger Moch ◽

Josef Jiricny

Keyword(s):

Dna Damage ◽

Oxidative Dna Damage ◽

Synthetic Lethality ◽

Oxygen Metabolism ◽

Parp Inhibitors ◽

Parp Inhibition ◽

Strand Breaks ◽

Hypoxic Conditions ◽

Single Strand Breaks ◽

Clinical Resistance

Abstract Poly(ADP-ribose) polymerases (PARPs) facilitate the repair of DNA single-strand breaks (SSBs). When PARPs are inhibited, unrepaired SSBs colliding with replication forks give rise to cytotoxic double-strand breaks. These are normally rescued by homologous recombination (HR), but, in cells with suboptimal HR, PARP inhibition leads to genomic instability and cell death, a phenomenon currently exploited in the therapy of ovarian cancers in BRCA1/2 mutation carriers. In spite of their promise, resistance to PARP inhibitors (PARPis) has already emerged. In order to identify the possible underlying causes of the resistance, we set out to identify the endogenous source of DNA damage that activates PARPs. We argued that if the toxicity of PARPis is indeed caused by unrepaired SSBs, these breaks must arise spontaneously, because PARPis are used as single agents. We now show that a significant contributor to PARPi toxicity is oxygen metabolism. While BRCA1-depleted or -mutated cells were hypersensitive to the clinically approved PARPi olaparib, its toxicity was significantly attenuated by depletion of OGG1 or MYH DNA glycosylases, as well as by treatment with reactive oxygen species scavengers, growth under hypoxic conditions or chemical OGG1 inhibition. Thus, clinical resistance to PARPi therapy may emerge simply through reduced efficiency of oxidative damage repair.

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The DNA Damaging Revolution: PARP Inhibitors and Beyond

American Society of Clinical Oncology Educational Book ◽

10.1200/edbk_238473 ◽

2019 ◽

pp. 185-195 ◽

Cited By ~ 46

Author(s):

Timothy A. Yap ◽

Ruth Plummer ◽

Nilofer S. Azad ◽

Thomas Helleday

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Synthetic Lethality ◽

Checkpoint Inhibitors ◽

Parp Inhibitors ◽

Therapeutic Benefit ◽

Cytotoxic Agents ◽

Parp Inhibition ◽

Breast Cancers ◽

Trial Testing

Cancer-specific DNA repair defects are abundant in malignant tissue and present an opportunity to capitalize on these aberrations for therapeutic benefit. Early preclinical data demonstrated the concept of synthetic lethality between BRCA genetic defects and pharmacologic PARP inhibition, suggesting that there may be monotherapy activity with this class of agents and supporting the early trial testing of this molecularly driven approach. Although the first foray into the clinic for PARP inhibitors was in combination with DNA-damaging cytotoxic agents, clinical development was limited by the more-than-additive toxicity, in particular dose-limiting myelosuppression. As more tolerable single agents, PARP inhibitors are now approved for the treatment of ovarian cancer in different settings and BRCA-mutant breast cancers. Beyond PARP inhibitors, there is now a large armamentarium of potent and relatively selective inhibitors in clinical trial testing against key targets involved in the DNA damage response (DDR), including ATR, ATM, CHK1/2, WEE1, and DNA-PK. These agents are being developed for patients with molecularly selected tumors and in rational combinations with other molecularly targeted agents and immune checkpoint inhibitors. We detail the clinical progress made in the development of PARP inhibitors, review rational combinations, and discuss the development of emerging inhibitors against novel DDR targets, including DNA repair proteins, DNA damage signaling, and DNA metabolism.

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PARP Inhibitors Are Effective in IDH1/2 Mutant MDS and AML Resistant to Targeted IDH Inhibitors

Blood ◽

10.1182/blood-2019-130814 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4222-4222 ◽

Cited By ~ 1

Author(s):

Rana Gbyli ◽

Yuanbin Song ◽

Wei Liu ◽

Yimeng Gao ◽

Namrata S Chandhok ◽

...

Keyword(s):

Research Funding ◽

Synthetic Lethality ◽

Parp Inhibitor ◽

Parp Inhibitors ◽

Parp Inhibition ◽

Resistance Mutations ◽

Single Strand Break ◽

Immunodeficient Mice ◽

Equity Ownership

Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are heterogeneous clonal disorders. Isocitrate dehydrogenase-1 and -2 (IDH1/2) mutations are detected in ~20% of AML and ~5% of MDS, in which they confer gain of a neomorphic function that leads to the production of (R)-2-hydroxyglutarate (2HG). Targeted inhibition of mutant IDH1/2 has resulted in significant responses in IDH1/2 mutant MDS and AML but is not curative and patients relapse (Stein et al. Blood 2016, DiNardo et al. N Engl J Med 2018). 2HG accumulation inhibits the function of histone demethylases (KDM4A and KDM4B) that are critical for the homologous recombination (HR) DNA repair pathway and consequently for the repair of DNA double strand breaks (DSBs) (Mallette et al. EMBO J 2012, Sulkowski et al. Sci Transl Med 2017). In HR deficient tumors, Poly-ADP-Ribose Polymerase (PARP) is essential for DNA single strand break (SSB) repair. In IDH mutant tumors PARP inhibitors induce synthetic lethality by suppressing the repair of SSBs, which eventually get converted into DSBs (Javle and Curtin Br J Cancer 2011). We previously demonstrated that in AML, IDH1/2 mutations impair DNA damage response by inducing a defect in HR, and that this renders leukemia cells susceptible to PARP inhibitors in vitro. We hypothesized that this vulnerability would also exist in IDH mutant MDS and more importantly, that this vulnerability would persist in MDS/AML resistant to IDH1/2 inhibitors. To determine whether PARP inhibition targets IDH mutant MDS/AML in vivo, we took advantage of 2 syngeneic mouse models of MDS and AML relying on co-mutation of SRSF2/IDH2 and FLT3/IDH2, respectively. Olaparib (PARP inhibitor) effectively targeted IDH2 mutant but not IDH2 wild type MDS/AML (Fig. 1A). We next sought to determine whether PARP inhibition mediated synthetic lethality persists in MDS/AML resistant to targeted IDH inhibition. We transduced IDH2 mutant murine cells with IDH2 WT or IDH2 MUT lentiviral vectors carrying one of two published resistance mutations. While these resistance mutations conferred resistance to the targeted IDH2 inhibitor Enasidenib, cells remained sensitive to Olaparib (Fig. 1B). Patient MDS/AML is heterogeneous and in general carries additional genetic mutations and epigenetic alterations. We therefore engrafted IDH1/2 WT and MUT MDS/AML patient samples in cytokine humanized immunodeficient mice and treated with vehicle of Olaparib. Engrafted mice were assigned to vehicle or Olaparib 8 weeks after transplantation based on equal engraftment levels determined by BM aspiration. Mice were treated with vehicle or Olaparib via IP injection for 21 days. Human engraftment levels and plasma 2-HG levels were significantly reduced in Olaparib treated animals when compared to pre-treatment and vehicle-treated mice (Fig. 1C). Of note, when equal numbers of huCD34+ cells from vehicle or Olaparib treated mice were transplanted into next generation mice, engraftment was significantly higher for recipients of human cells from vehicle than Olaparib treated mice, suggesting that Olaparib is toxic to leukemia initiating cells. In contrast, IDH WT MDS/AML was insensitive to Olaparib treatment (Fig. 1C). In conclusion, PARP inhibition is effective in vivo against IDH mutant MDS/AML and can overcome targeted IDH inhibitor resistance. Disclosures Flavell: Zai labs: Consultancy; SMOC: Equity Ownership; Troy: Equity Ownership; Artizan Biosciences: Equity Ownership; GSK: Consultancy; Rheos Biomedicines: Equity Ownership. Prebet:Boehringer Ingelheim: Research Funding; Boehringer Ingelheim: Research Funding; novartis: Honoraria; pfizer: Honoraria; Boehringer Ingelheim: Research Funding; Agios: Consultancy, Research Funding; novartis: Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; pfizer: Honoraria; Genentech: Consultancy; pfizer: Honoraria; novartis: Honoraria; Tetraphase: Consultancy; novartis: Honoraria; pfizer: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; novartis: Honoraria; pfizer: Honoraria. Bindra:Cybrexa: Consultancy, Equity Ownership.

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Flowsom: An R-Based Evaluation Strategy for Flow Cytometry-Based Measurable Residual Disease (MRD) Diagnostics in Acute Myeloid Leukemia (AML)

Blood ◽

10.1182/blood-2019-129866 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4656-4656

Author(s):

Veit Bücklein ◽

Alexandra Stein ◽

Benjamin Tast ◽

Thomas Koehnke ◽

Karsten Spiekermann ◽

...

Keyword(s):

Bone Marrow ◽

Flow Cytometry ◽

Overall Survival ◽

Myeloid Leukemia ◽

Research Funding ◽

Residual Disease ◽

Analysis Strategies ◽

Measurable Residual Disease ◽

Acute Myeloid

Patients with Acute Myeloid Leukemia (AML) frequently relapse due to chemorefractory AML cells persisting after intensive chemotherapy at levels below the 5% morphological detection threshold (measurable residual disease, MRD). MRD has been established as an important prognostic factor for relapse-free and overall survival, making it highly relevant for post-remission treatment stratification. In contrast to MRD assessment by molecular techniques, multiparameter flow cytometry (MFC)-based MRD measurements are applicable in more than 95% of AML patients, while still offering a sensitivity of 10-4 to 10-5. Current MFC MRD assessment strategies measure 8-10 fluorochromes in parallel, resulting in a high-dimensional data set. However, evaluation of this data is usually performed by scatterplot-based manual, two-dimensional analysis. This leads to loss of information and significant inter-observer variability in MRD diagnostics. We therefore established a computational data analysis strategy for MFC MRD diagnostics, based on the unsupervised FlowSOM algorithm. By comparison with healthy bone marrow (HBM) data, FlowSOM analysis can identify aberrant (sub-)populations of cells, clustered in nodes (according to similarity of their antigen profile). These nodes can be denoted as "nodes of interest" (NOI) to simplify MRD analysis after clustering. Aim of the project was to establish FlowSOM analysis protocols and retrospectively evaluate their prognostic significance in a cohort of 46 patients with known outcomes. Bone marrow samples of these patients were analyzed at aplasia (day 16 after initiation of induction chemotherapy). Only patients with morphological blast clearance at aplasia were included. Healthy reference FlowSOM trees were established by merging flow data of 17 HBM. Analysis protocols were developed to report individual ("any node" approach) and cumulative ("sum node" approach) differences in NOI percentages when comparing HBM and MRD samples. We then performed FlowSOM MRD analyses in a patient subcohort of 19 AML patients. Importantly, for these analyses, we excluded patients who underwent allogeneic stem cell transplantation in first remission (non-HSCT subcohort). Median follow-up time was 8.3 (range 2-40) months for this subcohort. Receiver operating characteristic (ROC) analyses were used to determine optimal threshold values to differentiate relapse (n=5) and non-relapse (n=14) patients within the cohort. For "sum node" analysis strategies (defining MRD levels as cumulative difference of NOI percentages) a threshold of -2.44% was identified, optimized for Youden (Y) index and diagnostic odds ratio (DOR). For the "any node" strategy (defining MRD levels by the maximum difference of any NOI), a threshold of 0.04%, also optimized for the Y-index and DOR, discriminated best between relapse and non-relapse patients. Relapse-free survival (RFS) was significantly shorter for MRD-positive (MRDpos) patients identified by "sum node" analysis (median 8 months vs. not reached, p=0.016) and tended to be shorter for MRDpos patients by "any node" analysis (median 8 months vs. not reached, p=0.1). When applying the thresholds identified in the non-HSCT cohort to the full set of 46 patients (median follow-up interval 10.6 months, range 2-40), median RFS was not reached for the MRD-negative group (both for "sum node" and "any node" analysis), and was 14 ("sum node", p=0.098) and 14 months ("any node", p=0.360) for the MRDpos patients. Median overall survival for MRDpos patients by "sum node" analysis was 27 months, whereas it was not reached for MRD-negative patients. However, this difference did not reach statistical significance (p=0.335), probably due to the small sample size. Taken together, FlowSOM-based analysis strategies seem well suited to identify patients with MRD positivity after intensive induction chemotherapy. MFC MRD positivity at aplasia, defined by FlowSOM-based analysis, is associated with inferior RFS in retrospective analyses of small patient cohorts. Due to the underlying computational, unsupervised data analysis, FlowSOM-based assessment can be a means to harmonize MFC MRD evaluation. These promising results need to be verified in larger cohorts, with inclusion of post-induction assessments, and should be followed by prospective analyses to delineate the diagnostic validity of FlowSOM for AML MRD diagnostics in clinical trials. Disclosures Subklewe: Janssen: Consultancy; Morphosys: Research Funding; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; Miltenyi: Research Funding; Oxford Biotherapeutics: Research Funding; Pfizer: Consultancy, Honoraria; AMGEN: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Research Funding.

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Failures and Successes in Pediatric Patients with Acute Myeloid Leukemia with First Relapse: A Large International Report on Current Treatment Strategies and Outcome

Blood ◽

10.1182/blood-2020-141774 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 6-7

Author(s):

Mareike Rasche ◽

Martin Zimmermann ◽

Emma Steidel ◽

Todd A. Alonzo ◽

Richard Aplenc ◽

...

Keyword(s):

Bone Marrow ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Pediatric Patients ◽

Advisory Committees ◽

First Relapse ◽

Pediatric Aml ◽

Acute Myeloid

BACKGROUND: Children with high risk acute myeloid leukemia (AML) still experience consistently high rates of relapse. Survival after first relapse increased from 21% between 1987 and 1997 up to 39% in recent studies. However, since 2009, there have been no publications on subsequent large pediatric AML relapse trials. As the indications for HSCT during first-line treatment have been extended since then, the current survival of these patients at relapse remains unclear. Herein, we report outcome results from the BFM and COG study group, which represents the largest available dataset analyzed for post-relapse survival. PATIENTS AND METHODS: Pediatric patients with first relapse of AML (no Down syndrome, secondary leukemia or FAB M3) have been analyzed from two large study groups with patients from the United States, Canada, Australia, New Zealand, Germany, Austria, Czech Republic and Switzerland. Out of 1222 patients in the BFM cohort (AML-BFM study 2004, registry 2012 and study 2012), 350 experienced at least one relapse and 197 of those had a first relapse after closure of the last I-BFM relapse trial (04/2009 through 2017). Within the Children's Oncology Group (COG) Phase 3 trials (AAML0531 and AAML1031, n=2119) 852 pediatric patients suffered a relapse. Five-year probability of overall survival (pOS) and event-free survival (pEFS) were calculated according to Kaplan-Meier. EFS was calculated for the BFM cohort as time from relapse to the next event (second relapse, death, failure to achieve a second remission or secondary malignancy) or until last follow-up, while OS reflects the time from relapse until death or last follow-up. The Cox proportional hazards model was used for multivariate analysis of outcomes. Living patients were censored at last follow-up with a median follow-up after relapse of 4·2 years (BFM) and 4·8 years (COG). Data have been frozen at 03/27/2020 (BFM) and 03/31/2020 (COG). RESULTS: In the 197 patients with relapse after closure of the last BFM relapse trial (04/2009 through 2017) the pOS at 5 years was 42±4% (BFM). The 5-year pOS in patients relapsing after COG trials 2006-2018 was 35±2% (n=852). Patients experiencing a relapse between 2014 to 2017 had a pOS of 49±6% (BFM, n=78) and 40±3% (COG, n=333). Risk classification at initial diagnosis and a short time from diagnosis to relapse predicted a diminished survival probability in both cohorts (see Table 1). However, the absence of full hematopoietic regeneration of the bone marrow after re-induction did not predict survival: Within the BFM dataset, a subgroup analysis in all patients receiving DNX-FLA (n=156) have been performed. Initial characteristics are comparable to the total cohort. Among these patients 147 were evaluable for response (7 excluded due to early death before evaluation, 2 for insufficient data). Eighty-nine (57%) achieved a CR (n=69) or CRp (n=20) and 52 (33%) no response. Overall survival was superior for patients with a CR/CRp (54±6% (CR/CRp) vs. 32±7% (No CR/CRp); p=0·0064), but long-term survival was still possible even with a poor re-induction response. Patients with a CRp had a comparable survival to those with a CR after a second re-induction (pOS 60±11% (CRp) vs. pOS 52±7% (CR); p=0·57). Patients with >5% leukemic blasts (n=32) had the lowest survival (pOS 27±9%). The 5-year pEFS for this cohort was 29±4% (pEFS 50±6% (CR) vs. pEFS 50±11% (CRp)). The analysis of post-relapse treatment showed that the vast majority of patients who survive had a HSCT following relapse. By landmark analysis, survival was significantly higher in patients with subsequent HSCT compared to that of non-transplanted patients (BFM: pOS 53±4%, n=154 vs. pOS 5±5%, n=21; p(Mantel-Byar)=0·0002). CONCLUSION: This is the largest report to date on post relapse survival in children with AML. Our analysis confirmed previously described risk factors for poor survival while also highlighting new findings contrary to established standards. Strikingly, the absence of full hematopoietic regeneration of the bone marrow after re-induction did not predict survival at first relapse, thereby questioning the current value of the established International Working Group Criteria published by Cheson et al for response-evaluation in pediatric AML. As the international pediatric AML community embarks on collaborative efforts to evaluate new therapies in children with relapsed AML, a comprehensive review of post relapse survival is critical. Disclosures Bourquin: Servier: Other: Travel Support. Reinhardt:Novartis: Membership on an entity's Board of Directors or advisory committees; CLS Behring: Research Funding; bluebird bio: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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