Intensive Chemotherapy Research Articles

Targeting LMO2-induced autocrine FLT3 signaling to overcome chemoresistance in early T-cell precursor acute lymphoblastic leukemia.

Early T-cell Precursor Acute Lymphoblastic Leukemia (ETP-ALL) is an immature subtype of T-cell acute lymphoblastic leukemia (T-ALL) commonly show deregulation of the LMO2-LYL1 stem cell transcription factors, activating mutations of cytokine receptor signaling, and poor early response to intensive chemotherapy. Previously, studies of the Lmo2 transgenic mouse model of ETP-ALL identified a population of stem-like T-cell progenitors with long-term self-renewal capacity and intrinsic chemotherapy resistance linked to cellular quiescence. Here, analyses of Lmo2 transgenic mice, patient-derived xenografts, and single-cell RNA-sequencing data from primary ETP-ALL identified a rare subpopulation of leukemic stem cells expressing high levels of the cytokine receptor FLT3. Despite a highly proliferative state, these FLT3-overexpressing cells had long-term self-renewal capacity and almost complete resistance to chemotherapy. Chromatin immunoprecipitation and assay for transposase-accessible chromatin sequencing demonstrated FLT3 and its ligand may be direct targets of the LMO2 stem-cell complex. Media conditioned by Lmo2 transgenic thymocytes revealed an autocrine FLT3-dependent signaling loop that could be targeted by the FLT3 inhibitor gilteritinib. Consequently, gilteritinib impaired in vivo growth of ETP-ALL and improved the sensitivity to chemotherapy. Furthermore, gilteritinib enhanced response to the BCL2 inhibitor venetoclax, which may enable "chemo-free" treatment of ETP-ALL. Together, these data provide a cellular and molecular explanation for enhanced cytokine signaling in LMO2-driven ETP-ALL beyond activating mutations and a rationale for clinical trials of FLT3 inhibitors in ETP-ALL.

The clinical observation of none-promyelocytic AML patients inducted with idarubicin or daunorubicin included standard regimens: a tertiary care center experience

BackgroundFew Chinese study compared the impacts of idarubicin and daunorubicin based “3+7” intensive chemotherapies on early and long-term outcomes of AML patients through exploring their real-world data.Patients and methodsOur none promyelocytic AML patients inducted with “3+7” regimens were studied to find out the factors relating with induction response and long term survival.ResultsIdarubicin induction was related with less chemotherapy refractory rate comparing with daunorubicin induction (10% vs 25%, P = 0.02). But cytogenetic molecular risk classification was the only independent factor relating with achieving CR after initial induction or chemotherapy refractory (P = 0.000 and 0.036). Both to overall survival (OS) and progress free survival (PFS), having transplantation and chemotherapy refractory were independent factors related, MLL rearrangement and DNA methylating related genes’ mutations as well. CR at time of transplantation and MLL rearrangement were independent factors relating both with OS after transplantation and relapse free survival after transplantation.ConclusionTraditional “3+7” chemotherapy regimen with idarubicin plays better in CR induction than that with daunorubicin. But the patient’s long-term survival related with clinical practice aspects, like having stem cell transplantation, as well as genetic alterations equally, like MLL rearrangement and DNA methylating related genes’ mutations.

Final Analysis of the Phase 1b Chemotherapy And Venetoclax in Elderly Acute Myeloid Leukaemia Trial (CAVEAT).

Venetoclax plus azacitidine represents a key advance for older, unfit patients with acute myeloid leukemia (AML). The chemotherapy and venetoclax in elderly AML trial (CAVEAT) was first to combine venetoclax with intensive chemotherapy in newly diagnosed patients ≥65 years. In this final analysis, 85 patients (median age 71 years) were followed for a median of 41.8 months. The CAVEAT induction combined cytarabine and idarubicin with 5 dose levels of venetoclax (50-600 mg) for up to 14 days. Two additional cohorts explored adjusted-dose venetoclax (50 mg, 100 mg) with posaconazole. CAVEAT induction was well tolerated, with low mortality (4%) and limited high-grade gastrointestinal toxicity (4%). Delayed hematological recovery after consolidation was ameliorated by omitting idarubicin from post-remission therapy. The overall response rate (ORR: CR + CRh + CRi) was 75% with a median overall survival (OS) of 19.3 months (95% CI 11.1-31.3). Among de novo AML, ORR was 88% and median OS 33.1 months (95% CI 19.3-54.3). Almost one-third have not relapsed, many benefiting from prolonged treatment-free remission (median 17.9 months). CAVEAT induction was well tolerated and associated with high ORR that was durable, particularly for de novo AML. CAVEAT represents an effective time-limited treatment option for fit older patients with AML. (https://www.anzctr.org.au; ACTRN12616000445471).

Multifaceted Roles of Nursing in the Care of Patients Receiving CAR T-cell Therapy for Pediatric Refractory or Relapsed Acute Lymphoblastic Leukemia

Pediatric acute lymphoblastic leukemia (ALL) is the most common cancer in children. Survival rates after initial diagnosis of ALL are quite high, however survival rates for patients with refractory or relapsed ALL remain poor despite intensive chemotherapy, indicating the need for novel therapies. Treatment for pediatric refractory and relapsed ALL has undergone a dramatic change over the past twelve years due to the success of targeted immunotherapy. In particular, chimeric antigen receptor-T (CAR-T) cell therapy has shown great promise in the treatment of pediatric refractory and relapsed ALL. Due to encouraging initial results, there are increasing numbers of trials utilizing this treatment. Patients and families have been given hope with the introduction and progress of this innovative therapy. Expert nursing care is crucial for successful patient outcomes. Nurses are integral to the management, care, and monitoring of CAR-T cell patients, ensuring study guidelines are followed and providing continuity. CAR-T cell therapy has the potential to cause severe toxicities. Therefore, nurses must be educated so that they can provide safe care and effectively educate patients and families regarding the associated risks. In this article we describe the CAR-T cell process and focus on the multiple roles of the nurse along with highlighting collaborative relationships with other disciplines.

Characteristics, outcomes and treatment patterns in acute myeloid leukemia patients 60 years or older in Colombia: a RENEHOC-PETHEMA study.

There is a limited information available on the clinical characteristics, treatment patterns and outcomes on older patients diagnosed with Acute Myeloid Leukemia (AML) in Latin-America. This multicenter retrospective study analyzed 269 patients over 60 years of age diagnosed with AML in Colombia, using data from RENEHOC-PETHEMA registry, from 2009 to 2023. The median age at diagnosis was 70 years (Range:60-98), 55% were men, 61% had an ECOG < 2, and 75.5% had de novo AML. FLT3-ITD or NPM1 mutations were performed in 23.4% and 15.6% patients, and detected in 14.3% and 16.7% of cases, respectively. Treatment included intensive chemotherapy (IC) (36.8%), Low-Intensity Regimen Based on Low-Dose Cytarabine (LDAC-based) (12.6%), hypomethylating agents (HMAs, with/without venetoclax) (35.3%), and supportive care (15.2%). The overall survival (OS) rate was 35.2% at 1 year and 5.6% at 5 years (13.7% for IC, 9.4% for LDAC-based, and 0% for other treatments); with median OS of 8.2 months (10.6 months after IC, 8.8 months after non-IC, 8.9 months after azacitidine/decitabine, 8.2 months after azacitidine-venetoclax, and 1.9 months with supportive care). Only 1.5% of patients underwent a transplant in the first line. The Leukemia-free survival (LFS) rate was 45.8% at 1-year and 13.7% at 5-years (22.4% for IC, 9.4% and 0% for other treatments); with median LFS of 9.5 months (17.3 months after IC, 7.4 months after LDAC-based, and 10.8 months after HMA). This study provides new insights into the management of patients in Colombia, highlighting the need for a highly individualized approach in treating AML in elderly patients.

Safety and Tolerability of Interval Compressed Chemotherapy Schedule in Children Receiving Treatment for Ewing Sarcoma: A Real-world Experience From India.

Chemotherapy with alternating cycles of vincristine-doxorubicin-cyclophosphamide and ifosfamide-etoposide, along with primary tumor treatment with surgery or radiotherapy or both, constitute the usual treatment of Ewing sarcoma. The AEWS0031 study demonstrated survival benefits after interval-compressed chemotherapy without significant toxicity. The aim of this study was to assess the tolerability of dose-intensified chemotherapy in developing countries like India. This was a retrospective analysis of children younger than 18 years of age with newly diagnosed Ewing sarcoma who came for treatment from December 2017 to December 2022. Children received vincristine (2mg/m2), doxorubicin (75mg/m2), and cyclophosphamide (1.2g/m2) alternating with ifosfamide (9g/m2), etoposide (500mg/m2) for 17 cycles, with filgrastim (5µg/kg; maximum 300µg) between cycles. Primary tumor treatment was provided with surgery or radiotherapy or both. Local treatment was given between weeks 12 to 16. Toxicity was assessed using the Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. Radiologic response assessment was carried out with restaging CT or MRI scans after 6 to 8 cycles of chemotherapy in nonmetastatic and metastatic settings, respectively. Thirty-one children were enrolled. Twenty-three children received all 17 cycles of chemotherapy. The median cycle interval was 18 days and 41% of children received chemotherapy at the 2-week interval. Grade 4 febrile neutropenia was observed in 32% of cycles but no treatment-related mortality was reported. Anemia and thrombocytopenia requiring transfusion support were recorded in 28 (5.6%) and 69 cycles (13.9%) of chemotherapy, respectively. There were 2 events of grade 4 cardiac toxicities in the form of cardiomyopathy and arrhythmia requiring intensive care management. After surgery, good necrosis was achieved in 61% of cases. Three children had a relapse with an event-free survival (EFS) of 87%. Intensified chemotherapy administered every 2 weeks intervals in Ewing sarcoma, is tolerable with adequate supportive care in resource-constrained settings.

Diverse real-life outcomes after intensive risk-adapted therapy for 1034 AML patients from the CETLAM Group

Given the heterogeneity of acute myeloid leukemia patients, it is necessary to identify patients considered fit for intensive therapy but who will perform poorly, and in whom alternative approaches deserve investigation. We analyzed 1034 fit adults ≤70 years intensively treated between 2012 and 2022 in the CETLAM group. Young adults ( ≤ 60 years) presented higher remission rates and improved survival than older adults above that age (CR 79% vs. 73%; p = 0.03 and 4-yr OS 53% vs. 33%; p < 0.001). Remission and survival outcomes varied among different genetic subsets. An especially adverse genetic group included complex, monosomal karyotype, TP53 alterations (deleted/mutated), and MECOMr. Transplant feasibility in this very adverse risk group was low, and OS and EFS at 4 years were 14% and 12%, in contrast to 70% and 57% in the favorable group and 38% and 32% in all other patients. We integrated clinical and genetic data into the Intensive Chemotherapy Score for AML (ICSA) with 6-risk categories with significantly different remission rates and OS, validated in another cohort of 581 AML patients from a previous CETLAM protocol. In summary, we identified groups of fit patients that benefit differently from an intensive approach which may be helpful in future treatment decisions.

Prognostic factors and outcomes of pediatric acute lymphoblastic leukemia using ThaiPOG protocols: a single institute experience

Background Acute lymphoblastic leukemia (ALL) is the most common malignancy among children. Disease-based risk stratification was incoporated in the Thai Pediatric Oncology Group (ThaiPOG) protocols to adjust intensive chemotherapies,and central nervous system-directed treatment. Although treatment outcomes have improved over the decade, excellent outcomes are counterbalanced by treatment-related toxicities, especially in countries with limited resources like Thailand. Objective The single institute study aimed to evaluate prognostic factors associated with survival outcomes in pediatric ALL using ThaiPOG protocols at Phramongkutklao Hospital. Materials and methods Pediatric patients with ALL treated at Phramongkutklao Hospital between 2014 and 2019 were retrospectively reviewed. Results In total, 50 patients with a median age of 9.64 (range, 0.34-19.81) years were studied. The most common immunophenotype was pre-B cell ALL (N = 42, 84%). The 5-year overall survival (OS) and event-free survival (EFS) were 80% and 76%, respectively. The major mortality cause was treatment-related infection (N = 7, 14%). Unfavorable cytogenetics was the only factor associated with OS (p = 0.006) and EFS (p &lt; 0.001). Conclusion The outcomes of pediatric ALL in Thailand were comparable to those of developed countries. Cytogenetic testing is essential for stratifying disease status and tailoring treatment protocol accordingly. Infections remain the leading cause of death among pediatric patients with ALL.

Clostridium perfringens Sepsis Complicated by Hepatic Abscess Following Intensive Chemotherapy in Mixed-Phenotype Acute Leukemia

Clostridium perfringens Sepsis Complicated by Hepatic Abscess Following Intensive Chemotherapy in Mixed-Phenotype Acute Leukemia

Investigating resistance to 5-Azacytidine and Venetoclax in PDX models of MDS/AML.

Progressing myelodysplastic syndrome (MDS) into acute myeloid leukemia (AML) is an indication for hypomethylating therapy (HMA, 5-Azacytidine (AZA)) and a BCL2 inhibitor (Venetoclax, VEN) for intensive chemotherapy ineligible patients. Mouse models that engraft primary AML samples may further advance VEN + AZA resistance research. We generated a set of transplantable murine PDX models from MDS/AML patients who developed resistance to VEN + AZA and compared the differences in hematopoiesis of the PDX models with primary bone marrow samples at the genetic level. PDX were created in NSGS mice via intraosseal injection of luciferase-encoding Lentivirus-infected MDS/AML primary cells from patient bone marrow. We validated the resistance of PDX-leukemia to VEN and AZA and further tested candidate agents that inhibit the growth of VEN/AZA-resistant AML. Transplantable PDX models for MDS/AML arise with 31 % frequency. The lower frequency of transplantable PDX models is not related to peritransplant lethality of the graft, but rather to the loss of the ability of short-term proliferation of leukemic progenitors after 10 weeks of engraftment. There exist subtle genetic and cytological changes between primary and PDX-AML samples however, the PDX models retain therapy resistance observed in patients. Based on in vitro testing and in vivo validation in PDX models, Panobinostat and Dinaciclib are very promising candidate agents that overcome dual VEN + AZA resistance.

The antibiotic de-escalation strategy in patients with multidrug-resistant bacterial colonization after allogeneic stem cell transplantation.

Colonization by multidrug-resistant (MDR) bacteria and related bloodstream infections (BSI) are associated with a high rate of mortality in patients with hematological malignancies after intensive chemotherapy and allogeneic stem cell transplantation (allo-SCT). In this retrospective study, we analyzed the outcomes of patients colonized with MDR bacteria (primarily carbapenem-resistant klebsiella pneumoniae, KPC), before allo-SCT. We also investigated the feasibility and safety of an antimicrobial de-escalating approach in these patients. Since 2021, 106 patients have been undergoing allo-SCT in our department, and 34 (32%) of them were colonized by MDR bacteria before allo-SCT. In the pre-engraftment period, 84% received an empiric antibiotic therapy (EAT) active against MDR bacteria and 16% were treated with a conventional EAT. The MDR translocation rate was null, and the overall de-escalation rate was 79%, with 75% in patients with fever of unknown origin (FUO). Among the cohort of patients with MDR-positive rectal swabs just before allo-SCT (n = 18), the de-escalation rate was 100%. The all-cause mortality rates at 30 and 100 days for the whole MDR patient population were 6% (2/34) and 12% (4/34), respectively. Day +30 infection-related mortality rate was 3%. In this study, we confirm the safety of the de-escalation approach in patients with previous MDR infection after allo-SCT. This could reduce the exposure time to EAT antibiotics, reducing the selective pressure.

Single-center experience of venetoclax combined with azacitidine in young patients with newly diagnosed acute myeloid leukemia.

Medical resources, especially blood products, were in short supply during the COVID-19. Less intensive therapy with hypomethylating agents/venetoclax (VEN) seems an effective treatment option for patients with acute myeloid leukemia (AML). To retrospectively analyze the efficacy and safety of VEN combined with azacitidine (AZA) in young adult patients with newly diagnosed (ND) AML. This was a retrospective study. The clinical data of 25 AML patients treated with the VEN + AZA regimen from January 2021 to December 2023 at our center were collected, compared with a randomized historical study cohort that was administered intensive chemotherapy (IC) from January 2018 to December 2019. No rate of complete remission/complete remission with incomplete count recovery differences observed between the two arms reached statistical significance. Compared to traditional IC, minimal residual disease (MRD)-negative remission was achieved more quickly in patients treated with VEN + AZA regimens (after cycle 1: 8% in the IC group vs 56% in the VEN group, p = 0.0004; after cycle 2: 16% in the IC group vs 72% in the VEN group, p = 0.0001), especially in those AML patients who had a poor prognosis. The dependency of transfusion of red blood cell (RBC) and platelets during induction treatment was significantly lower in the VEN + AZA group (RBC: p = 0.0269; platelet: p = 0.0054). Compared with the standard IC, the incidence rate of non-hematological adverse events in VEN + AZA group was significantly decreased (infection: 100% vs 20%, p = 0.0001; gastrointestinal side effects: 48% vs 12%, p = 0.0055). The total hospitalization cost of the VEN group was significantly less than that of the IC group (p = 0.0395). In conclusion, our study indicated that VEN + AZA with a higher MRD-negative remission rate and less toxic appeared to be a therapy option for young patients with ND AML. However, further well-designed studies with larger numbers of patients are needed to confirm the benefits of VEN + AZA in this population.

Reduced-intensity chemotherapy with tyrosine kinase inhibitor followed by allogeneic transplantation is effective in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia.

To determine the effectiveness of tyrosine kinase inhibitor (TKI) plus reduced-intensity therapy in adult patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL), this retrospective study compared treatment outcomes and induction mortality according to backbone regimen intensity. The data of 132 patients diagnosed with Ph-positive ALL were retrospectively collected from five centers. Patients received imatinib plus intensive chemotherapy (modified VPD, KALLA1407, or hyper-CVAD) or reduced-intensity chemotherapy (EWALL) for curative purposes. This study analyzed 117 patients, of which 35,22,46, and 14 received modified VPD, KALLA1407, hyper-CVAD, and EWALL, respectively. All patients used imatinib as a TKI. The median age of the patients who received reduced-intensity chemotherapy was 64.4 years, while that of the patients with intensive regimens was 47.5 years. There was no induction death in the reduced-intensity group, while nine patients died in the intensive therapy group. Major molecular response achievement tended to be higher in the intensive chemotherapy group than in the reduced-intensity group. More patients in the intensive chemotherapy group received allogeneic stem cell transplantation (allo-SCT). There was no statistically significant difference in long-term survival between the two groups in terms of relapse-free survival and overall survival rates. When imatinib plus reduced-intensity therapy was used as a frontline treatment, there was no inferiority in obtaining complete remission compared to imatinib plus intensive chemotherapy or significant difference in long-term survival. Since imatinib plus reduced-intensity therapy has limitations in obtaining a deep molecular response, proceeding to allo-SCT should be considered.

Unraveling the impact of noncoding RNAs in osteosarcoma drug resistance: a review of mechanisms and therapeutic implications.

Osteosarcoma (OS) is a prevalent primary malignant bone tumor, typically managed through a combination of neoadjuvant chemotherapy and surgical interventions. Recent advancements in early detection and the use of novel chemotherapeutic agents have significantly improved the 5-year survival rate of OS patients. However, some patients fail to achieve the desired treatment outcomes despite undergoing intensive chemotherapy and surgicals procedures, with chemotherapy resistance emerging as a critical factor contributing to therapeutic failure in OS. Noncoding RNAs (ncRNAs) are a group of RNAs that lack protein-coding capacity but play a crucial role in tumor progression by modulating various biological characteristics of cancer cells, such as proliferation, apoptosis, migration, invasion, and drug resistance. Emerging evidence indicates that the dysregulated expression of numerous ncRNAs in OS cells can influence the response to chemotherapeutic agents by modulating processes such as cell apoptosis, signaling pathways, intracellular drug concentrations, and cell autophagy. This review aims to elucidate the roles and mechanisms of ncRNAs in mediating drug resistance in OS, offering new insights for investigating novel pathways underlying drug resistance, overcoming tumor resistance to therapeutics, and developing innovative chemotherapeutic strategies.

Treatment of refractory and recurrent T-lymphoblastic lymphomas from progenitor cells in children and adolescents: current problem state and future perspectives

Introduction. Despite the successes achieved in the treatment of lymphoblastic lymphomas from progenitor cells (LBL), an important task in improving survival rates in the group of patients with T-cell lymphoblastic lymphomas (T-LBL) remains. The group of special unfavorable prognosis consists of patients with relapses and refractory forms (r/r) of T-LBL.Aim: to present a literature review on the use of targeted and immune drugs, as well as cellular and transplant methods in the treatment of r/r T-LBL.Main findings. Modern clinical onco-hematology has a broad spectrum of methods for the treatment of r/r T-LBL, including intensive chemotherapy, targeted, transplant and CAR-T technologies, but even a combination of these methods, currently, does not make it possible to achieve optimistic results in this prognostically unfavorable group of patients. It is possible that the creation of targeted drugs focused on signaling pathways (NOTCH, PI3K/ACT/mTOR, JAK/STAT and MAPK) with modern therapeutic potential could improve patient survival rates.

Tumor Lysis Syndrome in Acute Myeloid Leukemia Patients Treated With a Venetoclax Based Regimen.

Venetoclax with hypomethylating agents (HMA) is the standard of care for acute myeloid leukemia (AML) in patients ineligible for intensive chemotherapy and is associated with tumor lysis syndrome (TLS). TLS prophylaxis and the use of Cairo Bishop versus Howard diagnostic criteria are not standardized. Here we report TLS prophylaxis and incidence in a retrospective cohort of 100 consecutive AML patients treated with venetoclax and HMA. Thirty four patients developed laboratory Cairo Bishop TLS; 8 of these met criteria for clinical Cairo Bishop TLS. Only 6 of patients met Howard TLS criteria. Fourteen patients had spontaneous TLS. Ninety two out of 100 patients had a white blood cell count (WBC) < 25 000 cells/μL at treatment start. Prophylaxis like the original venetoclax trial with allopurinol (56%), intravenous fluids (21%), and frequent lab monitoring (56%) was less common. There was a trend toward increased Cairo Bishop TLS in patients with WBC ≥ 15 000 cells/μL. In our study Howard TLS criteria better identified patients with significant TLS. Aggressive TLS prophylaxis was uncommon in our cohort and is likely unnecessary for most patients at low risk of TLS.

Anti-CD19 CAR T-cell therapy for primary and secondary CNS lymphomas.

Central nervous system lymphomas (CNSL) are a heterogeneous group of generally aggressive tumors whose prognosis varies significantly, being more favorable in patients with primary disease and poorer in those with secondary lymphoma. Current treatments typically involve intensive chemotherapy followed by consolidation with autologous stem cell transplantation or whole-brain radiotherapy. However, if the disease relapses, there is no established standard of care. The recent approval of anti-CD19 chimeric antigen receptor (CAR) T-cell therapy for systemic B-cell lymphomas has shifted the treatment landscape for previously incurable patients. Even though this therapy was initially underexplored in the setting of CNSL due to safety and efficacy concerns, it could offer a new therapeutic avenue for these patients. In this review, we will provide a concise overview of the current treatment strategies for CNSL, highlighting their key limitations, including relapse rates and long-term toxicity. Following this, we will explore the most important studies and clinical trials on CNSL, focusing on recent advancements in anti-CD19 CAR T-cell therapy. This comprehensive analysis will offer insights into the successes and challenges of treating CNSL effectively.

Efficacy and safety of hypomethylating agents in the treatment of AML/MDS patients relapsed post allogenetic hematopoietic stem cell transplantation

IntroductionAcute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) constitute myeloid malignancies, and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is considered as a potentially optimal approach for achieving a long term cure. However, post-allo-HSCT relapse remains a leading cause of mortality and therapeutic failure.MethodsTo evaluate the efficacy and safety of combining hypomethylating agents (HMAs) with Bcl-2 inhibitors in the treatment of AML/MDS relapse following allo-HSCT, we retrospectively collected data from 42 patients who experienced relapse between April 2012 and March 2022 at Peking University First Hospital. Among these patients, 21 underwent intensive chemotherapy (IC) alone, while the other 21 received treatment with HMAs after IC treatment, either alone or in combination with the Bcl-2 inhibitor venetoclax (VEN).ResultsThe median overall survival (OS) was 9 ± 2.153 months, and the one-year OS rate was 41.5%. The overall response rate (ORR) in the chemotherapy group and the IC+HMAs ± VEN group was 52.38% (11/21) and 76.19% (16/21), respectively, with no significant difference found (P=0.107). Kaplan-Meier analysis revealed a significant difference in OS between the chemotherapy group and the IC+HMAs ± VEN group in our retrospective cohort study (P=0.041, χ2= 4.016). Additionally, a significant difference in overall survival (OS) rates was observed between the two groups for patients categorized as intermediate/high risk (P=0.008). The secondary relapse rate was 45.45% (5/11) in the IC cohort and 25% (4/16) in the IC+HMAs ± VEN group, respectively, with no significant difference identified between the two cohorts (P=0.268). Furthermore, upon assessing the risk of graft-versus-host disease (GvHD), infection, and agranulocytosis, no notable differences were observed with the use of HMAs, suggesting that HMAs did not increase the risk. In the IC+HMAs ± VEN group, 7 patients received VEN in addition to HMAs, and no significant statistical difference was found in OS when comparing patients who received HMAs alone and those who received HMA+VEN (P=0.183), also, a statistically significant difference in OS was noted between the two groups whenaccounting for competing risks (P=0.028).ConclusionsThis retrospective study highlights the efficacy of IC+HMAs ± VEN in treating AML/MDS patients experiencing relapse post allo-HSCT, improving survival rates, especially for those classified as intermediate/high risk, with favorable tolerability.

Trial eligibility, treatment patterns and outcome for venetoclax-based therapy in AML: a prospective cohort study.

Venetoclax (Ven) plus hypomethylating agents are considered standard-of-care for patients with acute myeloid leukemia (AML) judged ineligible for intensive chemotherapy (IC). Real-world studies complement clinical trials, since patterns of patient selection, treatment-exposure and post-remission management may vary. This prospective observational multi-center study included 209 newly diagnosed IC-ineligible patients with a median age 75 years (interquartile range, 71-81 years). A high proportion of patients had secondary AML (53.7%), adverse-risk disease (35.3%), and complex karyotype (15.5%). At a median follow-up of 22.5 months (range 0.1-43), median overall-survival (mOS) was 11.7 months (95% Confidence Interval [CI] 9.9,15.4). Composite complete remission (CRc) was achieved in 65.2% (CR 44.4%; CRi 20.8%). Of responding patients, 21.1% underwent stem-cell transplantation. When stratified based on VIALE-A original eligibility criteria, mOS was 17.8 months for patients meeting eligibility criteria and 10.7 months for patients who did not (p=0.027). AML ontogeny (p=0.024), reduced kidney function (p=0.001), Charlson co-morbidity index (CCI; p=0.0017), ELN-risk (p=0.01) and body-mass index (p=0.0298) were significantly associated with OS. Multivariant Cox-regression analysis confirmed independent association of OS with AML ontogeny (p=0.012), CCI (p=0.033) and ELN-risk (p=0.019). Patients enrolled in the latter half of the study period demonstrated improved OS compared to those enrolled earlier (p=0.026). This prospective observational study highlights outcomes of patient subgroups, including those excluded from registration trials. (clinicaltrials.gov: #NCT03987958).

Effects of Hypomethylating Agents on Gene Modulation in the Leukemic Microenvironment and Disease Trajectory in a Mouse Model of AML.

Hypomethylating agents (HMAs), such as decitabine and 5-azacytidine (AZA), are valuable treatment options for patients with acute myeloid leukemia that are ineligible for intensive chemotherapy. Despite providing significant extensions in survival when used alone or in combination, eventual relapse and resistance to HMAs are observed. The mechanisms leading to these outcomes are still not well defined and may, in part, be due to a focus on leukemic populations with limited information on the effects of HMAs on non-leukemic cells in the blood and other tissue compartments. In this study, we elucidated effects on immune-related gene expression in non-leukemic blood cells and the spleen during AZA treatment in leukemia-challenged mice. We observed significant changes in pathways regulating adhesion, thrombosis, and angiogenesis as well as a dichotomy in extramedullary disease sites that manifests during relapse. We also identify several genes that may contribute to the anti-leukemic activity of AZA in blood and spleen. Overall, this work has identified novel gene targets and pathways that could be further modulated to augment efficacy of HMA treatment.