abt-199 and Blast-Crisis

The management of patients with acute myeloid leukemia (blast phase) secondary to myeloproliferative neoplasms (MPNs) is extremely challenging and the outcome dismal, with a median overall survival of about 3-6 months. Effective therapeutic approaches are lacking, especially when intensive strategies followed by allogeneic transplantation are not feasible. The combination of venetoclax and hypomethylating agents has recently been established as standard for newly diagnosed, unfit patients with. The evolution into a blast phase represents a dramatic and often fatal event in the disease course of patients affected by myeloproliferative neoplasms. Aside from a minority of patients who can be offered an allogeneic transplant, the median survival from disease evolution is about 3–6 months. There is a serious unmet need for clinical trials with innovative approaches for this category of patients. In the ENABLE clinical trial, we aim to verify the efficacy and safety of the combination of venetoclax (a BCL2 inhibitor) and decitabine (a hypomethylating agent) in this disease subset, characterized by a complex dynamic of clonal evolution and a particularly unfavorable prognosis.

Topics: Antineoplastic Combined Chemotherapy Protocols; Blast Crisis; Bridged Bicyclo Compounds, Heterocyclic; Decitabine; Humans; Leukemia, Myeloid, Acute; Myeloproliferative Disorders

Despite recent advances in the treatment of de novo acute myeloid leukemia (AML), AML arising from antecedent chronic myelomonocytic leukemia (CMML) continues to have dismal outcomes. While the unique biological drivers of CMML and subsequent leukemic transformation (LT) have been revealed with advances in molecular characterization, this has not yet translated to the bedside. Here, we review these biologic drivers, outcomes with current therapies, and rationale avenues of future investigation specifically in blast phase CMML (CMML-BP).. CMML-BP outcomes are studied as an aggregate with more common categories of AML with myelodysplasia-related changes (AML-MRCs) or the even broader category of secondary AML (sAML), which illustrates the crux of the problem. While a modest survival advantage with allogeneic hematopoietic stem cell transplant exists, the difficulty is bridging patients to transplant and managing patients that require an allograft-sparing approach. Limited data suggest that short-lived remissions can be obtained employing CPX-351 or venetoclax-based lower intensity combination therapy. Promising future strategies include repurposing cladribine, exploiting the supportive role of dendritic cell subsets with anti-CD123 therapies, MCL-1 inhibition, dual MEK/PLK1 inhibition, FLT3 inhibition in RAS-mutated and CBL-mutated subsets, and immune therapies targeting novel immune checkpoint molecules such as the leukocyte immunoglobulin-like receptor B4 (LILRB4), an immune-modulatory transmembrane protein restrictively expressed on monocytic cells. The successful management of an entity as unique as CMML-BP will require a cooperative, concerted effort to design and conduct clinical trials dedicated to this rare form of sAML.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Blast Crisis; Bridged Bicyclo Compounds, Heterocyclic; Cladribine; Disease Management; Drug Discovery; Humans; Leukemia, Myelomonocytic, Chronic; Molecular Targeted Therapy; Mutation; Sulfonamides; Treatment Outcome

Topics: Antineoplastic Combined Chemotherapy Protocols; Blast Crisis; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid; Leukemia, Myeloid, Acute

Topics: Azacitidine; Blast Crisis; Bridged Bicyclo Compounds, Heterocyclic; Fusion Proteins, bcr-abl; Humans; Protein Kinase Inhibitors; Tyrosine Kinase Inhibitors

Topics: Blast Crisis; Bridged Bicyclo Compounds, Heterocyclic; Fusion Proteins, bcr-abl; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Sulfonamides

Myeloproliferative neoplasms in blastic phase (MPN-BP) have a dreadful prognosis. We report the characteristics and outcomes of five MPN-BP patients treated with a never-before-described combination of azacytidine and venetoclax (to control BP transformation), added to ruxolitinib (needed to control constitutional symptoms). Median age was 76 years (range 72-84), and worst performance status was 2. The overall response rate was 80%, and the complete remission rate was 40%. With median follow-up of 10.0 months (range 4.2-13.4), median overall survival was 13.4 months (95% CI 4.2-13.4). We did not detect any unexpected treatment-related toxicity, and quality of life was improved.

Topics: Aged; Aged, 80 and over; Azacitidine; Blast Crisis; Humans; Myeloproliferative Disorders; Quality of Life; Treatment Outcome

Topics: Azacitidine; Blast Crisis; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Myelomonocytic, Chronic; Sulfonamides

Venetoclax (Ven) combined with a hypomethylating agent (HMA) has now emerged as an effective treatment regimen for acute myeloid leukemia, in both de novo and relapsed/refractory setting. The current multicenter study retrospectively examined Ven + HMA treatment outcome among 32 patients (median age 69 years; 59% males) with blast-phase myeloproliferative neoplasm (MPN-BP). Pre-leukemic phenotype included essential thrombocythemia (ET)/post-ET myelofibrosis (34%), polycythemia vera (PV)/post-PV myelofibrosis (38%) and primary myelofibrosis (28%). Twenty-nine study patients were fully annotated cytogenetically and molecularly (NGS): 69% harbored complex karyotype and/or mutations, including TP53 (41%), IDH1/2 (21%), ASXL1 (21%), N/KRAS (14%), SRSF2 (10%), EZH2 (10%) and U2AF1 (7%). All patients received Ven combined with either azacitidine (n = 12) or decitabine (n = 20); either up front (n = 23) or after failing another induction therapy (n = 9). Complete remission with (CR) or without (CRi) count recovery was achieved in 14 (44%) patients and was more likely to occur in the absence of pre-leukemic PV/post-PV myelofibrosis phenotype (p < .01), complex karyotype (p < .01) or K/NRAS (p = .03) mutations; seven of eight patients (88%) without vs four of 21 (19%) with complex karyotype or K/NRAS mutation achieved CR/CRi (p < .01); all 11 informative patients with pre-leukemic PV/post-PV myelofibrosis phenotype displayed complex karyotype (p < .01). In contrast, neither TP53 (p = .45) nor IDH1/2 (p = .63) mutations affected response. Compared to historical controls treated with HMA alone (n = 26), the CR/CRi rate (44% vs 4%) and median survival (8 vs 5.5 months) were more favorable with Ven + HMA, but without significant difference in overall survival. Importantly, six patients with CR/CRi subsequently received allogeneic hematopoietic stem cell transplant (AHSCT). Note, Ven + HMA produces robust CR/CRi rates in MPN-BP, especially in the absence of RAS mutations and complex karyotype, thus enabling AHSCT, in some patients.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Blast Crisis; Bridged Bicyclo Compounds, Heterocyclic; Decitabine; Female; Humans; Male; Middle Aged; Myeloproliferative Disorders; Retrospective Studies; Sulfonamides; Survival Analysis; Treatment Outcome

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Blast Crisis; Bridged Bicyclo Compounds, Heterocyclic; Female; Humans; Leukemia, Myelomonocytic, Chronic; Male; Middle Aged; Sulfonamides; Treatment Outcome

Philadelphia chromosome-positive (Ph+) advanced leukemias, including acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) in myeloid blast phase (MBP), have poor outcomes. Venetoclax has shown synergism with BCR-ABL1 tyrosine kinase inhibitors (TKI) in preclinical studies. However, clinical activity of venetoclax and TKI-based regimens is unknown.. We conducted a retrospective study on patients with Ph+ AML (n = 7) and CML-MBP (n = 9) who received venetoclax combined with TKI-based regimens at our institution.. Median patient age was 42 years, and the median number of prior therapy cycles was 5 (range 2-8). Nine patients received decitabine-based, and 7 received intensive chemotherapy-based regimens. Ten patients (63%) received ponatinib. The overall response rate (ORR) in 15 evaluable patients was 60% (1 complete remission [CR], 6 CR with incomplete hematologic recovery [CRi], 1 morphologic leukemia-free state, and 1 partial response). The ORR was 43% in Ph+ AML and 75% in CML-MBP. The median overall survival (OS) for all patients was 3.6 months, for AML OS was 2.0 months, and for CML-MBP OS was 10.9 months. The median relapse-free survival for AML and CML-MBP was 3.6 and 3.9 months, respectively. Compared to nonresponders, patients achieving CR/CRi had higher baseline Ph+ metaphases and BCR-ABL1 PCR.. Combination therapy of venetoclax with TKI-based regimens shows encouraging activity in very heavily pretreated, advanced Ph+ leukemias, particularly CML-MBP.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Blast Crisis; Bridged Bicyclo Compounds, Heterocyclic; Disease-Free Survival; Female; Fusion Proteins, bcr-abl; Humans; Imidazoles; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Male; Middle Aged; Protein Kinase Inhibitors; Pyridazines; Retrospective Studies; Sulfonamides; Survival Rate

Bcl-2 inhibitors display an effective activity in acute myeloid leukemia (AML), but its clinical efficacy as a monotherapy was limited in part owing to failure to target other antiapoptotic Bcl-2 family proteins, such as Mcl-1. In this context, the combination strategy may be a promising approach to overcome this barrier. Here, we report the preclinical efficacy of a novel strategy combining ABT-199 with triptolide (TPL), a natural product extracted from a traditional Chinese medicine, in AML. Combination treatment exhibited markedly increased cytotoxicity in leukemic cells irrespective of p53 status while largely sparing normal cells of the hematopoietic lineage. Moreover, co-administration of ABT-199 with TPL dramatically suppressed leukemia progression as well as prolonged animal survival in a xenograft AML model. The potentiated effect of ABT-199 and TPL against AML was associated with activation of the mitochondrum-related intrinsic apoptotic pathway through a mechanism reciprocally modulating Bcl-2 family proteins. In this case, TPL not only downregulated Mcl-1 but also upregulated proapoptotic BH3-only proteins, thereby overcoming the resistance toward ABT-199. Conversely, ABT-199 abrogated Bcl-2-mediated cytoprotection against TPL. Together, these findings suggest that the regimen combining TPL and ABT-199 might be active against AML by inducing robust apoptosis through reciprocal regulation of anti- and proapoptotic Bcl-2 family proteins, therefore providing a strong rationale for the clinical investigation of this combination regimen for the treatment of AML.

Topics: Adolescent; Adult; Aged; Animals; Apoptosis; Blast Crisis; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Child; Diterpenes; Drug Synergism; Epoxy Compounds; Female; Humans; Leukemia, Myeloid, Acute; Male; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Mitochondria; Phenanthrenes; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Blast Crisis; Bridged Bicyclo Compounds, Heterocyclic; Disease-Free Survival; Female; Hematologic Neoplasms; Humans; Male; Middle Aged; Myeloproliferative Disorders; Retrospective Studies; Sulfonamides; Survival Rate