Venetoclax in combination with hypomethylating agents or low dose cytarabine for relapsed and refractory acute myeloid leukemia

Graveno, Molly; Carulli, Alison; Freyer, Craig W.; Mangan, Brendan L.; Nietupski, Robert; Loren, Alison W.; Frey, Noelle V.; Porter, David L.; Gill, Saar; Hexner, Elizabeth O.; Luger, Selina M.; Martin, Mary Ellen; McCurdy, Shannon R.; Perl, Alexander E.; Babushok, Daria V.; Pratz, Keith W.

doi:10.1080/10428194.2022.2042688

Cited by 9 publications

(5 citation statements)

References 18 publications

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“…The IC 50 values were 0.836 ± 0.276 and 1.08 ± 0.159 μM ( P > 0.05) for Ara-C and Ara-SH, respectively, indicating that our structural modification did not significantly impact the efficacy of the Ara-C component. It has been proved that cytarabine in combination with venetoclax showed impressive results for AML patients in the clinic. ,− In the present study, we set up a series of molar ratios of Ara-SH to Ven (10:1, 20:1, 40:1, 50:1, 100:1) for combination index (CI) calculation. The results showed that Ara-SH in combination with Ven could obviously inhibit the human AML MOLM-13 cell growth, and the CI value was the lowest, 0.66, when the molar ratio of Ara-SH and Ven was 40:1 (Figure S7).…”

Section: Resultsmentioning

confidence: 99%

Smart and Generalizable Cytarabine Derivative-Triggered Nanoparticles for Synergistic Therapy of Relapsed/Refractory Acute Myeloid Leukemia

Jia

Yang

Zheng

et al. 2023

ACS Appl. Mater. Interfaces

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Acute myeloid leukemia (AML) is rapidly progressed hematologic malignancy with relapsed and refractory characteristics. Cytarabine combined with the BCL2 inhibitor venetoclax showed impressive response rates in the treatment of relapsed/refractory acute myeloid leukemia (R/R AML), while it requires complicated administration regimens and brings added toxicity. In this work, we synthesized a mercaptopropionic acid-substituted derivative of Ara-C (Ara-SH) and used it as the trigger to fabricate a smart cytarabine and venetoclax-coloaded nanoparticle (AV-NP) through self-assembly. The AV-NP characterized with redox-responsive drug release, rapid uptake by leukemia cells, and long retention in circulation had the potential to accumulate in leukemia-enriched sites. It generated a remarkable synergistic effect with higher antileukemia activity in vitro and better safety in the hematologic system compared with free drugs and significantly improved the therapeutic effect on orthotopic AML mice in vivo. These similar results were also confirmed in primary cells from R/R-AML patients. Besides, the AV-NP has the superiority of facile fabrication and generalizability, rendering it easy for clinical translation.

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Section: Resultsmentioning

confidence: 99%

Smart and Generalizable Cytarabine Derivative-Triggered Nanoparticles for Synergistic Therapy of Relapsed/Refractory Acute Myeloid Leukemia

Jia

Yang

Zheng

et al. 2023

ACS Appl. Mater. Interfaces

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“…The patient herein achieved complete remission and sustained durable remission after the treatment of this regime, but another unknown was how long will this regime’s effects last? Venetoclax has shown a promising remission effect in patients with AML, but these patients’ progression-free survival has not yet been satisfied ( 20 , 21 ). The patient in this study was an older woman with adverse prognostic gene mutation.…”

Section: Discussionmentioning

confidence: 99%

The successful combination of grapefruit juice and venetoclax in an unfit acute myeloid leukemia patient with adverse risk: A case report

Long

Ruan²,

Wu³

et al. 2022

Front. Oncol.

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Venetoclax combined with hypomethylating agents such as azacitidine and decitabine is the standard regime for the elderly patient with acute myeloid leukemia (AML) unfit for intensive induction therapy. However, many patients struggle with finances and forgo treatments due to the high costs of venetoclax. In this study, we performed the regime with azacitidine, low-dose venetoclax, and grapefruit juice on an unfit AML patient with TP53 mutation. The peak venetoclax concentration (Cmax) and side effects on the patient were also monitored. The patient achieved complete remission with the venetoclax Cmax within the effective concentration range (1,000–3,000 ng/ml) and maintained durable remission until recently. Febrile neutropenia, thrombocytopenia, and pneumonia appeared during the first cycle and were recovered by stimulating agents and antibiotic treatment. This improvement combination approach by drug-food interaction may enlighten other similarly patients with AML, especially those in low-middle income countries.

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“…In the VIALE‐C trial, 36% of patients who received prior HMA achieved CR/CRi, while 55% of patients in this trial who did not receive prior HMA achieved CR/CRi 7 . Although HMA–venetoclax combinations are highly effective in the frontline, the combinations are less active in patients with R/R AML 8–13 . While therapies are frequently less active when used as second‐line treatments, the reduced efficacy of HMA–venetoclax combinations in the relapsed setting may reflect unique aspects to the mechanism of this combination, as discussed below.…”

Section: Venetoclax a Clinical ‘Blockbuster’ In Patients With Amlmentioning

confidence: 91%

“…7 Although HMA-venetoclax combinations are highly effective in the frontline, the combinations are less active in patients with R/R AML. [8][9][10][11][12][13] While therapies are frequently less active when used as second-line treatments, the reduced efficacy of HMA-venetoclax combinations in the relapsed setting may reflect unique aspects to the mechanism of this combination, as discussed below.…”

Section: E N Etocl a X A Cli N Ica L 'Block Buster' I N Patie N Ts W ...mentioning

confidence: 99%

Venetoclax resistance in acute myeloid leukaemia—Clinical and biological insights

Nachmias,

Aumann,

Haran

et al. 2024

Br J Haematol

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SummaryVenetoclax, an oral BCL‐2 inhibitor, has been widely incorporated in the treatment of acute myeloid leukaemia. The combination of hypomethylating agents and venetoclax is the current standard of care for elderly and patient's ineligible for aggressive therapies. However, venetoclax is being increasingly used with aggressive chemotherapy regimens both in the front line and in the relapse setting. Our growing experience and intensive research demonstrate that certain genetic abnormalities are associated with venetoclax sensitivity, while others with resistance, and that resistance can emerge during treatment leading to disease relapse. In the current review, we provide a summary of the known mechanisms of venetoclax cytotoxicity, both regarding the inhibition of BCL‐2‐mediated apoptosis and its effect on cell metabolism. We describe how these pathways are linked to venetoclax resistance and are associated with specific mutations. Finally, we provide the rationale for novel drug combinations in current and future clinical trials.

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Venetoclax in combination with hypomethylating agents or low dose cytarabine for relapsed and refractory acute myeloid leukemia

Cited by 9 publications

References 18 publications

Smart and Generalizable Cytarabine Derivative-Triggered Nanoparticles for Synergistic Therapy of Relapsed/Refractory Acute Myeloid Leukemia

Smart and Generalizable Cytarabine Derivative-Triggered Nanoparticles for Synergistic Therapy of Relapsed/Refractory Acute Myeloid Leukemia

The successful combination of grapefruit juice and venetoclax in an unfit acute myeloid leukemia patient with adverse risk: A case report

Venetoclax resistance in acute myeloid leukaemia—Clinical and biological insights

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