Younger Acute Myeloid Leukemia Patients Research Articles

Peripheral Blood Grafts Vs Bone Marrow Grafts in Young Acute Myeloid Leukemia Patients with HLA-Matched Sibling Donors Undergoing Myeloablative Conditioning

In allogeneic hematopoietic cell transplantation (allo-HSCT), graft source has been changed from bone marrow grafts (Bone marrow stem cell, BMSC) to peripheral blood grafts (Peripheral blood stem cell, PBSC) mobilized by granulocyte colony-stimulating factor. PBSC transplantation is known to have numerous advantages over BMSC, including faster engraftment, improved survival outcomes, and for the donor, the elimination of invasive marrow harvesting procedure under general anesthesia. However, previous studies regarding graft source included various hematologic malignancies and lacked consistency in conditioning intensity and disease status at allo-HSCT. Still, there are limited data on the comparison of graft sources specifically in patients with acute myeloid leukemia (AML) undergoing myeloablative conditioning. In this background, we conducted an analysis to investigate the impact of graft source on transplant outcomes in AML patients who underwent HLA A, B, C, DR-matched sibling donor (MSD) HSCT with myeloablative conditioning. This study was a retrospective, single-center study for patients with AML who received first allo-HSCT from 2002 to 2022. We included the patients aged < 60 at the time of allo-HSCT, in a state of complete remission (CR) or CR with incomplete hematologic recovery, from a MSD, and underwent myeloablative conditioning. We classified the patients into three groups: the BMSC graft group (BMSC group), the PBSC graft group without antithymocyte globulin (ATG) (PBSC/ATG- group), and the PBSC graft group with ATG (PBSC/ATG+ group). Patients who received both PBSC and BMSC grafts were excluded from the analysis. We examined the differences in overall survival (OS), relapse-free survival (RFS) among these three groups. A total of 480 patients were included in this analysis, with 234 patients in the BMSC group, 66 patients in the PBSC/ATG+ group, and 180 patients in the PBSC/ATG- group. BMSC transplantation was mostly performed before 2010, whereas PBSC transplantation started in 2007, and allo-HSCT with ATG administration were conducted after 2014. In the PBSC/ATG+ group, the median ATG dose was 2.5 mg/kg (Interquartile range, IQR: 1.6-2.5). The BMSC group tended to be younger at the time of HSCT (median 38 years [31-46]) compared to the other groups (median age of PBSC/ATG+ group: 44 years [37-51], PBSC/ATG- group: 46 years [39-51], p<0.01). Of total patients in the three groups, there was only 1 case of neutrophil engraftment failure (in the PBSC/ATG- group) and 5 cases of platelet engraftment failure (3 in the BMSC group and the other 2 in the PBSC/ATG- group). BMSC patients demonstrated superior OS compared to PBSC patients, with the most pronounced difference was observed over PBSC/ATG- group (Figure A). Similar trends were presented in relapse-free survival (RFS) as well. After adjusting for other covariates through multivariate Cox modeling, the difference caused by the graft source remained significant, particularly in terms of RFS (Figure B). The hazard ratios for RFS of PBSC comparing to BMSC were as follows; PBSC/ATG+: 1.64 [1.04-2.58], PBSC/ATG-: 1.95 [1.45-2.63]. In conclusion, Despite the clear differences in allo-HSCT era between groups, even BMSC patients underwent allo-HSCT at an earlier time, patients receiving BMSC grafts showed superior survival compared to those receiving PBSC grafts in young AML patients undergoing MSD myeloablative allo-HSCT. Parallel evaluation of the transplant outcomes between BMSC and PBSC would be crucial for assessing the advantages and disadvantages of PBSC and BMSC grafts in this setting.

Optimization of Idarubicin and Cytarabine Induction Regimen with Homoharringtonine for Newly Diagnosed AML Based on the Peripheral Blast Clearance Rate: First Result of the Multicenter, Randomized, Phase 3 Trial (RJ-AML 2016)

Background: Combination of idarubicin and cytarabine (IA) is still the basis of induction treatment for acute myeloid leukemia (AML). As previous reported in RJ-AML 2014 trial [1], day 5 peripheral blast clearance rate (D5-PBCR) can be used as an indicator of early treatment response, and for patients in the D5-PBCR (+) group, addition of homoharringtonine (HHT) to traditional IA induction showed good efficacy and safety. To further verify the efficacy in long-term outcome, we designed the RJ-AML 2016 trial. Here we report the latest response and survival results. Patients and Methods: The RJ-AML 2016 trial is a multicenter, randomized, phase 3 clinical trial, conducted to evaluate the efficacy of HHT in newly diagnosed young AML. Patients in D5-PBCR(+) group was eligible for addition of HHT, and were assigned in a 1:1 ratio, either to the intervention or control group. The primary end point was event-free survival (EFS). The secondary end points were composite complete remission (CR or CR with incomplete hematologic recovery), early death rate, measurable residual disease, drug toxicity, and safety. We hypothesized the 3-year EFS rate may increase from 30% to 50%, therefore the sample size of patients who enter randomization should be 250. Based on historical data, the rate of D5-PRCR(+) was 43%. Assume that 10% of patients may lost to follow-up, at least 638 eligible patients were needed. All patients enrolled in this study received induction regimen same as the RJ-AML 2014 trial. D5-PRCR(+) patients who assigned to the intervention group received additional chemotherapy (HHT 2 mg/m 2 on days 6-10). Favorable cytogenetic/molecular risks group received four courses of the HiDAC for consolidation. Patients with intermediate and unfavorable risks were recommended for allogeneic hematopoietic stem-cell transplantation. The trial is registered in the Chinese Clinical Trial Register, number ChiCTR-OIC-16007764. Results: From December 7, 2016, through April 29, 2023, a total of 747 patients underwent screening, 649 were included in the intention-to-treat (ITT) population and received IA induction from 6 sites in China. D5-PBCR were analyzed in 647 patients and 275 (42.5%) had D5-PBCR (+). Of the 275 D5-PBCR (+) patients, 145 were allocated to the intervention group, while 20 patients withdraw, of which 4 patients received additional FLT3 inhibitor and 16 cases continued IA induction; of the 130 patients allocated to the control group, 5 discontinued the IA regimen on day 6 or 7. Of the 372 D5-PBCR (-) patients, 2 patients discontinued IA. Baseline characteristics, including age, sex, blast counts in bone marrow, and cytogenetic parameters, were similar between two groups. While patients in D5-PBCR (-) group had higher white blood cell counts before treatment. Patients with CBFβ- MYH11 fusion, NPM1 and CEBPA bZIP mutations were more sensitive to IA induction. Meanwhile, high-risk gene mutations including ASXL1, RUNX1, TP53 and U2AF1 were more common in D5-PBCR (+) group. Details were showed in table. The overall composite CR rate after one course of induction was 73.2% in the ITT cohort. For patients in D5-PBCR (-) and D5-PBCR (+) groups, the CR rates were 82.8% and 60.4% , respectively (P<0.001). In the ITT cohort of D5-PBCR (+) group, CR rates were 51.1% and 68.3% for control and intervention arm, respectively (P=0.0046). In the Per-Protocol (PP) cohort, CR rates were 52.8% and 71.2% for IA and IA+HHT arm, respectively (P=0.0027). The overall early mortality rate was 4.9% in whole cohort, which were similar between two treatment arms. The last follow-up time was April 2023. Patients in the PP cohort who enrolled before April 2022 were included in this survival analysis (n=486), and the median duration of follow-up was 23.4 months. The median EFS was 40.6 months in the PP cohort, which showed significant difference between D5-PBCR (-) and D5-PBCR (+) groups [D5-PBCR (-): not reached, D5-PBCR (+): 16.0±1.9 months, P<0.001]. For patients in the D5-PBCR (+) group, no significant difference was found in 3-year EFS till the latest follow-up. While, the 3-year EFS was improved from 34.0±5.5% to 47.1±6.1% with the addition of HHT ( P=0.086). Conclusion: Current analysis indicated that addition of HHT can benefit young AML patients in the D5-PBCR (+) group. Complete follow-up combining with cytogenetic-molecular information can provide more reliable results. 1. Zhang Y, et al. Am J Hematol. 2022;97(1):43-51.

Venetoclax Plus Azacitidine, Low Dose Cytarabine, Aclarubicin and G-CSF (VA-CAG Regimen) for Newly Diagnosed Young Patients with Acute Myeloid Leukemia: A Prospective, Multicenter, Single-Arm Phase 2 Clinical Trial

Background: Venetoclax, in combination with hypomethylating agents or low-dose cytarabine, is approved for newly diagnosed acute myeloid leukemia (AML) patients who are over 75 years of age or not eligible for intensive chemotherapy, while the efficacy of venetoclax-based regimens in young fit AML patients still needs to be further explored. Although the combination of anthracycline and cytarabine has achieved a remission rate of about 70% in these patients, the low complete response rate in adverse-risk patients, strong adverse reactions, and long duration of myelosuppression limited the clinical benefit. We presumed that venetoclax plus azacitidine in combination with low-intensity regimens CAG (G-CSF priming, low dose cytarabine, and aclarubicin) could have a better composite complete remission with an acceptable safety profile. Methods: Patients who were newly diagnosed with AML aged from 18 to 65 years without active infection, bleeding and severe cardiopulmonary insufficiency were enrolled. Participants received induction as azacitidine 75 mg/m 2 subcutaneously once daily on days 1-7, cytarabine 10mg/m 2 subcutaneously q12h on days 1-7, aclacinomycin 12 mg/m 2 on days 1,3,5,7, granulocyte colony-stimulating factor 5µg/kg on days 1-7, and venetoclax orally once daily (100 mg d1, 200 mg d2, 400 mg d3-21). Venetoclax dose was adjusted based on concomitant CYP3A inhibitors. The efficacy were evaluated by bone marrow morphology and flow cytometry on day 28 cycle 1. The primary endpoints were safety and the composite complete remission rate. This study was approved for ethical review and registered with ClinicalTrials.gov (NCT05662956). Results: Twenty-six patients from eight sites were enrolled between January 1, 2023, and June 20, 2023. The median age was 52 years (range, 18-63years). Thirteen patients (50.0%) had adverse risk, 7 patients (26.9%) had intermediate risk, and 6 patients (23.1%) had favorable risk. All 26 patients (100%) achieved complete remission after cycle 1, and 21 patients (80.8%) was MRD negative by flow cytometry. Two patients (7.7%) were treated with venetoclax for 14 days due to ineffective platelet transfusion and severe infection during treatment. Twenty-two patients (84%) used azole drugs to prevent fungal infection. The median myelosuppression time was 13 days (range, 5-22days), and the median red blood cell and platelet transfusions were 5.5u (range, 0-11.5u) and 30u (range, 0-170u), respectively. Eleven patients (42.3%) experienced infection (including pulmonary fungal infection, oral cold herpes, novel coronavirus infection, etc.), and two of them (7.7%) had a breakthrough invasive fungal infection, but with good management. The most common grade 3/4 adverse events included bone marrow suppression (92.3%), liver injury (19.2%), gastrointestinal reaction (11.5%) and coagulation dysfunction (3.8%).No treatment-related death occurred. Conclusion: VA-CAG regimen achieved high rates of complete remission and MRD negative in young adult fit patients with newly diagnosed AML. This combined regimen has an acceptable safety profile, with low incidence of infection and transfusion dependence.

The pediatric leukemia oncoprotein NUP98-KDM5A induces genomic instability that may facilitate malignant transformation

Pediatric Acute Myeloid Leukemia (AML) is a rare and heterogeneous disease characterized by a high prevalence of gene fusions as driver mutations. Despite the improvement of survival in the last years, about 50% of patients still experience a relapse. It is not possible to improve prognosis only with further intensification of chemotherapy, as come with a severe cost to the health of patients, often resulting in treatment-related death or long-term sequels. To design more effective and less toxic therapies we need a better understanding of pediatric AML biology. The NUP98-KDM5A chimeric protein is exclusively found in a particular subgroup of young pediatric AML patients with complex karyotypes and poor prognosis. In this study, we investigated the impact of NUP98-KDM5A expression on cellular processes in human Pluripotent Stem Cell models and a patient-derived cell line. We found that NUP98-KDM5A generates genomic instability through two complementary mechanisms that involve accumulation of DNA damage and direct interference of RAE1 activity during mitosis. Overall, our data support that NUP98-KDM5A promotes genomic instability and likely contributes to malignant transformation.

Prognostic value of IDH2R140 and IDH2R172 mutations in patients with acute myeloid leukemia: a systematic review and meta-analysis

BackgroundWhether isocitrate dehydrogenase 2 (IDH2) R140 and R172 gene mutations affect the prognosis of patients with acute myeloid leukemia (AML) is controversial. Here, we performed a meta-analysis to assess their prognostic value.MethodsEligible studies were systematically searched from PubMed, Embase, the Cochrane Library and Chinese databases up to June 1, 2022. We extracted the hazard ratios (HRs) and their 95% confidence intervals (CIs) of overall survival (OS) and progression-free survival (PFS) to carry out a meta-analysis by a fixed effect model or random effect model according to the heterogeneity between studies.ResultsA total of 12725 AML patients from 11 studies were included in this meta-analysis, of which 1111 (8.7%) and 305 (2.4%) had IDH2R140 and IDH2R172 mutations, respectively. The results revealed that both IDH2R140 and IDH2R172 mutations had no significant effect on OS (IDH2R140: HR = 0.92, 95% CI: 0.77–1.10, P = 0.365; IDH2R172: HR = 0.91, 95% CI: 0.65–1.28, P = 0.590) or PFS (IDH2R140: HR = 1.02, 95% CI: 0.75–1.40, P = 0.881; IDH2R172: HR = 1.31, 95% CI: 0.78–2.22, P = 0.306) in AML patients. Subgroup analysis of AML patients with IDH2R140 mutation revealed that studies from the USA (HR = 0.60, 95% CI: 0.41–0.89, P = 0.010) and ≤ 50 years old (HR = 0.63, 95% CI: 0.50–0.80, P = 0.000) had longer OS. However, studies from Sweden (HR = 1.94, 95% CI: 1.07–3.53, P = 0.030) had shorter OS. Meanwhile, subgroup analysis of AML patients with IDH2R172 mutation showed that studies from Germany/Austria (HR = 0.76, 95% CI: 0.61–0.94, P = 0.012) and from Sweden (HR = 0.22, 95% CI: 0.07–0.74, P = 0.014) had longer OS, whereas studies from the UK (HR = 1.49, 95% CI: 1.13–1.96, P = 0.005) and studies with nonmultivariate analysis of data type (HR = 1.35, 95% CI: 1.06–1.73, P = 0.014) had shorter OS. In addition, our study also found that patients with IDH2R140 mutation had significantly longer OS (HR = 0.61, 95% CI: 0.39–0.96, P = 0.032) and PFS (HR = 0.31, 95% CI: 0.18–0.52, P = 0.021) than patients with IDH2R172 mutation, despite some degree of heterogeneity.ConclusionsThis meta-analysis demonstrates that IDH2R140 mutation improves OS in younger AML patients and that the prognostic value of IDH2R172 mutation is significantly heterogeneous. Differences in region and data type have a significant impact on the prognosis of AML patients with IDH2R140 and/or IDH2R172 mutations. Additionally, AML patients with IDH2R140 mutation have a better prognosis than those with IDH2R172 mutations, albeit with some degree of heterogeneity.

Association of social deprivation with survival in younger adult patients with AML: an Alliance study

Survival of patients with acute myeloid leukemia (AML) is influenced by genetic factors, age, and race. Social deprivation is increasingly recognized as an important contributor to disparities in cancer outcomes, but studies of adult AML are lacking. We analyzed associations between social deprivation index (SDI) and outcome in 1,893 patients with AML treated on Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology frontline protocols. Patients with low (first quartile, lowest deprivation) and high (quartiles 2-4) SDI were analyzed for associations with baseline clinical, cytogenetic and molecular features, and outcomes. Except for racial-ethnic identity, SDI was not associated with baseline clinical characteristics. Patients aged <60 years with high SDI harbored BCOR (3% vs 7%, P=.03), IDH1 (6% vs 11%, P=.03) and STAG2 (2% vs 5%, P=.02) mutations less often than patients with low SDI, suggesting possible differences in the underlying disease biology. High SDI patients had shorter disease-free (median: 1.5 vs 2.8 years, P=.02) and overall survival (OS; median: 1.9 vs 3.0 years, P=.005) than low SDI patients. In multivariable analysis, high SDI was associated with worse OS (HR: 1.28, 95% CI: 1.06-1.55, P=.001). Survival differences occurred mainly in the 2017 European LeukemiaNet favorable genetic-risk group. There were no significant associations between SDI and molecular features or survival among patients aged ≥60 years. We conclude that high SDI associated with worse survival, independent from other pretreatment prognostic factors, in younger AML patients. The role of socioeconomic factors in AML should be further investigated to overcome potentially avoidable survival disparities.

Analysis of epigenetic modification gene mutations among patients with acute myeloid leukemia

To investigate the carrier rate and clinical characteristics of epigenetic modification gene mutations (EMMs) among patients with acute myeloid leukemia (AML). One hundred seventy two patients who were initially diagnosed with AML at the First People's Hospital of Lianyungang from May 2011 to February 2021 were selected as the study subjects. Next-generation sequencing was carried out to detect variants of 42 myeloid genes among these patients. Clinical and molecular characteristics of patients with EMMs and the effect of demethylation drugs (HMAs) on their survival were analyzed. Among the 172 AML patients, 71 (41.28%) were found to harbor the EMMs, and carrier rates were TET2 (14.53%, 25/172), DNMT3A (11.63%, 20/172), ASXL1 (9.30%, 16/172), IDH2 (9.30%, 16/172), IDH1 (8.14%, 14/172), EZH2 (0.58%, 1/172). Patients with EMMs (+) had lower peripheral hemoglobin compared with those with EMMs(-) (72 g/L vs. 88 g/L, Z = -1.985, P = 0.041). The proportion of EMMs(+) among elderly AML patients was significantly higher than that of young AML patients[71.11% (32/45) vs. 30.70% (39/127), χ² = 22.38, P < 0.001]. EMMs(+) were significantly correlated with NPM1 gene variants (r = 0.413, P < 0.001), while negatively correlated with CEPBA double variants (r = -0.219, P < 0.05). Compared with conventional chemotherapy regimens, HMAs-containing chemotherapy regimens have improved the median progression-free survival (PFS) and median overall survival (OS) among intermediate-risk AML patients with EMMs(+) (PFS: 11.5 months vs. 25.5 months, P < 0.05; 12.5 months vs. 27 months, P < 0.05). Similarly, Compared with conventional chemotherapy regimens, chemotherapy with HMAs had increased median PFS and median OS in elderly AML patients with EMMs(+) (4 months vs. 18.5 months, P < 0.05; 7 months vs. 23.5 months, P < 0.05). Patients with AML have a high rate of EMMs carriage, and HMAs-containing chemotherapy regimens can prolong the survival of elderly patients with AML with poor prognosis, which may provide a reference for individualized treatment.

Frequency and pattern of chromosomal abnormalities in acute myeloid leukemia from Western India: A retrospective study

Chromosomal abnormalities play an important role in diagnosis and prognosis of hematological diseases. The aim of the present study was to study the pattern and frequency of chromosomal aberrations in acute myeloid leukemia (AML) subgroups from western India. A retrospective study was conducted through evaluating laboratory proforma which were filled during 2005 to 2014 for diagnosis and treatment of AML subjects. We have studied chromosomal aberrations in 282 subjects with AML from western India. AML patients were sub-grouped according to FAB classification. Cytogenetic study using conventional cytogenetics (GTG-banding) and Fluorescence in situ hybridization (FISH) was carried out using FISH probes (AML1/ETO, PML/RARA, CBFB). Student's t test for continuous variables and Pearson's Chi-squared test for categorical variables were used to identify the relationship between variables. Cytomorphological study revealed AML- M3 as most frequent (32.3%) group followed by AML-M2 (25.2%) and AML-M4 (19.9%). Chromosomal abnormalities were identified in 145 (51.42%) of the total AML cases. A high frequency (38.6%) of chromosomal abnormalities was identified in AML-M3 subgroup as compared to AML-M2 (31%) and AML-M4 (20.6%). Cytogenetic study is important for the diagnosis and management of the AML patients. Our study identified chromosomal abnormalities in AML subgroups with varied frequencies. It is important in diagnosis and monitoring of the disease. As younger AML patients were more affected in our study, etiological factors such as environmental factors need to be studied. Combination of conventional cytogenetics and FISH has an advantage of identifying high frequency of chromosomal aberrations in AML patients.

Improved Post-Transplant Outcomes in Recent Years for AML Patients with Intermediate Karyotype, FLT3-ITD and Wild Type NPM1: A Report from the EBMT Acute Leukemia Working Party

Rationale: Allogeneic hematopoietic cell transplantation (allo-HCT) is recommended in first complete remission (CR1) in acute myeloid leukemia (AML) patients harboring FLT3 internal tandem duplication (FLT3-ITD). However, historically, long-term survival has been poor due to early relapse, particularly for patients with wild-type NPM1. Recently, FLT3 inhibitors in combination with chemotherapy before allo-HCT, or as post-transplant maintenance, have significantly reduced the risk of relapse and improved survival. Here, we assessed real-world changes over time in transplant characteristics and post-transplant outcomes in young AML patients with FLT3 ITD and either NPM-1 mutated or wild type, using a large dataset from the European Society of Blood and Marrow Transplantation (EBMT) registry. Patients and Methods: We identified 1827 adult AML patients (54% female; median age 49 years, range 18-60) with FLT3 ITD, intermediate karyotype and available NPM1 mutation status, allografted between 2012 and 2021 in CR1 from a matched related (32%), matched unrelated (56%) or haploidentical donor (12%). NPM1 was mutated in 72% of patients. At transplant, 834 patients were measurable residual disease (MRD) positive, 464 MRD negative, and 529 were not evaluated or missing. Comorbidity index (CI) was zero in 59% of patients with available data. Conditioning was myeloablative (MAC) in 64% of patients. In vivo T cell depletion (TCD) graft was given to 62% of patients, post-transplant cyclophosphamide (PTCy) to 17%, and 87% received peripheral blood stem cells (PBSC). Most patients (66%) and donors (54%) were cytomegalovirus (CMV) positive. Median follow-up of alive patients was 30 months (IQR 28-32). Results: We compared changes in patient and transplant characteristics over time in 688 (38%) patients transplanted between 2012 and 2016 and 1139 (62%) patients transplanted between 2017 and 2021. Patients transplanted in recent years had a shorter follow up, were more likely to have NPM1 mutation, to be MRD positive, to have a higher CI, to receive a transplant from a haploidentical donor, a CMV positive donor, and to receive PBSC and PTCy. For patients with wild-type NPM1, day 100 acute graft-versus-host disease (GVHD) grade II-IV and grade III-IV were encountered in 29% and 11% of patients transplanted in 2021-2016, respectively, and 21% and 7% for patients transplanted in 2017-2021, respectively. The 2-year cumulative incidence of chronic and extensive chronic GVHD were 32% and 16%, respectively for 2012-2016 and 36% and 20%, respectively for 2017-2021. Over time, the 2-year cumulative incidence of relapse (CIR) significantly decreased from 43% to 31% between the two time periods (p<0.04) and non-relapse mortality (NRM) significantly decreased from 14% to 8% (p<0.05). The 2-year leukemia free survival (LFS) and overall survival (OS) significantly improved over time from 54% to 64% (p<0.02) and from 63% to 71% (p<0.05) respectively, whereas GVHD-free, relapse-free survival (GRFS) improved from 39% to 46% (p=0.08). In multivariate Cox analysis (MVA), transplantation in recent years significantly reduced the CIR (hazard ratio [HR]=0.65; p<0.01), and acute GVHD grade II-IV (HR=0.6; p<0.01) and significantly improved LFS (HR=0.67; p=0.02), OS (HR=0.66; p<0.03), and GRFS (HR=0.77; p<0.05). The use of unrelated donors increased the risk of acute GVHD but reduced the CIR whereas the use of haploidentical donors increased NRM. In vivo TCD reduced the risk of chronic GVHD whereas female donors to male recipients increased it. PTCy decreased the risk of NRM whereas MAC reduced the CIR. For patients with NPM1 mutation, no significant changes over time in post-transplant outcomes were noted except for decreased NRM from 15% for 217 patients transplanted in 2012-2016, to 10% for 288 patients transplanted in 2017-2021 (p<0.02). In MVA, transplantation in recent years did not significantly affect any of the post-transplant outcomes. Conclusion: In AML patients with FLT3 ITD and wild-type NPM1, we noticed a significant decrease over time in the CIR and a significant improvement of LFS, OS and GRFS, likely reflecting the efficacy of FLT-3 inhibitors, including when used as post-transplant maintenance, in this high-risk setting. On the contrary, no significant change over time was noticed in post-transplant outcomes of patients harboring NPM1 mutation.

Hypomethylating Agent Maintenance for Favorable and Intermediate Risk Acute Myeloid Leukemia

Background: Acute myeloid leukemia (AML) is a heterogenous disease with variable outcomes among different risk groups. Favourable risk group AML after consolidation chemotherapy have long-term- leukemia-free survival of 60-70% [1]. Also, many patients in India in the intermediate risk group do not opt for allogenic hematopoietic stem cell transplant due to financial constraints, non-availability of fully matched donors and due to reservations regarding non relapse mortality associated with transplant. Previous studies have shown the value of azacytidine maintenance in prolonging overall survival and relapse free survival in older patients of AML [2]. We conducted this study to assess the results of hypomethylating agents as maintenance in non-adverse risk, younger AML patients who did not receive allogeneic stem cell transplant. Methods: Adults with de-novo AML (>18 years) who received treatment at our centre from January 2021 to December 2021 were included in our retrospective analysis. Induction therapies used were out of these 4 as per physician's choice- 3days x daunorubicin+7 x cytarabine; 2days x daunorubicine + 5 x cytarabine +venetoclax; azacytidine+venetoclax; Fludarabine+Cytarabine+venetoclax. Complete remission was defined as per the ELN 2017 criteria [3]. Measureable residual disease assessment was done by multiparametric flowcytometry or by PCR for patients who had NPM1 mutation or inversion 16. Consolidation chemotherapy comprised of received 3-4 cycles of intermediate dose cytarabine at a dose of 1500mg/m2 twice daily on days 1, 3 and 5. Midostaurin was administered at a dose of 50mg twice daily on day 8 through 21 in FLT3 mutated patients. Patients who were in remission after consolidation therapy received maintenance using hypomethylating agents such as Azacytidine or decitabine alone or in combination (Venetoclax 100mg x 4 days with Voriconazole 200mg twice daily). Midostaurin 50mg twice daily or Sorafenib 200mg twice daily was given if FLT3-ITD/TKD mutated in addition to the hypomethylating agents. Our aim was to asses the tolerability and results of maintenance azacytidine in a non-selected cohort. Results Fifty-three AML patients received induction therapy during the study period and out of which 23 patients went on to receive consolidation with cytarabine. Seven patients were consolidated with allogeneic bone marrow transplant, 7 had refractory AML and 3 were induction deaths, (1) relapsed post consolidation, (1) did not receive maintenance. These were excluded from the analysis. Seventeen patients were lost to follow up after induction. Nineteen patients were started on hypomethylating agent maintenance. Baseline characteristics of the cohort are shown in Table 1. The median consolidation chemotherapy cycles were 3 (range 1-4). The cumulative doses of Daunorubicin used was 261mg (range-170 to345), cytarabine 1078mg (range 840 to 1351) and venetoclax 1200mg (range 600 to 3500mg). Post induction measurable residual disease MRD was positive in 01 out of 16 patients and post consolidation MRD was positive for 03 out of 08 patients. These 3 patients who were MRD positive post consolidation received azacytidine and venetoclax as maintenance. Table 2 showing the distribution of maintenance and the grade ¾ adverse events in patients who were on maintenance. Two patients in the maintenance cohort relapsed belonging to the MRD negative group. Both these patients received salvaged chemotherapies and are awaiting allogenic transplant. Conclusion Azacytidine maintenance is feasible option for preventing relapses in patients with favourable and intermediate risk AML who do not choose bone marrow transplant as consolidative therapy, however further studies are warranted. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Azacitidine Combined with Homoharringtonine, Idarubicin/Daunorubicin, Cytarabine for Previously Untreated Patients with Acute Myeloid Leukemia: A Single-Center, Phase 2 Study

Background Previous studies have reported that a combination of Homoharringtonine (HHT), a plant cytotoxic alkaloid derived from the trees of the genus Cephalotaxus, plus intensive chemotherapy (IC) improved the clinical responses of acute myeloid leukemia (AML). Azacitidine (Aza), a DNA hypomethylation agent, has been a "backbone" for novel combinational therapies. In this trial, we assessed the efficacy and safety of adding Aza to HIA/HDA regimen in previously untreated young or eligible for IC patients with AML. Methods This is a single-center, phase 2 trial (ClinicalTrials.gov: NCT04248595). Aza (75mg/m2/d on days1-5) administered in combination with HIA/HDA [HHT 2mg/m2/d on days 4-8, idarubicin 6mg/m2/d or daunorubicin 40 mg/m2/d on days 4-6, and cytarabine 100mg/m2/d on days 4-10] regimen for patients age<60 or eligible for IC (Fig.1A) The primary endpoint was the composite CR. Secondary endpoints were overall survival (OS), relapse-free survival (RFS), and adverse events (AEs). A leukemia targeted-exome-seq panel including 58 genes and leukemia 47 fusion gene panel were used for screening. Results Between Aug, 2019 to May, 2022, a total of 20 de novo AML patients were enrolled. The CR/CRi was achieved in 95.0% (19/20) (Fig. 1B). 94.7% (18/19) reached CR/CRi after the 1st cycle of induction therapy and the median time was 25.0d (IQR, 21.0 to 27.0). The median follow-up was 628 days (range, 107 to 905) and the median OS and RFS were not reached (Fig. 1C& 1D). The estimated 2-year OS and RFS were 87.4% (95%CI, 58.1% to 96.7%) (Fig. 1C) and 82.0% (95%CI, 53.1% to 94.0%), respectively (Fig. 1D). No survival difference was observed between the favorable and intermediate versus poor-risk groups in both OS and RFS (Fig. 1E& 1F). Meanwhile, the estimated 2-year OS and RFS possibility of the favorable and intermediate-risk group was 90.9% (95%CI, 50.8% to 98.7%) and 80.0% (95%CI, 20.4% to 96.9%), respectively (Fig. 1E& 1F). While the estimated 2-year OS and RFS possibility of the poor-risk group was 85.7% (95%CI, 33.4% to 97.9%), and 75.0% (95%CI, 12.8% to 96.1%), respectively (Fig. 1E& 1F). We detected 30 mutants in 17 of 58 leukemia driver genes at the timepoint of enrollment. The median mutation number/patient was 1.50 (range, 0-4), and 17 of 20 (85.0%) patients had more than one mutation (≥1) (Fig. 1G). The most frequently mutated genes were FLT3 (ITD/TKD) (20.0%), KIT (15.0%), NRAS (15.0%), and DNMT3A (15.0%) (Fig. 1G). More than half of the patients (11/20) harbored the mutated genes involved in signal transducers (FLT3, KRAS,NRAS, KIT, PTPN11, CSF3R; 11/20, 55.0%), and all these patients achieved CR/CRi (11/11, 100%) after induction therapy (Fig 1G). It is worth noticing that, we observed a high mutant's clearance with VAF (variant allele frequency) dramatical reduction (to <0.01%) (Fig. 1H) after the induction therapy, indicating that mutations involved in signal transducers were rapidly and significantly associated with high clinical response. We also identified 2 patients with MLL-AF9 and 4 patients with CBF-β-MYH11. Both patients with MLL-AF9 reached complete molecular remission (<0.1%) after induction. 3 of 4 patients with CBF-β -MYH11 reached complete molecular remission (<0.1%), and the expression level of the CBF-β -MYH11 fusion gene in 1 patient decreased over 1000-fold at the molecular level (512.16% to 0.28%) after 1 cycle of induction. The MRD negative was 84.2% (16/19) in patients who reached CR/CRi after the 1st cycle of induction therapy (Fig. 1I, 1J). Also, MRD were negative in all 3 patients with favorable risk, 77.8% with intermediate-risk, and 87.5% with poor-risk (Fig. 1K). Infection (grade 1-4) was the most common non-hematological AE (65.0%). Other AEs of grade 3 or higher included fatigue (5.0%), decreased appetite (5.0%), and hepatic dysfunction (5.0%). The most common grade 3-4 hematological AEs were neutropenia and thrombocytopenia. The median duration of neutropenia and thrombocytopenia were 12d (IQR, 11 to 15) and 14d (IQR, 12 to 16), respectively. No patients discontinued the induction treatment and no patient died within 8 weeks of the treatment. Conclusion This trial demonstrated that the adding of Aza to HIA/HDA regimen is an effective first-line therapy for previously untreated young or fit AML patients, with high efficacy and well tolerance. This study provides preliminary results for the clinical application of this novel combination therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Venetoclax Plus "2 + 5" Modified Intensive Chemotherapy with Daunorubicin and Cytarabine in Fit Elderly Patients with Untreated De Novo Acute Myeloid Leukemia: A Single-Center Retrospective Analysis

Background: Therapeutic options remain limited for elderly acute myeloid leukemia (AML) considering the poor tolerance to intensive chemotherapy. Venetoclax in combination with hypomethylation agents (HMAs) or low-dose cytarabine (LDAC) has been shown achieved significantly improved efficacy in elderly AML patients. Recently, we reported that an intensive chemotherapy regimen of venetoclax plus daunorubicin and cytarabine (DAV regimen) showed high complete remission (CR) rates of 91% after one cycle of induction therapy in newly diagnosed adult young AML patients, indicating the strong potential of the venetoclax-based intensive therapy to induce rapid remission (Lancet Hematol, 2022). For fit elderly AML patients, a prospective, phase Ib study demonstrated that venetoclax plus "2 + 5" (idarubicin and cytarabine) regimen achieved high CR rates of 68% (CR and CR with incomplete count recovery [CRi] rate 97%) in fit elderly patients with de novo AML. Unfortunately, delayed hematologic recovery, especially prolonged thrombocytopenia, was observed during consolidation therapy. Thus, an optimized venetoclax-based modified intensive therapy with the hope to achieve higher CR rates and better tolerance and improve long-term survival are urgently needed. Objective: To evaluate the efficacy and safety of modified intensive induction of venetoclax in combination with "2 + 5" (daunorubicin and cytarabine) chemotherapy and the following intermediate-dose cytarabine plus venetoclax consolidation in untreated fit de novo elderly AML. Design, setting and participants: Retrospective clinical trial conducted in the First Affiliated Hospital, Zhejiang University College of Medicine, China. Eligible patients (≥60 years old) with de novo AML (exclude acute promyelocytic leukemia) were enrolled since March 9, 2021, with final follow-up in July 15,2022. Interventions: Patients were treated with induction chemotherapy included daunorubicin (60mg/m2 days 1-2, intravenously), cytarabine (100mg/m2 days 1-5, intravenously), and venetoclax (100mg day 3, 200mg day 4, 400mg days 5-10, orally), followed by 3 consolidation cycles of venetoclax (400mg days 1-14, orally) in combination with intermediate-dose cytarabine (1g/m2 days 1-3, intravenously) and post-remission bone marrow transplantation when applicable. Venetoclax was administered for the maintenance therapy for one year (200mg days 1-14 in each 28-day cycle, orally). Main outcomes and measures: The primary endpoints included the rate of composite complete remission (CRc) after one cycle of induction treatment, including CR/CRi. The secondary endpoints were measurable residual disease detected by muti-parameter flow cytometry (MFC-MRD), adverse events, event-free survival (EFS) and overall survival (OS). Results: Twelve patients were enrolled. Median age was 64 years old (range, 61-71), with poor-risk in 33.3% (4/12) of patients (European LeukemiaNet 2022 risk). Other characteristics of patients were listed in Table 1. The CR rate were 91.7% (11/12) (Table 1). All patients with poor-risk achieved CR. Measurable residual disease-negative composite CR was attained in 100.0% (11 out 11) of total patients achieved CR (Table 1, Figure 1). Common adverse events (>30%) included thrombocytopenia. neutropenia, anemia, febrile neutropenia, nausea, and pneumonia. The main grade ≥ 3 hematologic toxicities during induction were neutropenia (100%), anemia (100%) and thrombocytopenia (100%). The main grade ≥ 3 nonhematologic toxicities during induction were febrile neutropenia (41.7%) and pneumonia (33.3%) (Table 1). No tumor lysis syndrome was observed. The median follow-up was 108 days. The median EFS was 398 days, with an estimated 1-year EFS rate of 75.0%. The median OS was not achieved, with an estimated 1-year OS rate of 100% (Table 1). 9 out of 11 patients achieving CR maintained the MRD-negative status until the last follow-up (Figure 1). No deaths occurred among the patients during follow-up. Conclusions: The novel combination of "2+5" (daunorubicin and cytarabine) with venetoclax (modified DAV regimen) showed encouraging efficacy and good tolerability in untreated fit elderly patients with de novo AML, with high CR rate and deep remission. Figure legends Figure 1 The clinical outcome of the 12 elderly patients with newly diagnosed acute myeloid leukemia who were treated with modified DAV. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Impaired Overall Survival in Young Patients With Acute Myeloid Leukemia and Variants in Genes Predisposing for Myeloid Malignancies.

Impaired Overall Survival in Young Patients With Acute Myeloid Leukemia and Variants in Genes Predisposing for Myeloid Malignancies.

Treatment options for acute myeloid leukemia patients aged

Treatment of acute myeloid leukemia (AML) has changed over the last few years, after the discovery of new drugs selectively targeting AML blasts. Although 3/7 remains the standard of care for most AML patients, several new targeted agents (such as FLT3 inhibitors, CPX-351, gemtuzumab ozogamicin, BCL-2 inhibitor, and oral azacitidine), either as single agents or combined with standard chemotherapy, are approaching clinical practice, starting a new era in AML management. Moreover, emerging evidence has demonstrated that high-risk AML patients might benefit from both allogeneic stem cell transplant and maintenance therapy, providing new opportunities, as well as new challenges, for treating clinicians. In this review, we summarize available data on first-line therapy in young AML patients focusing on targeted therapies, integrating established practice with new evidence, in the effort to outline the contours of a new therapeutic paradigm, that of a “total therapy”, which goes beyond obtaining complete remission.

Clinical Efficacy and Survival Analysis of Adult Patients with Acute Myeloid Leukemia after Microtransplantation

To investigate the clinical efficacy and survival factors of microtransplantation (MST) in adult patients with acute myeloid leukemia (AML). For a retrospective analysis of 27 adult patients with AML receiving MST from July 2014 to October 2021, the median age was 59(29-77) years old, 13 cases were ≥60 years old, 14 case were <60 years old, 13 cases were male and 14 cases were female. Classification by FAB: AML-M2 6 cases, AML-M4 6 cases, AML-M5 2 cases, AML-M6 2 cases, AML（Undivided type） 9 cases, AML myeloid sarcoma 2 cases (primary AML 21 cases, AML secondary to MDS 6 cases). Cytogenetic analysis showed 25 patients with a normal karyotype, 2 patients with an abnormal karyotype, and 20 patients with an abnormal molecular biology. Induction chemotherapy regimens mainly include: IA, DA, MA or HA regimen, including CAG or CIG in combination with decitabine, and single-agent decitabine. 17 patients achieved complete remission (CR) after 1 course of induction chemotherapy and 4 patients achieved CR after 2 courses of induction chemotherapy. 3 patients received CR by four courses of decitabine, 2 patients received no remission, and 1 patient underwent no induction chemotherapy and were treated direct MST. There were 16 patients with pretransplant CR and 11 patients were not in remission before transplantation. Follow-up mainly used consult patient's medical records and telephone inquiry to observe the adverse effects and efficacy of MST treatment. Survival analysis was performed by Kaplan-Meier method, with the main observation indicators overall survival(OS) and leukemia-free survival(LFS), and performed with the Log-rank test. Multivariate analysis was performed by the Cox regression model. A total of 79 MST were performed in 27 AML patients with good overall safety and no special serious adverse effects. The median time of leukocyte recovery was 13(4-28) days, and the median time of platelet recovery was 13(4-30) days. There were 50 cases of infection, 5 cases of abnormal liver function and 3 cases of abnormal cardiac function. Except for abnormal cardiac function, all other complications did not affect the treatment and were cure. Acute or chronic GVHD, renal insufficiency, abnormal coagulation function, and severe bleeding were not observed during treatment or during follow-up. As of the follow-up date, the median follow-up time of the 27 patients was 79(14-171) months, the median OS time was 62(1-171) months, and the median LFS time was 15(0-171) months. The 2-year OS rate was 65.7%（17/27）, and the 2-year LFS rate was 47.4%（12/27） . The complete response rate of 27 patients treated with MST was 48.1% (13/27). 8 patients relapsed during MST treatment, including 7 patients after the completion of the first MST course and 1 patient after the completion of the second MST course. 2 patients relapsed after the end of the course of MST. 13 patients died, including 10 patients because of disease progression, two patients from severe infection, and one patient from cardiac damage. MST has the advantages of small toxic side effects, complete compatibility of HLA matching is not required, effective avoidance of GVHD and rapid hematopoietic recovery, which can improve OS and LFS in elderly AML and young AML patients, and is one of the treatment options for patients without HLA matching.

Clinical Significance of RAS Gene Mutations in Patients with Acute Myeloid Leukemia

To investigate the clinical characteristics of RAS gene mutations in patients with acute myeloid leukemia (AML). 43 myeloid gene mutations were detected using next-generation sequencing (NGS) in 180 patients with AML who were first diagnosed between May 2011 and February 2021. The molecular and clinical features of RAS gene mutations and their effects on efficacy and survival of patients were retrospectively analyzed. Among 180 AML patients, the proportion of mutations in RAS pathway-related genes were NRAS (14.4%), KRAS (2.2%), FLT3-ITD (13.8%), PTPN11 (7.7%), KIT (5.0%), FLT3-TKD (3.8%) and CBL (2.7%). Seventy-three (40.6%) AML patients had gene mutations associated with the RAS pathway.The number of peripheral blood white blood cells and the proportion of bone marrow primitive juvenile cells in patients with NRAS/KRAS gene mutation were higher than those of patient with RAS wild-type, the difference was statistically significant (P<0.05). NRAS/KRAS gene mutations were significantly associated with the CBL gene mutation(r=0.287). In young AML patients (age <60 years), there were no significant differences in complete response rate (CR), progression-free survival (PFS), and overall survival (OS) between patients with RAS gene mutation and those with wild-type(P>0.05). In elderly AML patients (age≥60 years), PFS and OS in RAS mutants were significantly lower than those in wild-type patients(P<0.05). In AML patients, RAS gene mutation is relatively common, and RAS gene mutation is associated with clinical characteristics and efficacy of patients, and may be a molecular marker of poor prognosis for elderly AML.

AML-434 Retrospective Review of Outcomes in Newly Diagnosed Leukemia Patients Aged 65 and Older When Admitted to the Hospital: A Single Center Experience

Acute leukemia patients have a diminished survival inversely proportional to their age. 5-year overall survival in younger AML patients is 50%, however reduced to <10% if age >70. Factors contributing include poor performance status, decreased response to induction therapy, increased treatment related mortality, unfavorable cytogenetics and secondary leukemia. Report observed characteristics and outcomes of elderly leukemia patients. Retrospective chart review of newly diagnosed acute myeloid leukemia (AML) patients >65 admitted from 7/1/2015 through 6/30/2021. Demographic information, classification, duration of hospital stay, blood products administered, treatment, discharge condition, 3 and 6 month remission, and survival data collected. Academic medical center. 149 patients identified. AML[n=130], acute promyelocytic leukemia (APL)[n=9], and acute leukemia not otherwise specified (AML-NOS)[n=10]. 97 patients treated. AML treatment: Induction therapy, daunorubicin and cytarabine (liposomal), or hypomethylating agent +/-venetoclax. APL treatment: all-trans retinoic acid (ATRA) +/- arsenic trioxide (ATO). One patient with AML-NOS received hypomethylator. Patients separated into three groups: <70[n=55], 70 to 74[n=52], and >75[n=60]. Percent of patients who did not receive any therapy increased as age group increased (21.8%, 32.7%, and 41.7%). Length of hospital stay, reflective of treatment, was greatest in the younger population (28 days, 17.6 days, and 15.3 days). 6-month survival 51% younger, 42.3% middle and 23.4% for eldest cohort. Treatment related mortality (TRM) including transitioning to hospice care increased as age increased (29%, 34% and 50%). 25/130 patients received induction chemotherapy. Nineteen patients were <70. The expected TRM for the younger cohort was 10.68% (1 - 41%) and 10.1% (1-20%) for elder cohort. The observed TRM was 10.5% in the younger cohort and 50% in the older cohort. Most of the eldest AML patients received a hypomethylating mono- or combination therapy. Nearly 50% of all AML were discharged home. The 6-month survival was 50% for younger, 26.8% for middle and 13.3% for eldest cohort. Nine APL patients were identified with 5 being in the eldest cohort. Only 3(33.3%) survived 6 months. None of the patients with AML-NOS were alive at 6 months. Acute leukemia in the elderly population remains a challenge with poor outcomes despite considering patient's age and performance status.

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.

Outcomes By Treatment Setting and Genomic Profile in Patients with AML on Cladribine, Idarubicin, and Cytarabine

Outcomes By Treatment Setting and Genomic Profile in Patients with AML on Cladribine, Idarubicin, and Cytarabine