abt-199 and Myelodysplastic-Syndromes

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

Topics: Aged; Azacitidine; Hematologic Neoplasms; Humans; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Proto-Oncogene Proteins c-bcl-2

Currently, there is no standard treatment for managing relapse in patients with acute myeloid leukemia and myelodysplastic syndrome (AML/MDS) after allogeneic hematopoietic cell transplantation. Venetoclax-based therapies have been increasingly used for treating post-transplantation relapse of AML. The aim of this systematic review and meta-analysis was to evaluate the efficacy and adverse events of Venetoclax combined with hypomethylating agents (HMAs) for AML/MDS relapse post-transplantation.. We searched PubMed, Web of Science, Excerpta Medica Database, Cochrane Library, and Clinical. gov for eligible studies from the inception to February 2022. The Methodological Index for Non-Randomized Studies was used to evaluate the quality of the included literatures. The inverse variance method calculated the pooled proportion and 95% confidence interval (CI).. This study demonstrated a moderate benefit of Venetoclax in combination with HMAs for patients with relapsed AML/MDS post-transplantation (including those who have received prior HMAs therapy), and may become one of treatment options in the future. Large-scale prospective studies are needed to confirm the potential benefit from venetoclax combined with HMAs.

Topics: Bridged Bicyclo Compounds, Heterocyclic; Chronic Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Neoplasms, Second Primary

Venetoclax is a BCL-2 inhibitor that was approved in combination therapy with hypomethylating agents or low dose cytarabine for newly diagnosed acute myeloid leukemia (AML). The purpose of this review is to outline the most recent venetoclax-based combination therapies in newly diagnosed or relapsed myelodysplastic syndrome (MDS) and AML patients.. Venetoclax has been incorporated in various therapeutic regimens - either with chemotherapy, immunotherapy or targeted therapies. These combinations achieve high remission rates with deep molecular responses, as suggested by measurable residual disease measurements. There are concerns regarding the incomplete count recovery, prolonged cytopenia and infection rates, especially when combined with chemotherapy. There is also limited data concerning durability of these remissions, and the effectiveness in high-risk population (i.e. p53-mutated AML patients).. Venetoclax-based combination therapies encompass novel therapeutic possibilities in MDS and AML with encouraging initial results. However, the exact role of each combination therapy and the long-term effects on patients' outcome are yet to be defined.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Cytarabine; Humans; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Sulfonamides

We present a systematic review and meta-analysis to evaluate outcomes after venetoclax (VEN) with hypomethylating agents (HMA) in myelodysplastic syndromes (MDS). We performed a literature search on PubMed, Cochrane Library, EMBASE, and Clinicaltrials.gov. After screening 2004 manuscripts, 16 studies were included. Data was extracted following PRISMA guidelines. Pooled analysis was done using the meta-package by Schwarzer et al. Proportions with 95% confidence intervals (CI) were computed. We analyzed the outcomes of 373 patients from 11 retrospective studies and five phase 1 b clinical trials. Pooled complete response with or without hematological recovery was 60% (95% CI 0.49-0.7,

Topics: Antimetabolites, Antineoplastic; Humans; Myelodysplastic Syndromes; Prospective Studies; Retrospective Studies

Targeting TP53 mutated myelodysplastic syndromes and acute myeloid leukemia remains a significant unmet need. Recently, new drugs have attempted to improve the outcomes of this poor molecular subgroup. The aim of this article is to review all the current knowledge using active agents including hypomethylating agents with venetoclax, eprenetapopt or magrolimab. We include comprehensive analysis of clinical trials to date evaluating these drugs in TP53 myeloid neoplasms as well as discuss future novel combinations for consideration. Additionally, further understanding of the unique clinicopathologic components of TP53 mutant myeloid neoplasms versus wild-type is critical to guide future study. Importantly, the clinical trajectory of patients is uniquely tied with the clonal burden of TP53, which enables serial TP53 variant allele frequency analysis to be a critical early biomarker in investigational studies. Together, significant optimism is now possible for improving outcomes in this patient population.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Biomarkers; Biomarkers, Tumor; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials as Topic; Humans; Leukemia, Myeloid, Acute; Mutation; Myelodysplastic Syndromes; Precision Medicine; Quinuclidines; Sulfonamides; Treatment Outcome; Tumor Suppressor Protein p53

The unraveling of the pathophysiology of acute myeloid leukemia (AML) has resulted in rapid translation of the information into clinical practice. After more than 40 years of slow progress in AML research, the US Food and Drug Administration has approved nine agents for different AML treatment indications since 2017. In this review, we detail the progress that has been made in the research and treatment of AML, citing key publications related to AML research and therapy in the English literature since 2000. The notable subsets of AML include acute promyelocytic leukemia (APL), core-binding factor AML (CBF-AML), AML in younger patients fit for intensive chemotherapy, and AML in older/unfit patients (usually at the age cutoff of 60-70 years). We also consider within each subset whether the AML is primary or secondary (therapy-related, evolving from untreated or treated myelodysplastic syndrome or myeloproliferative neoplasm). In APL, therapy with all-trans retinoic acid and arsenic trioxide results in estimated 10-year survival rates of ≥80%. Treatment of CBF-AML with fludarabine, high-dose cytarabine, and gemtuzumab ozogamicin (GO) results in estimated 10-year survival rates of ≥75%. In younger/fit patients, the "3+7" regimen (3 days of daunorubicin + 7 days of cytarabine) produces less favorable results (estimated 5-year survival rates of 35%; worse in real-world experience); regimens that incorporate high-dose cytarabine, adenosine nucleoside analogs, and GO are producing better results. Adding venetoclax, FLT3, and IDH inhibitors into these regimens has resulted in encouraging preliminary data. In older/unfit patients, low-intensity therapy with hypomethylating agents (HMAs) and venetoclax is now the new standard of care. Better low-intensity regimens incorporating cladribine, low-dose cytarabine, and other targeted therapies (FLT3 and IDH inhibitors) are emerging. Maintenance therapy now has a definite role in the treatment of AML, and oral HMAs with potential treatment benefits are also available. In conclusion, AML therapy is evolving rapidly and treatment results are improving in all AML subsets as novel agents and strategies are incorporated into traditional AML chemotherapy. LAY SUMMARY: Ongoing research in acute myeloid leukemia (AML) is progressing rapidly. Since 2017, the US Food and Drug Administration has approved 10 drugs for different AML indications. This review updates the research and treatment pathways for AML.

Topics: Age Factors; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Bridged Bicyclo Compounds, Heterocyclic; Cladribine; Core Binding Factors; Cytarabine; Daunorubicin; Gemtuzumab; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Maintenance Chemotherapy; Mutation; Myelodysplastic Syndromes; Myeloproliferative Disorders; Neoplasm, Residual; Sulfonamides; Survival Rate; Translational Research, Biomedical; Tretinoin; Vidarabine

The prognosis in Myelodysplastic syndromes (MDS), although recently refined by molecular studies, remains largely based on conventional prognostic scores [International Prognostic Scoring System (IPSS), revised IPSS], classifying patients into "lower risk" MDS (LR-MDS) and "higher risk" MDS (HR-MDS). In LR-MDS, treatment mainly aims at improving cytopenias, principally anaemia, while in HR-MDS it aims at delaying disease progression and prolonging survival. In LR-MDS without deletion 5q, anaemia is generally treated first by erythropoietic stimulating factors, while second line treatments are currently not approved [lenalidomide, hypomethylating agents (HMA), luspatercept] or rarely indicated (antithymocyte globulin). Lenalidomide has major efficacy in LR-MDS with deletion 5q. Allogeneic stem cell transplantation (allo-SCT) is sometimes considered in LR-MDS, and iron chelation can be considered when multiple red blood cell transfusions are required. Allo-SCT is the only potentially curative treatment for HR-MDS; however, it is rarely applicable. It is generally preceded by intensive chemotherapy (IC) or HMA in patients with excess of marrow blasts (especially if >10%). In other patients, HMA can improve survival. The role of new drugs, including venetoclax or, in case of specific mutations, IDH1 or IDH2 inhibitors, is investigated. IC is mainly indicated as a bridge to allo-SCT, in the absence of unfavourable karyotype.

Topics: Activin Receptors, Type II; Adult; Antilymphocyte Serum; Bridged Bicyclo Compounds, Heterocyclic; Erythrocyte Transfusion; Female; Humans; Immunoglobulin Fc Fragments; Lenalidomide; Male; Mutation; Myelodysplastic Syndromes; Recombinant Fusion Proteins; Sulfonamides

BCL-2 is an antiapoptotic protein that plays a critical role acute and chronic leukemias. Venetoclax is an orally selective BCL-2 inhibitor and BH3 mimetic approved in chronic lymphocytic leukemia and in combination with low dose cytarabine or hypomethylating agent in acute myeloid leukemia for the treatment of patients unfit for intensive chemotherapy. This article reviews the biology of BCL-2, focusing on its relationship to the myeloid microenvironment, and discusses the rationale for BCL-2 inhibition in myelodysplastic syndrome (MDS). Clinical trials testing venetoclax in MDS patients are under way. Potential biomarkers for clinical response to BCL-2 inhibition are discussed. Therapeutic opportunities for venetoclax in the therapeutic landscape of MDS are explored.

Topics: Animals; Antineoplastic Agents; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Clinical Studies as Topic; Disease Management; Disease Models, Animal; Disease Susceptibility; Drug Evaluation, Preclinical; Humans; Leukemia, Myeloid, Acute; Mitochondria; Myelodysplastic Syndromes; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; Treatment Outcome

Topics: Aged; Allografts; Anemia, Refractory, with Excess of Blasts; Aniline Compounds; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Breast Neoplasms; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials, Phase III as Topic; Cytarabine; Daunorubicin; Fatal Outcome; Female; fms-Like Tyrosine Kinase 3; Humans; Leukemia, Myeloid, Acute; Liposomes; Male; Middle Aged; Myelodysplastic Syndromes; Neoplasm, Residual; Neoplasms, Radiation-Induced; Oncogene Proteins, Fusion; Peripheral Blood Stem Cell Transplantation; Point Mutation; Protein Kinase Inhibitors; Pyrazines; Remission Induction; Salvage Therapy; Staurosporine; Sulfonamides

Topics: Activin Receptors, Type II; Anemia; Antineoplastic Agents; Azacitidine; Bridged Bicyclo Compounds, Heterocyclic; Decitabine; Erythrocyte Transfusion; Hematinics; Humans; Immunoglobulin Fc Fragments; Iron Chelating Agents; Lenalidomide; Myelodysplastic Syndromes; Oligonucleotides; Prognosis; Recombinant Fusion Proteins; Risk Assessment; Stem Cell Transplantation; Sulfonamides; Thalidomide; Thrombopoietin; Transplantation, Homologous

Apoptosis results from the interaction between pro- and anti-apoptotic proteins, mediated by BCL-2 homology 3 (BH3) proteins. B cell lymphoma-2 (BCL-2) is an inhibitor of apoptosis which stabilizes the mitochondria, resulting in the prevention of activation of the pro-apoptotic proteins. In addition, BCL-2 is overexpressed in the leukemic stem cell (LSC) population, and its inhibition may lead to selective LSC eradication. Herein, we will discuss the mechanism and rationale of BCL-2 inhibition in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) with an overview of the selective BCL-2 inhibitor venetoclax.. Venetoclax has activity against AML and has displayed synergistic activity with hypomethylating agents in the preclinical setting. In the clinical setting, although it has only modest activity as a single agent in relapsed and refractory AML, in the older, treatment-naïve population, in combination with either a hypomethylator or low-dose cytarabine, it is well tolerated with impressive efficacy. In addition, BCL-2 inhibition may also have activity in MDS, and although clinical trials are in their early phases, this may be an effective strategy in both the up-front and relapsed setting. BCL-2 inhibition with venetoclax is well tolerated and active in older patients with newly diagnosed AML and in the relapsed setting has activity that may be improved in combination with other therapies. It may prove to be effective in MDS and is an exciting treatment strategy for myeloid malignancies.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Cytarabine; Humans; Leukemia, Myeloid, Acute; Mitochondria; Myelodysplastic Syndromes; Neoplastic Stem Cells; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Female; Humans; Leukemia, Myeloid, Acute; Male; Myelodysplastic Syndromes; Neutropenia; Sulfonamides; Treatment Outcome

Therapies beyond hypomethylating agents such as azacitidine are needed in high-risk myelodysplastic syndromes. Venetoclax is an orally bioavailable small molecule BCL-2 inhibitor that is synergistic with hypomethylating agents. We therefore aimed to evaluate the safety, tolerability, and preliminary activity of azacitidine combined with venetoclax for treatment-naive and relapsed or refractory high-risk myelodysplastic syndromes or chronic myelomonocytic leukaemia.. We did a single centre, dose-escalation, dose-expansion, phase 1-2 trial at the University of Texas MD Anderson Cancer Center (Houston, TX, USA). This Article details the phase 1 results. We enrolled patients (≥18 years) with treatment-naive or relapsed or refractory high-risk myelodysplastic syndromes or chronic myelomonocytic leukaemia and bone marrow blasts of more than 5%. No specific Eastern Cooperative Oncology Group status restriction was used. Patients were treated with intravenous or subcutaneous azacitidine (75 mg/m. Between Nov 12, 2019, and Dec 17, 2021, a total of 23 patients were enrolled in the phase 1 portion of this study (17 [74%] hypomethylating agent naive and six [26%] post-hypomethylating agent failure). 18 (78%) patients were male and five (22%) were female; 21 (91%) were white and two (9%) were Asian. Median follow-up was 13·2 months (IQR 6·8-18·3). The maximum tolerated dose was not reached and the recommended phase 2 dose was established as azacitidine 75 mg/m. Azacitidine with venetoclax is safe and shows encouraging activity in patients with high-risk myelodysplastic syndromes or chronic myelomonocytic leukaemia.. MD Anderson Cancer Center.

Topics: Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Bridged Bicyclo Compounds, Heterocyclic; Female; Humans; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Chronic; Male; Myelodysplastic Syndromes; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

Acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) is a heterogeneous disorder defined by multilineage dysplasia, myelodysplastic syndrome (MDS)-related karyotype, or history of prior MDS. We evaluated 415 patients with AML-MRC treated from 2013 to 2018 and analyzed their clinical outcomes based on the diagnostic criteria of AML-MRC, therapy type and mutation profile. Criteria for AML-MRC included: cytogenetic abnormalities (AML-MRC-C) in 243 (59%), prior history of MDS in 75 (18%) including 47 (11%) with previously untreated MDS (AML-MRC-H) and 28 (7%) with previously treated MDS (AML-MRC-TS), and 97 (23%) with multilineage dysplasia (AML-MRC-M). Median age was 70 years (range 18-94). Among 95 evaluable patients, a total of 37 (39%) had secondary-type (ASXL1, BCOR, EZH2, SF3B1, SRSF2, STAG2, U2AF1, ZRSR2) mutations. Mutations in ASXL1, BCOR, SF3B1, SRSF2, and U2AF1 tended to appear in dominant clones. By multivariate analysis, AML-MRC subtype, age and serum LDH levels were independent predictors of outcome, with patients with AML-MRC-M (HR 0.56, CI 0.38-0.84, P = .004) and AML-MRC-H having better OS. Compared to a cohort of 468 patients with AML without MRC, patients with AML-MRC-M/AML-MRC-H had similar outcomes to those with intermediate risk AML by European LeukemiaNet criteria. Intensive therapy was associated with improved OS in patients with AML-MRC-M (HR 0.42, CI 0.19-0.94, P = .036) and with improved EFS in AML-MRC-M and AML-MRC-H (HR 0.26, CI 0.10-0.63, P = .003). This data suggests that not all diagnostic criteria for AML-MRC define high-risk patients and that specific subgroups may benefit from different therapeutic interventions.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Cytarabine; Daunorubicin; Disease-Free Survival; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Mutation; Myelodysplastic Syndromes; Neoplasm Proteins; Sulfonamides; Survival Rate

The BCL-2 inhibitor venetoclax (ven) has revolutionized the treatment of acute myeloid leukemia (AML) in elderly adults, leading to its recent FDA approval for this population in combination regimens. Although extensive data exist for adult myeloid malignancies, there are limited preclinical data on the efficacy and/or dosing of venetoclax for pediatric myelodysplastic syndrome (MDS) or AML and thus little information to guide use of this regimen in pediatric patients. Our objective was to describe our single-center experience with venetoclax in combination with the hypomethylating agent 5-azacitidine (aza) in pediatric patients with MDS or AML.. We conducted a retrospective chart review of patients treated at Children's Hospital Colorado prior to March 2020 with at least one cycle of ven/aza. Patients were included if between the ages of 1 and 25 years with a diagnosis of high-grade MDS or AML. AML patients had relapsed or primary refractory disease or were deemed poor candidates for standard chemotherapy.. Eight patients received ven/aza, two for high-grade MDS and six for AML. Ven/aza was well tolerated by all patients. The most common adverse events seen with this regimen were gastrointestinal and hematologic. Morphologic responses were seen in six patients including both patients with MDS. All four AML responders became minimal residual disease negative. Three responders have thus far proceeded to allogeneic hematopoietic stem cell transplant following ven/aza.. Our clinical experience suggests that ven/aza is a safe and promising regimen that should be further explored with late-phase clinical trials.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Bridged Bicyclo Compounds, Heterocyclic; Child; Child, Preschool; Female; Follow-Up Studies; Humans; Infant; Leukemia, Myeloid, Acute; Male; Myelodysplastic Syndromes; Prognosis; Retrospective Studies; Sulfonamides; Young Adult

Treatment for myelodysplastic syndromes (MDS) remains insufficient due to clonal heterogeneity and lack of effective clinical therapies. Dysregulation of apoptosis is observed across MDS subtypes regardless of mutations and represents an attractive therapeutic opportunity. Venetoclax (VEN), a selective inhibitor of anti-apoptotic protein B-cell lymphoma- 2 (BCL2), has yielded impressive responses in older patients with acute myeloid leukemia (AML) and high risk MDS. BCL2 family anti-apoptotic proteins BCL-XL and induced myeloid cell leukemia 1 (MCL1) are implicated in leukemia survival, and upregulation of MCL1 is seen in VEN-resistant AML and MDS. We determined in vitro sensitivity of MDS patient samples to selective inhibitors of BCL2, BCL-XL and MCL1. While VEN response positively correlated with MDS with excess blasts, all MDS subtypes responded to MCL1 inhibition. Treatment with combined VEN + MCL1 inhibtion was synergistic in all MDS subtypes without significant injury to normal hematopoiesis and reduced MDS engraftment in MISTRG6 mice, supporting the pursuit of clinical trials with combined BCL2 + MCL1 inhibition in MDS.

Topics: Animals; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Disease Models, Animal; Leukemia, Myeloid, Acute; Mice; Myelodysplastic Syndromes; Myeloid Cell Leukemia Sequence 1 Protein; Proto-Oncogene Proteins c-bcl-2

Systemic mastocytosis (SM) results from clonal proliferation of neoplastic mast cells that infiltrate bone marrow and other organs. A major subset of patients with SM has a clonally related myeloid neoplasm and the SM itself (SM-AMN). We evaluated the efficacy of hypomethylating agent and venetoclax (HMA-VEN) to target both the myeloid neoplasm and mast cell infiltrate in a patient with SM associated with acute myeloid leukemia arising from myelodysplastic syndrome and illustrate complete elimination of bone marrow mast cells and complete remission of MDS/AML. This case illustrates the potent activity of HMA-VEN both against the AMN as well as the associated SM.

Topics: Bone Marrow; Humans; Leukemia, Myeloid, Acute; Mast Cells; Mastocytosis, Systemic; Myelodysplastic Syndromes; Myeloproliferative Disorders

Topics: Azacitidine; Bridged Bicyclo Compounds, Heterocyclic; Humans; Myelodysplastic Syndromes; Sulfonamides

The treatment of patients with refractory and/or relapsed (R/R) high-risk myelodysplastic syndrome (HR-MDS) remains a daunting clinical challenge. Venetoclax is a selective BCL-2 inhibitor, which combined with hypomethylating agents (HMAs), increased responses and prolonged survival in unfit and previously untreated acute myeloid leukemia. We performed a retrospective study of patients with R/R HR-MDS receiving combination azacytidine (AZA) plus 15-days duration of venetoclax (VEN-15d) in order to determine their efficacy and toxicity in this context. We showed that the overall response rate was 57.2% (20/35) and the median over survival was 14 months in R/R MDS. The most common treatment-emergent adverse events were peripheral blood cytopenias and infectious complications. Our retrospective study showed that the real-world experience of treating R/R MDS with AZA plus VEN-15d highlights an encouraging response rate with myelosuppression being the major toxicity. Of note, VEN-15d with AZA may salvage patients failing to respond optimally to HMAs and reduce the disease-burden for subsequent allogeneic stem cell transplantation in our analysis. These data of combination AZA plus VEN-15d in R/R MDS warrant further prospective evaluation in clinical trials.

Topics: Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Retrospective Studies

Topics: Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Humans; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Phenotype

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Female; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Male; Myelodysplastic Syndromes; Neoplasm Recurrence, Local; Retrospective Studies; Salvage Therapy; Sulfonamides

Treated secondary acute myeloid leukemia (ts-AML)-i.e., AML arising from a previously treated antecedent hematologic disorder-is associated with very poor outcomes. The optimal frontline treatment regimen for these patients is uncertain.. We retrospectively analyzed 562 patients who developed AML from preceding myelodysplastic syndrome or chronic myelomonocytic leukemia for which they had received a hypomethylating agent (HMA). Patients with ts-AML were stratified by frontline AML treatment with intensive chemotherapy (IC, n = 271), low-intensity therapy (LIT) without venetoclax (n = 237), or HMA plus venetoclax (n = 54).. Compared with IC or LIT without venetoclax, HMA plus venetoclax resulted in higher CR/CRi rates (39% and 25%, respectively; P = 0.02) and superior OS (1-year OS 34% and 17%, respectively; P = 0.05). The benefit of HMA plus venetoclax was restricted to patients with non-adverse risk karyotype, where HMA plus venetoclax resulted in a median OS of 13.7 months and 1-year OS rate of 54%; in contrast, for patients with adverse risk karyotype, OS was similarly dismal regardless of treatment approach (median OS 3-5 months). A propensity score analysis accounting for relevant clinical variables confirmed the significant OS benefit of HMA plus venetoclax, as compared with other frontline treatment approaches. In a landmark analysis, patients with ts-AML who underwent subsequent hematopoietic stem cell transplantation (HSCT) had superior 3-year OS compared to non-transplanted patients (33% vs. 8%, respectively; P = 0.003).. The outcomes of ts-AML are poor but may be improved with use of an HMA plus venetoclax-based regimen, followed by HSCT, particularly in those with a non-adverse risk karyotype.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Female; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Chronic; Male; Middle Aged; Myelodysplastic Syndromes; Neoplasms, Second Primary; Retrospective Studies; Sulfonamides; Young Adult

Myelodysplastic syndromes (MDS) are heterogeneous neoplastic disorders of hematopoietic stem cells (HSCs). The current standard of care for patients with MDS is hypomethylating agent (HMA)-based therapy; however, almost 50% of MDS patients fail HMA therapy and progress to acute myeloid leukemia, facing a dismal prognosis due to lack of approved second-line treatment options. As cancer stem cells are the seeds of disease progression, we investigated the biological properties of the MDS HSCs that drive disease evolution, seeking to uncover vulnerabilities that could be therapeutically exploited. Through integrative molecular profiling of HSCs and progenitor cells in large patient cohorts, we found that MDS HSCs in two distinct differentiation states are maintained throughout the clinical course of the disease, and expand at progression, depending on recurrent activation of the anti-apoptotic regulator BCL-2 or nuclear factor-kappa B-mediated survival pathways. Pharmacologically inhibiting these pathways depleted MDS HSCs and reduced tumor burden in experimental systems. Further, patients with MDS who progressed after failure to frontline HMA therapy and whose HSCs upregulated BCL-2 achieved improved clinical responses to venetoclax-based therapy in the clinical setting. Overall, our study uncovers that HSC architectures in MDS are potential predictive biomarkers to guide second-line treatments after HMA failure. These findings warrant further investigation of HSC-specific survival pathways to identify new therapeutic targets of clinical potential in MDS.

Topics: Bridged Bicyclo Compounds, Heterocyclic; Hematopoietic Stem Cells; Humans; Myelodysplastic Syndromes; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

Topics: Azacitidine; Bridged Bicyclo Compounds, Heterocyclic; Humans; Myelodysplastic Syndromes; Sulfonamides

Topics: Azacitidine; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Sulfonamides

Topics: Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Sulfonamides

Mutations of the nucleophosmin (NPM1) gene, encoding for a nucleolar multifunctional protein, occur in approximately one-third of adult acute myeloid leukemia (AML). NPM1-mutated AML exhibits unique molecular, pathological, and clinical features, which led to its recognition as distinct entity in the 2017 World Health Organization (WHO) classification of myeloid neoplasms. Although WHO criteria for the diagnosis of NPM1-mutated AML are well established, its distinction from other AML entities may be difficult. Moreover, the percentage of blasts required to diagnose NPM1-mutated AML remains controversial. According to the European LeukemiaNet (ELN), determining the mutational status of NPM1 (together with FLT3) is mandatory for accurate relapse-risk assessment. NPM1 mutations are ideal targets for measurable residual disease (MRD) monitoring, since they are AML specific, frequent, very stable at relapse, and do not drive clonal hematopoiesis of undetermined significance. MRD monitoring by quantitative polymerase chain reaction of NPM1-mutant transcripts, possibly combined with ELN genetic-based risk stratification, can guide therapeutic decisions after remission. Furthermore, immunohistochemistry can be very useful in selected situations, such as diagnosis of NPM1-mutated myeloid sarcoma. Herein, we present 4 illustrative cases of NPM1-mutated AML that address important issues surrounding the biology, diagnosis, and therapy of this common form of leukemia.

Topics: Age Factors; Aged; Algorithms; Allografts; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Bridged Bicyclo Compounds, Heterocyclic; Cell Lineage; Clinical Trials as Topic; Clonal Evolution; Combined Modality Therapy; Diagnosis, Differential; Disease Management; Female; fms-Like Tyrosine Kinase 3; Gemtuzumab; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Molecular Targeted Therapy; Myelodysplastic Syndromes; Neoplastic Stem Cells; Nuclear Proteins; Nucleophosmin; Oncogene Proteins, Fusion; Patient Selection; Practice Patterns, Physicians'; Remission Induction; Risk Assessment; Salvage Therapy; Sulfonamides

Topics: Allografts; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Bridged Bicyclo Compounds, Heterocyclic; Combined Modality Therapy; Decitabine; DNA Methylation; Drug Evaluation; Febrile Neutropenia; Germany; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Leukemia, Myeloid, Acute; Leukocyte Count; Myelodysplastic Syndromes; Recurrence; Retrospective Studies; Salvage Therapy; Sulfonamides; Thrombocytopenia; Transplantation Conditioning; Tumor Lysis Syndrome

Topics: Abnormal Karyotype; Age of Onset; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; CCAAT-Enhancer-Binding Proteins; DNA Methylation; Female; Humans; Kaplan-Meier Estimate; Leukemia, Myeloid, Acute; Male; Middle Aged; Myelodysplastic Syndromes; Myeloproliferative Disorders; Neoplasm Proteins; Prognosis; Proportional Hazards Models; Remission Induction; Sulfonamides

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Female; High-Throughput Nucleotide Sequencing; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myelomonocytic, Chronic; Male; Middle Aged; Myelodysplastic Syndromes; Sulfonamides

Venetoclax is a selective B-cell lymphoma 2 (BCL2) inhibitor, which is approved to treat elderly patients with newly diagnosed acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) in combination with either low-dose cytarabine (ARA-C) or hypomethylating agents. We aimed to collect and share data among the efficacy and safety of venetoclax both as a monotherapy or in combination with other drugs used to treat high-risk MDS or AML.. A total of 60 patients with a median age of 67 (30-83) years from 14 different centers were included in the final analysis. Thirty (50%) of the patients were women; 6 (10%) of the 60 patients were diagnosed with high-risk MDS and the remaining were diagnosed with AML.. The best objective response rate (complete remission [CR], complete remission with incomplete hematological recovery (CRi), morphological leukemia-free state [MLFS], partial response [PR]) was 35% in the entire cohort. Best responses achieved during venetoclax per patient number were as follows: 7 CR, 1 CRi, 8 MLFS, 5 PR, and stable disease. Median overall survival achieved with venetoclax was 5 months in patients who relapsed and not achieved in patients who were initially treated with venetoclax. Nearly all patients (86.7%) had experienced a grade 2 or more hematologic toxicity. Some 36.7% of these patients had received granulocyte colony stimulating factor (GCSF) support. Infection, mainly pneumonia (26.7%), was the leading nonhematologic toxicity, and fatigue, diarrhea, and skin reactions were the others reported.. Our real-life data support the use of venetoclax in patients with both newly diagnosed and relapsed high-risk MDS and AML.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Myelodysplastic Syndromes; Remission Induction; Sulfonamides; Survival Analysis; Treatment Outcome; Turkey

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Decitabine; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Myelodysplastic Syndromes; Progression-Free Survival; Prospective Studies; Recurrence; Sulfonamides; Transplantation Conditioning; Transplantation, Homologous; Young Adult

Topics: Azacitidine; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Sulfonamides

Topics: Abnormal Karyotype; Adolescent; Allografts; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Decitabine; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Male; Myelodysplastic Syndromes; Recurrence; Sulfonamides

Treatment with hypomethylating agents (HMAs) azacitidine or decitabine is the current standard of care for high risk myelodysplastic syndromes (MDSs) but is associated with low rates of response. The limited number of treatment options for patients with high risk MDS highlights a need for new therapeutic options. Venetoclax is an inhibitor of the BCL-2 protein which, when combined with an HMA, has shown high response rates in unfit and previously untreated acute myeloid leukemia. We performed a retrospective study of high risk MDS patients receiving combination HMA plus venetoclax in order to determine their effectiveness in this context. We show that in our cohort, the combination results in high response rates but is associated with a high frequency of myelosuppression. These data highlight the efficacy of combination HMA plus venetoclax in high risk MDS, warranting further prospective evaluation in clinical trials.

Topics: Azacitidine; Bridged Bicyclo Compounds, Heterocyclic; Decitabine; Humans; Myelodysplastic Syndromes; Retrospective Studies; Sulfonamides; Treatment Outcome

Topics: Aged; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Neoplasms, Multiple Primary; Remission Induction; Sulfonamides

Venetoclax (VEN), a selective BCL2 inhibitor, has single-agent activity in relapsed and refractory (R/R) acute myeloid leukemia (AML), and efficacy in lower intensity combinations for treatment-naïve elderly AML patients. VEN treatment combinations in R/R AML have not been previously reported.. All R/R myeloid patients (including AML, myelodysplastic syndrome (MDS), and blastic plasmacytoid dendritic cell neoplasm (BPDCN)) treated with VEN combinations in the salvage setting were reviewed.. Forty-three patients with median age 68 (range, 25-83) were treated for AML (91%), MDS (5%), or BPDCN (5%). Most (n = 36, 84%) were ≥ salvage-2 treatment status, including prior hypomethylating agent (HMA) in 77%. In combination with VEN, most patients received HMA therapy (n = 31, 72%); eight (19%) received low-dose cytarabine (LDAC). Patients received a median of 2 treatment cycles (range, 1-4). Objective response was observed in 9 (21%) patients, including 2 complete responses (CR), 3 CRi, and 4 morphologic leukemia-free state (MLFS). Median survival was 3.0 months (range, 0.5-8.0), and estimated 6-month survival was 24%. Responses were observed in five (24%) of 21 patients with intermediate-risk cytogenetics, 3 (27%) of 11 IDH1/2-mutant, and 4 (50%) of 8 RUNX1-mutated patients. Two (20%) of 10 TP53-mutated patients responded; both had concurrent RUNX1 mutations. Of the 3 (15%) responding patients with adverse cytogenetics, all had concurrent RUNX1 mutations.. Low-intensity chemotherapy, including HMAs or LDAC, in combination with VEN is a viable salvage option, even in multiply relapsed/refractory patients with AML, MDS, and BPDCN. Notable responses were identified in patients with diploid/intermediate cytogenetics, RUNX1, and/or IDH1/2 mutations.

Topics: Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; ATP Binding Cassette Transporter, Subfamily B, Member 1; Bridged Bicyclo Compounds, Heterocyclic; Core Binding Factor Alpha 2 Subunit; Cytochrome P-450 CYP3A Inhibitors; Dendritic Cells; Female; Genes, p53; Humans; Isocitrate Dehydrogenase; Leukemia, Myeloid, Acute; Male; Middle Aged; Molecular Targeted Therapy; Myelodysplastic Syndromes; Neoplasm Proteins; Proto-Oncogene Proteins c-bcl-2; Recurrence; Salvage Therapy; Sulfonamides

Deregulated apoptosis is an identifying feature of myelodysplastic syndromes (MDS). Whereas apoptosis is increased in the bone marrow (BM) of low-risk MDS patients, progression to high-risk MDS correlates with an acquired resistance to apoptosis and an aberrant expression of BCL-2 proteins. To overcome the acquired apoptotic resistance in high-risk MDS, we investigated the induction of apoptosis by inhibition of pro-survival BCL-2 proteins using the BCL-2/-XL/-W inhibitor ABT-737 or the BCL-2-selective inhibitor ABT-199. We characterized a cohort of 124 primary human BM samples from MDS/secondary acute myeloid leukemia (sAML) patients and 57 healthy, age-matched controls. Inhibition of anti-apoptotic BCL-2 proteins was specifically toxic for BM cells from high-risk MDS and sAML patients, whereas low-risk MDS or healthy controls remained unaffected. Notably, ABT-737 or ABT-199 treatment was capable of targeting the MDS stem/progenitor compartment in high-risk MDS/sAML samples as shown by the reduction in CD34(+) cells and the decreased colony-forming capacity. Elevated expression of MCL-1 conveyed resistance against both compounds. Protection by stromal cells only partially inhibited induction of apoptosis. Collectively, our data show that the apoptotic resistance observed in high-risk MDS/sAML cells can be overcome by the ABT-737 or ABT-199 treatment and implies that BH3 mimetics might delay disease progression in higher-risk MDS or sAML patients.

Topics: Apoptosis; Biphenyl Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cells, Cultured; Humans; Myelodysplastic Syndromes; Myeloid Cell Leukemia Sequence 1 Protein; Nitrophenols; Piperazines; Proto-Oncogene Proteins c-bcl-2; Stem Cells; Sulfonamides

Synergistic molecular vulnerabilities enhancing hypomethylating agents in myeloid malignancies have remained elusive. RNA-interference drug modifier screens identified antiapoptotic BCL-2 family members as potent 5-Azacytidine-sensitizing targets. In further dissecting BCL-XL, BCL-2 and MCL-1 contribution to 5-Azacytidine activity, siRNA silencing of BCL-XL and MCL-1, but not BCL-2, exhibited variable synergy with 5-Azacytidine in vitro. The BCL-XL, BCL-2 and BCL-w inhibitor ABT-737 sensitized most cell lines more potently compared with the selective BCL-2 inhibitor ABT-199, which synergized with 5-Azacytidine mostly at higher doses. Ex vivo, ABT-737 enhanced 5-Azacytidine activity across primary AML, MDS and MPN specimens. Protein levels of BCL-XL, BCL-2 and MCL-1 in 577 AML patient samples showed overlapping expression across AML FAB subtypes and heterogeneous expression within subtypes, further supporting a concept of dual/multiple BCL-2 family member targeting consistent with RNAi and pharmacologic results. Consequently, silencing of MCL-1 and BCL-XL increased the activity of ABT-199. Functional interrogation of BCL-2 family proteins by BH3 profiling performed on patient samples significantly discriminated clinical response versus resistance to 5-Azacytidine-based therapies. On the basis of these results, we propose a clinical trial of navitoclax (clinical-grade ABT-737) combined with 5-Azacytidine in myeloid malignancies, as well as to prospectively validate BH3 profiling in predicting 5-Azacytidine response.

Topics: Antimetabolites, Antineoplastic; Azacitidine; bcl-X Protein; Biphenyl Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Humans; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Myeloid Cell Leukemia Sequence 1 Protein; Myeloproliferative Disorders; Nitrophenols; Piperazines; Proto-Oncogene Proteins c-bcl-2; RNA Interference; Sulfonamides