Acute Myeloid Leukemia Induction Research Articles

Myeloid Sarcoma: Novel Advances Regarding Molecular Pathogenesis, Presentation and Therapeutic Options

Myeloid sarcoma (MS), an extramedullary form of acute myeloid leukemia (AML) is a rare tumor mass of myeloid blasts. It can disseminate to any one or multiple anatomical sites, with (synchronous MS) or without (isolated MS) bone marrow (BM) involvement. The aim of this review is to describe the most recent advances in MS regarding diagnosis, molecular background, various clinical manifestations from several organs, and treatment approaches. Due to the lack of prospective, randomized clinical trials, therapeutic decisions are a challenge for the clinician. In the era of novel targeted AML treatments, a critical analysis of how to decide the best option for individual patients, also covering the possible central nervous system (CNS) prophylaxis is provided. For the majority of the patients, AML induction chemotherapy, followed by hematopoietic stem cell transplantation (HSCT) is generally recommended. This paper discusses the role of radiotherapy, the treatment of refractory and relapsed disease, along with the therapeutic approach of difficult-to-treat patients, due to specific problems related to different anatomical sites of MS.

Clinical Effects of Venetoclax in the Treatment of Acute Myeloid Leukemia in the Elderly

Objective: To investigate the clinical efficacy of venetoclax in the treatment of elderly acute myeloid leukemia (AML). Methods: 50 cases of elderly AML patients receiving venetoclax for treatment in the hospital from January 2022 to January 2024 were selected, including 38 cases of patients whose primary treatment was not suitable for intensive chemotherapy and 12 cases of relapsed/refractory AML patients, to observe the therapeutic efficacy and safety of venetoclax. Results: Among the 38 patients whose primary treatment was not suitable for intensive chemotherapy, 5 cases were treated with venetoclax monotherapy, 33 cases were treated with venetoclax + azacitidine, and 25 patients (65.79%) achieved complete remission (CR) with incomplete hematologic recovery (CRi) after 28 days of treatment; 10 patients with relapsed/refractory AML were treated with venetoclax + azacitidine, and 2 patients were treated with venetoclax + azacitidine + chemotherapy, and 2 patients achieved optimal therapeutic response after 28 days of treatment and CR/CRi was achieved in 7 patients (58.33%). There were 47 (94.0%) patients with grade 3 or higher granulocytopenia, 46 (92.0%) patients with hemoglobin reduction, and 43 (86.0%) patients with thrombocytopenia, developed after 28 days of treatment. 11 patients developed infections after treatment and there was one case of tumor lysis syndrome. Conclusion: The response rate of venetoclax monotherapy and combination in elderly AML induction therapy is high, and the overall tolerability of elderly patients is good, so it can be popularized and applied.

Ocular manifestations of acute myeloid leukemia during induction phase of chemotherapy: A case series

The aim of this series is to report diverse ocular features noted in patients during the induction phase in acute myeloid leukemia (AML). Three female patients undergoing induction therapy for AML reporting for various ocular complaints were examined. Detailed history, including the onset of AML and chemotherapy and any past ocular or systemic ailment, was taken. Best-corrected visual acuity, anterior segment, and posterior segment examinations were performed. Intraocular pressure was measured, and color vision was tested. Routine hematological, and biochemical investigations and imaging were done when required. Patients with abnormal parameters were referred to an oncologist for management. A varied spectrum of ocular manifestations was noted in these three female patients, including preseptal cellulitis, orbital cellulitis, and subhyaloid hemorrhages. Immediate treatment was given to patients with vision-threatening conditions in consultation with an oncologist and otorhinolaryngologist, and patients responded well to the treatment. Owing to its cytoreductive action, AML induction therapy exposes the patient to various adverse events, causing significant ocular and systemic morbidity. All the diagnosed patients of AML are recommended to undergo a baseline ocular assessment.

Peroxisome proliferator-activated receptorα/γ agonist pioglitazone for rescuing relapsed or refractory neoplasias by unlocking phenotypic plasticity.

A series of seven clinical trials on relapsed or refractory (r/r) metastatic neoplasias followed the question: Are networks of ligand-receptor cross-talks that support tumor-specific cancer hallmarks, druggable with tumor tissue editing approaches therapeutically exploiting tumor plasticity? Differential recombinations of pioglitazone, a dual peroxisome-proliferator activated receptorα/γ (PPARα/γ) agonist, with transcriptional modulators, i.e., all-trans retinoic acid, interferon-α, or dexamethasone plus metronomic low-dose chemotherapy (MCT) or epigenetic modeling with azacitidine plus/minus cyclooxygenase-2 inhibition initiated tumor-specific reprogramming of cancer hallmarks, as exemplified by inflammation control in r/r melanoma, renal clear cell carcinoma (RCCC), Hodgkin's lymphoma (HL) and multisystem Langerhans cell histiocytosis (mLCH) or differentiation induction in non-promyelocytic acute myeloid leukemia (non-PML AML). Pioglitazone, integrated in differentially designed editing schedules, facilitated induction of tumor cell death as indicated by complete remission (CR) in r/r non-PML AML, continuous CR in r/r RCCC, mLCH, and in HL by addition of everolimus, or long-term disease control in melanoma by efficaciously controlling metastasis, post-therapy cancer repopulation and acquired cell-resistance and genetic/molecular-genetic tumor cell heterogeneity (M-CRAC). PPARα/γ agonists provided tumor-type agnostic biomodulatory efficacy across different histologic neoplasias. Tissue editing techniques disclose that wide-ranging functions of PPARα/γ agonists may be on-topic focused for differentially unlocking tumor phenotypes. Low-dose MCT facilitates targeted reprogramming of cancer hallmarks with transcriptional modulators, induction of tumor cell death, M-CRAC control and editing of non-oncogene addiction. Thus, pioglitazone, integrated in tumor tissue editing protocols, is an important biomodulatory drug for addressing urgent therapeutic problems, such as M-CRAC in relapsed or refractory tumor disease.

Prognostic significance of multiparametric flow cytometry minimal residual disease at two time points after induction in pediatric acute myeloid leukemia

BackgroundPrompt response to induction chemotherapy is a prognostic factor in pediatric acute myeloid leukemia. In this study, we aimed to evaluate the prognostic significance of multiparametric flow cytometry-minimal residual disease (MFC-MRD), assessed at the end of the first and second induction courses.MethodsMFC-MRD was performed at the end of the first induction (TP1) in 524 patients and second induction (TP2) in 467 patients who were treated according to the modified Medical Research Council (UK) acute myeloid leukemia 15 protocol.ResultsUsing a 0.1% cutoff level, patients with MFC-MRD at the two time points had lower event-free survival and overall survival. Only the TP2 MFC-MRD level could predict the outcome in a separate analysis of high and intermediate risks based on European LeukemiaNet risk stratification and KMT2A rearrangement. The TP2 MFC-MRD level could further differentiate the prognosis of patients into complete remission or non-complete remission based on morphological evaluation. Multivariate analysis indicated the TP2 MFC-MRD level as an independent adverse prognostic factor for event-free survival and overall survival. When comparing patients with MFC-MRD ≥ 0.1%, those who underwent hematopoietic stem cell transplant during the first complete remission had significantly higher 5-year event-free survival and overall survival and lower cumulative incidence of relapse than those who only received consolidation chemotherapy.ConclusionsThe TP2 MFC-MRD level can predict the outcomes in pediatric patients with acute myeloid leukemia and help stratify post-remission treatment.

Intensive chemotherapy with dual induction and ALL-like consolidation for childhood acute myeloid leukemia: a respective report from multiple centers in China.

Pediatric acute myeloid leukemia (AML) has poor prognosis and high rate of relapse and mortality, and exploration of new treatment options is still critically needed. To summarize the outcome of our new treatment strategies for pediatric AML, which is characterized by dual induction and acute lymphoblastic leukemia (ALL) elements consolidation. Retrospective, single-arm study. From July 2012 to December 2019, an intensive chemotherapy protocol was used for newly diagnosed children with AML, which contains dual induction, three courses of consolidations based on high-dose cytarabine, and two courses of consolidations composed of high-dose methotrexate, vincristine, asparaginase, and mercaptopurine (ALL-like elements). Blasts were monitored by bone marrow smears at intervals, and two lumbar punctures were performed during chemotherapy. We retrospectively analyzed the efficacy and safety of this study. The last follow-up was on 26 May 2023. A total of 70 pediatric AMLs were included. The median age at diagnosis was 6.7 (0.5-16.0) years. The median initial WBC count was 23.74 × 109/L, 11 of whom ⩾100 × 109/L. After dual induction, there were 62 cases of complete remission (CR), 5 cases of partial remission, and 3 cases of nonremission. The CR rate was 88.57%. The median follow-up time was 5.8 (0.2-9.4) years, the 5-year overall survival was 78.2% ± 5%, the event-free survival (EFS) was 71.2% ± 5.6%, and the cumulative recurrence rate was 27.75%. The 5-year EFS of patients with initial WBC < 100 × 109/L (n = 59) and ⩾100 × 109/L (n = 11) were 76.4% ± 5.7% and 45.5% ± 15% (p = 0.013), respectively. A total of 650 hospital infections occurred. The main causes of infection were respiratory tract infection (26.92%), septicemia (18.46%), stomatitis (11.85%), and skin and soft-tissue infection (10.46%). This intensive treatment protocol with dual induction and ALL-like elements is effective and safe for childhood AML. Initial WBC ⩾ 100 × 109/L was the only independent risk factor in this cohort. It is a retrospective study, and no registration on ClinicalTrials.gov.

Outcomes with two-drug induction of peditric acute myeloid leukemia (AML) patients treated at tertiary care centre in North India: A retrospective cross-sectional study

Outcomes with two-drug induction of peditric acute myeloid leukemia (AML) patients treated at tertiary care centre in North India: A retrospective cross-sectional study

Outcomes of Regimented Weight Monitoring on Morbidity and Mortality during AML Induction

Acute myeloid leukemia (AML) is characterized by the clonal expansion of myeloid blasts in the peripheral blood, bone marrow and other tissues. AML is a disease of elderly, with median age of 67 years at diagnosis. Current therapeutic options for elderly individuals with AML include intensive chemotherapy with a cytarabine and anthracycline backbone, hypomethylating agents (decitabine and azacytidine) alone or in combination with venetoclax. Targeted therapies, low dose cytarabine, investigational agents and supportive care with hydroxyurea and transfusions are other options. While monitoring daily weights has been well documented in APL due to concern for differentiation syndrome, little has been documented in AML. Monitoring daily weights can be a useful tool in maintaining patients' euvolemic status. This can help in appropriately resuscitating patients with AML as they are prone to sepsis due to their immunocompromised status. Also, it can help prevent fluid overload and prevent hypoxic respiratory failure. At our center over the last few years, we have standardized an approach to monitoring and maintaining the weights of our AML patients at or near their pre-admission level with IV fluids and diuresis, as needed. We report outcomes of regimented weight monitoring on morbidity and mortality during AML induction. METHOD We conducted a retrospective chart review of newly diagnosed AML patients treated at our center between January 2016 and May 2022. The cohort was divided into 2 groups; those treated prior to 2019 and those treated after. For each group, patients whose weights were monitored and maintained within 3 kilograms of admission weight were identified for comparison with those who were not. Induction regimens including 7 plus 3 with or without the addition of targeted therapies were reviewed. Patients who were ineligible for induction and those admitted directly to the ICU prior to the start of therapy were excluded from this study. We reviewed the records of 155 patients induced at our center; the mean age at diagnosis was 56 years (20-82). 74 (48%) of these 155 patients were females. Prior to 2019, 73 patients were induced; 68 of these patients did not have monitored weights. Of these 22 were ICU transfers (detailed in Table 2). The 5 remaining patients had weights monitored and none were transferred to the ICU. After January 1st 2019, weights were followed and euvolemia was maintained in 32 patients, of whom 3 (9.4%) were transferred to ICU. Of the 50 patients after 2019 in whom weights were not maintained, 12 were transferred to the ICU (as summarized in Table 1). Out of 155 patients, 118 patients did not have weights followed and had a weight change of more than 3 kilograms above or below from admission. Of these 118 patients, 34 were transferred to ICU. 37 patients had weights followed, of which 3 were transferred to ICU. (OR 0.22) (95% CI 0.06-0.75) (p=0.017). The characteristics, mean length stay (LOS) and reasons for ICU transfer have been detailed in table 1. The mean overall length of stay (LOS) for all patients was 31.21 days. Mean LOS was 23.94(n=37) and 33.50(n=118) days for patients whose weights were and were not followed, respectively (mean difference of 9.56 days) (95 % CI of 4.8115-14.3085) (p&amp;lt;0.01). Nineteen out of 160 patients died due to causes listed in Tables 1 and 2. Among the 37 patients in whom daily weights were maintained, 3 patients, all of whom were transferred to ICU, died during induction. Of 118 patients in whom daily weights were not maintained, 14 patients died in the ICU during induction, whereas 1 patient died in hospice after developing bacteremia and respiratory failure (OR 0.6059, 95 % CI= 0.1653-2.2205, p=0.4496). DISCUSSION Fluid overload is a significant concern in the treatment of AML. Our findings suggest that maintaining euvolemia and monitoring daily weights can effectively manage patients on the floor and prevent unnecessary ICU transfers. Although there are limitations to our study due to its retrospective, single-center nature but the cost-effectiveness and noninvasive mode of maintaining euvolemia support its potential application to standard treatment protocols. As we have demonstrated, this simple intervention may contribute to reducing ICU transfers, LOS and overall mortality during induction therapy for AML patients. Further prospective studies are warranted to validate these findings.

Outcomes of Children and Adolescents with Acute Myeloid Leukemia Given a Low-Versus Standard-Dose Chemotherapy Regimen for Remission Induction (CALSIII-AML18): A Multicenter, Phase 3, Randomized, Noninferiority Trial

Backgroun d: Intensive chemotherapy is recommended for remission induction of pediatric acute myeloid leukemia (AML). However, life-threatening complications are common especially in vulnerable populations. We investigated whether a low-dose chemotherapy (LDC) regimen would be noninferior to a standard-dose chemotherapy (SDC) regimen for induction remission.This study also aimed to assess whether LDC is not inferior to SDC in terms of survival outcomes. Methods: We conducted a randomized, noninferiority study in children with AML who were admitted to 14 medical centers in China. Patients were randomly assigned to receive two remission-induction courses of either low-dose chemotherapy (LDC) (cytarabine 10 mg/m 2, subcutaneous, q12 hours, 20 doses; mitoxantrone or idarubicin 5 mg/m 2, intravenous, days 1, 3 and 5; and G-CSF 5 mcg/kg, subcutaneous, daily, 10 doses) (n = 246) or standard-dose chemotherapy (SDC) (cytarabine 100 mg/m 2, intravenous, q12 hours, 20 doses; daunomycin 50 mg/m 2, intravenous, days 1, 3, 5; and etoposide 100 mg 2, intravenous, days 1 to 5) (n = 251). Depending on the risk of relapse, patients in complete remission (CR) in both arms received two to three cycles of intensive consolidation chemotherapy and/or underwent hematopoietic stem cell transplantation (HSCT). The primary endpoint was to compare CR rates in patients randomized to the LDC or SDC regimens. The secondary endpoints were to determine the safety of the LDC regimen and to compare the time to platelet and neutrophil count recovery in the two groups. Finally, in a multivariate analysis, we determined the impact of the type of remission induction on the outcome. This trial is registered at chictr.org as # ChiCTR-18000015883 and has been completed. Results: From June 2018 to June 2022,497 participants aged &amp;lt;18 years with de novo AML were randomized. Patients with Down syndrome, promyelocytic leukemia, or megakaryoblastic leukemia were excluded. There were no significant differences in age, sex, or genotype between the two arms. Complete morphologic remission with or without platelet recovery (CR/CRi) was attained in 72.8% and 70.3% of patients assigned to the LDC and SDC arms, respectively, after Induction I and in 95.5% and 95.7%, respectively, after Induction II ( P = .545 for Induction I and .898 for Induction II). Residual disease &amp;lt; 0.1%, as measured by flow cytometry, was observed in 54.8% and 58.9% of patients in the LDC and SDC arms, respectively, after Induction I and in 85.9% and 84.4%, respectively, after Induction II ( P = .229 for Induction I and .827 for induction II). Median time to neutrophil count recovery was 15 days for patients in the LDC arm vs. 22 days for those in the SCD arm after Induction I ( P&amp;lt; .001) and 12 days vs. 18 days for patients in the respective arms after Induction II ( P &amp;lt; .001). Median time to platelet count recovery was 13 days for patients in the LDC arm vs. 19 days for those in the SCD arm after Induction I ( P &amp;lt; .001) and 3 days vs. 8 days for patients in the respective arms after Induction II ( P&amp;lt; .001). Grade 3 and 4 toxicities were significantly lower in patients in the LDC arm than those in the SDC arm. In Induction I, febrile neutropenia occurred in 75.2% and 93.2% ( P &amp;lt; .001), colitis in 3.7% and 10.7% ( P = .003), and gastrointestinal hemorrhage in 0.4% and 4.4% ( P = .006) in the LDC and SDC arms, respectively. In Induction II, febrile neutropenia occurred in 34.4% and 66.9% ( P &amp;lt; .001), lung or sinus infection in 2.8% and 9.3% ( P = .008), and sepsis in 3.3% and 10.7% ( P = .004), in the LDC and SDC arms, respectively. There was no significant difference in treatment-related mortality between the two treatment arms ( P = 204).Compared to patients in the SDC arm, patients in the LDC arm had noninferior 3-year EFS of 61.9% (95% CI: 55.7 to 68.8) vs. 62.2% (95% CI: 56.1 to 68.8)( P = .994) (Figure 1A), and 3-year OS of 81.0% (95% CI: 75.7 to 86.6) vs. 83.2% (95% CI: 78.2 to 88.5) ( P = .485) (Figure 1B). In a multivariate analysis considering known prognostic indicators in pediatric AML, treatment arm was not associated with outcome. Conclusion: In children with AML, remission induction with a low-dose chemotherapy regimen with concurrent G-CSF administration was well tolerated and was associated with CR, EFS, and OS rates that were not inferior to those of patients treated with a standard chemotherapy regimen.

Picalm::MLLT10 can Identify a New Subgroup of Acute Leukemias of Ambiguous Lineage with Unique Extramedullary Disease and Treatment Response

Background: Mixed-phenotype acute leukemias (MPAL), which is included in acute leukemias of ambiguous lineage (ALAL), can be classified as four different subtypes based on recurring genetic alterations including BCR::ABL, KMT2A and ZNF384 gene rearrangement as well as BCL11B activation. The 2022 WHO classification has already mentioned PICALM::MLLT10 fusions are also enriched in MPAL but need more data. In 2022 ELN classification, PICALM::MLLT10 was identified as acute myeloid leukemia (AML) with other rare recurring translocations but not ALAL. In addition, there is no separate classification for PICALM::MLLT10 in the new ICC classification. Therefore, it is still confused whether PICALM::MLLT10 corresponds to AML or acute lymphoblastic leukemia (ALL) or ALAL. Methods: Fourteen PICALM::MLLT10 positive patients of 390 AL patients (14/390, 3.6%) were identified by RNA sequencing (RNA-seq) in our center from 2020-2022, including 8 female and 6 male, with a median age of 33 years (16-50 years). These patients were newly diagnosed AL according to bone marrow morphology and immunology including 5 ALAL, 5 T-ALL [ 4 early T-cell precursor ALL (ETP-ALL), 1 cortical T-ALL], 2 AML, 1 B-ALL with aberrant expression of myeloid antigen, and 1 B/T MPAL. Results: The mean white blood cell counts of these patients was 8.25×10 9/L (2.34-51×10 9/L) and platelet counts was 168.5×10 12/L (39-429×10 12/L) individually. It should be mentioned that extramedullary disease (EMD) was found in 7 cases (7/14), including mediastinum, tonsil, and skin. In terms of immunotyping, CD7 was identified in all patients (14/14) and CD33 in 71.4% (10/14) patients. The major concurrence mutations were PHF6 mutation (8/14), JAK3 mutation (5/14), and SUZ12 mutation (4/14). Characteristic cytogenetic abnormality t(10;11)(p12.3;q14.2) was only found in three cases (3/14) (Table 1). The PICALM breakpoints are mainly concentrated in exon 17 (n=6) and exon 19 (n=8). Exon 4 (n=8), exon 6 (n=2), exon 9 (n=2) and exon 10 (n=2) are the most commonbreakpointsof MLLT10. To our knowledge, this is the first report about the breakpoints and fusion gene forms of PICALM::MLLT10. For initial treatment, these patients individually received standard ALL induction chemotherapy (VDPCP, vincristine, idarubicin, pegaspargase, cyclophosphamide, prednisone) and AML induction chemotherapy (3+7 IA regimen including idarubicin, cytarabine). The initial complete remission (CR) rate was only 35.7% (5/14), and 9 patients showing no remission (NR). These NR patients subsequently received salvage chemotherapy. It is worth mentioning that 6 of them received combined chemotherapy regimen including low doses of cytarabine (LDAC), granulocyte colony-stimulating factor (G-CSF) and anthracyclines such as aclarubicin or idarubicin or homoharringtonine (CAG or IAG or HAG), and 2 of 6 patients also further received combination therapy with venetoclax (CAG or IAG +VEN). Finally, 5 of them dramatically achieved CR (5/6). In the other 3 patients, 1 patient who was failure to initial Hyper-CVAD A/B regimen also dramatically achieved CR after the more Hyper-CVAD A regimen combined with venetoclax, and 1 patient achieved CR while another still NR with both receiving CLAG (cladribine, cytarabine, G-CSF) regimen. Subsequently 11 patients (9 CR, 2 with refractory disease) received allogenic hematopoietic stem cell transplantation (allo-HSCT), and all the CR patients survived well after HSCT (follow up 3-24 months, median 15 months) without relapse, while 2 NR patients died soon after transplantation because of severe complications (Table 2). Conclusions: Our data suggested PICALM::MLLT10 positive AL should be more appropriately recognized as an independent ALAL entity and may benefit from LDAC, G-CSF and anthracyclines combination chemotherapy as well as venetoclax. Sequential HSCT after chemotherapy combined with venetoclax may further improve long-term survival in AL patients with CR even MRD positive.

Final Analysis for the Primary End-Point of Gimema AML1718, a Safety Run-in and Phase 2 Open-Label Study of Venetoclax, Fludarabine, Idarubicin and Cytarabine (V-FLAI) in the Induction Therapy of Non Low-Risk Acute Myeloid Leukemia

Background: Acute myeloid leukemia (AML) poses significant challenges, especially in intermediate and high-risk cases due to modest rates of complete remission (CR) of 50-60% yelding a 2-year survival probability of about 30-40%. Preliminary results from the AML1718 part 1 trial have demonstrated remarkable improvements, with a composite complete remission (CCR) rate reaching an impressive 82%, and a 1-year survival probability of 72%. These findings represent a substantial advancement compared to historical data. Hereby, we present the comprehensive results of the AML1718 study, with a primary focus on the CCR as the primary endpoint. Methods: The safety and efficacy of venetoclax (VEN) in combination with FLAI (fludarabine, cytarabine, and idarubicin as a first-line treatment for newly diagnosed adult patients with ELN 2017 intermediate- or high-risk AML) was investigated in the GIMEMA AML1718 phase 1/2 multicenter trial (NCT03455504). The study followed a modified two-stage Simon's design, including safety run-in cohorts (SRI-C1 and SRI-C2), an extension phase (Part 1 with P1-C1 and P1-C2 cohorts), and a confirmatory cohort (P2). VEN was administered at a daily dose of 400 mg in combination with FLAI (V-FLAI 400) in SRI-C1 and P1-C1, while in SRI-C2 and P1-C2, the VEN dose was escalated to 600 mg/day (V-FLAI 600). In P2 we used the lower effective dosage of V-FLAI 400, with centralized measurable residual disease (MRD) assessment with flow cytometry following ELN guidelines. After V-FLAI induction, consolidation therapy with cytarabine-based regimens and consideration for allogeneic stem cell transplant (HSCT) were conducted. Adjustments to the VEN dose were made for patients concurrently receiving posaconazole. VEN administration was discontinued until recovery for patients achieving remission by day 21 and during consolidation courses. Results: Since February 2019, a total of 124 patients were treated in this study, 6 in SRI-C1, 6 in SRI-C2, 22 in P1-C1, 23 in P1-C2, and 67 in P2. Among them, 95 patients received V-FLAI 400 and 29 patients received V-FLAI 600. Posaconazole was administered to 115 patients (93%) as antifungal prophylaxis during the first course. The patient population had a median age of 55 years (ranging from 18 to 66), with 70 patients (56%) being male. According to ELN 2017 risk, 67 patients (54%) were classified as intermediate- and 57 patients (46%) as high-risk. Sixteen (13%) patients had a seconday AML. Genetic mutation analysis showed that 4/56 tested patients (7.1%) had IDH1, 11/55 (20%) IDH2, 16/108 (14.7%) FLT3 ITD, 3/112 ( 2.8%) NPM1 mutation; TP53 data are not yet available. The primary endpoint, the CCR, was achieved in 93 out of 124 patients (75%) after the 1 st course (table 1). One patient initially in partial remission (PR) achieved CR after the second V-FLAI induction. In P2, 47/67 patients achieved CCR (70.0%, with 9 patients not yet tested). Central MRD analysis showed that that 31 out of 48 tested patients obtained MRD negativity at day 28 of course 1 (64.5%, treshold 0.1% by flow). With a median follow-up of 10 months, 60 patients (49%) underwent hematopoietic stem cell transplant (HSCT) in CR, and 1 patient underwent HSCT in partial remission. The median overall survival (OS) was 22.4 months (95% confidence interval [C.I.] 13.4 months - not reached, Figure 1), with a 12-month OS probability of 64% (95% C.I. 54% - 76%). The median disease-free survival (DFS) was 20.7 months (95% C.I. 12.1 months - not reached), and the 12-month DFS probability was 64% (95% C.I. 50% - 76%). The treatment was found to be safe, with only 4 deaths recorded during induction (3.2%), and a 60-day mortality rate of 6% including disease progression-related deaths. Infections were the most commonly reported grade 3+ adverse events. Overall, the safety profile of the treatment regimen was consistent with any intensified AML induction regimen. Among transplanted patients, no instances of graft failure or higher-than-expected incidence of graft-versus-host disease (GVHD) were observed. No significant differences were observed between the 400 mg and 600 mg arms. Conclusions: V-FLAI demonstrated remarkable efficacy without any safety concerns. Impressive CCR rate and MRD-negativity qualify the combination for randomized comparisons . A virtual-randomized phase 3 trial is currently being prepared.

The Occurrence of Infection and TP53 Mutation Are Risk Factors for Cardiovascular Toxicity of Acute Myeloid Leukemia Induction Therapy

Introduction: For almost 50 years,induction therapy (IT) is the standard of care for acute myeloid leukemia (AML) patients. Nevertheless, little is known about cardiovascular (CV) toxicity during IT. We aimed to describe CV events (CVE)occurring during IT and to identify clinical, hematological and molecular risk factors of such events. Methods: Two hundred and twenty-four patients of 18 years or more (median age 61 (51;67) years, 58% males), treated with ITbetween 2014 and 2021 were enrolled in this study. Two hundred and one (90%) received an anthracycline-based IT, the others received gemtuzumab ozogamicin as part of a clinical protocol research. Survival from the time from initiation of IT until death or until the initiation of the second course of therapy (either salvage regimen in case of primary refractory or relapsed AML, or intensive consolidation therapy in case of response) was considered. The primary endpoint was the time to occurrence of the first CVE after IT initiation, with death as a competing event. Multivariate analysis included significant covariate, identified by univariate models among initial characteristics and occurrence of infection (coded as time dependent covariate). Results: Hematological characteristics were as follows: European LeukemiaNet (ELN) 2022 risk of myelodysplastic neoplasm (MDS)/AML was low, intermediate and adverse in 13%, 29% and 58% of patients respectively. Main mutations encounters were: DNMT3A, FLT3, NPM1, TET2, NRAS, RUNX1, ASXL1, IDH2, PTPN11, BCOR, SRSF2, WT1 and TP53. Main CV risk factors were tobacco (36%), arterial hypertension (35%), obesity (24%), hyperlipidemia (22%), diabetes mellitus (11%). Baseline left ventricular ejection fraction (assessed by transthoracic echocardiography) was &amp;gt;45% in all patients, &amp;gt;55% in 95% of patients. Seventy-five patients (33%) presented a CVE during IT. Eighty-six percent of CVE were severe (grade 3 or more). Patients presenting CVE during IT were significantly older (p=0.02) and presented more often a past history of dilated cardiomyopathy (p=0.04), arterial hypertension (p=0.005) or dyslipidemia (p=0.005). At baseline, CVE patients presented a greater left auricle volume (p=0.005), higher tricuspid regurgitation grade (p=0.01), and more often a right ventricular dilatation or a significative valvopathy (respectively p=0.01 and p=0.03). There was no difference in CVE occurrence between patients treated with and without anthracyclin (p=0.2). Competing risk models identified the following adverse characteristic for the risk of first CVE, namely the occurrence of the first infectious event (Hazard ratio [HR]= 2.43, p=0.005), TP53 mutation (HR=1.79, p=0.04). No other clinical characteristics nor mutation (including TET2 and DNMT3A) were identified. Multivariate analyses demonstrated that TP53 mutation (HR=1.78, p=0.04) and occurrence of infection (HR=2.29, p=0.008) retained independent prognostic value, see Table 1. In a response stratified model, only TP53 mutation was a risk factor of first CVE (HR=2.46, p=0.008). Conclusions: CVE occurred in 33% of patients during IT and were severe. The major adverse role of onset of infection for CVE occurrence after IT could overcome the prognostic value of mutations usually associated with CV risk in the healthy population (i.e. TET2, DNMT3A, ASXL1, ...). TP53 mutation was the only molecular abnormality associated with CVE, in agreement with the increased risk of doxorubicin-induced cardiac toxicity in a mouse model of TP53 clonal hematopoiesis developed by Sano et al. These results suggest that TP53 mutated patients could benefit from careful CV monitoring and optimization of primary prevention treatment.

Azacitidine Plus Venetoclax Maintenance in Acute Myeloid Leukemia Produces Sustained Remissions with Low Toxicity: Results of a Phase 2 Study

Background: Most patients diagnosed with acute myeloid leukemia (AML) achieve remission following induction therapy. However, disease relapse remains a major clinical concern. The QUAZAR AML-001 study demonstrated improved overall and relapse-free survival with oral azacitidine (CC-486) maintenance. We designed a phase 2 study (NCT04062266) to evaluate low doses of azacitidine plus venetoclax as maintenance therapy following both intensive and low-intensity induction in AML. We present updated results of this study with close to 2 years of median follow-up. Methods: Patients ≥ 18 years of age with non-APL AML in first complete remission (CR) or CR with incomplete count recovery (CRi) not immediately eligible for allogeneic stem cell transplantation (SCT) were eligible. Cohort 1 enrolled patients who had received at least 2 cycles of intensive therapy (defined as containing intermediate to high-dose cytarabine). Cohort 2 enrolled patients who had received at least 3 cycles of low-intensity therapy (defined as hypomethylating agent or low-dose cytarabine-based). Patients with positive measurable residual disease (MRD) by flow cytometry were eligible in CR1 or beyond. Other inclusion requirements were ECOG ≤ 3, adequate hepatic/renal function, and adequate bone marrow reserve (defined as absolute neutrophil count &amp;gt; 0.5 x 10 9/L and platelets &amp;gt; 30 x 10 9/L). Treatment consisted of azacitidine 50 mg/m 2 SQ/IV on D1-5 and venetoclax 400 mg PO (adjusted for concomitant CYP3A inhibitors) on D1-14 in 28-day cycles, up to 24 cycles. Venetoclax duration could be reduced to D1-7 per physician discretion to mitigate myelosuppression and dose modifications during subsequent cycles were allowed. Antibacterial, antifungal, and antiviral prophylaxis were recommended in all patients. The primary objective was relapse-free survival (RFS, defined as time from enrollment to progression or death). Secondary objectives included overall survival (OS), safety/toxicity, and MRD clearance. Patients subsequently becoming eligible for SCT were taken off study and censored for analyses at the time of SCT. Results: 35 patients have been enrolled (25 in cohort 1 and 10 in cohort 2). The median age was 47 years in cohort 1 and 71 years in cohort 2. The baseline characteristics are shown in table 1. The median number of cycles given was 9 (range 1-24). 22/35 (63%) patients had 7 days of venetoclax during cycle 1. Median follow-up is currently 20.9 months (m). For the full cohort, the median RFS was not reached (NR; 2-year 60%) and the median OS was NR (2-year 75%). In cohort 1, the median RFS and OS were NR (2-year 71%) and NR (2-year 77%), respectively. In cohort 2, the median RFS and OS were 23.5 m (2-year 34%) and NR (2-year 67%), respectively. When stratified by ELN 2017, patients who were favorable (n=16), intermediate (n=11), and adverse (n=8) had a median RFS of NR (2-year 85%), NR (2-year 64%), and 4.0 m (2-year 0%), respectively. Corresponding median OS were NR (2-year 91%), NR (2-year 76%), and 14.9 m (2-year 27%), respectively. 4/8 (50%) of the ELN adverse patients had complex cytogenetics and/or TP53 mutations. Patients who were MRD-positive at enrollment (n=7, 3 with prior venetoclax exposure) had significantly shorter RFS compared to those who were MRD-negative (median 4.0 m versus NR, p&amp;lt;0.01). Only 2/7 (29%) MRD-positive patients converted to MRD-negative while on maintenance. As mutations in NPM1, IDH1, or IDH2 may sensitize AML to venetoclax, we analyzed RFS based on the presence or absence of these mutations (figure 1). Patients with sensitizing mutations had a trend towards longer RFS (median RFS NR versus 23.5 m, 2-year RFS 79% vs 36%, p=0.08). The most common grade 3/4 adverse events were infections (26%), neutropenia (17%), thrombocytopenia (17%), hypotension (6%), and neutropenic fever (6%). 4 (11%) patients required cycle 2 venetoclax dose reductions. 8 (23%) of patients went off protocol to receive SCT. All observed deaths (n=8) occurred following AML relapse (n=7) or SCT-related complications (n=1). Conclusions: Lower dose azacitidine plus venetoclax is a feasible and safe maintenance strategy in AML. This approach yields encouraging results in MRD-negative patients with non-adverse ELN risk (favorable or intermediate risk). A genetic-guided strategy may help select patients who benefit the most from this combination (i.e. those with NPM1, IDH1, or IDH2 mutations).

Assessing the impact of prophylactic anidulafungin during remission induction of acute myeloid leukemia - A propensity-score matching analysis.

Invasive fungal infection (IFI) accounts for substantial morbidity during the treatment of acute myeloid leukemia (AML) in adults. Antifungal prophylaxis (AP) is needed during intensive chemotherapy, and posaconazole is not widely available. In this study, we aimed to examine the impact of prophylactic anidulafungin during intensive AML remission induction. This is a retrospective cohort encompassing newly diagnosed AML adult patients. All subjects received intensive chemotherapy and were divided into three groups: patients who did not receive any AP and patients who received fluconazole (150-400mg/day) or anidulafungin (100mg/day). During AML induction, 82 patients did not receive AP, 108 and 14 patients received anidulafungin and fluconazole, respectively. IFI incidence was 27%, classified as possible, probable, and proven in 65, 2 and 33%, respectively. Multivariable analysis showed that lower neutrophil counts are associated with IFI (OR=2.8), whereas age, genetic classification, and lymphocyte counts were not. To examine the impact of anidulafungin in comparison with 'no AP', a propensity score matching analysis was performed. Use of anidulafungin was not related to less IFI during induction, while neutrophil counts remained significant. Patients under prophylactic anidulafungin received less amphotericin B (p<0.001) but not voriconazole (p=0.49). To our knowledge, this is the first study addressing the role of anidulafungin during AML induction. Here, the incidence of mold infections did not decrease with AP, suggesting that in a setting with a high incidence of IFI, broad spectrum AP might be more suitable.

A Prospective Study to Evaluate the Effect of Therapeutic Drug Monitoring-Based Posaconazole Prophylaxis on Invasive Fungal Infection Rate During Acute Myeloid Leukemia Induction Therapy.

The online version contains supplementary material available at 10.1007/s12288-023-01709-3.

Tocilizumab in combination with a standard induction chemotherapy in acute myeloid leukaemia patients (TOCILAM study): a single-centre, single-arm, phase 1 trial

In acute myeloid leukaemia (AML), interleukin-6 (IL-6) promotes chemo-resistance and its levels correlate with poor prognosis. IL-6 blockade may represent a promising therapeutic strategy. We aimed to test, tocilizumab, an anti-IL-6 receptor (R) monoclonal antibody in combination with standard intensive AML induction chemotherapy. This investigator-initiated single-centre phase 1 trial was conducted at Nantes University Hospital in France. According to a continual reassessment method, three escalating doses were tested of intravenous (IV) tocilizumab (4, 6, and 8mg/kg) administered at day (d) 8 of a standard AML induction chemotherapy (IV idarubicine 8mg/m2 d1 to d5+IV cytarabine 100mg/m2 d1 to d7). All adults (aged ≥ 18 years) with an Eastern Cooperative Oncology Group performance status of 0-2 and with a newly diagnosed (excluding patients with a favourable risk according to ELN-2017 classification if<60 year-old) or a relapsed/refractory AML were eligible. The primary objective was to determine the maximum tolerated dose of tocilizumab to administrate with a standard intensive AML induction. Safety outcomes were continuously monitored for at each participant contact. This trial is registered with ClinicalTrials.gov, NCT04547062. Between Dec 29, 2020 and Dec 1, 2022, 12 patients were enrolled, of whom 75% had an ELN-2017 high-risk profile, and were treated with tocilizumab- two patients at 4mg/kg, two at 6mg/kg and eight at 8mg/kg of tocilizumab. No dose-limiting toxicity related to tocilizumab was documented. There were nine serious adverse events, none of which were related to tocilizumab, and there was no treatment-related deaths. MTD was thus not reached. Two deaths occurred during induction. In the remaining ten evaluable patients, nine responded to treatment. The combination of tocilizumab with standard AML intensive induction appears to be safe and resulting responses are encouraging. A dose of 8mg/kg of tocilizumab given at day 8 of induction could be used for further phase 2/3 studies. The Leucémie Espoir Atlantique Famille (LEAF)-"Tous avec Fabien" association.

WT1-mutated acute myeloid leukemia is sensitive to fludarabine-based chemotherapy and conditioning regimens

We conducted a retrospective analysis of WT1-mutated acute myeloid leukemia (AML) patients who underwent allogeneic stem cell transplant. Thirty-seven patients with WT1-mutated AML were identified. Primary induction failure (40%) and early relapse rate (18%) after idarubicin/cytarabine (7 + 3) chemotherapy were observed. All patients with induction failure subsequently achieved CR with additional chemotherapy. There was no significant difference between outcomes after myeloablative vs. reduced intensity (Fludarabine/Melphalan [Flu/Mel]) conditioning regimens. RFS but not OS was significantly better in patients who received FLAG-IDA prior to transplant and/or a fludarabine-containing conditioning. In an independent ex vivo study, WT1-mutated AML samples exhibited greater sensitivity to fludarabine (p = 0.026) and melphalan (p = 0.0005) than non-WT1-mutated AML samples while there was no difference between sensitivity to cytarabine. Our data favor using a fludarabine-based induction for AML with WT1 mutation instead of 7 + 3. Fludarabine conditioning regimens for alloHCT showed better RFS but not OS.

FLAG based v/s Standard 3 + 7 induction therapy in treatment naïve Acute Myeloid Leukemia: Time to think “beyond anthracyclines”

Daunorubicin and Cytarabine (DA; 3 + 7) has been the standard frontline Acute Myeloid Leukemia (AML) induction regimen resulting in Complete Remission (CR) rates of 50–70%. It is associated with induction mortality of 15–30%. We report a comparative analysis of DA versus fludarabine, cytarabine, G-CSF (FLAG) + /- Venetoclax in resource constrained settings. We conducted a single center, retrospective analysis of 37 treatment naïve fit AML patients from May 2021 to December 2022 who received either standard DA regimen (Group 1) or FLAG + /- Venetoclax (Group 2). The median patient age was 36.6 years in DA arm (n = 18) as compared to 40.1 years in FLAG arm (n = 19). CR rates at day 28 were 55.5% in group 1 and 89.4% in group 2 (odds ratio [OR], 7.20; 95% confidence interval [CI], 1.274 −40.678; P = 0.012). Patients in FLAG based therapy arm had shorter duration of neutropenia (P = 0.003), fewer episodes of grade 3 febrile neutropenia (P = 0.0228), shorter duration of antibiotic therapy (P = 0.03), lesser need of 3rd line antibiotic therapy (P = 0.0228). Mortality rates were 16.6% (n = 3) in (group 1) and 0% (n = 0) in (group 2) (p = 0.105). Our analysis supports that FLAG based induction regimen is an effective and well-tolerated therapy in treatment naïve fit AML patients.

Prognostic value of combined WT1 and multiparameter flow cytometry assessment for measurable residual disease after induction in non-APL acute myeloid leukemia

The objective of this study was to investigate the expression pattern of Wilms tumor 1 (WT1) gene at diagnosis, complete remission (CR) and relapse status in non-acute promyelocytic leukemia (non-APL) acute myeloid leukemia (AML) patients, and further explore the prognostic value of measurable residual disease (MRD) assessment by WT1 gene and multiparameter flow cytometry (MFC). Our results showed that the average expression level of WT1 was 4026 ± 616.1 copies/104 ABL at diagnosis, 155.3 ± 36.03 copies/104 ABL at CR, and 1766 ± 238.8 copies/104 ABL at relapse, with statistically significant differences (p = .000). ROC analysis showed that WT1 expression levels were 118.1 copies/104 ABL and MFC-MRD was 0.155%, which had good predictive efficacy for relapse of patients during consolidation therapy. Both WT1-MRD and MFC-MRD had a significant impact on relapse-free survival (RFS) and overall survival (OS). Patients with WT1-MRD positive or MFC-MRD positive were associated with worse RFS (HR 3.840, 95% CI 1.582–9.320, p = .003), (HR 4.464, 95% CI 1.841–10.984, p = .001) and worse OS (HR 2.963, 95% CI 1.058–8.295, p = .039), (HR 3.590, 95% CI 1.254–10.280, p = .017). Besides, compared with patients who were negative for both WT1-MRD and MFC-MRD, patients who were positive both WT1-MRD and MFC-MRD were associated with worse RFS (HR 6.200, 95% CI 2.206–17.430, p = .001) and worse OS (HR 4.886, 95% CI 1.388–17.197, p = .013). This study demonstrates that combined assessment of MRD by WT1 and MFC improves relapse and prognosis prediction in non-APL AML patients, and may help guide interventions for disease relapse.

Acute myeloid leukemia induction in the age of novel therapeutic agents

Acute myeloid leukemia (AML) is a malignant neoplasm of the myeloid lineage characterized by the uncontrolled proliferation of immature myeloid blasts in the bone marrow and peripheral blood. AML is a heterogenous disease which occurs across the age spectrum, although with an increasing incidence with age. For decades, first-line, curative-intent therapy has been based on intensive therapy with anthracycline (typically daunorubicin or idarubicin) plus cytarabine (3+7), followed by additional consolidative chemotherapy and/or allogeneic stem cell transplantation. While improvements over the decades in overall survival have been observed, until recently this has been driven largely by advancements in supportive care leading to reduction in treatment-related mortality and allowing a greater proportion of patients (particularly older individuals) to safely undergo intensive therapy induction and consolidation. Despite this, five-year overall survival (OS) rates in older individuals are as low as 5% (age &gt; 70). Although OS for patients age 15-39 is now in the range of 50%-60%, a large portion of patients still succumb to their disease. Cytogenetic and molecular profiling has led to defined risk categories, and complete risk stratification for all patients eligible for intensive therapy is crucial to aiding in the selection of optimal induction and post- remission therapy. In recent years, an improved understanding of AML biology and genetics has led to the approval of a number of novel therapies for patients deemed fit and unfit for intensive therapy, which may finally be moving the needle beyond 3+7. This article will review a current approach to AML induction patients eligible for intensive therapy, with a focus on the utilization of available novel agents.