Intermediate-dose Cytarabine Research Articles

Dose Reduced Chemotherapy in Sequence with Blinatumomab for Newly Diagnosed Older Patients with B-Precursor Adult Lymphoblastic Leukemia (ALL): Results of the Ongoing GMALL Bold Trial

Dose Reduced Chemotherapy in Sequence with Blinatumomab for Newly Diagnosed Older Patients with B-Precursor Adult Lymphoblastic Leukemia (ALL): Results of the Ongoing GMALL Bold Trial

Gilteritinib Versus Salvage Chemotherapy for Relapsed/Refractory FLT3-Mutated Acute Myeloid Leukemia: A Phase 3, Randomized, Multicenter, Open-Label Trial in Asia

▪Background: Due to poor prognosis, treatment options for patients with FLT3-mutated (FLT3mut+) acute myeloid leukemia (AML) who are refractory to therapy or have relapsed (R/R) are needed globally. Gilteritinib is approved in multiple countries, including Japan, and has recently received conditional approval in China for the treatment of R/R FLT3mut+ AML; in the phase 3 ADMIRAL trial, superior survival benefit and a favorable safety profile were shown for patients receiving gilteritinib compared to those receiving salvage chemotherapy (SC) (HR 0.64 [95% CI: 0.49, 0.83]; P<0.001) in the R/R FLT3mut+ AML setting. While data from the Asian subpopulation of ADMIRAL have been evaluated, larger randomized, controlled trials of outcomes for treatments in a predominantly Asian population are lacking.Aim/Objective: To evaluate the efficacy and safety/tolerability of gilteritinib compared with SC in Asian patients with R/R FLT3mut+ AML after first-line therapy.Methods: In this phase 3, open-label, multicenter COMMODORE (NCT03182244) trial, adult patients in China, Russia, Singapore, Thailand, and Malaysia with R/R FLT3mut+ AML were randomized 1:1 to gilteritinib 120 mg orally per day or SC (low-dose cytarabine; mitoxantrone, etoposide, and intermediate-dose cytarabine; or fludarabine, high-dose cytarabine, and granulocyte colony-stimulating factor) over continuous 28-day cycles. Patients must have had an ECOG performance status score ≤2; those with acute promyelocytic leukemia, BCR-ABL-positive leukemia, clinically active central nervous system disease, or secondary AML were excluded. The primary endpoint was overall survival (OS), and key secondary efficacy endpoints were event-free survival (EFS) and complete remission (CR). Additional secondary endpoints included duration of remission, composite CR (CRc), and safety/tolerability. OS and EFS were analyzed with stratified Cox proportional hazard models, and response rates were analyzed with the Cochran-Mantel-Haenszel test. Results of the interim analysis are presented here.Results: As of June 30, 2020, a total of 234 patients were randomized (gilteritinib, n=116; SC, n=118). Median age was 51.5 and 49.5 years in the gilteritinib and SC groups, respectively; most patients had not previously received FLT3 inhibitors (87.9% and 93.2%, respectively). Baseline FLT3 mutations in the gilteritinib vs SC groups were: FLT3-ITD (91.4% vs 83.1%), FLT3-TKD (6.0% vs 11.9%), and both FLT3-ITD and FLT3-TKD (2.6% vs 5.1%). Median follow-up duration for OS was 11.1 months for gilteritinib and 6.9 months for SC. Median OS was significantly longer in the gilteritinib group (9.0 months) compared with the SC group (4.7 months; HR 0.549 [95% CI: 0.379, 0.795]; P=0.00126; Figure); 1-year survival rates were 33.3% and 23.2%, respectively. Patients on gilteritinib had significantly longer EFS than those receiving SC (median EFS 2.8 vs 0.6 months; HR 0.551 [95% CI: 0.395, 0.769]; P=0.00004). A higher proportion of patients achieved CR on gilteritinib (16.4%) compared with SC (10.2%; P=0.17690); CRc rates were 50.0% and 20.3% (P<0.00001). Grade ≥3 adverse events (AEs) in the gilteritinib (97.3%) vs SC (94.2%) groups were comparable; rates for serious AEs were higher for gilteritinib (73.5%) vs SC (61.5%). When adjusted for treatment exposure, AE rates were lower with gilteritinib (grade ≥3, 55.56 events/patient-year [E/PY]; serious, 6.19 E/PY) than with SC (grade ≥3, 164.00 E/PY; serious, 12.40 E/PY). The most common AEs occurring in the gilteritinib group were anemia (76.1%), thrombocytopenia (46.9%), pyrexia (41.6%), and increased blood lactate dehydrogenase (41.6%); for SC, the most common AEs were anemia (64.4%), decreased white blood cell count (41.3%), and thrombocytopenia (38.5%). AEs leading to death occurred in 22 (19.5%) and 15 (14.4%) of patients receiving gilteritinib or SC, respectively.Conclusions: Gilteritinib significantly prolonged OS and EFS compared with SC in patients with R/R FLT3mut+ AML in Asia. When adjusted for treatment exposure, safety/tolerability was favorable for gilteritinib compared with SC. The results of the COMMODORE trial further validate and affirm the clinical efficacy and safety data from the ADMIRAL trial, reinforcing the significant benefit of gilteritinib in R/R FLT3mut+ AML. [Display omitted] DisclosuresWang: AbbVie: Consultancy; Astellas Pharma, Inc.: Research Funding. Jiang: Astellas Pharma, Inc.: Research Funding. Li: Astellas Pharma, Inc.: Research Funding. Liu: Astellas Pharma, Inc.: Research Funding. Du: Astellas Pharma, Inc.: Research Funding. Jiang: Astellas Pharma, Inc.: Research Funding. Hu: Astellas Pharma, Inc.: Research Funding. Yuan: Astellas Pharma, Inc.: Current Employment. Sakatani: Astellas Pharma, Inc.: Current Employment, Current equity holder in publicly-traded company. Kadokura: Astellas Pharma, Inc.: Current Employment. Takeuchi: Astellas Pharma, Inc.: Current Employment. Izuka: Astellas Pharma, Inc.: Current Employment. Girshova: Astellas Pharma, Inc.: Research Funding. Tan: Astellas Pharma, Inc.: Research Funding. Wong: Astellas Pharma, INc.: Research Funding. Khuhapinant: Astellas Pharma, Inc.: Research Funding. Martynova: Astellas Pharma, Inc.: Research Funding. Hasabou: Astellas Pharma, Inc.: Current Employment. Tiu: Astellas Pharma, Inc.: Current Employment.

Intensified Cytarabine Dose during Consolidation Therapy in AML Patients Under 65 Years Is Not Associated with Survival Benefit

▪Background: Acute myeloid leukemia (AML) is characterized by a high relapse rate, indicating insufficient clearance of leukemia-initiating cells. Depending on genetic risk stratification, consolidating chemotherapy proves to significantly reduce the risk of relapse. In particular, in younger AML patients higher dosage of cytarabine appears to improve long-term outcome, while there is no apparent benefit of multiagent combination, compared to cytarabine monotherapy. However, to this end the optimal dosage of single agent cytarabine in consolidation therapy after 7+3 remission induction remains elusive.Methods: Here, we retrospectively assessed the impact of different dosages of cytarabine consolidation on outcome in a large real-world data set from the German Study Alliance Leukemia-Acute Myeloid Leukemia (SAL-AML) registry. Patients below 65 years of age, registered between April 2005 and September 2020 with non-acute promyelocytic leukemia, who attained complete remission after intensive induction and received at least one consolidation cycle with intermediate (IDAC) or high dose cytarabine (HiDAC) were selected. To account for differences in patient and disease characteristics between both groups, the average treatment effect was estimated by propensity score weighting.Results: 642 patients received HiDAC consolidation with a median dosage of 5794.88 (IQR, 4745.48-5971.56) mg/m 2/d with a median number of 3 cycles (IQR, 2-3), whereas 178 patients received IDAC consolidation with 1946.16 (IQR, 1869.51-2469.15) mg/m 2/d with a median of 2 cycles (IQR, 1-3). IDAC-treated patients showed in average a higher age (median (IQR) 58.5 (49-62) years vs. 50 (41-56) years) and more comorbidities with 43.8% having an HCT-CI score of 2-4, compared to 22.3% among HiDAC-treated patients. Alongside, significantly more secondary (5.1% vs. 3.1%) and therapy-related (12.4% vs. 4.1%) AML as well as more adverse (14.5% vs. 6.5%) and less favorable (40.6% vs. 56%) genetic risk features according to ELN 2017 risk classification were found among IDAC-treated patients. After propensity score weighting for differences in patient and disease characteristics, overall survival after 5 years was comparable between HiDAC-treated (71.1 %) and IDAC-treated (67.7%) patients. Moreover, no significant differences in relapse-free survival were observed after 5 years (47.4 vs. 45.2%). Notably, more patients treated with IDAC received allogeneic stem cell transplantation in first remission (37.6 vs. 19.8%) while significantly more HiDAC-treated patients underwent allogeneic stem cell transplantation in relapse (30.8 vs. 20.2%). Censoring for allogeneic stem cell transplantation in first remission revealed no significant survival difference with regard to cytarabine dosage. Considering only ELN favorable risk AML patients, there was no difference in 5-years overall (80.5% vs. 83.9%) nor relapse-free (57.7% vs. 56.8%) survival. Of note, significantly more patients treated with HiDAC suffered from ≥3 CTCAE infectious complications (56.7 vs. 44.1%), which was more striking in patients above 50 years of age. The rate of other ≥3 CTCAE non-hematological toxicities and secondary malignancies was comparable in both treatment groups.Conclusion: This retrospective analysis suggests no significant benefit of high dose cytarabine compared to intermediate dosages in consolidation for AML patients under 65 years of age, independent of ELN risk group. DisclosuresKrause: Siemens: Research Funding; Takeda: Honoraria; Pfizer: Honoraria; art-tempi: Honoraria; Kosmas: Honoraria; Gilead: Other: travel support; Abbvie: Other: travel support. Schliemann: Philogen S.p.A.: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Other: travel grants; Astellas: Consultancy; AstraZeneca: Consultancy; Boehringer-Ingelheim: Research Funding; BMS: Consultancy, Other: travel grants; Jazz Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy; Roche: Consultancy; Pfizer: Consultancy. Haenel: Jazz: Consultancy, Honoraria; GSK: Consultancy; Bayer Vital: Honoraria; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy; Celgene: Consultancy, Honoraria. Brummendorf: Takepart Media: Honoraria; Repeat Diagnostics: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Patents & Royalties, Research Funding; Janssen: Honoraria; Bristol Myers: Research Funding. Fransecky: Abbvie: Honoraria, Research Funding; Medac: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Takeda: Honoraria. Einsele: Janssen, Celgene/BMS, Amgen, GSK, Sanofi: Consultancy, Honoraria, Research Funding. Held: MSD: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Roche: Research Funding; Acortech Biopharma: Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Platzbecker: Janssen: Honoraria; Celgene/BMS: Honoraria; AbbVie: Honoraria; Geron: Honoraria; Takeda: Honoraria; Novartis: Honoraria. Baldus: Amgen: Honoraria; Celgene/BMS: Honoraria; Novartis: Honoraria; Jazz: Honoraria. Mueller-Tidow: Janssen Cilag: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Bioline: Consultancy, Research Funding.

Midostaurin in Patients (Pts) with Newly Diagnosed FLT3-Mutation Negative Acute Myeloid Leukemia (AML): Final Results and Measurable Residual Disease (MRD) Analyses from the Unify Trial

Midostaurin in Patients (Pts) with Newly Diagnosed FLT3-Mutation Negative Acute Myeloid Leukemia (AML): Final Results and Measurable Residual Disease (MRD) Analyses from the Unify Trial

Safety and feasibility of outpatient high-dose cytarabine and intermediate-dose cytarabine for consolidation therapy in acute myeloid leukemia.

The standard of care consolidation therapy for acute myeloid leukemia is high-dose cytarabine or intermediate-dose cytarabine, which are traditionally given inpatient. At Moffitt Cancer Center, we have moved the administration of high-dose cytarabine and intermediate-dose cytarabine to the outpatient setting through the inpatient/outpatient program. To facilitate outpatient administration, high-dose cytarabine and intermediate-dose cytarabine are given in a shorter interval of every 10 h instead of 12 h. The safety of a shorter duration interval of high-dose cytarabine and intermediate-dose cytarabine is unknown. This study aims to assess the safety and feasibility of administering high-dose cytarabine and intermediate-dose cytarabine consolidation therapy in the inpatient/outpatient setting. This is a retrospective chart review to analyze acute myeloid leukemia patients treated with inpatient/outpatient high-dose cytarabine or intermediate-dose cytarabine consolidation therapy at Moffitt Cancer Center from January 1, 2015, through November 1, 2018. The primary objective was to determine the incidence of hospitalization during the inpatient/outpatient administration of high-dose cytarabine or intermediate-dose cytarabine. Two hundred fifty-three of 255 cycles of high-dose cytarabine/intermediate-dose cytarabine were delivered outpatient over the reviewed time period to 118 patients. No patients receiving outpatient high-dose cytarabine/intermediate-dose cytarabine consolidation required hospitalization during chemotherapy. Our incidence of hospitalization (24%) after chemotherapy is consistent with the reported literature. Through the inpatient/outpatient administration of high-dose cytarabine and intermediate-dose cytarabine, 1265 inpatient days were saved with an approximate revenue of $3,135,176 generated in our study period. Inpatient/outpatient administration of high-dose cytarabine and intermediate-dose cytarabine is both safe and feasible. Moving high-dose cytarabine/intermediate-dose cytarabine administration to the outpatient setting resulted in significant additional revenue vs. inpatient administration.

The Intermediate Dose Verse Conventional Dose Cytarabine in Induction Therapy in Adult Acute Myeloid Leukemia: A Phase Ⅲ Randomized Controlled Trial

▪Purpose: A daily dose of 100 to 200 mg/m2 cytarabine for induction therapy in adult acute myeloid leukemia (AML) has been widely used. There is no consensus whether higher dosages of cytarabine can improve outcomes of adult AML.Patients and Methods: A phase Ⅲ randomized parallel controlled trial was conducted. The patients were randomly assigned to receive either intermediate-dose cytarabine, 100 mg/m2 per day as a 12-hour IV infusion on days 1 through 4 and 1,000 mg/m2 every 12 hours as a 3-hour IV infusion on days 5, 6, and 7, or conventional dose cytarabine, 100 mg/m2 per day as a 12-hour IV infusion for 7 days, combined with homoharringtonine 2mg/m2 for 7 days and daunorubicin 40mg/m2 for 3 days for induction therapy in adult AML. All patients who achieved CR were randomly assigned to receive either high dose of cytarabine (3,000 mg/m2every 12 hours as a 3-hour IV infusion on days 1, 2, and 3) or intermediate dose of cytarabine (1,500 mg/m2every 12 hours as a 3-hour IV infusion on days 1, 2, and 3) combined with anthracycline (daunorubicin or mitoxane). Allogeneic stem-cell transplantation was based on genetic risk and patients' intention. The study was approved by the ethical committee of Blood Disease Hospital, CAMS and was conducted in accordance with the Declaration of Helsinki. All patients signed the informed consent. The primary endpoint is disease-free survival (DFS). The duration of neutropenia and thrombocytopenia was analyzed in patients who achieved CR and defined as the time from start of induction treatment to the last day on which neutrophil count was less than 0.5 × 109 neutrophils per L and platelet count was less than 25 × 109 platelets per L. The trial is registered at www.chictr.org.cn (identifier: ChiCTR-TRC-10001202)Results: Five hundred and ninety-six newly diagnosed patients with de novo AML were enrolled. Five patients were excluded for misdiagnosis (3 patients), withdrawal of consent (1 patent), and not meeting inclusion criteria (1 patent). Overall, the median age of eligible 591 randomized patients was 36 (15 to 55) years. Two hundred and twenty-nine of 296 patients (77.4%) in the conventional dose group, and 256 of 295 (86.8%) in the intermediate dose group, achieved CR (P=0.003). Early death within 30 days was 2.4% and 1.4% in intermediate and conventional dose group, respectively, and without significant difference (P=0.355). There was no significant difference in the duration of neutropenia between intermediate and conventional dose group (21 vs 20 days, respectively, P=0.520). But patients receiving intermediate dose required a slightly but significantly longer time to recover from thrombocytopenia. Median duration with a platelet count less than 25 × 109/L was 20 days for the conventional dose group and 22 days for the intermediate dose group (P=0.020). There was a trend toward more bacteria sepsis and RBC transfusion in intermediate dose group compared with conventional dose group (P=0.092 and P=0.093, respectively).The median follow-up of survivors is 30.4(5.1-74.4) months. The probability of 3-year DFS patients were 66.7% for the intermediate dose group (95% CI 60.4% to 72.9%) and 55.4% for the conventional dose group (95% CI 48.3% to 62.4%), respectively (P=0.013). And the probability of 3-year overall survival (OS) were 67.7% for the intermediate dose group (95% CI 61.8% to 73.7%) and 59.3% for the convention al dose group (95% CI 53.1% to 65.5%), respectively (P=0.0604). Subgroup analysis was performed to reveal whether different risk groups benefited from dose escalation of cytarabine. For patients in non-adverse risk subgroup, the 3-year DFS were 69.7% in the intermediate dose group and 56.1% in the conventional dose group (P= 0.004). The 3-year OS were 72.0% in the intermediate dose group and 60.8% in the conventional group (P= 0.017).Conclusion: Induction regimen with dose escalation of cytarabine in adult AML is well tolerated and superior to conventional dose for DFS, especially for patients in non-adverse risk patients.Acknowledgments: This study was supported, in part, by State Key Program of National Natural Science of China (81430004),Foundation for Innovative Research Groups of the NaturalScience Foundation of China (81421002) DisclosuresNo relevant conflicts of interest to declare.

Phase II Trial of Vosaroxin and Infusional Cytarabine for Frontline Treatment of Acute Myeloid Leukemia (VITAL) Patients Eligible for Intensive Chemotherapy: A Planned Interim Analysis

Phase II Trial of Vosaroxin and Infusional Cytarabine for Frontline Treatment of Acute Myeloid Leukemia (VITAL) Patients Eligible for Intensive Chemotherapy: A Planned Interim Analysis

Comparison of Frontline Induction Therapy Using Idarubicin in Combination with High-Dose (HDAC3) Versus Intermediate-Dose Cytarabine (IDAC3) in Adult Acute Myeloid Leukemia

BackgroundThe utility of high-dose cytarabine during induction chemotherapy for adult acute myeloid leukemia (AML) remains contentious. Intermediate-dose cytarabine may maintain a high first-cycle complete remission (CR) rate, whilst reducing treatment-related toxicity.AimWe examined the outcomes of adult AML patients treated with idarubicin (12 mg/m2 days 1-3) in combination with high-dose (3 g/m2; HDAC3) or intermediate-dose cytarabine (1.5 g/m2; IDAC3) given twice daily on days 1, 3, 5, and 7.MethodsConsecutive AML patients aged ≤60 years at 2 major tertiary referral centers, the Alfred and Austin Hospitals, were treated with sequential protocols of HDAC3 (n=52; 2010-2014) and then IDAC3 (n=58; 2014-2017). Planned consolidation chemotherapy consisted of up to 2 cycles of idarubicin 9 mg/m2 days 1-2, cytarabine 100 mg/m2 days 1-5, and etoposide 75 mg/m2 days 1-5 (IcE). Favorable-risk karyotype was excluded from this analysis. We assessed treatment responses (2017 European LeukaemiaNet recommendations), 30 and 60-day mortality, ability to deliver consolidation therapy (number of cycles and days from induction to first consolidation chemotherapy), rates of allogeneic hematopoietic stem cell transplant (allo-HSCT) in first remission (CR1), rates of total parenteral nutrition (TPN) usage, haematologic toxicities (days to platelet and neutrophil recovery), and relapse-free (RFS) and overall survival (OS) censored for allo-HSCT or loss to follow-up. Statistical analysis was performed using R version 3.3.2.ResultsIDAC3-treated patients were younger than those receiving HDAC3 (median 44 vs 48 years) but had a higher frequency of secondary AML (16% vs 4%); (Table 1). Other baseline characteristics were balanced between both groups. No significant differences were observed for any outcome (Table 2), except the use of TPN which is most likely a result of change in practice over time rather than a true reflection of mucositis. Response rates including CR or CR with incomplete haematologic recovery (CRi) were similar: 79% (HDAC3) vs 83% (IDAC3) after 1 cycle of induction. There was no death at 30 days and only 1 death at 60 days. Allo-HSCT in CR1 was similar; among patients with adverse-risk karyotype, allo-HSCT in CR1 was performed for 9/15 (60%) after IDAC3 and 7/11 (64%) after HDAC3. Days to neutrophil and platelet recovery were also similar.Delivery of consolidation chemotherapy was similar between both groups. After excluding treatment failure and partial remission (PR), 94 patients were eligible for first consolidation chemotherapy (3 patients with PR were considered near CR), of which 14 (15%) did not receive further consolidation therapy with the following reasons: allo-HSCT in CR1 (n=10); prolonged cytopenias (n=3); and maintenance clinical trial (n=1). Twenty-nine patients (31%) received only 1 consolidation therapy due to the following reasons: allo-HSCT in CR1 (n=14); prolonged cytopenias (n=10); non-hematologic toxicities (n=2); relapse (n=2); and unknown (n=1). IcE chemotherapy was administered in all except 2 cases: one received high-dose cytarabine for 1 cycle, and another had reduced idarubicin dose for 1 cycle.Survivors were followed up for a median of 8 (IDAC3) and 37 months (HDAC3), respectively. Median OS were 11.5 and 18.6 months for IDAC3 and HDAC3 (p=0.3), respectively (Figure 1A), and the corresponding median RFS were 8.4 and 9.4 months (p=0.5), respectively (Figure 1B). Overall, the median OS for adverse-risk karyotype remained significantly inferior compared to intermediate-risk (5.6 vs 20.9 months, p=0.009 by log-rank test); among adverse-risk karyotype, this was 5.1 vs 6.5 months for IDAC3 and HDAC3, respectively. Similarly, patients with FLT3 -ITDpos/ NPM1WT had inferior median OS (n=7, 6.1 months) when compared with FLT3 -ITDneg/ NPM1WT (n=55, 15.9 months), FLT3 -ITDpos/ NPM1MUT (n=14, 20.9 months), and FLT3 -ITDneg/ NPM1MUT (n=16, 40.6 months, p=0.06 by log-rank test).ConclusionIDAC3 and HDAC3 were both well tolerated in adult patients with AML with high first-cycle CR/CRi rates observed and low early mortality. No significant differences in hematopoietic recovery or delivery of post-remission therapy was apparent. With the caveat of limited sample size and follow-up duration, survival outcomes appeared equivalent. [Display omitted] DisclosuresGrigg:Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Takeda: 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; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Merck Sharpe Dohme: Membership on an entity's Board of Directors or advisory committees. Wei:AbbVie, Celgene, Servier: Research Funding; AbbVie, Celgene, Novartis, Amgen, Servier: Membership on an entity's Board of Directors or advisory committees; AbbVie, Celgene, Novartis, Amgen, Servier: Honoraria.

Impact of the Type of Anthracycline and of Allogeneic Stem Cell Transplantation in the Treatment of Younger Acute Myeloid Leukemia Patients: Long-Term Follow-up of the EORTC-Gimema AML-10 Trial

FB, FE and SS contributed equally to the work.Background. The best post-remission treatment for younger acute myeloid leukemia (AML) patients remains controversial (Cornelissen JJ & Blaise D, Blood 2016, 127, 62-70). Most prospective studies comparing autologous (auto-) to allogeneic (allo-) hematopoietic stem cell transplantation (HSCT) have been published with a relatively short follow-up.Aim. The main objective of this study was to provide a long-term follow-up evaluation of patients previously enrolled in the EORTC/GIMEMA AML-10 study.Methods. In the EORTC/GIMEMA AML-10 prospective trial, 2157 patients aged 15-60 years were randomized to receive either daunorubicin (DNR) (50 mg/m2/d), mitoxantrone (MXR) (12 mg/m2/d), or idarubicin (IDA) (10 mg/m2/d) on days 1, 3 and 5 in addition to standard-dose cytarabine and etoposide for induction chemotherapy. A second cycle of induction was administered in patients who achieved a partial response while patients who achieved a CR or a CR with incomplete counts recovery (CRi) after 1 or 2 courses of induction chemotherapy received consolidation chemotherapy with the same anthracycline as in the induction course plus intermediate dose cytarabine. Young (≤ 45 years old) patients were then scheduled to receive an allo-HCT in first CR/CRi if they had an HLA-identical sibling donor or an auto-HCT otherwise. Median follow-up at the time of the initial report was 5.6 years (Mandelli et al., J Clin Oncol 2009, 27, 5397-5403). For the current analyses, cytogenetics were centrally reviewed and re-classified using the UK Medical Research Council (MRC) classification.Results. In the current report, median follow-up was 11 (95% CI, 9-15) years. The 5-, 10-, 15- and 20-year overall survival (OS) rates were 33.2%, 30.1%, 28.0% and 26.1% respectively. No significant difference between the 3 randomized groups regarding OS was observed (Table 1). In young patients, the OS was comparable in the 3 treatment groups, whereas, in older patients, who had generally a worse outcome, OS was prolonged in the MXT and IDA groups as compared to the DNR group (Table 1). As expected, the initial MRC cytogenetic risk group had an important impact on OS. Within each subgroup, treatment outcomes were quite homogeneous (Table 1).The impact of auto- versus allo-HCT was assessed in a cohort of 839 patients ≤ 45 years old who achieved a CR/CRi after induction chemotherapy, who generally received consolidation chemotherapy, and who were HLA-typed. A total of 330 patients had an HLA-identical sibling (donor group) while the remaining 509 patients had not (Table 2). The 10- and 15-year DFS and OS rates from CR were approximately 10% higher in patients with a donor as compared to those without (Table 2). Assessing the impact of donor availability on the DFS according to cytogenetic risk group, we observed that patients with a donor had a higher 10- and 15- yr DFS rates in all but those in the favorable MRC cytogenetic subgroup (table 2).Among patients aged 46-60 years, 635 reached CR/CRi. The outcomes (DFS and OS) of CR/CRi patients with a donor were only marginally prolonged as compared to those without a donor, which can be explained by the positive effect of decreased relapse rate being neutralized by an increased risk of death in CR/CRi. The 10- and 15-yr DFS rates were increased by 6-11% in the MXR and IDA groups as compared to the DNR (overall logrank P=0.12); the HR (MXR vs DNR) was 0.88 (99% CI, 0.66-1.17), and the HR (IDA vs DNR) was 0.79 (99% CI, 0.58-1.06). The 10- and 15-yr OS rates were also increased, by 7-14% in the MXR and IDA groups as compared to the DNR (overall logrank P=0.04); the HR (MXR vs DNR) was 0.86 (99% CI, 0.64-1.16) and the HR (IDA vs DNR) was 0.74 (99% CI, 0.54-1.10).Conclusions. Long-term follow-up of the EORTC/GIMEMA AML-10 trial confirmed that, overall, similar outcomes were obtained by using either DNR, MXR or IDA. In young patients without favorable cytogenetic features, who reached CR/CRi, the long-term outcome of those with a HLA-identical donor, who generally received AlloHSCT, was improved as compared to those without a donor. In older patients who reached CR/CRi, allo-HSCT and auto-HSCT yielded similar outcomes; however, MXR and IDA administered during induction and consolidation, provided better results than DNR. [Display omitted] DisclosuresEfficace:Incyte: Consultancy; Lundbeck: Research Funding; TEVA: Consultancy, Research Funding; Seattle Genetics: Consultancy; Amgen: Consultancy, Research Funding. Guimaraes:Janssen: Speakers Bureau; Pfizer: Honoraria; Servier: Honoraria; Roche: Honoraria; Incyte: Speakers Bureau.

The Impact of Cytogenetic Clonality on Outcomes in Younger Acute Myeloid Leukemia Patients: Results on 1290 Patients Included in the EORTC/Gimema AML-10 and AML-12 Trials

Background. A recent large retrospective study has observed that the presence of cytogenetic clonal heterogeneity, as detected by metaphase karyotyping, was associated with poor prognosis in patients (pts) with AML (Bochtler et al., J Clin Oncol 2013, 31: 3898-905).Objectives. The aims of the current study were to reassess the impact of cytogenetic clonal heterogeneity on outcomes in younger AML pts (age 15-60 yrs) and to determine how clonal heterogeneity modified the effects of the type of remission-induction chemotherapy and of having a donor in an independent sample of AML pts < 60 years of age with an abnormal karyotype.Methods. In the AML-10 trial pts were randomized to receive either daunorubicin (DNR), mitoxantrone (MTX), or idarubicin (IDA) in addition to standard-dose cytarabine and etoposide for induction chemotherapy. In the AML-12 trial, pts were randomized between SDAC and high dose cytarabine (HiDAC) induction, both with DNR and etoposide. In both trials, a second cycle of the same induction chemotherapy was administered in patients who achieved a PR. Patients who achieved a CR or a CRi after 1 or 2 courses of induction chemotherapy received a consolidation chemotherapy with the same anthracycline as in the induction course plus intermediate dose cytarabine. Thereafter, patients were scheduled to receive in first CR/CRi an allogeneic HCT if they had an HLA-identical donor or an autologous HCT otherwise. Cytogenetic analyses were performed at diagnosis and centrally reviewed. For the current analysis, cytogenetics were re-classified using the MRC classification. The definition of a (sub)clone was according to the international System of Human Cytogenomic Nomenclature (2016). Abnormal karyotypes were classified as no subclone (cytogenetic abnormality present in a single clone), subclones (presence of multiple (2, 3 or 4) clones) and composite karyotypes (CK) when clonal heterogeneity was too complex to allow enumeration of individual subclones.Results. In the AML-10 trial, 2157 pts were randomized to receive DNR, MTX or IDA. The current analysis was performed in a subgroup of 684 pts with an abnormal karyotype: 555 of them had no subclones, 109 at least 1 subclone and 20 a CK. In the AML-12 trial, 1942 pts were randomized between HiDAC and SDAC. The current analysis was performed in a subgroup of 606 pts with an abnormal karyotype: 470 of them had no subclones, 117 at least 1 subclone and 19 a CK (Table 1). Pts with a CK (n=39) were older than 25 years and 84.6% had adverse MRC cytogenetic features. In comparison to pts with no subclones, those with subclones had a similar probability of achieving a CR and had similar DFS from CR/CRi and OS from randomization (Table 1). However, in comparison to pts with no subclones, those with a CK had a similar probability of achieving a CR/CRi but a shorter DFS (HR=2.10, 95% CI: 1.39-3.16) and OS (HR= 1.54, 95% CI: 1.07-2.21). In multivariate Cox model stratified by protocol and adjusted for age, cytogenetic risk group, secondary versus primary AML and PS, neither the presence of subclones (HR 1.11, 95% CI: 0.92-1.33) nor CK (HR 0.93, 95% CI: 0.64-1.34) were associated with shorter OS (P=0.49). Comparable findings were obtained after restricting the analyses to pts with adverse/intermediate cytogenetic features.Among pts included in the AML-10 trial, the impact on the OS of the type of anthracycline used (IDA vs MTZ vs DNR) was not significant, and its magnitude was not statistically different according to the clonal heterogeneity status (no subclones versus subclones versus CK)(P=0.24). Further, among pts included in the AML-12 trial, the difference regarding OS between HiDAC and SDAC was limited (HR=0.94), and its magnitude was not impacted by the clonal heterogeneity status (P=0.54). Finally, in the whole cohort, DFS from CR/CRi was significantly longer in the subgroup of pts with a donor (n=250) than in those without a donor (n=449) (HR=0.72, 95% CI: 0.58-0.89, P=0.002); the impact on DFS of having a donor vs no donor was similar in the 3 clonal subgroups (P-value for interaction from the Cox model: P=0.26).Conclusions. The influence of clonal heterogeneity on outcome was evaluated in an independent sample of AML patients. Clonal heterogeneity as defined by the presence of subclones showed no effect on OS as compared to cytogenetic abnormal patients without clonal subclones. The dismal outcome in the pts with a CK could be explained by the known predictors of poor prognosis. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

A Single Institution Comparison of Mitoxantrone, Etoposide and Cytarabine (MEC) Vs High-Dose Cytarabine and Mitoxantrone (Ara-C Couplets) for Treatment of Patients with Relapsed or Refractory Acute Myeloid Leukemia

Background:Relapsed or refractory acute myeloid leukemia (R/R AML) is a common occurrence and remains a therapeutic challenge due to its poor prognosis. Hematopoietic cell transplantation (HCT) is the only curative approach for R/R AML, and while chemotherapy regimens are generally used as a bridge to HCT, the ideal second-line therapy is unknown. For decades cytarabine (Ara-C) has been the backbone of a number of regimens that are frequently used in this R/R setting. At our academic institution patients who can tolerate aggressive therapy are treated with either MEC (mitoxantrone 8 mg/m2 IV, etoposide 80 mg/m2 IV and intermediate dose cytarabine 1 g/m2 daily for 5 days) or Ara-C couplets (mitoxantrone 30 mg/m2 x 1 and high dose cytarabine (2 g/m2) twice daily, on days 1 and 5). MEC is among the most studied regimens for R/R AML; up to 66% of patients achieve complete remission (CR), with a median survival of 36 weeks (Arcese et al., J Clin Oncol . 1991). The Ara-C couplets regimen has been shown to have a similar overall response rate of 55%, in a single study (Larson et al., Leukemia & Lymphoma . 2012). Currently, there are no studies that have directly compared these two treatments. The objective of this single institution retrospective analysis is to assess the efficacy and toxicity of MEC and Ara-C couplets therapy.Methods:R/R AML patients treated from January 1998 through May 2015 were identified using our hospital and pharmacy billing records. From a review of 118 patient charts a total of 51 R/R AML adult patients were identified who had received either MEC or Ara-C couplets, and all were included in this analysis. The efficacy and toxicity of the two regimens were compared by assessing the rates of CR, progression free survival (PFS), overall survival (OS), the duration of hospitalization, hematologic and non-hematologic toxicities and success in proceeding to HCT.Results:Fifteen patients, ages 20-64, were treated with MEC, and 36 patients, ages 22-75, were treated with Ara-C couplets. Baseline characteristics, including gender, race, and Charlson Comorbidity Index (CCI) were well balanced. Within the MEC group, there were an equal number of White, Black and Hispanic patients (n=4), and 3 patients who identified as other. Amongst the Ara-C couplets patients, 14 were White, 11 Black, 7 Hispanic, and 4 identified as other. Six of the MEC patients (9%) and 9 of the Ara-C couplets patients (25%) had unfavorable cytogenetics. The time from initial diagnosis to relapse or refractory disease was similar between the 2 groups, 253 days (MEC) and 244 days, respectively (p=0.38)CR was achieved in 64% of the MEC patients and 57% of the Ara-C couplets patients (p=0.75). OS was 6.5 months and 8 months respectively (p=0.35). PFS was 5.2 months in the MEC group and 4 months in the Ara-C couplets group (p=0.86). In both groups, 47% of patients (7 in MEC, 17 in Ara-C couplets) underwent HCT. Within the MEC group, the median number of days to ANC and platelet recovery was 45 days and 65 days respectively, and was similar within the Ara-C couplets group, 40 days and 55 days, respectively. The median duration of hospitalization for patients receiving MEC was 34 days while the median for those receiving Ara-C couplets was 31 days (p=0.2).The most common adverse event was febrile neutropenia, occurring in 100% of the MEC and 89% of the Ara-C couplets patients (p=0.3). Non-hematologic toxicities were minimal and there were no significant differences between groups in terms of pulmonary, liver or gastrointestinal toxicities. Within the Ara-C couplets group, one patient experienced grade 3, and another grade 4 cardiac toxicity (CHF).Conclusions:This is the first study that directly compares MEC and Ara-C couplets regimens in R/R AML patients; two salvage therapies commonly used at our institution. We show that both therapies are equally effective as second-line regimens with equivalent toxicities in a racially diverse population (n= 51). Our data suggests either regimen can be considered in those able to tolerate aggressive therapy and can serve as a bridge to HCT. A significant portion of patients with AML relapse, and, surprisingly, very few comparative studies have been performed in this population. In the future, large multi-center studies should be performed in order to establish the optimal chemotherapy regimen for these patients. DisclosuresPatel:Celgene: Consultancy, Honoraria. Khan:Takeda: Research Funding; Gilead: Consultancy; Teva: Speakers Bureau.

Acute Myeloid Leukemia in Pregnancy

Introduction: The management of acute myeloid leukemia (AML) in pregnancy remains a daunting clinical challenge for oncologists, obstetricians, patients, and their families. Although the incidence of AML in pregnancy is low at 1 in 75,000 pregnancies, cancer represents the second most common cause of maternal death behind gestation-related vascular complications. Due to the small number of patients diagnosed during this time, there are only retrospective reviews and case series to guide complex management decisions. Case Report: A 26-year-old Caucasian woman presented to our institution at 17 weeks gestation after she was found to have an absolute monocytosis, neutropenia, and anemia on routine prenatal evaluation. The bone marrow aspirate demonstrated a diagnosis of AML. The blast population compromised 14% of cellular elements, and fluorescence in situ hybridization (FISH) karyotyping was positive for inversion 16. She and her husband were extensively counseled regarding the diagnosis and wished to proceed with the pregnancy. She received standard dose induction chemotherapy with daunorubicin and cytarabine and achieved a complete remission. Starting at 22 weeks gestation, we proceeded with consolidation chemotherapy using intermediate-dose cytarabine 1.5 grams/m2 every 12 hours on days 1, 3, and 5 of the 6 day cycle. Fetal status was monitored with serial growth ultrasounds and daily tocographic assessment. She tolerated the first cycle well and starting at 28 weeks gestation she began the second cycle of consolidation. She was induced at 35 weeks gestation and delivered a morphologically normal male in good health weighing 5 pounds and 9 ounces. She received her final two cycles of consolidation post-partum, and cytarabine dose was increased to 3 grams/m2 for the standard high-dose regimen. Throughout pregnancy, her care was managed by a multidisciplinary team which included neonatology, maternal fetal medicine, and oncology. Expert opinion was solicited from top medical centers across the country for guidance on consolidation therapy. Discussion: Our case highlights the complexities of AML management in pregnancy. There are no formal management guidelines and sparse data on consolidation during this period. The appropriate dosing of chemotherapy, fetal monitoring, and timing of delivery all represent challenges in providing optimal care and improving maternal and fetal overall survival. In a recent meta-analysis, the maternal median overall survival rate for 87 women with AML in pregnancy was found to be 30%. The live birth rate in this study for chemotherapy-exposed neonates was 87%, and the complication rate was 16%. These complications included unspecified deformations, patent ductus arteriosus, hydrocephalus, ventricular septal defect, cytopenias, intracranial hemorrhage, and respiratory compromise. Management recommendations from experts in the field showed significant heterogeneity underscoring the need for consensus guidelines. Conclusion: There is a critical need of management guidelines to address timing and dosing of anthracycline/cytarabine based regimens, potential drug toxicity to the mother and fetus, and transplant considerations in intermediate and high-risk patients. A national registry for leukemia patients treated in pregnancy could be formed to help answer these questions and improve maternal and fetal overall survival rates. Delays in chemotherapy should be avoided, and a multidisciplinary team is needed to provide comprehensive care to patients and their families. Follow Up: The end of treatment bone marrow examination was negative for leukemia by morphology, cytogenetics, and FISH. The patient and child are in good health now more than two years after completion of chemotherapy. Disclosures Powell: Rafael Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Clofarabine-Based Consolidation Improves Relapse-Free Survival of Patients with Acute Myeloid Leukemia with Complex or Micro-Complex Karyotype: Results from the Randomized ALFA-0702 Study

Introduction. Acute myeloid leukemia (AML) encompasses heterogeneous entities, but global outcome remains poor. Among genetic AML subgroups, complex karyotypes represent one of the most difficult-to-treat. Genomic alterations arising from recent approaches in molecular genetics have allowed describing new subsets with potential therapeutic implications. Besides, the latter AML classification (“2017 European LeukemiaNet (ELN) risk stratification”) integrates both molecular alterations and conventional cytogenetics. High-resolution single-nucleotide polymorphism array (SNP-Array) identifies copy number alterations (CNA) and copy-neutral losses of heterozygosity (CN-LOH). In the randomized ALFA-0702 study (NCT 00932412), we have recently reported the effects of a CLARA combination (clofarabine + intermediate-dose cytarabine) as compared to standard high-dose cytarabine (HDAC) regimen as consolidation chemotherapy in younger adults with AML. Here, we aimed at evaluating the effects of the CLARA regimen according to patient subsets defined by SNP-array abnormalities.Methods. A total of 221 patients aged 18-59 years old with intermediate- or adverse-risk de novo AML in first complete remission (CR/CRp) after a common intensive induction course were randomized in the ALFA-0702 trial (Thomas et al. JCO 2017). The primary endpoint was relapse-free survival (RFS). Bone marrow or peripheral blood samples at diagnosis were analyzed by Cytoscan HD array (Affymetrix) according to the manufacturer's instructions. Data were screened according to the ChAS 3.1 algorithm, with stringent filter retaining CNA larger than 20 kb - 20 markers, telomeric CN-LOH > 3Mb and interstitial CN-LOH > 10Mb.Results. SNP-array was successfully performed in 187 out of the 221 randomized patients (92 CLARA arm, 95 HDAC arm). Twenty-three patients could not be analyzed in SNP-array for the following reasons: DNA sample was not available (15 patients) or in insufficient quantity (8 patients). SNP-array analysis failed in 11 patients. Median number of genomic SNP-Array abnormalities reached 2 per patient (range, 0-46) and did not significantly differ between both randomization arms (p=0.41). CNA accounted for the most common SNP-Array abnormalities (Loss=54%, Gain=38%, vs. CN-LOH=8%). Conventional cytogenetic analysis showed a complex karyotype (defined by at least 3 chromosomal abnormalities) in 37 patients (11 CLARA, 16 HDAC). In such patients, CLARA consolidation improved RFS (median RFS, 22 vs. 8 months; p=0.027). Interestingly, a similar impact was observed in the 56 patients (27 CLARA, 29 HDAC) with micro-complex karyotypes defined by 4 or more SNP-Array abnormalities. Notably, 7 patients with complex karyotype did not display micro-complex karyotype because of low bone marrow/blood blast infiltration and/or balanced alterations. In patients with micro-complex karyotypes, median RFS was 22 months in the CLARA arm compared to 10 months in the HDAC arm (p<.0001). The rate of patients who received allogeneic stem cell transplantation in first CR did not differ between the two arms (p=0.99). Importantly, CLARA consolidation tended to overcome the poor prognostic impact of patients with micro-complex karyotype. Indeed, patients with such lesions had similar 4-years RFS than other patients in the CLARA arm (44% vs. 47%) while it remained a poor prognosis factor in the HDAC arm (14% vs. 47%; Figure 1).Conclusion. As compared to conventional cytogenetics, SNP-array represents a high-resolution approach to better characterize molecular profile of AML patients by pointing out cryptic molecular abnormalities. Our results suggest that clofarabine-based consolidation benefits both patients with complex karyotypes and micro-complex karyotypes defined by 4 and more SNP-Array abnormalities. Therefore by delineating micro-complex karyotypes in SNP-array, we have defined a new subset of AML patients that could potentially benefit from a clofarabine-based consolidation regimen (21 additional patients in comparison with complex karyotypes). SNP-array could thus help to improve AML management by refining adverse patient subgroups that could potentially benefit from new alternative consolidation regimen. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Role of Allogeneic Reduced Intensity Conditioning Stem Cell Transplantation (RIC-SCT) in Older Patients with Acute Myeloid Leukemia (AML): Analysis of the ALFA-1200 Study

Background - According to recommendations, AML patients with intermediate- or adverse-risk genetics are candidates for allogeneic SCT in first complete remission (CR1). In practice, only a minority of them undergoes SCT because of older age, comorbidities, poor tolerance of prior therapy, inability to achieve CR, or early relapse. The benefit associated with RIC-SCT is particularly difficult to assess in older patients, due to lower SCT numbers and strong selection biases.Patients & Methods - Between 2012 and 2016, 509 patients aged ≥60 years (median, 68 years [60-85]) were enrolled in the prospective older AML ALFA-1200 trial. Eighty-eight patients (17%) had secondary or therapy-related AML. ECOG performance status was 0/1/2/3/NA in 219/219/57/9/5 patients and comorbidity index (HCT-CI) was 0/1/2/3/4+/NA in 226/92/66/61/54/10 patients, respectively. Risk subgroup distribution was 76 favorable (15%), 347 intermediate (68%), and 86 adverse (17%), according to the ELN-2010 classification retaining double mutations only as favorable CEBPA mutations. Chemotherapy consisted of cytarabine (200 mg/m2/d CIV on day 1-7) and idarubicin (12 mg/m2/d on day 1-3) followed by 2 courses with intermediate-dose cytarabine at 1500 mg/m2/12h on days 1/3/5, reduced to 1000 mg/m2/dose in patients aged ≥70 years. Patients with intermediate- or adverse-risk AML and/or those who needed two courses to reach CR were eligible for allogeneic SCT in CR1 if a suitable donor (HLA-identical [id] sibling or 9-10/10 matched unrelated donor) and no acquired contra-indication.Overall Results - During first induction, 43 patients died before response evaluation, while 335 patients reached CR. Among the 131 patients with resistant AML, 71 received a second intensive course and 34 achieved CR (overall CR rate, 72.5%). The 60- and 100-day mortality rates were 9.4 and 13.0%, respectively. With a median follow-up of 26 months, 201/369 CR patients relapsed and 164 died, including 30 deaths in CR1. Median overall survival (OS) was 20.7 months (95% CI, 17.5-24.8) and OS was 46.8% (95% CI, 41.9-51.4) at 2 years. Median OS was 49.7, 22.5 and 9.4 months in the favorable, intermediate and adverse ELN-risk subgroup, respectively.Role of SCT - Among the 305 CR patients eligible for SCT, 93 proceeded to SCT in CR1. In addition, 22 patients with primary refractory AML and 25 patients relapsing prior to SCT eventually received SCT. Patients transplanted in CR1 were younger (median age, 64 [60-73] vs 70 [60-81] years; p<0.001) and had lower comorbidity index (HCT-CI≥3, 14 vs 26%; p=0.025) than the remaining eligible patients. We thus analyzed the role of SCT in CR1 in the 214 eligible patients aged 70 years old or less (ELN-risk: 2 favorable, 176 intermediate, 38 adverse). Ninety of them were actually transplanted in CR1 (ELN risk: 75 intermediate, 15 adverse; median time from CR to SCT, 113 days; stem cell source: 28 geno-id, 50 pheno-id, 8 haplo-id, 4 cord blood; conditioning regimen: 12 NMA, 66 RIC, 12 sequential-RIC). These 90 transplanted patients were still younger than the 124 non-transplanted patients (p=0.005) but their ELN-risk and HCT-CI distribution were similar. Among them, 22 patients relapsed and 29 died, including 18 deaths in CR1. At 2 years post-SCT, transplant related mortality (TRM) was 20.4% (95% CI, 13.2-30.9), cumulative incidence of relapse was 22.7% (95% CI, 15.0-33.4), and OS was 65.1% (95% CI, 52.9-75.0). Age, secondary AML, ELN-risk, type of stem cell source, or conditioning regimen did not significantly influence post-transplant survival. In a time-dependent SCT analysis, OS was not significantly prolonged in the SCT cohort (HR, 0.77 [95% CI, 0.49-1.21]; p=0.26). As illustrated on Figure 1, an OS benefit associated with SCT was only observed in the adverse ELN-risk subset (HR, 0.20 [95% CI, 0.07-0.63]: p=0.006), while not in the intermediate ELN-risk subset (HR, 1.08 [95% CI, 0.65-1.80]; p=0.76), with a significant interaction (p=0.005). Finally, SCT did not significantly prolonged OS in the 47 out of 319 patients with refractory/relapsed AML who eventually received SCT (HR, 0.69 [95% CI, 0.39-1.22]: p=0.21).Conclusion - In older AML patients, due to persistent high TRM and relapse incidence, RIC-SCT significantly prolongs survival in the adverse ELN-risk AML subset only. Even if a longer follow-up is needed, patients with intermediate ELN-risk AML do no seem to benefit from SCT in CR1 as compared to standard chemotherapy. [Display omitted] DisclosuresDe Botton:Servier: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Agios: Honoraria, Research Funding. Socié:Alexion Pharmaceuticals, Inc.: Consultancy.

High risk of relapse with intermediate dose cytarabine for consolidation in young favourable‐risk acute myeloid leukaemia patients following induction with 7+3: a retrospective multicentre analysis and critical review of the literature

Following the 2017 European LeukemiaNet (ELN) guidelines, we changed our practice from using high-dose cytarabine (HIDAC-3 g/m2 q12h-D1,3,5) to intermediate-dose cytarabine (IDAC-1·5 g/m2 q12h-D1,3,5/D1-3) for consolidation in young(<60years) favourable-risk acute myeloid leukaemia (AML) patients. We assessed the clinical impact of this practice change. Of 80 patients, 51 received HIDAC prior to the protocol change, and subsequently, 29 received IDAC. The three-year risk of relapse was significantly higher with IDAC [61%; 95% confidence interval (CI) 40-82] compared with HIDAC (22%; 10-34), P<0·01. Our findings suggest HIDAC, rather than IDAC, is the preferred dose for single-agent cytarabine consolidation in young, favourable-risk AML following 7+3 induction.

Outcomes of HIDAC 18g Versus IDAC 9g in Consolidation Therapy of Acute Myeloid Leukemia: A Retrospective Study.

Cytarabine based therapy has been the standard consolidation regimen for AML (acute myeloid leukemia) for decades. However, the optimal dose, regimen and schedule is not known. HIDAC (high dose cytarabine at 18g/m2) has been the conventional standard, however, recent studies have shown that intermediate doses of cytarabine (IDAC) have equal efficacy and lesser toxicities. We retrospectively analysed 75 AML patients who entered consolidation out of 167 patients who underwent induction therapy between 2014 and 2018. HIDAC (at 18g/m2) was given to 39 patients and 36 patients received IDAC at 9g/m2. Median age was 28years (range 2-60). Male: female ratio was 1.02. More courses were administered in out-patient setting in IDAC group 61% (n = 58/95 courses) than in HIDAC 29% (n = 29/101 courses); p < 0.001. Incidence of clinically documented infection (CDI) was higher in HIDAC group (23.7%) compared to IDAC (8.4%), p = 0.004, and diarrhea showed a higher trend in the HIDAC group (9.9% vs. 3.1%; p = 0.052). Other toxicities were similar in both groups. There were 4 consolidation deaths in HIDAC whereas 3 deaths in IDAC group (p = 0.775). Median OS was 19.7 vs. 16.2months and 3years OS was 49.1% vs. 34.7% in HIDAC and IDAC groups respectively (p = 0.570). Median LFS was 12.6 versus 11.8months; 3years LFS was 46.4% versus 31% in HIDAC and IDAC groups respectively (p = 0.278). For AML consolidation IDAC had lesser toxicity when compared with HIDAC though comparable efficacy needs to be confirmed with longer follow up and with prospective studies. The online version contains supplementary material available at 10.1007/s12288-021-01430-z.

Addition of lenalidomide to intensive treatment in younger and middle-aged adults with newly diagnosed AML: the HOVON-SAKK-132 trial

AbstractLenalidomide, an antineoplastic and immunomodulatory drug, has therapeutic activity in acute myeloid leukemia (AML), but definitive studies about its therapeutic utility have been lacking. In a phase 3 study, we compared 2 induction regimens in newly diagnosed patients age 18 to 65 years with AML: idarubicine-cytarabine (cycle 1) and daunorubicin and intermediate-dose cytarabine (cycle 2) without or with lenalidomide (15 mg orally on days 1-21). One final consolidation cycle of chemotherapy or autologous stem cell transplantation (auto-SCT) or allogeneic SCT (allo-SCT) was provided according to a prognostic risk and minimal residual disease (MRD)–adapted approach. Event-free survival (EFS; primary end point) and other clinical end points were assessed. A second random assignment in patients in complete response or in complete response with incomplete hematologic recovery after cycle 3 or auto-SCT involved 6 cycles of maintenance with lenalidomide (10 mg on days 1-21) or observation. In all, 392 patients were randomly assigned to the control group, and 388 patients were randomly assigned to lenalidomide induction. At a median follow-up of 41 months, the study revealed no differences in outcome between the treatments (EFS, 44% ± 2% standard error and overall survival, 54% ± 2% at 4 years for both arms) although in an exploratory post hoc analysis, a lenalidomide benefit was suggested in SRSF2-mutant AML. In relation to the previous Dutch-Belgian Hemato-Oncology Cooperative Group and Swiss Group for Clinical Cancer Research (HOVON-SAKK) studies that used a similar 3-cycle regimen but did not pursue an MRD-guided approach, these survival estimates compare markedly more favorably. MRD status after cycle 2 lost prognostic value in intermediate-risk AML in the risk-adjusted treatment context. Maintenance with lenalidomide showed no apparent effect on relapse probability in 88 patients randomly assigned for this part of the study.

Optimized clinical application of minimal residual disease in acute myeloid leukemia with RUNX1–RUNX1T1

Minimal residual disease (MRD) levels monitored by polymerase chain reaction are associated with outcomes in acute myeloid leukemia with RUNX1-RUNX1T1. The objectives of our study were to quantitatively compare the predictive value of MRD reduction and absolute copies and assess the influence of other prognostic factors on MRD. A total of 224 consecutive patients with RUNX1-RUNX1T1 aged ≤55 years were included in the MRD study. Patients received different induction regimens including conventional- or intermediate-dose cytarabine plus low-dose daunorubicin and omacetaxine mepesuccinate or daunorubicin at 60 mg/m2/day on days 1-3. As continuous variables, both MRD reduction and absolute MRD level were significantly associated with cumulative incidence of relapse (CIR; hazard ratio [HR] = 1.610, 95% confidence interval [CI]: 1.370-1.890, p < 0.001, and HR = 1.170, 95% CI: 1.120-1.230, p < 0.001, respectively). For the CIR, the area under the curves (AUCs) of MRD reduction and absolute MRD level after the first consolidation chemotherapy were 0.629 and 0.629, respectively. Intermediate-dose cytarabine induction (HR = 0.494; p = 0.039 for CIR, HR, 0.451; p = 0.014 for RFS, and HR, 0.262; p = 0.006 for OS) remained significantly associated with outcomes after adjusting for MRD reduction after the first consolidation therapy (HR = 1.456, p < 0.001, for CIR; HR = 1.467, p = 0.001, for relapse-free survival; and HR = 1.468, p = 0.014, for overall survival) in multivariate analyses. In conclusion, the prognostic significance of MRD after the first consolidation therapy was influenced by the induction regimen in acute myeloid leukemia with RUNX1-RUNX1T1.

Intermediate dose cytarabine improves survival and relapse-free rate compared with standard-dose cytarabine as post-remission treatment for acute myeloid leukemia: A retrospection study.

The exact dose of cytarabine still remain controversial for the management of patients with acute myeloid leukemia (AML) after complete remission (CR), but recent studies favor lower doses. This study aimed to investigate the toxic effects of single-intermediate dose (ID) cytarabine in patients with AML after achieving CR, compared with standard-dose cytarabine.In this retrospective study, AML patients who achieved CR after consolidation therapy before enrollment between 07/2008 and 05/2019 were included. All patients were divided into single-ID cytarabine and standard-dose cytarabine. The Kaplan-Meier method was used to compare overall survival (OS) and relapse-free time (RFS). Cox regression models were used to assess factors independently associated with OS and RFS. The toxic side effects of hematology and non-hematology were observed.52 patients were enrolled. There were 33 in ID group, 19 in Standard dose group. The 3-year RFS rate (40.4% vs 22.2%, P = .031) was better in the ID group than in the standard-dose group, while the 3-year OS rate was not different between the 2 groups (50.2% vs 27.8%, P = .074). Treatment stratage of ID cytarabine chemotherapy significantly improve the prognosis of AML regardless of patient age, risk grade, WBC count. There were no significant differences between the 2 groups in grade 3 to 4 bone marrow suppression, gastrointestinal symptoms, blood transfusion, infections.Patients with AML receiving ID cytarabine showed better survival and similar toxicity profiles compared with patients who received standard-dose cytarabine.

Efficacy and safety of consolidation therapy with intermediate and high dose cytarabine in acute myeloid leukemia patients

ABSTRACT Objectives The primary objective was to compare the efficacy of intermediate-dose cytarabine (IDAC) and high-dose cytarabine (HiDAC) as consolidation chemotherapy for acute myeloid leukemia (AML) in terms of a one-year-relapse-free survival rate (RFS). The secondary objectives were one-year-overall survival rate (OS) and adverse effects. Methods This was a retrospective study conducted at Chiang Mai University Hospital. AML patients who achieved complete remission after 7 + 3 induction regimen and received consolidation therapy with either IDAC or HiDAC during January 2015 and January 2018 were eligible. Data about clinical characteristics, efficacy and safety of IDAC and HiDAC regimens were collected. Results Sixty-two AML patients were enrolled (30 patients in IDAC and 32 patients in the HiDAC regimen). The one-year RFS in the IDAC group was 63.33% and 46.87% in the HiDAC group (P = 0.137). The 1-year OS was 93.33% and 84.37% in the IDAC and HiDAC, respectively (P = 0.691). The duration of grade 3–4 thrombocytopenia was significantly shorter in IDAC than HiDAC (mean duration 14.69 vs. 23.84 days; P = 0.045). There was no significant difference in other parameters including hemoglobin nadir, absolute neutrophil count nadir, platelet nadir, febrile neutropenia, duration of grade 3–4 neutropenia, and duration of hospitalization. Discussion and conclusions There was no significant difference in the one-year RFS and OS between IDAC and HiDAC. The IDAC regimen is an acceptable option for consolidation treatment in AML.