Courtney D. DiNardo, MD, MSCE

Associate Professor

Department of Leukemia

Division of Cancer Medicine

The University of Texas MD Anderson Cancer Center

Associate Member

The MD Anderson Cancer Center

UTHealth Houston Graduate School of Biomedical Sciences

Houston, Texas

Although patients with acute myeloid leukemia (AML) glean positive benefit from standard induction treatment that frequently involves intensive chemotherapy (IC), a significant portion of patients, especially older ones, remain IC- ineligible. For these patients, the emergence of venetoclax (Venclexta) and venetoclax combination regimens have been a welcome advance.

For example, DiNardo et al¹ have demonstrated in the Viale-A trial (NCT02993523) a median overall survival of 14.7 months in the azacitidine (Vidaza)-venetoclax group (n = 286) vs 9.6 months in the azacitidine-placebo group (n = 145) at a median follow-up of 20.5 months in previously untreated older patients. The incidence of remission was also higher in the combination group.

Unfortunately, the challenge of resistance arises in patients treated with venetoclax, which continues to be a source of frustration among clinicians and investigators.

In a presentation during the 2023 American Association for Cancer Research Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome, held January 23-25, 2023, in Austin, Texas, Courtney D. DiNardo, MD, MSCE, provided an overview of venetoclax resistance and interrelated mechanisms, with a spotlight on kinase signaling pathways, TP53 mutation, monocytic, and other forms of resistance.²

Resistance is commonly associated with the expansion or acquisition of signaling pathways such as TP53 or FLT3-ITD, DiNardo added.³

“When we’re discussing venetoclax in combinations, we need to keep in mind that continuous venetoclax is not very well tolerated,” DiNardo, an associate professor in the Department of Leukemia, The University of Texas MD Anderson Cancer Center in Houston and associate member in The MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, said.

“Most patients are receiving venetoclax for 21 days followed by a 2-week break,” DiNardo added.

Signaling/Kinase Resistance

Investigators conducted a retrospective study that evaluated 87 older or unfit patients with a new diagnosis of FLT3-mutated AML who were treated with low-intensity chemotherapy (LIC) plus a FLT3 inhibitor and venetoclax (n = 27) or a doublet regimen of LIC plus an FLT3 inhibitor (n = 60; VISUAL SYNPOSIS).⁴
According to the investigators, the triplet regimen was associated with significantly higher rates of complete remission (CR; 67% vs 32%, P = .002), CR/CR with incomplete hematologic recovery (CRi; 93% vs 70%, P = .02), FLT3-PCR negativity (96% vs 54%, P < .01), and flow-cytometry negativity (83% vs 38%, P < .01) than the doublet.

In a phase 1/2 trial (NCT05520567), the triplet regimen azacitidine, venetoclax, and gilteritinib (Xospata) was evaluated in 21 patients with newly diagnosed FLT3-mutated AML and 19 patients who were relapsed/refractory.⁵ In the newly diagnosed cohort, all patients responded, with 20 (95%) achieving CR and 81% who were minimal residual disease negative. Nineteen percent proceeded to allogeneic stem cell transplantation.

DiNardo noted that although there is some hesitancy with giving continuous venetoclax, dose optimization of triplet therapies is critical. Additionally, many older patients do well on it when this strategy is followed.

Monocytic Resistance

In a study by Pei et al,⁶ responses to azacitidine and venetoclax in patients with AML correlated closely with developmental stage.

The investigators noted that phenotypically primitive AML is sensitive but monocytic AML is more resistant.

They suggested that resistance can arise because of biologic properties intrinsic to monocytic differentiation. Alternative treatment strategies that target molecular and metabolic properties of monocytic AML cells could be an approach worthy of further investigation, DiNardo said.

She noted that cladribine was particularly effective in eradicating stem and progenitor potential of monocytic leukemia stem cells in preclinical models. Following on the cladribine approach, DiNardo discussed findings from a phase 2 trial (NCT03586609)⁷ that investigated the combination of venetoclax and cladribine and low-dose cytarabine (LDAC) that was alternated with venetoclax and azacitidine in 60 older or unfit patients with AML (TABLE).

Ninety-three percent of evaluable patients responded and 84% of patients were negative for minimal residual disease. The median overall survival and disease-free survival was not reached after a median follow-up of 22.1 months.

TP53 Resistance

Turning to TP53 resistance, DiNardo said that the efficacy of azacitidine and venetoclax was about 50% and short-lived. Pollyea et al⁸ reported that the median survival was about 5 months.⁸

In the study (NCT02993523), 127 patients with poor-risk cytogenetics were treated with azacitidine and venetoclax compared with 56 patients who received azacitidine alone.

For patients who received the combination therapy, investigators reported a composite remission rate of 70% vs 23% for patients treated with azacitidine alone.

The investigators noted that the median duration of remission was 18.4 months vs 8.5 months, respectively, and the median overall survival was 23.4 months vs 11.3 months, respectively.

Magrolimab

The monoclonal antibody magrolimab has shown promising results in late-stage trials. “What’s exciting is that patients with TP53 mutations may be benefiting from CD47 inhibition,” DiNardo said. Magrolimab prevents the SIRP-α receptor on macrophages from recognizing CD47, allowing macrophages to phagocytose cancer cells.

Findings from a phase 1/2 trial presented by Daver et al⁹ (NCT04435691) during the 64th American Society of Hematology Annual Meeting and Exposition suggest that frontline treatment with magrolimab plus azacitidine and venetoclax resulted in high complete response rates and was well tolerated in patients with high-risk de novo and secondary AML regardless of TP53 mutation status.

Another magrolimab study, the phase 3 ENHANCE-2 trial (NCT04778397), is the first study of AML that is TP53-mutated specific.

Patients are randomly assigned to receive azacitidine plus magrolimab versus physician’s choice of venetoclax plus azacitidine or 7 + 3 chemotherapy.¹⁰ The primary end point is overall survival and key secondary end points include event-free survival, transfusion independence, and complete response.

Looking Ahead

DiNardo said emerging immune-based approaches in AML spotlight antibody-drug conjugates, such as CD33, CD123, and CLL1, and adaptive or innate immune systemharnessing therapies. The latter includes bispecific antibodies (CD3 × AML antigen and CD47 × CD3), immune checkpoint-based approaches (such as T-cell and macrophage checkpoints), chimeric antigen receptor (CAR) T-cell therapy, CAR natural killer cells, and vaccines.

“There are multiple interrelated mechanisms that contribute to resistance, and future trials will work to address many of these mechanisms,” DiNardo concluded.

REFERENCES

1. DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383(7):617-629. doi:10.1056/NEJMoa2012971

2. DiNardo CD. Understanding and preventing resistance to BCL2 inhibitor therapy in AML. Presented at: 2023 American Association for Cancer Research Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; January 23-25, 2023; Virtual. Accessed February 8, 2023. https://bit.ly/3Xtl5Um

3. DiNardo CD, Tiong IS, Quaglieri A, et al. Molecular patterns of response and treatment failure after frontline venetoclax combinations in older patients with AML. Blood. 2020;135(11):791-803. doi:10.1182/blood.2019003988

4. Yilmaz M, Kantarjian H, Short NJ, et al. Hypomethylating agent and venetoclax with FLT3 inhibitor “triplet” therapy in older/unfit patients with FLT3 mutated AML. Blood Cancer J. 2022;12(5):77. doi:10.1038/s41408-022-00670-0

5. Short N, DiNardo CD, Daver N, et al. Updated results from a phase I/II study of the triplet combination of azacitidine, venetoclax and gilteritinib for patients with FLT3-mutated acute myeloid leukemia. Abstract presented at: 64th American Society of Hematology Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA. Accessed February 8, 2023. http://bit.ly/3XhC5wD

6. Pei S, Pollyea DA, Gustafson A, et al. Monocytic subclones confer resistance to venetoclax-based therapy in patients with acute myeloid leukemia. Cancer Discov. 2020;10(4):536-551. doi:10.1158/2159-8290.CD-19-0710

7. Kadia TM, Reville PK, Wang X, et al. 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. J Clin Oncol. 2022;40(33):3848-3857. doi:10.1200/JCO.21.02823

8. Pollyea DA, Pratz KW, Wei AH, et al. Outcomes in patients with poor-risk cytogenetics with or without TP53 mutations treated with venetoclax and azacitidine. Clin Cancer Res. 2022;28(24):5272-5279. doi:10.1158/1078-0432.CCR-22-1183

9. Daver N, Senapati J, Maiti A, et al. Phase I/II study of azacitidine (AZA) with venetoclax (VEN) and magrolimab (Magro) in patients (pts) with newly diagnosed (ND) older/unfit or high-risk acute myeloid leukemia (AML) and relapsed/refractory (R/R) AML. Blood. 2022;140(suppl 1):141-144. doi:10.1182/blood-2022-170188

10. Daver NG, Vyas P, Kambhampati S, et al. Tolerability and efficacy of the first-in-class anti-CD47 antibody magrolimab combined with azacitidine in frontline TP53m AML patients: phase 1b results. J Clin Oncol. 2022;40(suppl 16):7020. doi: 10.1200/JCO.2022.40.16_suppl.7020