Acute Myeloid Leukemia In Older Patients Research Articles

Age and sex associate with outcome in older AML and high risk MDS patients treated with 10-day decitabine

Treatment choice according to the individual conditions remains challenging, particularly in older patients with acute myeloid leukemia (AML) and high risk myelodysplastic syndrome (MDS). The impact of performance status, comorbidities, and physical functioning on survival is not well defined for patients treated with hypomethylating agents. Here we describe the impact of performance status (14% ECOG performance status 2), comorbidity (40% HCT-comorbidity index ≥ 2), and physical functioning (41% short physical performance battery < 9 and 17% ADL index < 6) on overall survival (OS) in 115 older patients (age ≥ 66 years) treated on a clinical trial with a 10-day decitabine schedule. None of the patient-related variables showed a significant association with OS. Multivariable analysis revealed that age > 76 years was significantly associated with reduced OS (HR 1.58; p = 0.043) and female sex was associated with superior OS (HR 0.62; p = 0.06). We further compared the genetic profiles of these subgroups. This revealed comparable mutational profiles in patients younger and older than 76 years, but, interestingly, revealed significantly more prevalent mutated ASXL1, STAG2, and U2AF1 in male compared to female patients. In this cohort of older patients treated with decitabine age and sex, but not comorbidities, physical functioning or cytogenetic risk were associated with overall survival.

Preclinical Validation of an Advanced Therapy Medicinal Product Based on Cytotoxic T Lymphocytes Specific for Mutated Nucleophosmin (NPM1mut) for the Treatment of NPM1mut-Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) with nucleophosmin (NPM1) genetic mutations is the most common subtype in adult patients. Refractory or relapsed disease in unfit patients or after allogeneic hematopoietic stem cell transplantation (allo-HSCT) has a poor prognosis. NPM1-mutated protein, stably expressed on tumor cells but not on normal tissues, may serve as an ideal target for NPM1-mutated AML immunotherapy. The study aim was to investigate the feasibility of producing mutated-NPM1-specific cytotoxic T cells (CTLs) suitable for somatic cell therapy to prevent or treat hematologic relapse in patients with NPM1-mutated AML. T cells were expanded or primed from patient or donor peripheral blood mononuclear cells by NPM1-mutated protein-derived peptides, and tested for leukemia antigen-targeted cytotoxic activity, cytokine production and hematopoietic precursor inhibitory effect. We found that mutated-NPM1-specific CTLs, displaying specific cytokine production and high-level cytotoxicity against patients' leukemia blasts, and limited inhibitory activity in clonogenic assays, could be obtained from both patients and donors. The polyfunctional mutated-NPM1-specific CTLs included both CD8+ and CD4+ T cells endowed with strong lytic capacity. Our results suggest that mutated-NPM1-targeted CTLs may be a useful therapeutic option to control low-tumor burden relapse following conventional chemotherapy in older NPM1-mutated AML patients or eradicate persistent MRD after HSCT.

Research Strategy for the Development of a Quality-of-Life Decision-Making Model for Older Patients With Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is a deadly cancer, especially for patients over 60 years of age who face the dilemma of choosing the best treatment during a time of crisis. Current research in the older AML population is focused on survival without addressing quality of life (QOL). Survival and QOL data are essential for patients to decide which treatment best aligns with their goals, whether for survival or improved QOL. Research aims: The aims of this study are to: (1) Describe differences in QOL among newly diagnosed older AML patients receiving intensive chemotherapy compared with nonintensive chemotherapy (at baseline, and days 30, 60, 90, and 180 post treatment); (2) Identify the individual clinical disease characteristics and patient factors of newly diagnosed AML patients that predict QOL among those receiving two treatment intensities; and (3) Design a patient decision-making model that integrates the significant clinical disease and patient factor predictors of QOL for newly diagnosed older AML patients. Methods: An exploratory observational design will be used to address aims 1 and 2. Data will be collected from 200 patients ≥ 60 years of age with newly diagnosed AML. Subjects will complete the Functional Assessment of Cancer Therapy-Leukemia, Brief Fatigue Inventory, and Memorial Symptom Assessment Short Form within 7 days of beginning new treatment and at days 30, 60, 90 and 180. Clinical disease characteristics will be completed by the health-care team. A patient decision-making model will be developed to provide survival and quality-of-life data for intensive and nonintensive chemotherapy.

Acute myeloid leukemia: Incidence, transplantation and survival through Italian administrative healthcare data.

To identify newly diagnosed patients with acute myeloid leukemia in 2017 treated with intensive chemotherapy or unfit for intensive chemotherapy, and to assess their probability of receiving allogeneic stem cell transplantation and survival, from the Italian National Health Service perspective. From the Ricerca e Salute database, adults with an in-hospital diagnosis of acute myeloid leukemia (International Classification of Disease-9th version-Clinical Modification code 205.0x) in 2017 (index date), without any identifying acute myeloid leukemia criteria within the preceding year, were selected. Among them, subjects treated with intensive chemotherapy (chemotherapy during an overnight hospitalization) within one year after index date were identified. The remaining were considered unfit for intensive chemotherapy. Gender, age and comorbidities were described. Within the follow-up period, probabilities of in-hospital allogeneic stem cell transplantation and overall survival were assessed through Kaplan Meier analyses. From 4,840,063 beneficiaries of the Italian National Health Service, 368 newly acute myeloid leukemia diagnosed adults (9.0 *100,000) were selected. Males comprised 57%. Mean age was 68±15. There were 197 patients treated with intensive chemotherapy. The remaining 171 unfit for intensive chemotherapy were older (72±14) and with more comorbidities (e.g. hypertension, chronic lung diseases and chronic kidney disease). Only patients treated with intensive chemotherapy underwent an allogeneic stem cell transplantation (41; 33%) during the one year after the index date. Within the first and second follow-up year, respectively: 41.1% and 26.9% of subjects treated with intensive chemotherapy (144) survived (median survival time: 7.8 months); 25.7% and 18.7% of those unfit for intensive chemotherapy (139) survived (1.2 months). Difference was significant (p<0.0001). Within one and two years after transplantation (41 patients), 73.5% and 67.3% of subjects survived, respectively. This study, by showing the incidence of acute myeloid leukemia in Italy in 2017, the proportion of patients treated with intensive chemotherapy from the new diagnosis, the use of allogeneic stem cell transplantation and two-year survival, integrated evidence on large and unselected populations and may help to improve treatment strategies of older acute myeloid leukemia patients.

Clinical efficacy of azacytidine and venetoclax and prognostic impact of Tim-3 and galectin-9 in acute myeloid leukemia and high-risk myelodysplastic syndromes: A single-center real-life experience.

Treatment of acute myeloid leukemia (AML) and high-risk myelodysplastic syndromes (MDS) is difficult in older patients with comorbidities and high-risk disease factors. Venetoclax, the first-in-class Bcl-2 inhibitor, has proven efficacy and safety in combination with azacytidine for treatment of high-risk myeloid diseases. In this single-center real-life retrospective study, a total of 27 consecutive patients treated with azacytidine plus venetoclax were included, and clinical outcomes, hematological improvements, and biomarkers of responsiveness to therapy were compared to those observed in an historical cohort of 95 consecutive patients treated with azacytidine as single agent. Azacytidine plus venetoclax was effective and safe in older and frail AML and high-risk MDS patients, with median overall survival of 22.3months, higher than that reported in phase III trial (14.7months), and higher than that of historical cohort (5.94months). Progression-free survival was higher in patients treated with the drug combination compared to those treated with azacytidine as single agent (p = 0.0065). Clinical benefits might increase when azacytidine and venetoclax are administered as upfront therapy (p = 0.0500). We showed that Tim-3 expression could be a promising therapeutic target in refractory/relapsed patients, and galectin-9 a biomarker of responsiveness to therapy. Moreover, patients treated with azacytidine and venetoclax displayed a higher overall survival regardless the presence of negative prognostic markers at diagnosis (e.g., increased WT1 copies and/or normalized blast count). These encouraging results in a real-world setting supported efficacy and safety of azacytidine plus venetoclax as upfront therapy in AML and high-risk MDS, with clinical outcomes comparable to those of clinical trials when an appropriate venetoclax management with bone marrow assessment at every first, second, fourth, and eighth cycle, and dose adjustments for toxicities are performed.

A Randomized Comparison of the Fractionated Versus Single Dose Schedule of Gemtuzumab Ozogamicin at Induction with Determinants of Benefit for Older AML Patients: UK NCRI AML18 Trial Results

The addition of Gemtuzumab Ozogamicin (GO) to induction chemotherapy has been demonstrated to improve outcomes in older adults with non-adverse cytogenetic risk acute myeloid leukemia (AML) but it is currently uncertain whether a higher dose, delivered as a fractionated schedule as per the ALFA0701 trial, provides a survival benefit over a single lower dose (GO 3mg/m2) as given in the NCRI AML16 trial. The AML18 trial evaluated this and we now report 5yr overall survival (OS) results together with information from response assessment by measurable residual disease (MRD) and molecular stratification. Methods The NCRI AML18 trial randomised older AML or high-risk MDS patients (>10% blasts) who were not known to have adverse cytogenetics at trial entry to receive course 1 DA induction (Daunorubicin 60mg/m2 d1, 3, 5, AraC 100mg/m2 bd d1-10) with either GO 3mg/m2 on day 1 (GO1), or fractionated GO on days 1 and 4, maximum 5mg per dose (GO2). Further courses did not include GO. Of 852 enrolled patients, 8 withdrew trial consent. Baseline cytogenetics and molecular profiling included a 95-gene targeted NGS panel. Following course 1 MRD response was assessed by flow cytometry (results available for 608 patients including 453 in remission [CR+CRi] post course 1) with any measurable level of MRD considered positive. Randomisations for course 2 were MRD directed and will be reported separately. Results Treatment arms (GO1, n=422; GO2, n=422) were balanced for baseline characteristics. Median age was 68 years. 79.7% had de novo AML, 10.6% clinical secondary AML, 9.7% high risk MDS. Of patients with cytogenetic data (n=782), 4.4% and 80.9% had favourable or intermediate risk cytogenetics respectively. 114 patients (14.6%) were found to have adverse risk cytogenetics after trial entry. Median follow-up was 50.2 months (quartiles: 44 to 60). GO1 and GO2 were comparable for day 30 mortality (7.6% vs 8.0%), time to count recovery (median 29 vs 29 days for neutrophils to 1 x 109, median 29 vs 30 days for platelets to 100 x 109/L), toxicity profiles and post course 1 response rates (56.6% vs 62.5% for CR, 63.5% vs 67.3% for CR+CRi). However lower post course 1 MRD levels (Figure A) and a higher MRD negative response rate were observed for the GO2 arm (57.3% GO2 vs 49.7% GO1 for MRD negative, 72.2% GO2 vs 62.4% GO1 for MRD <0.1%). This differential response for GO2 versus GO1 varied across molecular subtypes, greatest for IDH mutations (MRD <0.1%, 71% GO2 vs 47% GO1 for IDH2, 76% GO2 vs 62% GO1 for IDH1) and then NPM1 mutated patients (MRD <0.1%, 81% GO2 vs 73% GO1). 5yr OS rates were 29% for GO2 and 24% for GO1 patients (p=0.14). In a sensitivity analysis excluding patients with adverse cytogenetics / TP53 mutations, 5yr OS rates were 33% for GO2 and 26% for GO1 (p=0.045). Survival advantage from GO2 vs GO1 was most apparent for the subgroup of patients with DNA methylation-type mutations (including mutated IDH 1/2, DNMT3A) (HR 0.77, 95%CI 0.63-0.93). 27% of patients received a CR1 allogenic stem cell transplant (ASCT) (122 GO1, 106 GO2) with a survival advantage for transplant on Mantel-Byar analysis (HR 0.76, 95%CI 0.62-0.93, P=0.007). Survival was superior for transplanted patients on the GO2 arm compared to GO1 (HR 0.66, 95%CI 0.47-0.91, P=0.01) (Figure B). The overall survival benefit from GO2 was lost when patients were censored at ASCT. Additionally, GO2 did not provide a survival advantage for patients over 70yrs by age subgroup analyses (test for trend, P=0.019). Conclusions Compared to single dose GO, the fractionated schedule (GO2) was associated with greater reduction in MRD, and improved overall survival in older adults with non-adverse risk genetics; comparable differences by molecular subtype were observed for MRD response and survival. AML18 trial results suggest that the differential benefit from GO2 for older adults is dependent on delivery of ASCT in order to translate the better leukemia clearance from induction into a significantly higher 5yr survival. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Response to Intensive Induction Chemotherapy after Failure of Frontline Azacitidine+Venetoclax in Acute Myeloid Leukemia

Introduction: Venetoclax (Ven) in combination with hypomethylating agent (HMA) is approved for the treatment of newly diagnosed acute myeloid leukemia (AML) in patients 75 years or older or who are not candidates for standard intensive induction chemotherapy (IC) due to comorbidities. Due to the high efficacy of HMA/Ven, an increasing number of newly diagnosed AML patients who may have historically been considered to be candidates for IC are instead receiving HMA/Ven due to patient and/or provider preference, especially patients who are >= 60 years or those with adverse risk disease biology. Several ongoing studies are also evaluating the efficacy of Ven/HMA in newly diagnosed younger AML patients (NCT03573024, NCT04801797, NCT04752527). Although response rates with HMA/Ven are high, approximately 1/3 of patients are refractory and many patients relapse. It is unknown whether salvage IC after Ven/HMA failure is feasible or whether initial therapy with HMA/Ven may impact response to subsequent IC. Methods: To investigate outcomes of patients treated with IC after failure of frontline HMA/Ven, charts of patients with newly diagnosed AML treated with azacitidine (Aza) + Ven (Aza/Ven) between January 2015 and December 2021 at a single institution were reviewed. Patients that were either refractory to or relapsed on Aza/Ven and received IC (7+3 or other cytarabine-based regimen) as immediate next-line therapy were identified. Baseline patient demographic and clinical information was recorded. The primary endpoint was overall response rate (ORR) with IC after Aza/Ven failure. Secondary endpoints included rate of CR/CRi, the rate of bridging to allogeneic transplant, and overall survival (OS). Responses were assessed according to ELN criteria. An exemption for this retrospective study was obtained from the Institutional Review Board. Results: Of 208 patients treated with frontline Aza/Ven, 19 received IC as immediate next-line therapy after Aza/Ven failure, including 13 patients who were treated with IC after their AML was refractory to Aza/Ven up front and 6 patients who received IC after relapsing following a prior response to first-line Aza/Ven. The median age of this cohort was 62 years (range 22 to 68 years) (Table 1). Most patients had unfavorable cytogenetics (16/19, 84.2%) and ELN adverse risk disease (15/19, 78.9%). The median number of cycles of Aza/Ven received prior to IC was 2 (range 1 to 5 cycles). Regarding IC regimen selected, 17 patients received 7+3, including 3 where midostaurin was added due to the presence of a FLT3 mutation, 1 patient received GCLAC, and 1 received FLAG-Ida+venetoclax. Among all patients, the ORR with IC was 57.9% (11/19) (Table 2). The rate of CR/CRi was 52.6% (10/19). Seven patients (36.8%) had AML that was refractory to IC, and 1 subject died within 30 days of IC. Of the 13 patients who had AML that was refractory to Aza/Ven up front, the CR/CRi rate was 61.5% (8/13), including 6 patients who achieved a CR and 2 who achieved a CRi. Of the 11 patients who responded to IC, 9 (81.8%) proceeded to allogeneic stem cell transplant. One patient declined transplant, and 1 transitioned to hospice due to a progressing fungal infection. Conclusions: For a select patient population, salvage IC after Aza/Ven failure is feasible. In our cohort of patients with predominantly adverse risk disease biology who received IC after failure of Aza/Ven, the ORR with IC was 57.9%, which compares favorably to response rates observed with frontline IC. Whether Aza/Ven and IC targeted different subclones and represent complementary sequential therapies in this high-risk group of AML patients is an ongoing correlative investigation. Overall, this data suggests that initial therapy with HMA/Ven in older and/or adverse risk AML patients with a plan to proceed with IC as second line therapy in the event of Aza/Ven failure is a reasonable strategy in select patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Standard Risk-Assessment of AML Doesn't Predict the Outcome in Older AML Patients Undergoing Non-Intensive Chemotherapy

Background: Acute myeloid leukemia (AML) still has a poor prognosis for elderly patients, both because of specific characteristics of the disease in this population, and especially because of their frailty that limits the use of intensive treatments (IT). Low dose Aracytine (LDAC) and 5-Azacitidine (5-AZA) are the 2 options currently recommended for these patients, but real-life data are lacking about response rates, survival, and superiority of one treatment over the other. Methods: In our multi-center study based on the French Hauts-de-France AML observatory, we enrolled all patients with newly diagnosed AML treated in first line with LDAC and 5-AZA. The primary endpoint was the overall survival (OS). Our secondary objectives were: evaluating the response rates, identifying predicting factors of early mortality and the profile of long-term survivors (i.e alive 6 months after the diagnosis). Results: Between January 2009 and September 2019, 279 patients who received LDAC (n=87) or 5-AZA (n=192) were included. Median age was 76 years (IQR 70 - 81) (LDAC 79 years (IQR 75 - 83) and 5-AZA 74 years (IQR 68 - 79), p<0.001)) and the Charlson comorbidity index was significantly higher in the LDAC arm: 7 (IQR 6 - 8) versus 6 (IQR 5 - 7) in 5-AZA, p=0.007). Leukocytosis was significantly lower in the 5-AZA group: 3.2G/L (IQR 1.8- 7.7) versus 8.5G/L in LDAC (IQR 2.3-35), p<0.001. Patients treated with 5-AZA predominantly had AMLs associated with myelodysplasia-related changes and adverse cytogenetics according to ELN 2017, whereas those treated with LDAC predominantly had AML NOS with intermediate karyotype. After a median follow-up of 6.9 months (IQR 1.9-11.6), median OS (Figure 1A) was 7.8 months (IQR 2.5 - 13.6): 4.8 months (IQR 2.13 - 14.41) for the LDAC group versus 8.9 months (IQR 3.2 - 13.5) for the 5-AZA group (p=0.046), but there was no significant difference in OS at the end of the study (Figure1B). Complete remission rate was 27.3% without any difference between the 2 groups. At day 30, on the basis of Kaplan-Meier estimates, 25.3% of patients in the LDAC group had died compared to 9.4% in the 5-AZA group (OR 0.28; 95% CI (0.09 - 0.84), p<0.023). After six months of treatment, there was no difference in OS between LDAC and 5-AZA groups (HR 1.37; 95% CI (0.92-2.04), p= 0.116). The predicting factors of mortality at day 30, at 6 months and after 6 months are summarized in the Table 1 (multivariate analysis, odds-ratio). Interestingly, the predictive factors of early mortality were albuminemia less than 30g/L (adjusted OR 6.25; 95% CI (2.08 - 20.00); p<0.001) and treatment with LDAC (adjusted OR 3.57; 95%CI (1.19 - 11.11); p=0.023). At 6 months, ECOG 2-3, high bone marrow blast count at diagnosis and albuminemia less than 30g/L significantly impaired the OS. After 6 months, the only predictive factor of survival was albuminemia greater than 30g/L (adjusted HR 0.65, 95% CI (0.44- 0.96); p=0.030). Usual molecular markers and prognosis classifications (ELN and Lindsley) were not helpful to predict mortality (both early and late) of this specific population. Discussion: Standard prognostic classifications of AML, such as the ELN 2017 and Lindsley classifications, which have been evaluated in patients eligible for IT, do not appear to be accurate in predicting outcome in older unfit patients treated with LDAC or 5-AZA. Albumin, a simple biomarker, was the strongest predictor of early mortality and prolonged survival beyond 6 months, highlighting that nutritional status and global fitness are the key determinants of survival in older patients non eligible for IT. Overall, the low survival emphasizes the poor prognosis of AML in these patients, and the urgent need for innovative therapies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Phase 2 Randomized Study Comparing Venetoclax and Azacitidine to Conventional Induction Chemotherapy for Newly Diagnosed Fit Adults with Acute Myeloid Leukemia

Background: The standard therapy for acute myeloid leukemia (AML) for younger, functionally fit patients has not substantially changed in the last 40 years. Intensive induction chemotherapy (IC), with various schedules of cytarabine and an anthracycline, remains the mainstay of therapy. Conventional IC results in complete remission rates of 60-75% of younger and 40-60% of older adults. Despite this, rates of long-term survival and cure remain sub-optimal. These regimens are also associated with significant risk and burden of morbidity, including substantial marrow suppression, mucosal toxicity, high rates of infectious and bleeding complications, potential cardiac injury, prolonged hospitalization, and long-term risk of secondary malignancies. Recently, a placebo-controlled randomized phase 3 trial of older AML patients, and those with comorbidities precluding intensive IC, compared azacitidine and venetoclax to azacitidine and revealed a significant overall survival (OS) advantage for the combination, impressive tolerability, with a markedly higher remission rate at 66% and median OS of 14.7 months, and improvements in other outcome parameters. These recent data compare favorably to outcomes expected from conventional IC, particularly considering their evaluation to date in older, frailer patients, in whom outcomes would be expected to be poorer than younger patients. Based on these considerations, the current randomized phase 2 study seeks to test the hypothesis that treatment with venetoclax and azacitidine will lead to an improved event-free survival (EFS) among fit patients with newly diagnosed AML, when compared to IC. We hypothesized that rates of composite remission for azacitidine and venetoclax will be similar to conventional IC, with an improved safety profile, fewer and less prolonged hospitalizations, lower cost of care, improved candidacy for stem cell transplantation (SCT), and fewer post-SCT complications. Study Design and Methods: This is an open-label, multicenter, phase II randomized clinical trial comparing the therapeutic activity of conventional IC (7+3 regimen or liposomal daunorubicin and cytarabine) to the combination of venetoclax and azacitidine among IC-eligible patients, excluding those with protocol-defined favorable risk genetics or FLT3 mutations. The primary outcome is EFS, where an event is defined as progressive disease (>50% increase in marrow blasts, >50% increase in peripheral blasts, new extramedullary disease), change in therapy due to persistent leukemic disease, relapse after remission, transition to hospice, or death. This study randomizes, in 1:1 fashion, to conventional IC (SOC) or venetoclax plus azacitidine (investigational). Patients will be stratified by age (≥ 65 versus < 65 years old). There is a preselection prior to randomization for either 7+3 or liposomal daunorubicin and cytarabine, to apply to those who are subsequently assigned to the SOC arm. With 172 patients, 86 allocated per arm, the study will achieve 85% power to detect a treatment difference at the one-sided 10% type I error rate, assuming the true hazard ratio is 0.635, based on assumptions of 1-year EFS of 55% on the investigational arm (azacitidine-venetoclax) and 39% on SOC (IC). Before study completion, futility analysis will be trigged after accruing 50% of the subjects and observing 40% of required EFS events. Assuming a failure rate of 30% on the SOC arm and 50% on the investigational arm, if 43 or more events are seen in the latter group, the trial will be stopped for futility. O'Brien-Fleming boundaries set on the p-value due to interim analysis are handled with the Lan-DeMets procedure with the interim p-value = 0.693, and the final p-value = 0.1. Assessments of differences in EFS between the arms will be made with the log rank test; modeling will employ the Cox proportional hazards regression. Differences in EFS at 1-year will also be estimated using the Kaplan Meier method, with standard deviations calculated by Greenwood's formula. Secondary endpoints include composite remission rates, OS, toxicity, rate of measurable residual disease, number and duration of hospitalizations, cost and quality of life measures. Accrual is assumed to be 24 months with a minimum follow up of 15 months, yielding an estimated study duration of 39 months. The study is currently enrolling patients and will be open to accrue at seven hospitals across the United States.

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.

The Growing Role of the BH3 Mimetic Drug Venetoclax in the Therapy of Acute Myeloid Leukemia.

Despite recent progress, acute myeloid leukemia (AML) remains a disease associated with poor prognosis, particularly in older AML patients unfit to tolerate intensive chemotherapy treatment. The development and introduction in the therapy of Venetoclax (VEN), a potent BH3 mimetic targeting the antiapoptotic protein BCL-2, inducing apoptosis of leukemic cells, has shown to be a promising treatment for newly diagnosed, relapsed, and refractory AML patients ineligible for induction chemotherapy. Combination treatments using Ventoclax and a hypomethylating agent (azacitidine or decitabine) or low-intensity chemotherapy have shown in newly diagnosed patients variable response rates, with highly responsive patients with NPM1, IDH1-IDH2, TET2, and RUNX1 mutations and with scarcely responsive patients with FLT3, TP53 and ASXL1 mutations, complex karyotypes, and secondary AMLs. Patients with refractory/relapsing disease are less responsive to Venetoclax-based regimens. However, in the majority of patients, the responses have only a limited duration, and the development of resistance is frequently observed. Therefore, understanding the resistance mechanisms is crucial for developing new strategies and identifying rational drug combination regimens. In this context, two strategies seem to be promising: (i) triplet therapies based on the combined administration of Venetoclax, a hypomethylating agent (or low-dose chemotherapy), and an agent targeting a specific genetic alteration of leukemic cells (i.e., FLT3 inhibitors in FLT3-mutated AMLs) or an altered signaling pathway; (ii) combination therapies based on the administration of two BH3 mimetics (i.e., BCL-2 +MCL-1 mimetics) and a hypomethylating agent.

A high hematopoietic cell transplantation comorbidity Index (HCT-CI) does not impair outcomes after non-myeloablative allogeneic stem cell transplantation in acute myeloid leukemia patients 60 years or older

For most acute myeloid leukemia (AML) patients an allogeneic hematopoietic stem cell transplantation (HSCT) offers the highest chance of cure. The introduction of less toxic non-myeloablative conditioning (NMA) regimes enabled older and/or comorbid patients to be consolidated with an allogeneic HSCT. While the hematopoietic cell transplantation comorbidity index (HCT-CI) predicted outcomes in many younger patient cohorts its impact in older AML patients receiving NMA-HSCT remains unknown. Here we analyzed 289 AML patients 60 years or older (median age 66, range 60-77 years) undergoing NMA-HSCT (2 or 3 Gray total body irradiation and 3 days of fludarabine 30 mg/m2). HCT-CI risk was low, intermediate, or high in 36%, 31%, and 33% of patients, respectively. Non-relapse mortality (NRM), cumulative incidence of relapse (CIR), and overall survival (OS) did not differ between HCT-CI groups. The HCT-CI also did not impact outcomes when considering the European LeukemiaNet 2017 risk at diagnosis or the measurable residual disease (MRD) status at HSCT. Notably, MRD-negative older NMA-transplanted AML patients had a beneficial OS of 49% after 5 years. Since a higher HCT-CI did not impair outcomes, age or comorbidities per se should not impede NMA-HSCT, presenting a feasible consolidation option for this group of AML patients.

AML-021 A Retrospective Study of Clinical Characteristics and Outcomes of Elderly Acute Myeloid Leukemia (AML) Patients at Oncology Center Mansoura University (OCMU)

Acute myeloid leukemia incidence increases progressively with advancing age and represents a therapeutic challenge. The tools used for comprehensive geriatric assessment (CGA) in elderly AML are not uniform. Outcome of treatment for patients of advanced age is often compromised by comorbidities and an enhanced susceptibility to toxicities from therapy. This study intended to determine the demographic data, clinical characteristics, and the treatment and outcomes in de novo elderly AML patients. This is a retrospective single-center study of 226 patients; (≥ 60 years) with a diagnosis of AML identified from the Database (2010- 2020) and were followed till the end of 2021. It was carried out at Oncology Center Mansoura University (OCMU). The median age were 67.12±5.65 years, M/F: 128/98. 196 (86.7%) showed ECOG ≥2 performance status at diagnosis. Eighty-three patients received standard induction treatment (7+3), 83 received reduced-intensity treatment (LDAC, azacytidine) and 60 patients were unfit for treatment. At the end of the review of the study, 65 were alive. Comorbidities were assessed using Charlson Comorbidity Index (CCI) and Cumulative Illness Rating Scale-Geriatric (CIRS-G) scores. Treatment-associated adverse events were evaluated by WHO toxicity grades. The Cox regression model was used to examine predictors affecting overall survival (OS). Hypertension (37%), pulmonary infections (24.7%) and diabetes mellitus (20.8%) were the most common comorbidities. 207 patients were available for response assessment: 35(16.9%) achieved CR, 57 (27.5%) achieved PR. Grade 3-4 hematological toxicities were: anemia (62.7%), granulocytopenia (63.85%) and thrombocytopenia (82%). The median OS was 2 (95%CI 1.66-2.34) months. PS ≥2, CCI >4 and high CIRS-G scores were shown to be risk factors of dismal OS in older AML patients (P<0.001, 0.021 and 0.001, respectively). Patients with CR had better median OS (21 months (95%CI 7.55-34.45, P<0.001) and DFS (12 months (95%CI 6.74-17.26, P<0.001). Early mortality in elderly AML patients is common, especially in institutions with low resources due to lack of novel therapies and clinical trials. Geriatric assessment tools should be updated for detection and prediction of prognostic factors and plan management strategies according to disease risk stratification.

Management of Acute Myeloid Leukemia: A Review for General Practitioners in Oncology.

Acute myeloid leukemia (AML) is a hematologic malignancy that most frequently develops in older adults. Overall, AML is associated with a high mortality although advancements in genetic risk stratification and new treatments are leading to improvements in outcomes for some subgroups. In this review, we discuss an individualized approach to intensive therapy with a focus on the role of recently approved novel therapies as well as the selection of post-remission therapies for patients in first remission. We discuss the management of patients with relapsed and refractory AML, including the role of targeted treatment and allogeneic stem cell transplant. Next, we review non-intensive treatment for older and unfit AML patients including the use of azacitidine and venetoclax. Finally, we discuss the integration of palliative care in the management of patients with AML.

PB1845: ACUTE MYELOID LEUKEMIA IN THE ELDERLY: A MULTICENTER EXPERIENCE IN COLOMBIA, ON BEHALF OF ACHO’S RENEHOC INVESTIGATORS

Background: The overall survival (OS) of acute myeloid leukemia (AML) decreases as age increases among patients. There are clinical and biological differences in AML in older patients. Even with actual treatments, 70% of patients older than 65 years will die of their disease within 1 year of diagnosis. Aims: Our aim was to characterize the elderly patients (>65 years old) with acute myeloid leukaemia (AML), who were attended in 13 health institutions in Colombia, from 2009 to 2021, including RENEHOC (online platform) and PETHEMA date base (Spanish Program for Hematology Treatments). Methods: An ambispective registry of elderly AML patients, treated in approved centers over the last 12 years. Descriptive statistics were used for patient’s demographic and clinical characteristics. The Kaplan-Meier method was used to assess RFS and OS. Results: A total of 175 patients were included. 54,86% were male and the median age at diagnosis was 73 years old. Most of the patients were classified according to the Eastern Cooperative Oncology Group (ECOG) as ECOG 0-1 (52,7%), ECOG 2 (25 %) and ECOG > 2 (22.3%). 24,26% presented as secondary AML, from these 34% had previous history of myelodysplasic syndrome. At presentation, fever was the main symptom (39,16), followed by bleeding (18,56%). The most frequent comorbidities were hypertension in 20% and diabetes in 9,4%. 24.34% of the patients had one comorbidity while 21.6% of the population had 3 or more. For treatment: 32,9% of the patients received hypomethylating agents, 23,2% received intensive chemotherapy with cytarabine and idarrubicine, 14,1 % had FLUGA (fludarabine low dose and cytarabine) and supportive therapy in 16,7% of the patients. After induction, complete remission (CR) was achieved in 16,9% of patients; CR with incomplete hematologic recovery (Cri) in 7% and 20,9% had primary refractory disease. Mortality during in induction therapy was 12,9%. The median age of patients in the intensive chemotherapy group was 66 years old (66-70), with ECOG 0-2 in 63,8%. The OS was 36.1% (95%CI: 27.0%–45%) at 1 year and 0 % at 5 years of follow-up, the relapse-free survival (RFS) was 38.3 % (95%CI: 27.4%- 49.1%) at 1 year and 0% at 5 years. According to the ECOG. the OS at 1 year was 50,9 % (95%CI: 36.1%–63.9%) for patients with ECOG <2, while the OS at 1 year was 22.7% (95%CI: 12.7%–34.4%) for ECOG >2 with p<0.001. Image:Summary/Conclusion: Management of AML in older patients remains a medical challenge, not only because of the age, but also because older adults are more likely to have impaired functional status and comorbidities that limit treatment options. More refined assessments tools and scales are needed to differentiate between fit and fragile older adults. This multicenter report analyzing real world data from AML patients in Colombia confirmed the impact of clinical factors: age, ECOG on OS and RFS. Challenges includes access to newer treatments with novel, targeted and less intensive therapies. Keywords: acute myeloid leukemia, survival, elderly

Evaluating immune response and metabolic related biomarkers pre-allogenic hematopoietic stem cell transplant in acute myeloid leukemia.

Although hematopoietic stem cell transplantation (HCT) is the only curative treatment for acute myeloid leukemia (AML), it is associated with significant treatment related morbidity and mortality. There is great need for predictive biomarkers associated with overall survival (OS) and clinical outcomes. We hypothesized that circulating metabolic, inflammatory, and immune molecules have potential as predictive biomarkers for AML patients who receive HCT treatment. This retrospective study was designed with an exploratory approach to comprehensively characterize immune, inflammatory, and metabolomic biomarkers. We identified patients with AML who underwent HCT and had existing baseline plasma samples. Using those samples (n = 34), we studied 65 blood based metabolomic and 61 immune/inflammatory related biomarkers, comparing patients with either long-term OS (≥ 3 years) or short-term OS (OS ≤ 1 years). We also compared the immune/inflammatory response and metabolomic biomarkers in younger vs. older AML patients (≤30 years vs. ≥ 55 years old). In addition, the biomarker profiles were analyzed for their association with clinical outcomes, namely OS, chronic graft versus host disease (cGVHD), acute graft versus host disease (aGVHD), infection and relapse. Several baseline biomarkers were elevated in older versus younger patients, and baseline levels were lower for three markers (IL13, SAA, CRP) in patients with OS ≥ 3 years. We also identified immune/inflammatory response markers associated with aGVHD (IL-9, Eotaxin-3), cGVHD (Flt-1), infection (D-dimer), or relapse (IL-17D, bFGF, Eotaxin-3). Evaluation of metabolic markers demonstrated higher baseline levels of medium- and long-chain acylcarnitines (AC) in older patients, association with aGVHD (lactate, long-chain AC), and cGVHD (medium-chain AC). These differentially expressed profiles merit further evaluation as predictive biomarkers.

Treosulfan compared with reduced-intensity busulfan improves allogeneic hematopoietic cell transplantation outcomes of older acute myeloid leukemia and myelodysplastic syndrome patients: Final analysis of a prospective randomized trial.

The phase III study was designed to compare event-free survival (EFS) after treosulfan-based conditioning with a widely applied reduced-intensity conditioning (RIC) busulfan regimen in older or comorbid patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing allogeneic hematopoietic cell transplantation (HCT). A previously reported confirmatory interim analysis of the randomized clinical study including 476 patients demonstrated statistically significant noninferiority for treosulfan with clinically meaningful improvement in EFS. Here, the final study results and pre-specified subgroup analyses of all 570 randomized patients with completed longer-term follow-up are presented. Patients presenting HCT-specific comorbidity index >2 or aged ≥50 years were randomly assigned (1:1) to intravenous (IV) fludarabine with either treosulfan (30 g/m2 IV) or busulfan (6.4mg/kg IV) after stratification by disease risk group, donor type, and participating institution. The primary endpoint was EFS with disease recurrence, graft failure, or death from any cause as events. EFS of patients (median age 60 years) was superior after treosulfan compared to RIC busulfan: 36-months-EFS rate 59.5% (95% CI, 52.2-66.1) vs. 49.7% (95% CI, 43.3-55.7) with a hazard ratio (HR) of 0.64 (95% CI, 0.49-0.84), p= 0.0006. Likewise, overall survival (OS) with treosulfan was superior compared to busulfan: 36-month-OS rate 66.8% vs. 56.3%; HR 0.64 (95% CI, 0.48-0.87), p= 0.0037. Post hoc analyses revealed that these differences were consistent with the confirmatory interim analysis, and thereby the treosulfan regimen appears particularly suitable for older AML and MDS patients.

Deficit Accumulation Frailty Index (DAFI) scores and acute myeloid leukemia outcomes.

12040 Background: Novel strategies are needed to assess frailty in the context of therapy decisions for older adults with acute myeloid leukemia (AML). Our objectives were to describe pre-treatment DAFI scores for older AML patients treated on clinical trials and explore their relationship with treatment outcomes. Methods: We conducted a exploratory analysis utilizing data from two clinical trials of adults aged ≥60 years with newly diagnosed AML (Alliance/CALGB 11001 [intensive therapy] and Alliance/CALGB 11002 [non-intensive therapy]). We included the subset of patients in each trial enrolled on geriatric assessment companion studies (Alliance/CALGB 361006, 361101). A DAFI score was calculated for each patient using 51 variables including demographic, geriatric assessment, and laboratory data derived from the geriatric assessment. Individuals with ≥90% items were included (consistent with other studies); DAFI scores ranged from 0 to 1 and were evaluated using established categories (0- &lt;.2 [robust]; 0.2-&lt;.35 [pre-frail]; 0.35+ [frail]) and as a continuous score. Associations between DAFI scores and toxicity and overall survival (OS) were evaluated with Fisher’s exact-testing and Kaplan Meier/cox proportional hazards, respectively. Results: The median age was 68 years (range 61, 82) and 72 years (range 61, 92) for those getting intensive (N=31) and less intensive therapy (N= 75), respectively. Individuals in the intensive study had a median pre-treatment DAFI score of 0.15 (range 0.05, 0.31) and were all categorized as robust (75%) or pre-frail (25%). There was no significant difference in median OS (14.6 vs. 14.7 months) or non-hematological grade 3+ adverse events (AEs; 85% vs. 89%) between robust vs. pre-frail individuals in this trial, respectively. However, pre-frail adults experienced a trend towards greater grade 4 non-hematological toxicity than robust individuals (67% vs 26%, p=0.05). In the non-intensive trial, the median DAFI score was 0.24 (range 0.04, 0.48) and most individuals were pre-frail (49.3%) or frail (17.3%). Non-hematologic grade 3+ AEs did not vary by DAFI group, 88% robust, 95% pre-frail, and 77% frail (p=0.15). Median OS was 7.4, 10.8, and 6.3 months for robust, pre-frail, and frail respectively (p=0.17). Adjusting for age, each 0.1 increase in DAFI score was associated with increased mortality hazard (HR 1.8, 95% CI 1.0-3.2). Conclusions: DAFI score calculation provides a potential novel strategy for categorization of frailty in AML. In our assessment, higher DAFI scores were associated with toxicity during intensive induction and mortality in the less intensive setting. This method should be studied in larger samples randomized by treatment intensity. Support: UG1CA189823; Bayer Healthcare/Berlex (CALGB 11001); NCT01253070 (CALGB 11001). Clinical trial information: NCT01253070, NCT01420926.

Evolution of Therapy for Older Patients With Acute Myeloid Leukemia: How Should We Use Currently Available Agents?

Most patients with newly diagnosed acute myeloid leukemia (AML) are 65 years or older. The treatment of AML in older patients has been characterized by distinct patient- and disease-related challenges that have impeded the meaningful progress that has been observed in younger patients with AML. Higher rates of comorbidities and frailty contribute to higher rates of treatment-related complications, whereas adverse disease features such as poor-risk genomics and secondary AML are associated with therapeutic resistance and shortened survival. Intensive chemotherapy and allogeneic stem cell transplant, although still considered standard for many newly diagnosed patients with AML, may not be appropriate for a larger subset of older patients with AML. Lower-intensity approaches such as hypomethylating agents have been widely applied for newly diagnosed older and unfit patients with AML, improving tolerability among this subset, but providing more modest response rates. Numerous analyses have attempted to tackle the utility of higher- versus lower-intensity therapy in older AML and identify the factors that can help choose the approach that best optimizes tolerability and efficacy. Recently, a greater understanding of the genomic and biologic heterogeneity of AML has led to better risk stratification and has contributed to the development of specific targeted therapies that are starting to narrow the gap between safety and efficacy. Newly approved agents, such FLT3 (FMS-like tyrosine kinase 3) inhibitors, IDH1 and IDH2 inhibitors, and the BCL2 inhibitor venetoclax, as well postremission maintenance therapy with CC-486 (oral 5-azacitidine), are being systematically incorporated into the evolving treatment of older patients with newly diagnosed AML.

Venetoclax resistance: mechanistic insights and future strategies.

Acute myeloid leukemia (AML) is historically associated with poor prognosis, especially in older AML patients unfit for intensive chemotherapy. The development of Venetoclax, a potent oral BH3 (BCL-2 homology domain 3) mimetic, has transformed the AML treatment. However, the short duration of response and development of resistance remain major concerns. Understanding mechanisms of resistance is pivotal to devising new strategies and designing rational drug combination regimens. In this review, we will provide a comprehensive summary of the known mechanisms of resistance to Venetoclax and discuss Venetoclax-based combination therapies. Key contributing factors to Venetoclax resistance include dependencies on alternative anti-apoptotic BCL-2 family proteins and selection of the activating kinase mutations. Mutational landscape governing response to Venetoclax and strategic approaches developed considering current knowledge of mechanisms of resistance will be addressed.