Phase II Study of Venetoclax Added to Cladribine Plus Low-Dose Cytarabine Alternating With 5-Azacitidine in Older Patients With Newly Diagnosed Acute Myeloid Leukemia

Kadia, Tapan M.; Reville, Patrick K.; Wang, Xuemei; Rausch, Caitlin R.; Borthakur, Gautam; Pemmaraju, Naveen; Daver, Naval; DiNardo, Courtney D.; Sasaki, Koji; Issa, Ghayas C.; Ohanian, Maro; Montalban‐Bravo, Guillermo; Jain, Nitin; Ferrajoli, Alessandra; Bhalla, Kapil N.; Takahashi, Koichi; Malla, Rashmi; Quagliato, Kelly; Kanagal‐Shamanna, Rashmi; Popat, Uday; Andreeff, Michael; Garcia‐Manero, Guillermo; Konopleva, Marina; Ravandi, Farhad; Kantarjian, Hagop M.

doi:10.1200/jco.21.02823

Cited by 64 publications

(42 citation statements)

References 22 publications

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“…Kadia et al have evaluated in a group of 60 older (≥60 years) AML patients a peculiar therapeutic regimen based on VEN added to cladribine (CLAD) plus LDAC, alternating with AZA; after treatment, 93% of patients had CR+CRi, 84% were MRD-negative, and after 22 months of follow-up the median OS and DFS were not reached. 16 These results support the conclusion that VEN+CLAD/LDAC alternating with VEN+AZA is an effective regimen in older or unfit patients with ND-AML.…”

Section: Venetoclax In Newly Diagnosed Amlsupporting

confidence: 82%

The Growing Role of the Bh3 Mimetic Drug Venetoclax in the Therapy of Acute Myeloid Leukemia

Castelli¹,

Testa²

2022

Mediterr J Hematol Infect Dis

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In spite recent progresses, acute myeloid leukemia (AML) remains a disease associated with poor prognosis, particularly in older AML patients unfit to tolerate intensive chemotherapy treatment. The development and introduction in therapy of the drug Venetoclax, a potent BH3 mimetic targeting the antiaopoptotic protein BCL-2, inducing apoptosis of leukemic cells, has shown to be a promising treatment for newly diagnosed, relapsed and refractory AML patients ineligible for induction chemotherapy. Combination treatments using Ventoclax and a hypomethylating agent (azacytidine or decitabine) or low-intensity chemotherapy have shown in newly diagnosed patients variable response rates, with highly responsive patients with NPM1, IDH1-IDH2, TET2 and RUNX1 mutations and with scarcely responsive patients with FLT3, TP53 and ASXL1 mutations, complex karyotypes and secondary AMLs. Patients with refractory/relapsing disease are less responsive to Venetoclax-based regimens. However, in the majority of patients the responses have only a limited duration and development of resistance is frequently observed. Understanding mechanisms of resistance is of crucial importance for the development of new strategies and identification of rational drug combination regimens. In this context, two strategies seem to be promising: (i) triplet therapies based on the combined administration of Venetoclax, a hypomethylating agent (or low-dose chemotherapy) and an agent targeting a specific genetic alteration of leukemic cells (i.e., FLT3 inhibitors in FLT3-mutated AMLs) or an altered signaling pathway; (ii) combination therapies based on the administration of two BH3 mimetics (i.e., BCL-2 +MCL-1 mimetics) and a hypomethylating agent.

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Section: Venetoclax In Newly Diagnosed Amlsupporting

confidence: 82%

The Growing Role of the Bh3 Mimetic Drug Venetoclax in the Therapy of Acute Myeloid Leukemia

Castelli¹,

Testa²

2022

Mediterr J Hematol Infect Dis

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“…Patients were subdivided by treatment type which included: intensive chemotherapy (HiDAC based) and intensive + venetoclax; hypomethylating agents (HMA: decitabine, azacytidine) and HMA + venetoclax; cladribine + low‐dose cytarabine (Clad‐LDAC) 19 and Clad‐LDAC + venetoclax 20 …”

Section: Methodsmentioning

confidence: 99%

Implications of RAS mutational status in subsets of patients with newly diagnosed acute myeloid leukemia across therapy subtypes

et al. 2022

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Activating mutations in RAS have been reported in about 10-15% of patients with AML; previous studies have not identified a prognostic significance. However, RAS mutations have emerged as a potential resistance mechanism to treatment with inhibitors of FLT3, IDH, and BCL2. We aimed to determine the characteristics and outcomes of patients with RAS-mutated (RAS-mut) AML across therapy subsets of 1410 patients newly diagnosed (ND AML). RAS-mut was observed in 273 (20%) patients. Overall, patients with RAS-mut AML had an estimated 3-year survival rate of 38% vs. 28% in those with RAS wild type (RAS-wt), p = .01. Among patients with RAS-mut, favorable karyotype and concomitant NPM1 mutations were associated with a higher CR/CRi rate, OR 23.2 (95% CI: 2.7-192.7; p < .001) and OR 2.8 (95% CI: 1.1-6.9; p = .02), respectively, while secondary and treated secondary (ts)-AML were associated with low response rates, OR 0.34 (95% CI: 0.1-0.9; p = .04) and OR 0.22 (95% CI: 0.09-0.5; p = .001), respectively. Intensive chemotherapy was associated with high response rates OR 5.9 (95% CI: 2.9-12.2; p < .001). Better median OS was observed among those with favorable karyotype, HR 0.28 (95% CI: 0.1-0.6; p = .002), and those treated with intensive chemotherapy, HR 0.42 (95% CI: 0.2-0.6 p < .001). Conversely, ts-AML and co-occurrence of mutations in TP53 were associated with poor median OS; HR 2.3 (95% CI: 1.4-3.9; p = .001) and HR 1.7 (95% CI: 0.9-3.1; p = .06), respectively. The addition of venetoclax was associated with a non-significant improvement in CR/CRi and OS. | INTRODUCTIONAcute Myeloid leukemia (AML), the most frequent acute leukemia in adults, is an aggressive hematologic malignancy presenting with an uncontrolled expansion of the myeloid blasts resulting in impaired hematopoiesis. Patient-related features such as age, performance status, prior malignancy, and exposure to cytotoxic therapies have been associated with an impact on outcomes. 1 Disease-related features such as conventional cytogenetics and mutational status of CEBPA, NPM1, and FLT3-ITD have been used in clinical practice to determine prognosis. More recently, with the advent of nextgeneration sequencing (NGS) technologies, additional recurrent

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“…We demonstrate that addition of cladribine to the VEN+AZA regimen increases eradication of primary AML containing m-LSC activity in both in vitro and in vivo preclinical models. We believe these findings provide important mechanistic insights that may explain results from several recent clinical trials reporting superior CR/CRi and MRD negativity rates when venetoclax is combined with chemotherapy regimens especially ones that contain cladribine or its close analogue fludarabine, namely FLAG-Ida, CLIA or Clad-LDAC/AZA (35)(36)(37)(38). Notably, the addition of cladribine in these three trials was mainly based on empirical clinical experience and the long history of using cladribine-containing chemotherapy regimens for relapse/refractory stages of AML.…”

Section: Discussionmentioning

confidence: 64%

A novel type of monocytic leukemia stem cell revealed by the clinical use of venetoclax-based therapy

Pei

Gillen

Shelton

et al. 2022

Preprint

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The BCL-2 inhibitor venetoclax has recently emerged as an important component of acute myeloid leukemia (AML) therapy. Notably, use of this agent has revealed a previously unrecognized form of pathogenesis characterized by monocytic disease progression. We demonstrate that this form of disease arises from a fundamentally different type of leukemia stem cell (LSC), which we designate as monocytic LSC (m-LSC), that is developmentally and clinically distinct from the more well-described primitive LSC (p-LSC). The m-LSC is distinguished by a unique immunophenotype (CD34-, CD4+, CD11b-, CD14-, CD36-), unique transcriptional state, reliance on purine/pyrimidine metabolism, and selective sensitivity to cladribine. Critically, in some instances m-LSC and p-LSC subtypes can co-reside in the same AML patient and simultaneously contribute to overall tumor complexity. Thus, our findings demonstrate that LSC heterogeneity has direct clinical significance and highlights the need to distinguish and target m-LSCs as a means to improve clinical outcomes with venetoclax-based regimens.

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Phase II Study of Venetoclax Added to Cladribine Plus Low-Dose Cytarabine Alternating With 5-Azacitidine in Older Patients With Newly Diagnosed Acute Myeloid Leukemia

Cited by 64 publications

References 22 publications

The Growing Role of the Bh3 Mimetic Drug Venetoclax in the Therapy of Acute Myeloid Leukemia

The Growing Role of the Bh3 Mimetic Drug Venetoclax in the Therapy of Acute Myeloid Leukemia

Implications of RAS mutational status in subsets of patients with newly diagnosed acute myeloid leukemia across therapy subtypes

A novel type of monocytic leukemia stem cell revealed by the clinical use of venetoclax-based therapy

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