Acute Myeloid Leukemia Regimens Research Articles

Effectiveness and safety of granulocyte colony-stimulating factor priming regimen for acute myeloid leukemia: A systematic review and meta-analysis of the Clinical Practice Guideline for the use of G-CSF 2022 from the Japan Society of Clinical Oncology.

The outcomes of relapsed or refractory acute myeloid leukemia (AML) remain poor. Although the concomitant use of granulocyte colony-stimulating factor (G-CSF) and anti-chemotherapeutic agents has been investigated to improve the antileukemic effect on AML, its usefulness remains controversial. This study aimed to investigate the effects of G-CSF priming as a remission induction therapy or salvage chemotherapy. We performed a thorough literature search for studies related to the priming effect of G-CSF using PubMed, Ichushi-Web, and the Cochrane Library. A qualitative analysis of the pooled data was performed, and risk ratios (RRs) with confidence intervals (CIs) were calculated and summarized. Two reviewers independently extracted and accessed the 278 records identified during the initial screening, and 62 full-text articles were assessed for eligibility in second screening. Eleven studies were included in the qualitative analysis and 10 in the meta-analysis. A systematic review revealed that priming with G-CSF did not correlate with an improvement in response rate and overall survival (OS). The result of the meta-analysis revealed the tendency for lower relapse rate in the G-CSF priming groups without inter-study heterogeneity [RR, 0.91 (95% CI 0.82-1.01), p=0.08; I2=4%, p=0.35]. In specific populations, including patients with intermediate cytogenetic risk and those receiving high-dose cytarabine, the G-CSF priming regimen prolonged OS. G-CSF priming in combination with intensive remission induction treatment is not universally effective in patients with AML. Further studies are required to identify the patient cohort for which G-CSF priming is recommended.

Safety and Efficacy of High-Dose Chemotherapy with TreoMel 200 vs. TreoMel 140 in Acute Myeloid Leukemia Patients Undergoing Autologous Stem Cell Transplantation.

(1) Background: Treosulfan and melphalan (TreoMel)-based high-dose chemotherapy (HDCT) has shown promising safety and efficacy as a conditioning regimen for acute myeloid leukemia (AML) patients undergoing autologous stem cell transplantation (ASCT). However, despite intensive first-line induction treatment and upfront consolidation with HDCT and ASCT, AML relapse rates are still high, and further efforts are needed to improve patient outcomes. The aim of this study was to compare two melphalan dose schedules in regard to the safety of TreoMel HDCT and patient outcomes. (2) Methods: We retrospectively analyzed the safety and efficacy of two melphalan dose schedules combined with standard-dose treosulfan in AML patients undergoing HDCT and ASCT at the University Hospital of Bern, Switzerland, between August 2019 and August 2023. Patients received treosulfan 42 g/m2 combined with either melphalan 140 mg/m2 (TreoMel 140) or melphalan 200 mg/m2 (TreoMel 200). Co-primary endpoints were progression-free survival (PFS), overall survival (OS), as well as safety profile. (3) Results: We included a total of 51 AML patients: 31 (60.8%) received TreoMel 140 and 20 (39.2%) TreoMel 200. The patients' basal characteristics were comparable between both cohorts. No significant differences in the duration of hospitalization or the adverse event profile were identified. There were no statistically significant differences in relapse (0.45 vs. 0.30, p = 0.381) and mortality rates (0.42 vs. 0.15, p = 0.064) between the melphalan 140 mg/m2 and 200 mg/m2 cohorts, nor for PFS (HR: 0.81, 95% CI: 0.29-2.28, p = 0.70) or OS (HR: 0.70, 95% CI: 0.19-2.57, p = 0.59) for the TreoMel 140 vs. TreoMel 200 cohort. (4) Conclusions: A higher dose of melphalan (TreoMel 200) was well tolerated overall. No statistically significant differences for patient outcomes could be observed, possibly due to the relatively small patient cohort and the short follow-up. A longer follow-up and prospective randomized studies would be required to confirm the safety profile and clinical benefit.

Abstract 3821: Real world outcomes among patients with newly diagnosed acute myeloid leukemia

Abstract Introduction: Treatment options for patients with acute myeloid leukemia (AML) have expanded in recent years. Although new treatments have demonstrated efficacy in clinical trials, less is known about their effect on outcomes in routine clinical practice. We examined outcomes for patients with newly-diagnosed AML (ND-AML) using real world data (RWD). Methods: This retrospective observational study was conducted using the COTA real-world (rw) database, a de-identified source of longitudinal electronic health record data pertaining to the diagnosis, management, and outcomes of patients with cancer. Adult patients with ND-AML, diagnosed January 1, 2013 to March 20, 2023 were included. First-line treatment regimens were grouped into therapeutic categories and outcomes were summarized. The index date was defined as date of initiation of first-line therapy. Results: Among 2516 patients with ND-AML included (Table), the most common regimens used were intensive chemotherapy with cytarabine (IC w/ara-C), hypomethylating agents with venetoclax (HMA+ven), and HMA alone. Complete response rate was highest in patients treated with IC w/ara-C or investigational regimen(s). Median overall survival (OS) was 16 mo overall, with highest median OS seen in patients treated with IC w/ara-C and investigational regimen(s). Median OS for patients treated with HMA+ven was 13.5 mo. Thirty-day mortality was lowest in patients treated with IC w/ara-C, CPX-351 (liposomal daunorubicin + cytarabine), and HMA+ven. Conclusions: Results suggest that IC w/ara-C remains the standard of care for most patients with ND-AML and this regimen has a higher CR rate and median OS. Variation of patient demographics and clinical characteristics across treatment groups did not permit cross-treatment comparisons, though future analyses evaluating these subgroups may provide further insight into effectiveness and safety of AML regimens in routine care for populations underrepresented in clinical trials. rwCR rate Median rwOS 30-day mortality N % (95% CI) Months (95% CI) % (95% CI) Overall 2516 45.3 (43.2, 47.3) 16.0 (14.9, 17.3) 5.9 (5.0, 6.8) IC w/ara-C 1171 60.6 (57.8, 63.4) 36.4 (31.0, 46.0) 1.6 (0.9, 2.3) HMA+ ven 300 33.7 (28.3, 39.3) 13.5 (11.4, 15.5) 3 (1.1, 4.9) Decitabine 242 12.8 (8.9, 17.7) 8.4 (6.7, 9.9) 10.4 (6.5, 14.2) Azacitidine 206 7.8 (4.5, 12.3) 7.2 (5.3, 9.6) 10.7 (6.4, 14.8) Investigational 206 61.6 (54.6, 68.3) 21.3 (15.2, 27.8) 3.4 (0.9, 5.9) Lower dose cytarabine 62 12.9 (5.7, 23.9) 8.7 (5.4, 16.1) 14.9 (5.4, 23.4) CPX-351 based 61 55.7 (42.4, 68.5) 9.3 (7.3, 15.1) 0.0 No treatment 188 NA 1.9 (1.5, 2.8) 30 (22.7, 36.6) Citation Format: Elizabeth D. Pulte, Laura L. Fernandes, Joseph Wynne, Eric Hansen, Andrew J. Belli, Anna Barcellos, Christina M. Zettler, Rebecca Bystrom, Jonathon Vallejo, Wenjuan Gu, Catherine Lerro, Kelly Norsworthy, Angelo DeClaro, Marc R. Theoret, Donna Rivera, Ching-Kun Wang. Real world outcomes among patients with newly diagnosed acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3821.

Emerging and Future Targeted Therapies for Pediatric Acute Myeloid Leukemia: Targeting the Leukemia Stem Cells.

Acute myeloid leukemia (AML) is a rare subtype of acute leukemia in the pediatric and adolescent population but causes disproportionate morbidity and mortality in this age group. Standard chemotherapeutic regimens for AML have changed very little in the past 3-4 decades, but the addition of targeted agents in recent years has led to improved survival in select subsets of patients as well as a better biological understanding of the disease. Currently, one key paradigm of bench-to-bedside practice in the context of adult AML is the focus on leukemia stem cell (LSC)-targeted therapies. Here, we review current and emerging immunotherapies and other targeted agents that are in clinical use for pediatric AML through the lens of what is known (and not known) about their LSC-targeting capability. Based on a growing understanding of pediatric LSC biology, we also briefly discuss potential future agents on the horizon.

Mitocurcumin utilizes oxidative stress to upregulate JNK/p38 signaling and overcomes Cytarabine resistance in acute myeloid leukemia

Acute myeloid leukemia (AML) is a type of blood cancer that is characterized by the rapid growth of abnormal myeloid cells. The goal of AML treatment is to eliminate the leukemic blasts, which is accomplished through intensive chemotherapy. Cytarabine is a key component of the standard induction chemotherapy regimen for AML. However, despite a high remission rate, 70–80% of AML patients relapse and develop resistance to Cytarabine, leading to poor clinical outcomes. Mitocurcumin (MitoC), a derivative of curcumin that enters mitochondria, leading to a drop in mitochondrial membrane potential and mitophagy induction. Further, it activates oxidative stress-mediated JNK/p38 signaling to induce apoptosis. MitoC demonstrated a preferential ability to kill leukemic cells from AML cell lines and patient-derived leukemic blasts. RNA sequencing data suggests perturbation of DNA damage response and cell proliferation pathways in MitoC-treated AML. Elevated reactive oxygen species (ROS) in MitoC-treated AML cells resulted in significant DNA damage and cell cycle arrest. Further, MitoC treatment resulted in ROS-mediated enhanced levels of p21, which leads to suppression of CHK1, RAD51, Cyclin-D and c-Myc oncoproteins, potentially contributing to Cytarabine resistance. Combinatorial treatment of MitoC and Cytarabine has shown synergism, increased apoptosis, and enhanced DNA damage. Using AML xenografts, a significant reduction of hCD45+ cells was observed in AML mice bone marrow treated with MitoC (mean 0.6%; range0.04%–3.56%) compared to control (mean 38.2%; range10.1%–78%), p = 0.03. The data suggest that MitoC exploits stress-induced leukemic oxidative environment to up-regulate JNK/p38 signaling to lead to apoptosis and can potentially overcome Cytarabine resistance via ROS/p21/CHK1 axis.

Fludarabine and Melphalan Reduced Toxicity Versus a Myeloablative Fludarabine and Busulfan Conditioning Regimen for Acute Myeloid Leukemia

Introduction: The optimal induction regimen for an allogeneic hematopoietic cell transplant (allo-HCT) for a young adult patient diagnosed with acute myeloid leukemia (AML) remains to be defined. Among reduced intensity regimens (RIC), retrospective registry data from both CIBMTR and EBMT would suggest that a Fludarabine / Melphalan (Flu/Mel) regimen was superior to a Fludarabine / Busulfan x 2 (Flu/Bu2) regimen. The need for a myeloablative conditioning regimen over a RIC has been evaluated in at least six randomized clinical trials (RCT), and the results have yet to be uniform. Published meta-analysis suggests equipoise. The studies are further limited by including a heterogenous group of conditioning regimens, especially in the reduced intensity arm; they all come from developed countries, a mix of AML and MDS in most studies, and variation in age groups enrolled in them. In India and developing countries, there remain significant challenges with multi-drug resistant infections, financial constraints, and challenges with intensive care support. We hypothesize that in this setting, a reduced toxicity regimen, such as a combination of Fludarabine with Melphalan (140 mg/m 2) (Flu/Mel), may be preferable to a myeloablative regimen. Methods: A single-center retrospective analysis was undertaken to study the impact of a reduced toxicity Flu/Mel regimen versus a myeloablative Fludarabine combined with Busulfan (130 mg/m 2/day x 4 days) regimen (Flu/Bu4). All consecutive patients in all age groups with a diagnosis of AML who underwent an allo-HCT between Jan 2005 and Dec 2021 were included in this analysis. The conditioning regimen used was as per physician discretion with a broad guideline within the department to use a myeloablative Flu/Bu4 regimen in a young fit patient with high-risk features such as high-risk ELN at diagnosis, CR2, and beyond, or requiring more than one cycle of induction chemotherapy to achieve a complete remission (CR). Results: 439 patients underwent an allo-HCT for a diagnosis of AML at our center in the given time. The median age was 33 years (range: 1 - 63), and there were 267 (60.8%) males. The transplants were done in CR1 in 236 (54%), CR2 in 90 (20.5%), CR3 in 13 (3%), and in relapsed/refractory or with active disease in 100 (22.8%). The majority were matched sibling/related donors (MRD) in 284 (64.7%), followed by matched unrelated (MUD) in 75 (17.1%) and haploidentical in 80 (18.2%). The conditioning regimen used was Flu/Mel in 170 (38.7%), Flu/Bu4 in 185 (42.1%), and a mix of other regimens in 84 (19.1%). At an actuarial median follow-up of 4 years, the overall survival (OS) and event-free survival (EFS) of the entire cohort were 40.8% ± 3.0% and 38.6% ± 3.0%, respectively. The EFS of cases in CR1, CR≥2, and in relapsed/refractory/active disease were 47.7% ± 3.8%, 45.0% ± 5.5%, and 12.3% ± 3.6%, respectively. The baseline characteristics and clinical outcome of cases that received a Flu/Mel condition versus Flu/Bu4 conditioning are summarized in Table 1. In summary, baseline characteristics were comparable between the two groups, except that significantly more cases underwent a haploidentical transplant in the Flu/Bu4 group. In contrast, in the Flu/Mel group, there were significantly more cases in CR1, and the median age was also significantly older. The 5-year KM EFS of the Flu/Mel and Flu/Bu4 cohort was 51.7±3.9% and 43.9±3.9% (P-value = 0.297), respectively (Figure 1). On univariate analysis, only CR1 status before transplant and the presence of chronic GVHD impacted EFS positively, and on multivariate analysis, only CR1 status affected EFS. Conclusion: In conclusion, in one of the most extensive retrospective studies comparing a uniform reduced toxicity conditioning regimen with Flu/Mel versus a standard myeloablative Flu/Bu4 conditioning regimen, we find no significant advantage of Flu/Bu4 over a Flu/Mel conditioning regimen.

Idarubicin Plus Azacitidine + Venetoclax As Induction Therapy Achieved High Remission in Elderly Fit- Acute Myeloid Leukemia Patients: Preliminary Results of a Phase II Study

Background The diagnosed age of de novo acute myeloid leukemia (AML) increased over the years, with a median current age of 68 years old. Elderly AML patients characterized by harboring high-risk mutations and significant comorbidities, usually display resistance to conventional chemotherapy, leading to poor outcomes. Although encouraging results from VIALE-A were reported in these years, over 30% participants had limited responses to the regimen of azacitidine + venetoclax after first-cycle induction. Thus, the selection of initial regimen for elderly AML is worth further exploration, especially for those with good fitness (the fitness was evaluated based on the physical ability, emotional status, cognitive function, and comorbidities). Here, we added idarubicin to azacitidine + venetoclax as the induction regimen (IAV regimen) for elderly fit-AML, and reported the preliminary results of efficacy and safety. Methods This single-center, single-arm, phase II trial (ChiCTR2300070190) was conducted at Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (Shanghai, China). Elderly patients (aged 60-75 years) of newly diagnosed acute myeloid leukemia (AML) were assessed via modified comprehensive geriatric assessment (mCGA) for the fitness. From April 2023, 22 patients have been enrolled for the treatment of IAV regimen (cycle 1: IDA 6 mg/m 2 d1-3, AZA 75 mg/m 2 d1-7, VEN 100 mg d1, 200 mg d2, 400 mg d3-14; cycle 2: IDA 6 mg/m 2 d1-2, AZA 75 mg/m 2 d1-5, VEN 400 mg d1-14). Among them, 19 patients and 13 patients who have completed cycle 1 and cycle 2 treatment, respectively, were available for analyzing the preliminary efficacy and safety in the trial. The primary objective of this study was to access the composite complete remission (cCR: CR + CRi) rate of IAV treatment. The secondary objective was to evaluate the MRD-negative rate, regimen-related toxicity, and safety. The duration of CR, overall survival rate and event-free survival rate would also be further accessed with sufficient follow-up time. Results The median age of currently enrolled patients was 64 (61-69) years old, and males accounted for 68.4%. Detailed baseline characters were summarized in Table 1. Composite complete remission rate after 1-cycle IAV treatment was achieved in 89.5% (17/19) participants, among which 52.9% (9/17) got MRD-negative status. One patient (1/19, 5.26%) got partial remission, with 7.5% blasts remained. After cycle 2 treatment, the CR rate increased to 92.9% (13/14), and 92.3% (12/13) CR participants were MRD-negative (Table 1). Till now, only 1 patient with chromothripsis-associated rearrangements showed no response and died on day 40 after treatment initiation. The median recovery time of neutrophils (ANC > 0.5×10 9/L) and platelet (PLT > 50×10 9/L) was 20.5 (16-30) days and 20.5 (15-43) days, respectively (Table 1). The most frequent grade 3/4 non-hematological adverse events (according to CTCAE version 5.0) were febrile neutropenia (grade 3, n = 14; grade 4, n = 5), pneumonia (grade 3, n = 5) and sepsis (grade 3, n = 2; grade 4, n = 1) (Table 2). Conclusion In this study, IAV regimen showed promising efficacy on elderly fit-AML patients, with high rates of MRD-negative remission. Non-hematological toxicities were tolerable under current observation. Based on the invigorating preliminary results, the efficacy and potential benefit of IAV regimen on elderly fit AML is worthy of follow-up in the future.

Phosphodiesterase 3A Acts As a Tumor Activator and Its Inhibitor Anagrelide Combined with Idarubicin Represents a Potential Therapeutic Approach for PDE3A High Expressed Acute Myeloid Leukemia through Pyroptosis By Triggering Cleavage of Gasdermin E

Acute myeloid leukemia (AML) is a clinically aggressive and heterogeneous hematologic neoplasm with a poor overall outcome. Platelets can interact with malignant cells including leukemic blasts and play a crucial role in cancer progression, metastasis and angiogenesis, budding of platelet microparticles can transfer a plethora of bioactive molecules to cancer cells upon internalization and in AML this can induce chemoresistance. Anti-platelet therapy using Phosphodiesterase 3A (PDE3A) inhibitors, such as anagrelide (ANA), holds promise in tumor elimination. Additionally, upregulation of PDE3A in solid tumors is associated with a poor prognosis in patients and activates inflammatory pathways, impacting cancer cell stemness. However, the role of PDE3A in AML remains unclear. This study aims to investigate the correlation between PDE3A expression and AML prognosis, as well as to characterize the feasibility and mechanism of ANA as a potential anti-leukemia therapy and its synergistic effect to chemotherapeutic drugs. To explore the correlation between PDE3A expression and AML prognosis, we initially analyzed its expression in AML patients and healthy donors from the Children's Hospital of Soochow University. The results demonstrated significantly higher levels of PDE3A in bone marrow mononuclear cells (BMMNCs) from AML patients, both at the protein and mRNA levels, compared to BMMNCs from healthy donors. Subsequently, we investigated PDE3A expression and survival data of 152 AML patients from our center, revealing that patients with high PDE3A expression exhibited significantly lower overall survival (OS), relapse-free survival (RFS), and event-free survival (EFS) compared to those with low PDE3A expression. These findings were further corroborated by data from other databases (R2 and GEPIA), confirming the significant role of PDE3A in AML. Among AML cell lines, HEL and MOLM-16 cells exhibited notably higher PDE3A expression at both the protein and mRNA levels, which were chosen for further study. ANA treatment specifically inhibited the proliferation of PDE3A-high-expressing AML cells but not low expression cells in vitro, which was further confirmed in the HEL-mediated xenograft leukemia model. Notably, the RNA sequencing data revealed ANA treatment significantly downregulated several chemotherapy-resistant genes, including PAK1, HMGCS1, p-SRC, DUSP16 and EGR1, indicating ANA has the potential to synergize with chemotherapeutic drugs for AML therapy. Therefore, we combine ANA and chemotherapy drugs to investigate the synergetic inhibitory effect. IDA with ANA simultaneously exerted the strongest synergistic effect among the six anti-leukemia drugs depend on the judgement of CI value and had the synergistic effect in HEL, MOLM-16 and primary cells from PDE3A high expressed AML patients. The GSEA analysis of RNA sequencing data showed that the IDA-ANA combination treatment led to a significant enrichment of the inflammatory response. Moreover, at the protein level, pyroptosis-related proteins including NLRP3, Cleaved-CASP3, Cleaved-CASP8 and GSDME-N were notably upregulated in IDA-ANA combination group compared to IDA or ANA group. Finally, we established an AML xenograft mouse model using the HEL cell line and administered different treatments: vehicle (control), IDA (0.5 mg/kg), ANA (5 mg/kg), or the indicated combination of IDA and ANA. The results demonstrated that the IDA-ANA combination treatment significantly extended the survival time of the mice and reduced the leukemia burden when compared to the individual treatments with either IDA or ANA. In second HEL xenograft mice study, separate cohorts of vehicle and drug treated mice were sacrificed and leukemic livers as well as spleens were harvested and weighed, the IDA-ANA combination treated mice exhibited smaller and lighter livers and spleens than the other groups and controls. HE results explained the histological decrease of HEL cells infiltration of IDA-ANA combination treatment in the livers, spleens and bone marrow compared with the treatment of IDA or ANA. Congruently, the analysis of IHC confirmed the same result. In summary, high expression of PDE3A related to poor prognosis in AML and PDE3A inhibitor ANA combined with IDA exerted anti-leukemia effect through pyroptosis on PDE3A high expressed AML. Our findings represent a potential therapeutic regimen for AML.

Down Syndrome with Acute Myeloid Leukemia in an Adolescent Male Successfully Treated with Low Dose Ara-C in Combination with Hypomethylating Agent

Introduction Patients with Down syndrome (DS) are prone to developing hematological malignancies, with risk of acute myeloid leukemia (AML) being 150 -fold higher compared to the general population. DS patients with leukemia are likely to experience significant chemotherapy related toxicities, hence require dose modifications. The myeloid leukemia of Down Syndrome (ML-DS) typically reflects acute megakaryoblastic leukemia (AMKL) a rare subtype of AML. ML-DS typically evolves from transient aberrant/abnormal myelopoiesis (TAM), aka transient myeloproliferative disorder (TMD), a pre-leukemic syndrome that almost always precedes myeloid leukemia in Down syndrome. GATA1, the hallmark driver mutation of TAM, is found in all TMD/TAM cases. AML in DS can occur de-novo which represents a different entity, appears immunophenotypically as (non-AMKL) AML, but differs morphologically from the classical ML-DS. The de-novo type AML in DS is reported to have worse prognosis. Poor outcomes are due to increased chemosensitivity and resulting chemotherapy-related toxicities when treated on standard high dose Ara-C based AML regimens. There is currently a lack of consensus on standard-of-care AML therapy applicable to this population. Methods Case report, retrospective electronic medical record review with institutional board review exemption Results We report a case of a 25-year-old male with trisomy 21, presenting with a one-month history of low-grade fevers, fatigue, and upper back pain. Initial laboratories showed a white cell count of 6.6 K/uL, hemoglobin 11.9 gm/dL, platelets 352 K/uL. CT chest showed a large right-sided pleural effusion, pleural thickening and multiple sclerotic bone lesions concerning for malignancy. Positron emission tomography (PET) CT revealed multiple hypermetabolic foci in the pelvis, spine, ribs, and cervical lymph nodes. Thoracocentesis was completed and pleural fluid pathology revealed atypical cells, flow cytometry showed 18% blasts positive for CD38, CD45, CD117 and negative for CD34 and HLA DR indicative of a myeloid neoplasm. Bone marrow aspirate and biopsy showed 10% CD117 positive immature myeloid cells. Morphology was not megakaryoblastic. Bone marrow flow cytometry results were consistent with that of pleural fluid with CD117 and myeloperoxidase (MPO) positive blasts. Fluorescent in-situ hybridization was negative for fusions/rearrangements. Next generation sequencing (NGS) detected NPM1 mutation and also a low level (variant allelic frequency <3%) FLT3 p.Y599C mutation (not internal tandem duplication or tyrosine kinase domain). GATA1 mutation was absent. A diagnosis of AML with NPM1 mutation and staging CNS1 was confirmed. Our patient was defined as DS and AML. Given innate fragility and higher chemo sensitivity in patients with DS, we elected to treat him off protocol with Cladribine and low dose Ara-C alternating with Decitabine. This regime was derived from an adult leukemia protocol. Cycle 1 was complicated by central line related occlusive thrombus requiring anticoagulation, slow count recovery, and a brief episode of febrile neutropenia managed with antibiotics. End of induction marrow evaluation was negative for minimal residual disease (MRD). Flow cytometry on pleural fluid was also negative for abnormal blasts that were previously detected. Repeat molecular testing with NGS was negative for NPM1, DNMT3A, and FLT3 mutations. The patient received a total of 8 cycles of chemotherapy. On subsequent bone marrow evaluations, blasts remained <5% and MRD was negative. Interval PET scan showed significant improvement. Patient is currently more than a year off therapy and remains in remission. Conclusion Patients with DS and AML have a higher mortality due to increased risk of cardiotoxicity and infection from chemotherapy. There is a risk of either undertreatment or less commonly overtreatment leading to early mortality. Our case describes an adolescent male with DS and AML with pulmonary comorbidity who was successfully treated with a low-dose Ara-C regimen adapted from an adult protocol and had great clinical outcome. AML treatment in DS remains a challenge and further research is warranted to develop tailored regimens effectively balancing curative intent and reduced toxicity. This regimen could be considered in pediatric patients with Down Syndrome and other comorbidities.

Azacitidine and lenalidomide combination: a novel relapse prophylaxis regimen after allogeneic hematopoietic stem-cell transplantation in patients with acute myeloid leukemia.

While allogeneic hematopoietic stem cell transplantation (allo-HSCT) can be a curative regimen for acute myeloid leukemia (AML), relapse of AML remains a serious risk post-transplantation. Once relapsed, salvage options are limited and management of AML is difficult. Here we designed a prospective study to examine the efficacy and tolerability of maintenance therapy with azacytidine (AZA) plus low-dose lenalidomide (LEN) to prevent relapse after allo-HSCT for AML patients (ChiCTR2200061803). AML patients post-allo-HSCT were treated with AZA (75 mg/m2 for 7 days), followed by LEN (5 mg/m2, day 10-28), and a 4-week resting interval, which was defined as one treatment cycle. A total of 8 cycles was recommended. 37 patients were enrolled, 25 patients received at least 5 cycles, and 16 patients finished all 8 cycles. With a median follow-up time of 608 (43-1440) days, the estimated 1-year disease free survival (DFS) was 82%, cumulative incidence of relapse (CIR) was 18%, and overall survival (OS) was 100%. Three patients (8%) had grade 1-2 neutropenia without fever; one patient developed grade 3-4 thrombocytopenia and minor subdural hematoma; 4/37 patients (11%) developed chronic GVHD with a score of 1-2, without requiring systemic treatment; No patient developed acute GVHD. After AZA/LEN prophylaxis, increasing numbers of CD56+NK and CD8+ T, and decreasing of CD19+ B cells were observed. Azacitidine combined with low-dose lenalidomide was observed to be an effective relapse prophylaxis option after allo-HSCT in AML patients, and can be administered safely without significantly increasing the risk of GVHD, infection and other AEs. www.chictr.org, identifier ChiCTR2200061803.

Olutasidenib in post-venetoclax patients with mIDH1 AML.

e19041 Background: Olutasidenib is a potent, selective, oral inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1). Olutasidenib is FDA approved for the treatment of relapsed/refractory (R/R) acute myeloid leukemia (AML) based on the registrational cohort (n = 153) of the Phase 2 trial, which demonstrated a rate of complete remission (CR) or CR with partial hematologic recovery (CRh) of 35%, with a duration of response of 25.9 months. Venetoclax (VEN) in combination with a hypomethylating agent (HMA) is standard treatment for AML patients unfit for chemotherapy and has adequate efficacy in IDH1-mutated AML. The sequence of therapy following failure of a VEN-based regimen in IDH1-mutated AML has not been established. We evaluated the efficacy and safety of olutasidenib in a subset of 17 patients from the Phase 2 trial (NCT02719574) previously treated with VEN combination regimens. Methods: Adults with mIDH1 R/R AML received olutasidenib 150 mg twice daily alone (n = 15) or in combination with azacitadine (AZA) (n = 2). The primary endpoint was achievement of a CR/CRh. Secondary endpoints included time to and duration of CR+CRh and rate of transfusion independence (TI). Data cut-off for the analysis was 18 June 2021. Results: Of 17 patients with prior VEN treatment, 5 are ongoing and 12 discontinued due to progressive disease (6), adverse events (4), or withdrawal by subject (2). Median age was 73 (range 65-83). Median time since diagnosis was 19.5 months (1.2-41). Cytogenetic risk class was intermediate in 9, poor in 6, favorable in 1 and unknown in 1. Most patients had relapsed; 6 were refractory to prior treatment. The median number of prior regimens was 2 (range 1-6); 13 had prior HMA, 2 had prior olutasidenib. VEN was generally used for induction. Some patients received VEN in multiple regimens. VEN was used with azacytidine (AZA) in 8 patients, after AZA (1), and with decitabine (5), cytarabine +/- idarubicin (5), and dinaciclib (2). The best response to olutasidenib was CR/CRh in 5/17 (29.4%), of which 4 (23.5%) were CR. In the 8 patients who previously received the combination of VEN-AZA, 3 (37.5%) patients achieved a CR/CRh. Time to CR/CRh was median 2.1 months (actual: 1, 1.9, 2.1, 2.8 and 2.8). Duration of CR/CRh was median 18.5+ months (4.8, 9.0+, 18.5+, 22.6+, and 28.5+ months as of cut-off date). Other responses included CR with incomplete blood count recovery (CRi) in 2 patients, stable disease (SD) in 2, progressive disease (PD) in 3, not done (ND) in 2, not evaluable (NE) in 1 and not listed in 2. At baseline 14/17 were red blood cell (RBC) dependent, and 4 of the 14 (28%) had a 56-day period of RBC transfusion independence (TI). Ten were platelet dependent at baseline and 5 of the 10 (50%) had a 56-day period of platelet TI while receiving olutasidenib. Conclusions: Olutasidenib induced durable remissions in patients with mIDH1 R/R AML, including those failing prior treatment with a venetoclax-based regimen. Clinical trial information: NCT02719574 .

Real-life monocentric experience of venetoclax-based regimens for acute myeloid leukemia.

Combination of venetoclax and hypomethylating agents (HMAs) has become a standard of care in acute myeloid leukemia (AML) aged >75 years or who have comorbidities that preclude intensive induction chemotherapy. We conducted a monocentric retrospective analysis on adult patients affected by treatment-naïve AML not eligible for standard induction therapy or refractory/relapsed (R/R) AML treated with venetoclax combinations outside clinical trials. Venetoclax was administered at the dose of 400 mg/daily after a short ramp-up and reduced in case of concomitant CYP3A4 inhibitors. Sixty consecutive AML were identified. Twenty-three patients (38%) were affected by treatment-naïve AML and 37 (62%) by R/R AML. Median age was 70 years. Among R/R AML 30% had received a prior allogeneic stem cell transplantation (allo-HSCT). In combination with venetoclax, 50 patients (83%) received azacitidine. Antifungal prophylaxis was performed in 33 patients (55%).Overall response rate was 60%, with 53% of complete remission (CR; 78% for treatment-naïve and 49% for R/R, p 0.017). Median overall survival was 130 days for R/R patients and 269 days for treatment-naïve patients; median event free survival was 145 days for R/R cohort and 199 days for treatment-naïve AML.Measurable residual disease was negative in 26% of evaluable patients in CR/CR with incomplete hematologic recovery after 2 cycles and in 50% after 4 cycles, with no significant association with survival.Eleven patients (18%) received an allo-HSCT after venetoclax combinations. Most common grade 3/4 adverse events were infectious (51% of the patients), or hematological without infections (25% of the patients). Use of CYP3A4 inhibitors was associated with a trend to shorter cytopenias and with a lower rate of infections. Invasive fungal infections were less frequent among patients receiving azole prophylaxis (6% vs 26%; p 0.0659). Venetoclax-based regimens are a viable option for AML considered not eligible for standard induction therapy and a valid rescue therapy in the R/R setting.Azole prophylaxis did not significantly affect response and it was associated with a lower rate of invasive fungal infections. Despite a limited number of patients, the association of venetoclax and HMAs proved to be also a feasible bridging therapy to transplantation.

Synergistic effect of HDAC inhibitor Chidamide with Cladribine on cell cycle arrest and apoptosis by targeting HDAC2/c-Myc/RCC1 axis in acute myeloid leukemia

BackgroundMore effective targeted therapy and new combination regimens are needed for Acute myeloid leukemia (AML), owing to the unsatisfactory long-term prognosis of the disease. Here, we investigated the synergistic effect and the mechanism of a histone deacetylase inhibitor, Chidamide in combination with Cladribine, a purine nucleoside antimetabolite analog in the disease.MethodsCell counting kit-8 assays and Chou-Talalay’s combination index were used to examine the synergistic effect of Chidamide and Cladribine on AML cell lines (U937, THP-1, and MV4-11) and primary AML cells. PI and Annexin-V/PI assays were used to detect the cell cycle effect and apoptosis effect, respectively. Global transcriptome analysis, RT-qPCR, c-MYC Knockdown, western blotting, co-immunoprecipitation, and chromatin immunoprecipitation assays were employed to explore the molecule mechanisms.ResultsThe combination of Chidamide with Cladribine showed a significant increase in cell proliferation arrest, the G0/G1 phase arrest, and apoptosis compared to the single drug control in AML cell lines along with upregulated p21Waf1/Cip1 expression and downregulated CDK2/Cyclin E2 complex, and elevated cleaved caspase-9, caspase-3, and PARP. The combination significantly suppresses the c-MYC expression in AML cells, and c-MYC knockdown significantly increased the sensitivity of U937 cells to the combination compared to single drug control. Moreover, we observed HDAC2 interacts with c-Myc in AML cells, and we further identified that c-Myc binds to the promoter region of RCC1 that also could be suppressed by the combination through c-Myc-dependent. Consistently, a positive correlation of RCC1 with c-MYC was observed in the AML patient cohort. Also, RCC1 and HDAC2 high expression are associated with poor survival in AML patients. Finally, we also observed the combination significantly suppresses cell growth and induces the apoptosis of primary cells in AML patients with AML1-ETO fusion, c-KIT mutation, MLL-AF6 fusion, FLT3-ITD mutation, and in a CMML-BP patient with complex karyotype.ConclusionsOur results demonstrated the synergistic effect of Chidamide with Cladribine on cell growth arrest, cell cycle arrest, and apoptosis in AML and primary cells with genetic defects by targeting HDAC2/c-Myc/RCC1 signaling in AML. Our data provide experimental evidence for the undergoing clinical trial (Clinical Trial ID: NCT05330364) of Chidamide plus Cladribine as a new potential regimen in AML.

Change in Programmed Death-1 And Inducible Costimulator Expression in Patients with Acute Myeloid Leukemia Following Chemotherapy and Its Cytogenetic Abnormalities

Background: Programmed death-1 (PD-1) and inducible costimulator (ICOS) are immune checkpoint receptors participating in tumor immune evasion, which counters the activation signal provided through the T-cell receptor ligation. This study aimed to investigate the relationship between the expression of PD-1 and ICOS on mononuclear cells (MNCs) isolated from the peripheral blood of acute myeloid leukemia (AML) patients and their response to induction chemotherapy. Materials and Methods: Peripheral blood samples (5cc) were collected from 56 AML patients at first diagnosis before and after the induction therapy regimen for AML. PD-1 and ICOS expression were analyzed in all patients before and after the standard induction therapy regimen. Results: The expression of PD-1 and ICOS significantly decreased (66.7 and 16.3 fold, respectively) in AML patients following chemotherapy compared to its baseline value (P=0.01 and P=0.001, respectively). The expressions of PD-1 and ICOS were significantly different between favorable and poor risk groups. Conclusions: Lower PD-1 and ICOS expressions on the surface of MNCs before induction therapy were associated with a better response to treatments. In addition, PD-1 and ICOS expression on MNCs decreased after induction therapy.

Role of Bcl-2 inhibition in myelodysplastic syndromes.

Myelodysplasic syndromes (MDS) are diseases occurring mainly in the elderly population. Although hematopoietic stem cell transplantation is the only hope for cure, a majority of the patients suffering from MDS are too old or frail for intensive treatment regimens such as intensive chemotherapy and transplantation. The gold standard for those patients is currently treatment with hypomethylating agents, although real-life data could not reproduce the overall survival rates reported for the pivotal azacitidine phase III study. MDS treatment is often inspired by treatment for acute myeloid leukemia (AML). The new gold standard for elderly and frail patients not able to undergo intensive treatment regimens in AML is the combination of hypomethylating agents with venetoclax, a BCL-2 inhibitor that also showed excellent treatment outcomes in other hematological malignancies. In this review, we explain the rationale for the use of venetoclax in hematological malignancies, study outcomes available so far and the current knowledge of its use in MDS.

A Polish Acute Leukemia Group Prospective Multicenter Clinical Trial to Compare the Efficacy of Two Standard Induction Therapies (DA-90 vs DAC) and Two Standard Salvage Regimens (FLAG-IDA vs CLAG-M) in Acute Myeloid Leukemia (AML) Patients ≤ 60 Years Old (PALG-AML1/2016)

Background: AML is the most common acute leukemia in adults. While most adults < 60 years achieve complete remission (CR) with intensive induction chemotherapy, approximately one third have primary refractory disease and, overall, the majority of AML patients still relapse despite having attained initial remission (Dohner et al, 2017). The combination of an anthracycline and cytarabine has been the mainstay of intensive AML induction for more than 50 years. Combined with cytarabine (AraC), high-dose daunorubicin (90 mg/m2) in induction (DA-90) resulted in a higher rate of CR (70.6% vs. 57.3%, P<0.001) and improved overall survival (OS) (median 23.7 vs. 15.7 months; P = 0.003), without increased serious adverse events compared with DA-45 (Fernandez et al, 2009). In two PALG randomized trials, the combination of cladribine with DA (DAC regimen) also resulted in significantly increased CR after a single induction course, compared with the standard two-drug induction (DA-60) (Holowiecki et al, 2012). Both regimens have a recommendation from the National Cancer Comprehensive Network (NCCN) for routine use. For patients with primary refractory disease, the commonly used FLAG-IDA (fludarabine, cytarabine, idarubicin, GCSF) regimen results in a CR rate of 52% (Pastore et al, 2003). Two previous PALG studies confirmed that another standard regimen, CLAG-M (a combination of cladribine, Ara-C, G-CSF and mitoxantrone) is also effective with tolerable toxicity in refractory/relapsed AML patients (Wierzbowska et al, 2008; Jaglal et al, 2014). PALG-AML1/2016 aims to compare the safety and efficacy of two commonly used induction and salvage regimens in AML. This trial is also the first international randomized trial in AML induction to prospectively evaluate the impact of measurable residual disease (MRD) on overall survival, using multi-modality testing (flow-cytometry, next-generation sequencing, and PCR) of serial samples. The study is conducted in accordance with the principles of the "Declaration of Helsinki". Study Design and Methods: PALG-AML1/2016 is a multicenter, randomized, Phase III study which will include 582 patients with newly-diagnosed AML treated at multiple centers across Poland and at Weill Cornell Medicine and The New York Presbyterian Hospital in New York City. This will allow a 10% difference in CR rate between the DAC and DA-90 induction regimens to be confirmed with a power of 80% and level of significance 0.05. Eligible patients must be 18 to 60 years of age with untreated AML, Eastern Cooperative Oncology Group performance status 0-2 and HCT-CI Index of comorbidities, ≤ 3. The trial schema is shown in Figure 1. The trial was initiated in July 2017; 408 patients have been enrolled to date and accrual is ongoing. Preliminary safety and efficacy data were reviewed by the data safety monitoring committee after 194 patients and the recommendation was to proceed without changes. The CR, CRi, CRh after single or double induction were achieved in 63.4%, 16.5% and 0.6% patients, respectively leading to an overall composite CR (cCR) rate 80.5%. Thirty-day mortality, mainly due to infectious complications in aplasia, were observed in 5% and 14.5% did not achieved cCR. Serial samples for MRD are being collected from all patients at multiple time points and analysis is ongoing. ClinicalTrials.gov Identifier: NCT03257241 Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Survival and Outcomes after Relapse in Newly Diagnosed Acute Myeloid Leukemia (AML) Patients Treated with Venetoclax-Based Chemotherapy

Background Venetoclax (bcl-2 inhibitor) was first approved in 2018 for use in combination with hypomethylating agents (HMA) or low-dose cytarabine (LDAC) for treatment of newly diagnosed acute myeloid leukemia (AML) in older patients, or those who have comorbidities that preclude use of intensive induction chemotherapy. However, AML is also known to evolve and undergo clonal selection when treated with venetoclax, leading to treatment failure. Mechanisms for adaptive resistance include kinase activation (e.g. FLT3-ITD), clones that acquire biallelic silencing of TP53, and monocytic AML cells that upregulate MCL1 to evade BCL2 blockade. Other issues with venetoclax-based regimens include prolonged cytopenias and increased risk of infection. Our aim was to investigate survival after relapse, subsequent responses to second- line agents, and pattern of infections in patients treated with first-line venetoclax-based combination therapies. Methods This was a retrospective study of patients who received venetoclax-based regimens for untreated AML or myelodysplastic syndrome with excess blasts (MDS-EB) at LAC+USC Medical Center and Norris Cancer Center in Los Angeles, CA from January 1, 2018 to June 30, 2022. The electronic medical record was reviewed for demographics, disease characteristics, clinical history, transplant status, and survival. Results 61 patients received frontline venetoclax-based regimens for untreated AML or MDS-EB with a mean age of 65 (range 22-84); 36% were female, 44% non-Hispanic white and 31% were Hispanic/Latino. 41% had AML-MRC (myelodysplasia-related changes), 36% had De Novo AML, 16% had therapy-related AML, and 7% had MDS-EB. The majority (70%) were adverse risk group per ELN 2017 and 46% had complex cytogenetics. 58 patients had available myeloid mutation panel at time of diagnosis. The most common mutations (median allele frequencies) were: TP53=33% (0.45), ASXL1=17% (0.37), NPM1=16% (0.39), IDH2=9% (0.42), IDH1=7% (0.29), FLT3-ITD=5% (0.51). 70% received venetoclax with decitabine, 21% received venetoclax with azacitidine, and 2% received venetoclax with LDAC. Median number of cycles was 3 (1-16). 10 patients underwent allogeneic stem cell transplant. Out of 61 patients, 12 (20%) had primary refractory disease and 23 (38%) relapsed on frontline venetoclax. 49% of these relapsed/refractory patients received salvage chemotherapy. The median time to relapse and number of cycles prior to relapse was 6.3 months (1.6-17.4) and 4 (1-12) respectively. There was no correlation between cytogenetics and genetic variables and risk of relapse. Only 3 (19%) out of 16 patients and 3 (27%) out of 11 patients who received second- and third-line treatment achieved CRi respectively. Myeloid mutation panel was available for 12 patients at time of relapse. Most common mutations were FLT3-ITD/TKD (n=5), TP53 (n=3) and NPM1 (n=3). Six patients acquired new mutations at the time of relapse: FLT3-ITD (n=2), TP53 (n=1), WT1 (n=2) and ETV6 (n=1). Median time from relapse to death was 3 months (1-23). Median overall survival was 10.2 months. Median survival in responder compared to non-responders after cycle 1 and cycle 2 was 16.8 vs. 5.3 months (p <0.001) and 19.4 months vs. 7.4 months (p=0.031) respectively. Median survival in patients with relapse compared to non-relapse was 12.1 vs 6 months (p=0.187). 40 (66%) patients died; major causes of death were disease progression (50%), bleeding (10%) and infection (25%). 28% patients died in intensive care unit. 9 patients had fungal infections; most common were aspergillosis (n=5) and mucormycosis (n=2). Conclusions Venetoclax-based regimens are effective options for untreated AML in elderly patients. Response to first and second cycle of combination treatment predict survival. Although we observed clonal evolution in relapsed patients, it did not affect their survival. FLT3-ITD was a commonly acquired mutation at time of relapse, thus patients received salvage with targeted agents. Also, as patients relapse, the chance of attaining CR/CRi with subsequent lines of treatment is less than 30% and risk of invasive fungal infection was approximately 15%. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Prospective Assessment of Measurable Residual Disease Kinetics in Intensively Treated Patients with Acute Myeloid Leukemia - Results of the Polish Adult Leukemia Group PALG-AML1/2016 Study

Background: Measurable residual disease (MRD) is an important biomarker in acute myeloid leukemia (AML). Among patients who achieve remission after standard chemotherapy, detection of MRD (MRD+) after two cycles of intensive chemotherapy, at the end of consolidation and/or before allogeneic stem cell transplantation (alloHSCT) is a strong prognostic factor for relapse and shorter overall survival (OS) (Short NJ, JAMA Oncol. 2020). Optimal MRD assessment time-points, methodologies, and cut-offs, as well as whether elimination of MRD with subsequent chemotherapy improves outcomes, remain open questions. PALG-AML1/2016 study aims to compare the safety and efficacy of two commonly used induction and salvage regimens in AML (NCT03257241) and is the first international randomized trial in AML induction to prospectively evaluate the impact of MRD on overall survival using multi-modality testing (flow-cytometry, FC; next-generation sequencing, NGS) of serial samples. Study Design: In this ongoing study, 582 adult patients with newly-diagnosed AML are randomized to daunorubicin and cytarabine +/- cladribine induction. Patients with complete remission (CR) or CR with incomplete hematologic recovery (CRi) or CR with partial hematologic recovery (CRh) receive further post-remission therapy based on predefined risk groups. Serial samples for MRD are collected at time of CR/CRi/CRh after one or two induction cycles (MRD1), and after each consolidation cycle (MRD2, -3, -4). Material and Methods. The aim of this preliminary analysis was to evaluate the kinetics of MRD using multiparameter flow cytometry (MFC) during post-remission treatment and the influence of subsequent consolidation cycles on MRD status. MRD was assessed according to ELN recommendations using the threshold of ≥0.1% for MRD positivity (MRD+). Results. To date of analysis, 408 pts have been enrolled (female 54.9%), 366 (89.7%) with de novo AML and 42 (10.3%) with secondary AML, with mean age 45 years. Responses are evaluable in 333 pts. CR, CRi, CRh after single or double induction were achieved in 211 (63.4%), 55 (16.5%) and 2(0.6%) patients, respectively leading to an overall composite CR (cCR) rate of 80.5%. Forty-eight (14.4%) pts were non-responders and 17 (5%) pts died in aplasia. To date, 124 pts with cCR, have data available on consecutive MRD1, 2 and 3 time points. Among these pts, 118 (95%) pts achieved cCR after single induction and 6 (5%) after double induction. MRD negative (MRD-) cCR was observed in 46/124 (37.1%) pts. Overall, baseline characteristics were generally similar between MRD+ and MRD- pts regarding median age (45 vs. 48 years), WBC at diagnosis (5.8 vs. 11.0 G/L) as well as de novo vs. sAML (89.1% and 10.9% vs. 90.7% and 9.3% respectively). There was a trend toward higher frequency of poor-risk ELN category among MRD+ pts (42.2% vs. 30.1% respectively; p=0.066). After 1st consolidation (MRD2), the conversion rate from from MRD+ to MRD- was 33.3 % (n=26); MRD- to MRD+ conversion was also noted in 17.4% (n=8), ultimately resulting in a significantly increased rate of MRD- cCR rate to 51.1% (p=0.0035). After second consolidation (MRD2), MRD+ to MRD- conversion was 23.3 % (n=26) and MRD- to MRD+ was 15.6% (n=10), leading to an insignificant further increase in MRD- cCR to 54.8% (p=0.54). Conclusions: Preliminary data from PALG-AML1/2016 suggest that post-remission consolidation with a single cycle of intensive chemotherapy results in improved rates of MRD negativity, but the incremental value of additional consolidation cycles is uncertain. Loss of MRD negativity is observed in a proportion of patients even at early post-remission time points. Data correlating MRD status and relapse-free survival (RFS) will be presented at the meeting. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Venetoclax (VEN) Plus Intensive Chemotherapy (IC) with FLAG-IDA in Patients (Pts) with Newly Diagnosed (ND) and Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML)

Background: Despite the high complete remission (CR) rates achieved with IC, relapse rates remain high underscoring the need for novel combination regimens capable of inducing deeper remissions via eradicating measurable residual disease (MRD). Recently, several studies have shown promising clinical activity of VEN when combined with different IC regimens in pts with ND AML with composite CR rates (CRc) above 90% and MRD-ve rates exceeding 80% (Wang 2022; Kadia 2021). FLAG-IDA + VEN has also shown significant clinical activity in pts with ND AML with a CRc rate of 89% and MRD-ve remission rate of 93% (DiNardo 2022). Methods: We conducted a single-center retrospective study to assess the clinical activity of FLAG-IDA + VEN in pts with AML. During induction, VEN was initially given for 14 days which was later on reduced to 7 days due to encouraging results by Kadia et al. Standard cytogenetic (CN) analysis was performed and molecular data was obtained using a 40-gene NGS platform. Responses were assessed using the modified International Working Group response criteria and included CR, CR with incomplete count recovery (CRi), morphologic leukemia-free state (MLFS), and partial remission (PR). Time-to-event analyses were estimated using the Kaplan-Meier method and compared using the log rank test. Results: From March 2020 to May 2022, 24 pts with AML (17 ND and 7 R/R) were treated using FLAG-IDA + VEN (Table 1). Median age was 48 years (range, 21-68) with male predominance (67%). Among the 17 pts with ND AML (8 de novo, 5 AML-MRC, 2 treated-secondary, 2 therapy-related), 3 had extramedullary disease (EMD). The most common ELN CN risk groups were complex (N=5), KMT2A-rearranged (N=4), other adverse (N=3), and diploid (N=3). Eight pts (47%) harbored a RAS mutation. Median time to initiation of therapy was 5 days (range, 2-14). Twelve pts (71%) [KMT2A-rearranged, N=4; complex CN, N=3; diploid, N=3; other adverse, N=1; other intermediate, N=1] achieved CR/CRi including 1 pt with EMD. Median time to ANC (≥ 500) and platelet (≥ 50,000) recovery were 29 days (range, 19- 42) and 25 days (range, 17- 42), respectively. Median number of consolidation cycles given were 1.5 (range, 1- 5). MRD status was available in 6 out of 12 pts and all 6 pts achieved MRD negativity using flow cytometry (<10-3). Median follow-up among ND AML pts was 4.3 months (mths) (range, 0.7- 13.2). Among the 12 responders: (1) 3 pts received allo-SCT [KMT2A-rearranged, N=2; (-7), N=1] after 7, 4, and 3 mths, respectively, and remain alive in CR 10+, 7.5+, and 3+ mths, respectively, after initiation of therapy, (2) 6 pts with ELN favorable (N=3), intermediate (N=2), and adverse (N=1) risk AML remain in CR/CRi for 6+, 4+, 1+, 3+, 2+, and 2+ mths, respectively, (3) 3 pts with ELN adverse risk AML (including 1 pt with de novo MLLr AML and EMD) achieved CR and relapsed after 0.7, 1.7, and 7.6 mths, respectively. One pt died due to progressive disease (PD) 4.7 mths after relapse and the remaining 2 pts are receiving salvage therapy and alive 4.3+ and 5.2+ mths after relapse, respectively. All nonresponders (N=5) had ELN adverse risk AML including 2 pts with EMD and 2 pts with treated secondary AML. All 5 nonresponders died due to PD including 3 pts who had no response to HMA+VEN based salvage therapy. Among the 7 pts with R/R AML, 6 were in salvage 1 and 1 pt received prior allo-SCT. Responses were observed in all pts: 4 CR, 1 CRi, 1 MLFS, and 1 PR. Median time to count recovery in R/R AML pts was 33 days (range, 24-78). Median follow-up in R/R AML pts was 6.2 mths (range, 1.5- 15.6). Of the 5 pts who achieved CR/CRi, 4 were bridged to allo-SCT and 1 pt died in CR after 3 cycles of consolidation due to sepsis. Of the 4 SCT recipients: (1) 2 pts relapsed 2 mths after allo-SCT and died 4 and 6.5 mths, respectively, after allo-SCT; (2) 2 pts (KMT2A-rearranged and NPM1mut) remain alive in CR for 8+ and 14+ mths, respectively. Two pts with complex CN achieved MLFS and PR after 1 cycle of therapy and died due to PD and fungal pneumonia after 5.3 and 1.5 mths of starting therapy, respectively. Median overall survival (OS) for pts with ND AML and R/R AML were 13.2 mths (95% CI: Not reached) and 6.2 mths (95% CI: 5-7), respectively (p=0.62; Figure 1). Among pts with ND AML, median OS was not reached among responders and was 2.6 mths in non-responders (p=0.002). Conclusion: FLAG-IDA + VEN is a feasible and active regimen in AML. Longer follow-up and larger multicenter studies are needed to confirm the efficacy of this regimen. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The Effect of Comorbidities and Choice of Treatment on Overall Survival in Elderly Patients with Acute Myeloid Leukemia: A Beaumont Experience

CONTEXT: First line therapy for acute myeloid leukemia (AML) is the 7+3 regimen, consisting of cytarabine and an anthracycline. Due to its high intensity, it often cannot be used in elderly patients. Venetoclax in combination with a hypomethylating agent (HMA) is approved for AML treatment in these patients who will likely be unable to tolerate the traditional 7+3 regimen. In our study, we investigate the efficacy of venetoclax + HMA in a community setting. OBJECTIVE: The primary outcome of our study was overall survival of patients greater than 65 years of age with a diagnosis of AML who received 7+3 therapy versus those who received venetoclax + HMA. Secondary outcomes included median survival time in each group, as well as characteristics of those who received 7+3 versus venetoclax + HMA therapy. DESIGN: A retrospective chart review was conducted using the Electronic Medical Record at the Royal Oak and Troy locations of Beaumont Health which are community based tertiary referral centers. Inclusion criteria included patients seen by the Beaumont Hematology and Oncology Group that were 65 years of age or older with a diagnosis of AML by bone marrow biopsy who received treatment for AML. Patients were seen between September 01, 2019 and September 01, 2022. Data collection was completed February 1, 2022. INTERVENTION: Standard dosing of cytarabine and daunorubicin were used in the 7+3 regimen. Standard dosing of venetoclax plus an HMA (azacitidine or decitabine) were used. Dose adjustments were made according to physician discretion. RESULTS: Overall survival of those receiving 7+3 was significantly higher than those who received venetoclax + HMA as initial treatment (p=0.0403). Of the 23 patients who received 7+3 as their initial treatment, 13 passed away with a median time of death of 1.98 years. The median time of death of the 17 of 26 patients who passed away in the HMA + venetoclax regimen was 0.71 years (p=0.039). The initial treatment of HMA + venetoclax was associated with 2.19-fold greater hazard of mortality as compared to 7+3 (HR:2.19; P = 0.0403). Patients that received initial treatment of 7+3 had less comorbid conditions (4.5 versus 6.1; p=0.04) and were younger (60 versus 75.5; p<0.0001) than those that did not receive the initial treatment of 7+3. CONCLUSION: Median survival for those who received HMA + venetoclax was less than those who received 7+3, likely due to the selection bias of older age and higher comorbdities in those who received HMA + venetoclax versus those who received the 7+3 regimen. Our hospital appears to be using the HMA + venetoclax regimen in appropriate patients; those who were older or had a higher number of comorbidities. HMA + venetoclax still appears to be a good alternative for those who cannot tolerate the first line 7+3 chemotherapy regimen for acute myeloid leukemia, and further studies comparing it to elderly patients with AML who choose not to undergo treatment would be helpful.