Broad Activity for the Pivekimab Sunirine (PVEK, IMGN632), Azacitidine, and Venetoclax Triplet in High-Risk Patients with Relapsed/Refractory Acute Myeloid Leukemia (AML)

Daver, Naval; Montesinos, Pau; Aribi, Ahmed; Marconi, Giovanni; Altman, Jessica K.; Wang, Eunice S.; Roboz, Gail J.; Burke, Patrick W.; Gaïdano, Gianluca; Walter, Roland B.; Thomas, Xavier; Jeyakumar, Deepa; DeAngelo, Daniel J.; Erba, Harry P.; Todisco, Elisabetta; Begna, Kebede H.; Advani, Anjali S.; Gastaud, Lauris; Fuente, Adolfo de la; Curti, Antonio; Mendez, Lourdes M.; Vyas, Paresh; Boissel, Nicolas; Vey, Norbert; Récher, Christian; Longval, Thomas; Platzbecker, Uwe; Kapp-Schwoerer, Silke; Schliemann, Christoph; Konopleva, Marina; Torres, Laura; Sallman, David A.; Marcucci, Guido; Pemmaraju, Naveen; Martinelli, Giovanni; Kantarjian, Hagop; Sloss, Callum M.; Malcolm, Kara E; Zweidler‐McKay, Patrick A.; Sweet, Kendra

doi:10.1182/blood-2022-158030

Cited by 18 publications

(15 citation statements)

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“…The majority of patients who benefit from flotetuzumab are primary refractory and TP53- mutated, which is related to a distinct immune microenvironment compared to non- TP53- mutated AML. An ongoing phase 1b/2 study is also evaluating the combination of pivekimab sunirine (IMGN632), a CD123-targeting antibody–drug conjugate, with AZA/VEN [ 190 ]. Patients with R/R AML treated with this were reported to have CRc rates of 31%, including 26% in those with ELN adverse disease and 64% of those with FLT3- ITD, with minimal additive myelosuppression beyond that of AZA/VEN.…”

Section: Investigational Agents and Future Directionsmentioning

confidence: 99%

Recent advances in targeted therapies in acute myeloid leukemia

2023

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Acute myeloid leukemia (AML) is the most common acute leukemia in adults. While survival for younger patients over the last several decades has improved nearly sixfold with the optimization of intensive induction chemotherapy and allogeneic stem cell transplantation (alloHSCT), this effect has been largely mitigated in older and less fit patients as well as those with adverse-risk disease characteristics. However, the last 10 years has been marked by major advances in the molecular profiling of AML characterized by a deeper understanding of disease pathobiology and therapeutic vulnerabilities. In this regard, the classification of AML subtypes has recently evolved from a morphologic to a molecular and genetic basis, reflected by recent updates from the World Health Organization and the new International Consensus Classification system. After years of stagnation in new drug approvals for AML, there has been a rapid expansion of the armamentarium against this disease since 2017. Low-intensity induction therapy with hypomethylating agents and venetoclax has substantially improved outcomes, including in those previously considered to have a poor prognosis. Furthermore, targeted oral therapies against driver mutations in AML have been added to the repertoire. But with an accelerated increase in treatment options, several questions arise such as how to best sequence therapy, how to combine therapies, and if there is a role for maintenance therapy in those who achieve remission and cannot undergo alloHSCT. Moreover, certain subtypes of AML, such as those with TP53 mutations, still have dismal outcomes despite these recent advances, underscoring an ongoing unmet need and opportunity for translational advances. In this review, we will discuss recent updates in the classification and risk stratification of AML, explore the literature regarding low-intensity and novel oral combination therapies, and briefly highlight investigative agents currently in early clinical development for high-risk disease subtypes.

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Section: Investigational Agents and Future Directionsmentioning

confidence: 99%

Recent advances in targeted therapies in acute myeloid leukemia

2023

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“…In this phase 1b/2 study of the triplet regimen of PVEK, azacitidine (AZA), and venetoclax (VEN) presented by Dr. Daver, there was an ORR of 45% (41/91) with CRc of 25% (23/91), with higher responses (ORR 53% and CRc 38%) in the 47 patients who were VEN-naïve. The drug was well tolerated, with infusion reactions occurring in 22% (20/91) of patients, and only 5% discontinued treatment due to PVEK-related adverse events [5].…”

Section: Novel Regimens In Amlmentioning

confidence: 99%

Novel agents and regimens in acute myeloid leukemia: latest updates from 2022 ASH Annual Meeting

2023

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Developments in investigational agents and novel regimens in acute myeloid leukemia (AML) were reported in the 2022 American Society of Hematology (ASH) annual meeting. Encouraging efficacy data were presented from first-in-human studies of two investigational menin inhibitors, SNDX-5613 and KO-539, in relapsed and refractory (R/R) acute myeloid leukemia (AML) with KMT2A rearrangement or mutant NPM1, with overall response rates (ORR) of 53% (32/60) and 40% (8/20), respectively. The addition of the novel drug pivekimab sunirine, a first-in-class antibody–drug conjugate targeting CD123, to azacitidine and venetoclax in R/R AML resulted in an ORR of 45% (41/91), which rose to 53% in those who were venetoclax naïve. Additional novel triplet treatment combinations included the addition of magrolimab, an anti-CD47 antibody, to azacitidine and venetoclax, with an ORR of 81% (35/43) in newly diagnosed AML, including an ORR of 74% (20/27) in TP53 mutated AML. The addition of the FLT3 inhibitor gilteritinib to azacitidine/venetoclax was also featured, with an ORR of 100% (27/27) in newly diagnosed AML and an ORR of 70% (14/20) in R/R AML.

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“…Another anti-CD123 antibody-drug conjugate, pivekimab sunirine, which causes DNA alkylation, 127 led to objective response rates (ORR) of 51% when combined with venetoclax/azacitidine in CD123-positive R/R AML, with auspicious activity in the FLT3-ITD subgroup, where ORR was 82%. 128 Bispecific antibodies, typically bispecific T-cell engagers, recruit T cells to tumors via an anti-CD3 moiety by binding to a tumor-specific antigen. An exemplar is blinatumomab, used to treat B-cell acute lymphoblastic leukemia.…”

Section: Surface Protein Targetingmentioning

confidence: 99%

An Overview of Targeted Therapies in Acute Myeloid Leukemia

2023

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Acute myeloid leukemia (AML) is the most aggressive adult leukemia, characterized by clonal differentiation arrest of progenitor or precursor hematopoietic cells. Intense preclinical and clinical research has led to regulatory approval of several targeted therapeutics, administered either as single agents or as combination therapies. However, the majority of patients still face a poor prognosis and disease relapse frequently occurs due to selection of therapy-resistant clones. Hence, more effective novel therapies, most likely as innovative, rational combination therapies, are urgently needed. Chromosomal aberrations, gene mutations, and epigenetic alterations drive AML pathogenesis but concurrently provide vulnerabilities to specifically target leukemic cells. Other molecules, either aberrantly active and/or overexpressed in leukemic stem cells, may also be leveraged for therapeutic benefit. This concise review of targeted therapies for AML treatment, which are either approved or are being actively investigated in clinical trials or recent preclinical studies, provides a flavor of the direction of travel, but also highlights the current challenges in AML treatment.

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Broad Activity for the Pivekimab Sunirine (PVEK, IMGN632), Azacitidine, and Venetoclax Triplet in High-Risk Patients with Relapsed/Refractory Acute Myeloid Leukemia (AML)

Cited by 18 publications

References 0 publications

Recent advances in targeted therapies in acute myeloid leukemia

Recent advances in targeted therapies in acute myeloid leukemia

Novel agents and regimens in acute myeloid leukemia: latest updates from 2022 ASH Annual Meeting

An Overview of Targeted Therapies in Acute Myeloid Leukemia

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