Management Of Acute Myeloid Leukemia Research Articles

A dual-targeting approach with anti-IL10R CAR-T cells engineered to release anti-CD33 bispecific antibody in enhancing killing effect on acute myeloid leukemia cells.

Immunotherapies, including chimeric antigen receptor (CAR) T cells and bispecific antibodies (BsAbs), encounter several challenges in the management of acute myeloid leukemia (AML), including limited persistence of these treatments, antigen loss and resistance of leukemia stem cells (LSCs) to therapy. Here, we proposed a novel dual-targeting approach utilizing engineered anti-IL10R CAR-T cells to secrete bispecific antibodies targeting CD33. This innovative strategy, rooted in our previous research which established a connection between IL-10 and the stemness of AML cells, designed to improve targeting efficiency and eradicate both LSCs and AML blasts. We first demonstrated the superior efficacy of this synergistic approach in eliminating AML cell lines and primary cells expressing different levels of the target antigens, even in cases of low CD33 or IL10R expression. Furthermore, the IL10R CAR-T cells that secret anti-CD33 bsAbs (CAR.BsAb-T), exhibited an enhanced activation and induction of cytotoxicity not only in IL10R CAR-T cells but also in bystander T cells, thereby more effectively targeting CD33-positive tumor cells. Our in vivo experiments provided additional evidence that CAR.BsAb-T cells could efficiently redirect T cells, reduce tumor burden, and demonstrate no significant toxicity. Additionally, delivering bsAbs locally to the tumor sites through this strategy helps mitigate the pharmacokinetic challenges typically associated with the rapid clearance of prototypical bsAbs. Overall, the engineering of a single-vector targeting IL10R CAR, which subsequently secretes CD33-targeted bsAb, addresses the issue of immune escape due to the heterogeneous expression of IL10R and CD33, and represents a promising progress in AML therapy aimed at improving treatment outcomes.

Measurable Residual Disease Analysis by Flow Cytometry and Correlation With Molecular Measurable Residual Disease in Acute Promyelocytic Leukemia: A Real-World Prospective Study.

Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia distinguished by its rapidly progressive and fatal clinical course. Measurable/minimal residual disease (MRD) monitoring is vital for the prognosis and clinical management of acute myeloid leukemia. To examine the immunophenotypes of the residual leukemic cells, evaluate the performance of multiparametric flow cytometry (FCM) measuring MRD, and compare it with molecular monitoring in patients diagnosed with APL. Two hundred seventy-seven patients with APL were enrolled. Immunophenotypes were prospectively analyzed by a 1-tube-10-color antibody panel via FCM. MRD of APL with PML::RARα was detected by real-time quantitative polymerase chain reaction (RQ-PCR). The clinical value of MRD as an indicator of survival was also examined. APL showed 5 distinct patterns of residual leukemic cells, based on CD45 and side-scatter scattergram, all with CD9 positivity and a previously unrealized loss of CD117. FCM-based MRD evaluation showed a concordance rate of 87.7% with PCR. At the end of the consolidation therapy, MRD measured by both PCR and FCM could differentiate patients with longer and shorter overall survival (OS) (P = .04 and P = .03, respectively). Patients with APL variant had a shorter OS than patients with APL who harbored PML::RARα (P < .001). CD9 is a reliable marker to differentiate residual leukemic cells from normally differentiating myeloid cells. FCM demonstrated a high comparability to PCR-MRD and an excellent performance in predicting OS, and thus could potentially be used as a routine indicator in the clinical management of patients with APL.

Relapse Prevention in Acute Myeloid Leukemia: The Role of Immunotherapy with Histamine Dihydrochloride and Low-Dose Interleukin-2.

The treatment and management of acute myeloid leukemia (AML) has improved in recent decennia by targeted therapy for subgroups of patients, expanded indications for allogeneic stem cell transplantation (allo-SCT) and surveillance of residual or arising leukemia. However, hematological relapse among patients who have attained complete remission (CR) after the initial courses of chemotherapy remains a significant cause of morbidity and mortality. Here, we review an immunotherapeutic option using histamine dihydrochloride and low-dose interleukin-2 (HDC/LD-IL-2) for remission maintenance in AML. The treatment is approved in Europe in the post-consolidation phase to avoid relapse among patients in CR who are not candidates for upfront allo-SCT. We present aspects of the purported anti-leukemic mechanism of this regimen, including translation of preclinical results into the clinical setting, along with relapse prevention in subgroups of patients. We consider that HDC/LD-IL-2 is a conceivable option for younger adults, in particular patients with AML of normal karyotype and those with favorable responses to the initial chemotherapy. HDC/LD-IL-2 may form an emerging landscape of remission maintenance in AML.

Reactive oxygen species and its role in pathogenesis and resistance to therapy in acute myeloid leukemia.

Relapse following a short clinical response to therapy is the major challenge for the management of acute myeloid leukemia (AML) patients. Leukemic stem cells (LSC), as the source of relapse, have been investigated for their metabolic preferences and their alterations at the time of relapse. As LSC rely on oxidative phosphorylation (OXPHOS) for energy requirement, reactive oxygen species (ROS), as by-products of OXPHOS, have been investigated for their role in the effectiveness of the standard AML therapy. Increased levels of non-mitochondrial ROS, generated by nicotinamide adenine dinucleotide phosphate oxidase, in a subgroup of AML patients add to the complexity of studying ROS. Although there are various studies presenting the contribution of ROS to AML pathogenesis, resistance, and its inhibition or activation as a target, a model that can clearly explain its role in AML has not been conceptualized. This is due to the heterogeneity of AML, the dynamics of ROS production, which is influenced by factors such as the type of treatment, cell differentiation state, mitochondrial activity, and also the heterogeneous generation of non-mitochondrial ROS and limited available data on their interaction with the microenvironment. This review summarizes these challenges and the recent progress in this field.

Integrative single-cell expression and functional studies unravels a sensitization to cytarabine-based chemotherapy through HIF pathway inhibition in AML leukemia stem cells.

Relapse remains a major challenge in the clinical management of acute myeloid leukemia (AML) and is driven by rare therapy-resistant leukemia stem cells (LSCs) that reside in specific bone marrow niches. Hypoxia signaling maintains cells in a quiescent and metabolically relaxed state, desensitizing them to chemotherapy. This suggests the hypothesis that hypoxia contributes to the chemoresistance of AML-LSCs and may represent a therapeutic target to sensitize AML-LSCs to chemotherapy. Here, we identify HIFhigh and HIFlow specific AML subgroups (inv(16)/t(8;21) and MLLr, respectively) and provide a comprehensive single-cell expression atlas of 119,000 AML cells and AML-LSCs in paired diagnostic-relapse samples from these molecular subgroups. The HIF/hypoxia pathway signature is attenuated in AML-LSCs compared with more differentiated AML cellsbut is more expressed than in healthy hematopoietic cells. Importantly, chemical inhibition of HIF cooperates with standard-of-care chemotherapy to impair AML growth and to substantially eliminate AML-LSCs in vitro and in vivo. These findings support the HIF pathway in the stem cell-driven drug resistance of AML and unravel avenues for combinatorial targeted and chemotherapy-based approaches to specifically eliminate AML-LSCs.

Budget impact analysis of venetoclax for the management of acute myeloid leukemia from the perspective of the social security and the private sector in Argentina.

This study aimed to estimate the budget impact of the incorporation of venetoclax for the treatment of patients with Acute Myeloid Leukemia (AML) over 75 years of age or those with comorbidities and contraindications for the use of intensive chemotherapy, from the perspective of the social security and the private third-party payers in Argentina. A budget impact model was adapted to estimate the cost difference between the current scenario (azacitidine, decitabine and low doses of cytarabine) and the new scenario (incorporation of venetoclax) for a third-party payer over a time horizon of three years. Input parameters were obtained from a literature review, validated or complemented by expert opinion using a modified Panel Delphi approach. All direct medical costs were estimated by the micro-costing approach and were expressed in US dollars (USD) as of September 2020 (1 USD = 76.18 Argentine pesos). For a third-party payer with a cohort of 1,000,000 individuals covered, incorporating venetoclax was associated with an average budget impact per-member per-month (PMPM) of $0.11 USD for the social security sector and $0.07 USD for the private sector. The duration of treatment with venetoclax was the most influential parameter in the budget impact results. The introduction of venetoclax was associated with a positive and slight budget impact. These findings are informative to support policy decisions aimed to expand the current treatment landscape of AML.

Neighborhood Disadvantage Is Associated with Inferior Overall Survival for Acute Myeloid Leukemia Patients Treated with Standard Intensive Induction

Background: Identifying biologic and socioeconomic contributors to disparities in outcomes is critical for the management of acute myeloid leukemia (AML). Prior studies in AML revealed that Black patients (pts) have inferior survival compared to White pts, with more striking disparity for Black pts aged &amp;lt;60. We previously explored our large and diverse AML cohort from urban and large rural areas and did not identify inferior survival for pts with self-reported Black race or Hispanic ethnicity. Although no surrogates for social determinants of health (SDOH) or insurance status were recognized as contributing to survival differences, oncology nurse navigation (ONN) was associated with a survival benefit, with no significant difference in access to ONN among racial or ethnic groups. To further evaluate socioeconomic drivers of disparities in this population supported by ONN, we aim to use the Area Deprivation Index (ADI) to determine the impact of neighborhood disadvantage on survival in AML. Methods: AMLpts diagnosed at Levine Cancer Institute between 12/2015 and 12/2020 were included. Pts with acute promyelocytic leukemia (APL) were excluded from this analysis. Details regarding insurance coverage, ONN services, induction therapy, stem cell transplant (SCT) status, and survival outcomes were collected. Race and ethnicity were self-reported. European LeukemiaNet (ELN) 2017 criteria were used to assign AML risk. Pt and disease characteristics were summarized, described, and compared with Fisher exact tests and Wilcoxon rank-sum tests for categorical and continuous data, respectively. Pts were grouped into 4 quartiles based on ADI national percentile. Subsequent models were fit with ADI dichotomized at the median after adjacent ADI groups were removed with backward elimination. Associations between overall survival (OS) and pt and disease characteristics, insurance status, race, ethnicity, ONN services, and ADI were investigated. OS was defined as the time from diagnosis (dx) to death from any cause, with surviving subjects censored at the time of last follow-up. Kaplan-Meier methods were used to summarize OS and calculate landmark survival rates. Survival was compared with unadjusted log-rank tests. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CIs) associated with OS. Results: Three hundred eighty pts with available baseline characteristics were included in our analysis ( Table 1) . For pts &amp;lt;60 who received intensive induction and had available ADI (N=86), there was a significant difference in OS amongst the quartiles of ADI (P=0.007), with differences even more pronounced with dichotomized ADI (P&amp;lt;0.001) ( Figure 1). With a median follow-up of 38.1 months for the intensively treated pts &amp;lt;60, the estimated two-year OS was 96.6% for more advantaged/low ADI pts and 55.4% for less advantaged/high ADI pts (HR 5.21; 95% CI 1.82 to 14.95). Within the cohort of pts &amp;lt;60 who received intensive induction, sixty-eight percent were Non-Hispanic White and 28% were Non-Hispanic Black. Many (66%) were privately insured at dx, with 24% uninsured or with Medicaid. ONN services were accessed by most (72%) pts with known ADI. Care barriers were expressed by pts of all ADI quartiles, with transportation being the only barrier most reported by pts of increased disadvantage (P&amp;lt;0.01). Forty-two percent of pts received SCT (N=38). Nearly 60% of socially advantaged pts (ADI≤51) received SCT versus 33% of socially disadvantaged pts (P=0.03). In univariate models, receipt of SCT (P=0.016) was associated with improved OS while receiving navigation services (P=0.32) was not. Conclusions: Higher ADI was associated with inferior OS in AML pts &amp;lt;60 who received intensive induction. Receipt of SCT was observed more often in pts with more neighborhood advantage, which is of great importance since SCT improved OS in this cohort. Although insurance status is often linked to SCT access, insurance status did not significantly impact OS. Of the ONN reported barriers to care, transportation issues had a greater impact on pts with more neighborhood disadvantage. Expanding access to SCT and addressing barriers to care, such as transportation, is necessary to overcome the detrimental impact of neighborhood disadvantage on survival in AML.

Antithymocyte Globulin in Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia: Evaluating Outcomes According to Cytogenetic Risk

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an essential therapeutic approach for the management of acute myeloid leukemia (AML). Nevertheless, graft-versus-host disease (GVHD) remains a significant complication, significantly affecting the recipients' quality of life and overall survival. Antithymocyte globulin (ATG) has demonstrated promise in preventing GVHD during allo-HSCT. However, concerns persist regarding its potential impact on disease relapse. This retrospective single-center study aims to evaluate the prognostic implications of ATG based on cytogenetic risk stratification in AML patients undergoing transplantation from an HLA-matched sibling. A total of 124 AML patients who underwent allo-HSCT from an HLA-matched sibling in their first complete remission state between 2003 and 2022 were eligible for the study. Among them, fifty patients received rabbit ATG at a dose of 2.5mg/kg/day for days -2 to -1, while 74 patients did not receive ATG. All patients received cyclosporine and methotrexate in addition to their respective conditioning regimens (ATG or no ATG). The ATG group consisted of 38 patients classified as having a non-high cytogenetic risk, and 12 patients classified as having a high cytogenetic risk. Conversely, the non-ATG group included 68 patients with a non-high cytogenetic risk and 6 patients with a high cytogenetic risk. After a median follow-up of 48 months, there were no significant differences in median overall survival between the ATG and Non-ATG groups, regardless of cytogenetic risk status (non-high cytogenetic risk; 12.4 months vs. NA, p = 0.578; high cytogenetic risk; 13.2 months vs. 14.2 months, p = 0.729, Figure A-1,B-1). The ATG group in the non-high cytogenetic risk group demonstrated a significant decrease in the 1-year cumulative incidence (CI) of chronic GVHD compared to the non-ATG group (21.7% vs. 54.4%, p = 0.001, Figure A-2; and in those with moderate to severe cGVHD, it was 21.6% vs. 51.5%, p = 0.003, respectively). Additionally, the 1-year Chronic GVHD-free and relapse-free survival (cGRFS) was higher in the ATG group of the non-high cytogenetic risk group (45.8vs. 26.5%; p = 0.048, Figure A-3). Moreover, there were no significant differences in 1-year CI of relapse and 1-year non-relapse mortality (NRM) within the non-high cytogenetic risk group (ATG vs. non-ATG; 29.7% vs. 20.6%, p = 0.225; 8.4% vs. 4.4%, p = 0.635, Figure A-4,5). In the subgroup analysis of patients with high cytogenetic risk, although there was no statistical significance, the ATG group showed a trend towards decreased 1-year CI of chronic GVHD and higher cGRFS compared to the non-ATG group (10.4% vs. 40.0%, p = 0.342; 31.2% vs. 16.7%, p = 0.929, Figure B-2,3). However, the ATG group exhibited a significantly higher 1-year CI of relapse compared to the non-ATG group (60.0% vs. 16.7%, p = 0.019, Figure B-4). In conclusion, our study findings indicate that ATG was effective in preventing chronic GVHD and demonstrated higher cGRFS in AML patients undergoing matched sibling donor HSCT. However, AML patients with high cytogenetic risk should carefully consider the use of ATG due to the associated higher risk of relapse. Further investigations are warranted to validate these findings and determine the appropriate dosage of ATG for high cytogenetic risk AML patients.

Analysis of Post-Transplant Clinical Outcomes and Prognostic Factors in FLT3-ITD Mutated Acute Myeloid Leukemia Patients Under ELN 2022 Risk Stratification

Background In 2022 European LeukemiaNet (ELN) recommendations for diagnosis and management of acute myeloid leukemia (AML), one of the most important changes made to the genetic risk classification of AML is that the FLT3-ITD allelic ratio (AR) is no longer considered in the risk classification; consequently, AML with FLT3-ITD (without adverse-risk genetic lesions) are now categorized in the intermediate-risk group, irrespective of the allelic ratio or concurrent presence of NPM1 mutation. Aims To investigate the survival outcomes of FLT3-ITD mutated AML patients underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT), based on prognostic stratification defined by the 2017 and 2022 ELN guidelines, and to analyze the risk factors affecting transplant prognosis. Methods A total of 163 FLT3-ITD mutated AML patients underwent allo-HSCT were enrolled in this study. Bone marrow aspirates were obtained, cytogenetic and molecular characteristics were collected at the time of diagnosis. Genetic risk category was classified according to the 2017 and 2022 edition of the European LeukemiaNet (ELN) recommendations. HLA-haploidentical donor transplants were performed if no HLA matched sibling or unrelated donor was available. Patients received myeloablative conditioning with a modified Bu/Cy/Flu/Ara-c (busulfan/cyclophosphamide/fludarabine/cytarabine) or MCBC (melphalan/cladribine/busulfan/cyclophosphamide) preparative regimen. The therapeutic process and clinical outcomes were retrospectively analyzed. Results We assessed 163 adults with FLT3-mutated AML (median age 37 years) allografted between 2017 and 2022 in our clinical center. The median follow-up of alive patients was 24.9 months. The 2-year relapse-free survival (RFS) and overall survival (OS) were 67.2% and 71.9%, respectively. The 2-year incidences of relapse and non-relapse mortality were 27.9% and 12.5%, respectively. There was no significant difference in survival outcomes between the intermediate and high-risk groups after transplantation, both defined by the 2017 and 2022 ELN guidelines. High FLT3-ITD allelic ratio (≥0.5) at initial diagnosis was associated with elevated WBC counts ( P&amp;lt;0.001), but did not affect the response ratefollowing induction chemotherapy ( P=0.059) . Patients with high allelic ratio were more likely to benefit from maintenance therapy after transplantation ( P=0.048 for OS). In univariate analysis, presence of NPM1 mutation and the allelic ratio of FLT3-ITD did not affect any of the transplant outcomes. In multivariate analysis, MRD-negative at transplantation, occurrence of chronic GVHD and posttransplant maintenance therapy improved OS and RFS. Conclusion Allo-HSCT can overcome the poor prognosis in patients with FLT3-ITD mutated AML. Neither the presence of NPM1 mutation nor the FLT3-ITD allelic ratio affected survival. Prevention of disease relapse after transplantation remains a challenge. The main prognostic factors affecting transplant outcomes included pre-transplant MRD status and the application of maintenance therapy. Thus, introduction of FLT3 inhibitors as post-transplant maintenance therapy and the development of highly sensitive MRD assays will further reduce disease recurrence and improve survival.

Toward a Measurable Residual Disease-Based Algorithm for Selection of Allogeneic Hematopoietic Stem Cell Transplant in Acute Myeloid Leukemia

Background: The diagnosis and management of acute myeloid leukemia (AML) have transformed in recent years with an improved understanding of leukemogenesis and improved methods of measurable residual disease (MRD) detection. Current treatment algorithms include consideration of allogeneic hematopoietic stem cell transplant (HCT) for intermediate and adverse-risk AML. MRD negativity is widely accepted as a predictive and prognostic marker for disease-free survival and overall survival. However, the clinical use of MRD status in consolidative HCT planning remains unclear. Methods: Two hundred thirty-three consecutive patients achieving complete remission (CR) as defined in ELN 2022 after receiving therapy at Massey Cancer Center were analyzed. MRD status was determined either by multiparameter flow cytometry, PCR-based sequencing, and/or next-generation sequencing. Patients were analyzed via retrospective chart review to obtain baseline characteristics, molecular and cytogenetic profiles, and survival data. Median overall survival (mOS) was calculated and compared using the Kaplan-Meier method. Continuous variables were compared using one-way ANOVA. Categorical variables were analyzed using Fisher's exact test. Results: In total,109 patients achieved MRD-negative CR and 124 patients achieved an MRD-positive CR. Of the MRD-negative patients, 42 went received HCT (39%). In the MRD-positive cohort, 44 underwent HCT (35%). Among the MRD negative group, those receiving HCT tended to be younger (52.1 y. [range: 24.8-71.7] vs 61. 8 y. (range: 27.1-82.9) p = 0.026) with fewer co-morbidities (Charlson comorbidity index [CCI] score: 3 [range: 2-9] vs 4 (range: 0-14), p = 0.322). We observed a similar trend in those who had MRD positivity at best response or at the time of transplant (age 55 y. [range: 24.5-72.2] vs 62 y. [range: 25.1-88], p = 0.142; CCI 4 [range: 2-7] vs 5 (range 2-11], p = 0.014). In the MRD-negative/no HCT group, 49.3% had ELN favorable-risk disease at initial AML diagnosis, 28.4% had intermediate risk, and 22.4% had adverse risk. In the MRD-negative/HCT group, 31% were favorable risk, 33.3% intermediate risk, and 35.7% were adverse risk. In the MRD-positive/HCT group, 46.3% favorable risk, 23.8% intermediate risk, and 29.5% were adverse risk. There were no significant differences in ELN risk between any group. MRD-positive patients who underwent HCT had a mOS of 25.7 m. vs 20.7 m. for no HCT (HR=0.68 [95% CI, 0.41-1.11], p = 0.125). The median OS was not reached for MRD-negative patients, regardless of receipt of HCT (HR=0.61 [95% CI, 0.30-1.23], p = 0.168). Patients undergoing HCT in MRD-negative CR had improved OS compared to those undergoing HCT with persistent MRD positivity (p = 0.006). Discussion: MRD positivity is a known predictor of relapse and decreased survival despite HCT. However, the use of MRD as a decision point predicting which patients will benefit from transplant a priori needs to be better understood. Our data suggest that MRD negativity has a more significant impact on overall prognosis than HCT status.Likewise, the negative impact of MRD positivity was not significantly abrogated by subsequent HCT. This highlights the need for refinement in HCT selection beyond ELN 2022 intermediate/adverse-risk patients, and new validated algorithms incorporating MRD status are warranted.

Cytogenetic profile of 1791 adult acute myeloid leukemia in India

BackgroundCytogenetic analysis continues to have an important role in the management of acute myeloid leukemia (AML) because it is essential for prognostication. It is also necessary to diagnose specific categories of AML and to determine the most effective form of treatment. Reports from South Asia are few because the availability of cytogenetic services is relatively limited. MethodsWe performed a retrospective analysis of the cytogenetic findings in adults with AML seen consecutively in a single centre in India. The results were categorised according to the 2022 World Health Organisation (WHO), International Consensus Classification (ICC) and European LeukemiaNet (ELN) classifications.ResultsThere were 1791 patients aged 18–85 years (median age 42, 1086 males). Normal karyotypes were seen in 646 (36%) patients. The 1145 (64%) abnormal karyotypes comprised 585 (32.7%) with recurrent genetic abnormalities (RGA), 403 (22.5%) with myelodysplasia-related cytogenetic abnormalities (MRC), and 157 (8.8%) with other abnormalities. There were 567 (31.7%) patients with solitary abnormalities and 299 (16.7%) with two abnormalities. Among the 279 (15.6%) patients with ≥ 3 abnormalities, 200 (11.2%) had complex karyotypes (CK) as per the WHO/ICC and 184 (10.3%), as per the ELN definition. There were 158 (8.8%) monosomal karyotypes (MK). Patients with normal karyotypes had a higher median age (45 years) than those with abnormal karyotypes (40 years, p < 0.001), and those with ≥ 3 abnormalities (43 years), than those with fewer abnormalities (39 years, p = 0.005). Patients with CK (WHO/ICC) and monosomal karyotypes had a median age of 48 years. Those with RGA had a lower median age (35 years, p < 0.001) than MRC (46 years) or other abnormalities (44 years). The t(15;17) was the most common abnormality (16.7%),followed by trisomy 8 (11.6%), monosomy 7/del 7q (9.3%), t(8;21) (7.2%), monosomy 5/del 5q (6.7%) and monosomy 17/del 17p (5.2%). ConclusionOur findings confirm the lower age profile of AML in India and show similarities and differences with respect to the frequencies of individual abnormalities compared to the literature. The frequencies of the t(15;17), trisomy 8 and the high-risk abnormalities monosomy 7 and monosomy 5/del 5q were higher, and that of the inv(16), lower than in most reports.

Olutasidenib: A ray of hope in the treatment of acute myeloid leukaemia

Acute myeloid leukaemia (AML) or Myelodysplastic syndrome (MDS) is one of the most common and life-threatening forms of blood cancer spreading worldwide. AML is characterized by some common sign and symptoms including fever, fatigue, easy bruising/bleeding, and sometimes with major differentiation syndrome. The pathogenesis of AML is attributed to the extreme differentiation of abnormally proliferated myeloid cell i.e., myeloblasts. Due to the cytotoxic potential of available chemical agents towards healthy cell, there is emerging need to develop target based selective medication with least adverse effects. Olutasidenib, is a quinoline-2-one analogue that selectively binds to mutated isocitrate dehydrogenase-1 to resist the formation of oncometabolite 2-hydroxyglutarate (2-HG) and hence, leads to cancerous cell apoptosis. Olutasidenib was approved on December 1, 2022, by FDA with the brand name Rezlidhea as one of the effective treatments against acute myeloid leukaemia via targeting IDH1m gene. In this review, a comprehensive report has been derived on olutasidenib with keen emphasis on pathophysiology of AML, mechanism of action, adverse effects along with pharmacokinetics and pharmacodynamics aspects of olutasidenib. Also, this review is focused on different clinical trials associated with the drug. Olutasidenib is a mutant IDH1 (Isocitrate dehydrogenase-1) inhibitor with significant potential in the management of acute myeloid leukaemia.

Novel Investigational Agents and Pathways That May Influence the Future Management of Acute Myeloid Leukemia.

Acute Myeloid leukemia (AML) is a clinically heterogeneous disease with a 5-year overall survival of 32% between 2012 to 2018. The above number severely dwindles with age and adverse risk of disease, presenting opportunities for new drug development and is an area of dire unmet need. Basic science and clinical investigators across the world have been working on many new and old molecule formulations and combination strategies to improve outcomes in this disease. In this review, we discuss select promising novel agents in various stages of clinical development for patients with AML.

Venetoclax combined with daunorubicin and cytarabine (2 + 6) as induction treatment in adults with newly diagnosed acute myeloid leukemia: a phase 2, multicenter, single-arm trial

BackgroundVenetoclax (Ven) combined with intensive chemotherapy was proven effective in the management of acute myeloid leukemia (AML). However, the severe and prolonged myelosuppression remains a concern to worry about. To explore more appropriate combination regimens, we designed Ven combining daunorubicin and cytarabine (DA 2 + 6) regimen as induction therapy, aimed to evaluate the effectiveness and safety in adults de novo AML.MethodsA phase 2 clinical trial was performed in 10 Chinese hospitals to investigate Ven combined with daunorubicin and cytarabine (DA 2 + 6) in patients with AML. The primary endpoints were overall response rate (ORR), comprising of complete remission (CR), complete remission with incomplete blood cell count recovery (CRi), and partial response (PR). Secondary endpoints included measurable residual disease (MRD) of bone marrow assessed by flow cytometry, overall survival (OS), event-free survival (EFS), disease-free survival (DFS), and the safety of regimens. This study is a currently ongoing trial listed on the Chinese Clinical Trial Registry as ChiCTR2200061524.ResultsOverall, 42 patients were enrolled from January 2022 to November 2022; 54.8% (23/42) were male, and the median age was 40 (range, 16–60) years. The ORR after one cycle of induction was 92.9% (95% confidence interval [CI], 91.6–94.1; 39/42) with a composite complete response rate (CR + CRi) 90.5% (95% CI, 89.3–91.6, CR 37/42, CRi 1/42). Moreover, 87.9% (29/33) of the CR patients with undetectable MRD (95% CI, 84.9–90.8). Grade 3 or worse adverse effects included neutropenia (100%), thrombocytopenia (100%), febrile neutropenia (90.5%), and one mortality. The median neutrophil and platelet recovery times were 13 (5–26) and 12 (8–26) days, respectively. Until Jan 30, 2023, the estimated 12-month OS, EFS, and DFS rates were 83.1% (95% CI, 78.8–87.4), 82.7% (95% CI, 79.4–86.1), and 92.0% (95% CI, 89.8–94.3), respectively.ConclusionVen with DA (2 + 6) is a highly effective and safe induction therapy for adults with newly diagnosed AML. To the best of our knowledge, this induction therapy has the shortest myelosuppressive period but has similar efficacy to previous studies.

Molecular MRD Assessment in Acute Myeloid Leukemias

AbstractDetection of measurable residual disease (MRD) is of significant value in the management of acute myeloid leukemia (AML) patients. Along with multicolor flowcytometry (MFC), molecular techniques form an integral tool in AML MRD detection. Multiple studies have reiterated the role of molecular MRD evaluation in AML at defined timepoints during the course of therapy, helping in risk stratification, prediction of relapse, and as guide for pre-emptive therapy. The latest World Health Organization (WHO) classification (WHO-HEME5) has refined the classification of AML bringing forth newer entities defined by molecular abnormalities, especially fusions. AML is a clonally heterogeneous disease characterized by a spectrum of multiple molecular abnormalities including gene mutations and fusions. Accordingly, the molecular methods employed are also diverse and need robust technical standardization in clinical laboratories. Real-time quantitative polymerase chain reaction (PCR), digital PCR, and next-generation sequencing (NGS) are the major molecular platforms for AML MRD. The European LeukemiaNet (ELN) MRD Working Party consensus document recently updated in 2021 for the first time has reflected on the technical recommendations for NGS MRD in AML and stressed the value of an integrated approach. It is, therefore, desirable for physicians, scientists, and pathologists alike to thoroughly understand these molecular methods for appropriate utilization and interpretation. In this article, we discuss the various facets of molecular methods for MRD detection in AML including technical requirements, advantages, drawbacks, and applications.

Validation of the prognostic significance of the 2022 European LeukemiaNet risk stratification system in intensive chemotherapy treated aged 18 to 65 years patients with de novo acute myeloid leukemia.

The European LeukemiaNet (ELN) recently proposed a revised recommendation for the diagnosis and management of acute myeloid leukemia (AML) in adults, recognized as ELN-2022. However, validation in a large real-world cohort remains lacking. In this study, we aimed to validate the prognostic relevance of the ELN-2022 in a cohort of 809 de novo, non-M3, younger (ages 18-65 years) AML patients receiving standard chemotherapy. The risk categories of 106 (13.1%) patients were reclassified from that determined using ELN-2017 to that determined using ELN-2022. The ELN-2022 effectively helped distinguish patients as favorable, intermediate, and adverse risk groups in terms of remission rates and survival. Among patients who achieved first complete remission (CR1), allogeneic transplantation was beneficial for those in the intermediate risk group, but not for those in the favorable or adverse risk groups. We further refined the ELN-2022 system by re-categorizing AML patients with t(8;21)(q22;q22.1)/RUNX1::RUNX1T1 with KIThigh , JAK2 or FLT3-ITDhigh mutations into the intermediate risk subset, AML patients with t(7;11)(p15;p15)/NUP98::HOXA9 and AML patients with co-mutated DNMT3A and FLT3-ITD into the adverse risk subsets, and AML patients with complex or monosomal karyotypes, inv (3)(q21.3q26.2) or t(3;3)(q21.3;q26.2)/GATA2,MECOM(EVI1) or TP53 mutation into the very adverse risk subset. The refined ELN-2022 system performed effectively to distinguish patients as favorable, intermediate, adverse, and very adverse risk groups. In conclusion, the ELN-2022 helped distinguish younger, intensively treated patients into three groups with distinct outcomes; the proposed refinement of ELN-2022 may further improve risk stratification among AML patients. Prospective validation of the new predictive model is necessary.

Bone marrow CD34+ molecular chimerism as an early predictor of relapse after allogeneic stem cell transplantation in patients with acute myeloid leukemia.

Minimal residual disease (MRD) monitoring is an important tool to optimally address post-transplant management of acute myeloid leukemia (AML) patients. We retrospectively analyzed the impact of bone marrow CD34+ molecular chimerism and WT1 on the outcome of a consecutive series of 168 AML patients submitted to allogeneic stem cell transplantation. The cumulative incidence of relapse (CIR) was significantly lower in patients with donor chimerism on CD34+ cells ≥ 97.5% and WT1 < 213 copies/ABL x 10^4 both at 1st month (p=0.008 and p<0.001) and at 3rd month (p<0.001 for both). By combining chimerism and WT1 at 3rd month, 13 patients with chimerism < 97.5% or WT1 > 213 showed intermediate prognosis. 12 of these patients fell in this category because of molecular chimerism < 97.5% at a time-point in which WT1 was < 213. Our results confirm that lineage-specific molecular chimerism and WT1 after allo-SCT (1st and 3rd month) are useful MRD markers. When considered together at 3rd month, CD34+ molecular chimerism could represent an earlier predictor of relapse compared to WT1. Further studies are necessary to confirm this preliminary observation.

An Update on FLT3 in Acute Myeloid Leukemia: Pathophysiology and Therapeutic Landscape.

This review aims to summarize the pathophysiology, clinical presentation, and management of acute myeloid leukemia (AML) with FMS-like tyrosine kinase-3 (FLT3) mutations. The recent European Leukemia Net (ELN2022) recommendations re-classified AML with FLT3 internal tandem duplications (FLT3-ITD) as intermediate risk regardless of Nucleophosmin 1 (NPM1) co-mutation or the FLT3 allelic ratio. Allogeneic hematopoietic cell transplantation (alloHCT) is now recommended for all eligible patients with FLT3-ITD AML. This review outlines the role of FLT3 inhibitors in induction and consolidation, as well as for post-alloHCT maintenance. It outlines the unique challenges and advantages of assessing FLT3 measurable residual disease (MRD) and discusses the pre-clinical basis for the combination of FLT3 and menin inhibitors. And, for the older or unfit patient ineligible for upfront intensive chemotherapy, it discusses the recent clinical trials incorporating FLT3 inhibitors into azacytidine- and venetoclax-based regimens. Finally, it proposes a rational sequential approach for integrating FLT3 inhibitors into less intensive regimens, with a focus on improved tolerability in the older and unfit patient population. The management of AML with FLT3 mutation remains a challenge in clinical practice. This review provides an update on the pathophysiology and therapeutic landscape of FLT3 AML, as well as a clinical management framework for managing the older or unfit patient ineligible for intensive chemotherapy.

Clinical Utility of Azacitidine in the Management of Acute Myeloid Leukemia: Update on Patient Selection and Reported Outcomes.

Acute myeloid leukemia (AML) is predominantly a disease of the elderly, and a significant proportion of these patients are not candidates for intensive, curative-intent therapies. Epigenetic dysregulation resulting in abnormal DNA hypermethylation is one of the hallmarks of AML pathogenesis. For the past two decades, hypomethylating agents including azacitidine (AZA) have been the mainstay of treatment for AML patients who are ineligible to receive intensive chemotherapies. As our understanding of AML disease biology has improved, several novel treatment combinations have been developed to improve the outcome of AML patients, with remarkable success. A considerable proportion of these novel combinations have utilized AZA as the backbone of their treatment scheme. In this review, we have highlighted the evolution of AML treatment, focusing on novel AZA-based treatment combinations and their clinical efficacy.

Role of Extracorporeal Membrane Oxygenation (ECMO) and Stem Cell Transplant in the Management of Acute Myeloid Leukaemia with Pulmonary Involvement.

Role of Extracorporeal Membrane Oxygenation (ECMO) and Stem Cell Transplant in the Management of Acute Myeloid Leukaemia with Pulmonary Involvement.