Should we target demethylation in acute myeloid leukemia?

Aberrant methylation patterns were first documented in the genome of leukemic cells (1), however, cancer cells also sustain an aberrant expression of epigenetic regulator enzymes, such as lysine-specific demethylase 1 (LSD1) (2). LSD1, also known as KDM1A, is the first discovered histone lysine demethylase: it specifically targets histones H3 lysine 4 and regulates balance between self-renewal and differentiation in hematopoietic stem cells. LSD1 is highly expressed by leukemic stem cells, and also regulates p53 expression and is particularly relevant for megakaryocyte differentiation (3). Therefore, irreversible LSD1 inhibitors are currently being tested in chronic myeloproliferative neoplasms (4).

Iadademstat, a small molecule soluble in a water solution for oral administration, binds covalently to LSD1’s catalytic center thus uncoupling its synergic interaction with GFI1B-based transcriptional repressor complex and blocking LSD1 demethylating activity to histones. This results in a strong differentiating effect and reduction in proliferative capacity of leukemic cells (5) and both safe and effective as a single drug in a phase 1 study enrolling 27 relapsed/refractory acute myeloid leukemia (AML) patients (6).

The ALICE open-label phase-2 trial (7) enrolled 36 patients (safety cohort) newly diagnosed with AML and unfit for (or refusing) intensive chemotherapy. Median age was 76 years and 64% of the patients harbored adverse risk disease: a high portion (50%) of myelodysplasia-related AML and high-risk mutations (TP53 28%, RAS 14%) was included. Treatment backbone included azacitidine standard schedule (75 mg/m² days 1 to 5 and days 8 to 9) while iadademstat was administered at doses of 60 or 90 mcg/m²/day on days 1 to 5 of each week in 28-day cycles. In the safety cohort, two treatment-related grade 5 events were reported out of 12 deaths incurred in the treatment period: intracranial hemorrhage sustained one of the two fatal episodes. One case of differentiation syndrome was also ascertained, while the most frequent non-hematologic adverse event was grade 1–2 dysgeusia, complained by 42% of the patients. Prolonged cytopenia was registered in most of the individuals, especially those receiving iadademstat at the higher dose. Infective episodes during the trial, which spanned from 2018 to 2021, included 8 coronavirus disease 2019 (COVID-19) infections, 3 of whom leading to death. Of notice, on converse, very few treatment-related febrile neutropenia episodes were registered (3%), while 7 non-related infective episodes led to treatment discontinuation. These rates compare favorably with the infective risks reported by the venetoclax plus azacitidine combination in VIALE-A trial: febrile neutropenia occurred in 31% of the patients and serious infections in 61% (8). Moreover, discontinuation rate (except death) was 28%: only 17% of the patients stopped treatment due to investigator decision or toxicity; however, treatment holds and dose reductions were requested for 17 patients and the median number of cycles was 3.0. Thirty-day mortality in the trial was 11%, which is comparable to the 7% rate reported by VIALE-A trial (8); however, 3 cases of fatal intracranial hemorrhage occurred and 69% of the patients developed grade 3–4 on-target thrombocytopenia posing a warning on full dose administration in severely thrombocytopenic patients. Despite this issue, 3 patients remain on long-term compassionate use 3–4 years after initiation.

Unexpectedly, the overall response rate in the efficacy (27 patients) and the safety cohorts was 82% and 61%, and complete remission with complete or incomplete hematologic recovery (deep response) was 52% and 39%, respectively. Moreover, most of non-responder patients showed stable non-progressing disease. Deep response rate in patients assigned to 90 mcg/m²/day iadademstat was 64%, which compares favorably with the rate reported by azacitidine combination with venetoclax (66.4%) (8) and the rate of deep response reported in patients treated with azacitidine plus gilteritinib (58.1%) (9). In addition, ad-hoc assessment of response rates in the ALICE trial according to 2022 European LeukemiaNet criteria (10) still showed a high rate of overall response (52%) and deep response (44%) in the efficacy cohort. Response was rapid (median time to response 64 days) and durable (18-month persistence of deep response 40–56%), possibly due to absence of measurable residual disease in 91% patients who reached deep response according to 2022 European LeukemiaNet criteria. Nevertheless, deep response rates were dose-dependent: 39% in the lower dose cohort versus 64% in the higher dose one; therefore, the recommended phase 2 dose of iadademstat was 90 µg/m² per day with azacitidine. Hematologic response was also high, since 45% of transfusion-dependent individuals were free of transfusions at 6 months. Median survival in the ALICE efficacy cohort was 11 months at a median follow-up of 22 months, which is an intermediate value between single demethylating agent therapy and venetoclax-combination strategies (11,12). These still dismal results highlight the master role of hematopoietic stem cell transplantation in granting prolonged survival for AML (13). However, the larger the number of treatment options, the better the overall survival for cancer patients (14).

Subgroup analysis of this small phase 2 trial identified patients with monocytic or myelo-monocytic AML subtype as the best responders (88% deep response and 60% overall survival at 18-month milestone). In addition, surprisingly all the patients carrying mutations in the RAS pathway, NPM1, DNMT3A or RUNX1 achieved a response. Complete remission with incomplete hematologic recovery was also achieved in 5 out of 8 patients carrying TP53 mutations and median survival in the TP53-mutated subgroup was 305 days, which compares much favorably with this subgroup survival in VIALE A trial, namely 5.5 months (15). Most recently, inhibition of LSD1 in a mouse melanoma model was shown to enhance CD8⁺ T cell differentiation and anti-tumor activity; therefore, immunomodulation is one of the possible unique actions of iadademstat, which might explain such high response rates in difficult-to-treat subgroups (16).

Mutation-targeted therapies, such as FLT3 inhibitors and isocitrate dehydrogenase inhibitors, have enhanced the treatment choices for newly-diagnosed AML, and other, such as menin inhibitors, were effective in specific relapsed/refractory AML subgroups. Therefore, patients will be briefly offered a real chance of personalized treatments. However, a number of new challenges now need to be faced, including optimal combination or sequencing of drugs, frailty-based and response-based adaptations of both treatments and schedules (17). ALICE trial showed that host-based adaptation of the dose can enhance the benefit-to-risk balance of effective drugs and suggests to develop and validate robust bleeding-risk scores in AML patients.

ALICE study showed some limitations (18): similar to most phase 2 trials for AML patients, dose optimization by standard 3+3 design is sometimes burdensome and several risk-benefit issues may still be pending after the study. Moreover, in combination trials, attribution of side effects to the disease itself or any of the combined drugs is always very difficult for the clinical investigators. Another limitation of the safety report of the ALICE trial resides in the lack of reported causes of the second of the two treatment-related deaths.

Other randomized phase 2 and phase 3 trials tested the synergic efficacy and the safety of combination therapies based on azacitidine backbone but no study achieved deep response rates higher than 50%. Azacitidine plus cusatuzumab, an anti-CD70 monoclonal antibody, achieved 30–40% deep response rate at two different doses (19). Azacitidine combined with pracinostat, an oral pan-histone deacetylase (HDAC) inhibitor, did not significantly improve deep response, which was reported in 36% of the patients (20). Similarly, combination with durvalumab, a checkpoint inhibitor, did not allow to achieve complete response with complete or incomplete blood recovery in more than 35% of the patients with no advantage versus azacitidine alone (21).

In conclusion, demethylation is a mechanism of anti-neoplastic therapy that is continuously being exploited (22). Iadademstat is a virtuous example of a target molecule developed by a public biopharmaceutic company specialized in epigenetic-based therapies (23). Provided that venetoclax-based combinations may not equally benefit all the unfit AML patients (15), targeted demethylation with iadademstat is one of the most promising strategies for AML patients with TP53 or RAS-pathway mutations. As a result of ALICE trial results, iadademstat has achieved orphan drug designation for AML both in the United States (US) and European Union (EU). Current trials are exploring iadademstat combinations with azacitidine plus venetoclax (NCT06357182, NCT06514261) and with gilteritinib in refractory/relapsed FLT3-ITD AML patients (NCT05546580). Furthermore, iadademstat combination with demethylating agents is also being tested in high-risk myelodysplastic syndrome (NCT06502145). Finally, other LSD1 inhibitors are currently being developed, in particular, reversible inhibitors have started being assessed in phase 1–2 clinical trials for different cancers.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-210/prf

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-210/coif). M.M. reports consulting fees from Novartis, Roche and Gilead, honoraria for lectures from Novartis and MSD, and support for attending meetings and/or travel from Johnson & Johnson, Abbvie. The author has no other conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Baylin SB, Fearon ER, Vogelstein B, et al. Hypermethylation of the 5' region of the calcitonin gene is a property of human lymphoid and acute myeloid malignancies. Blood 1987;70:412-7. [Crossref] [PubMed]
2. Saleque S, Kim J, Rooke HM, et al. Epigenetic regulation of hematopoietic differentiation by Gfi-1 and Gfi-1b is mediated by the cofactors CoREST and LSD1. Mol Cell 2007;27:562-72. [Crossref] [PubMed]
3. Huang J, Sengupta R, Espejo AB, et al. p53 is regulated by the lysine demethylase LSD1. Nature 2007;449:105-8. [Crossref] [PubMed]
4. Goethert JR, Gill H, Palandri F, et al. Bomedemstat (IMG-7289), an LSD1 Inhibitor, Manages the Signs and Symptoms of Essential Thrombocythemia (ET) While Reducing the Burden of Cells Homozygous for Driver Mutations. Blood 2023;142:747. [Crossref]
5. Maes T, Mascaró C, Tirapu I, et al. ORY-1001, a Potent and Selective Covalent KDM1A Inhibitor, for the Treatment of Acute Leukemia. Cancer Cell 2018;33:495-511.e12. [Crossref] [PubMed]
6. Salamero O, Montesinos P, Willekens C, et al. First-in-Human Phase I Study of Iadademstat (ORY-1001): A First-in-Class Lysine-Specific Histone Demethylase 1A Inhibitor, in Relapsed or Refractory Acute Myeloid Leukemia. J Clin Oncol 2020;38:4260-73. [Crossref] [PubMed]
7. Salamero O, Molero A, Pérez-Simón JA, et al. Iadademstat in combination with azacitidine in patients with newly diagnosed acute myeloid leukaemia (ALICE): an open-label, phase 2a dose-finding study. Lancet Haematol 2024;11:e487-98. [Crossref] [PubMed]
8. Pratz KW, Jonas BA, Pullarkat V, et al. Long-term follow-up of VIALE-A: Venetoclax and azacitidine in chemotherapy-ineligible untreated acute myeloid leukemia. Am J Hematol 2024;99:615-24. [Crossref] [PubMed]
9. Wang ES, Montesinos P, Minden MD, et al. Phase 3 trial of gilteritinib plus azacitidine vs azacitidine for newly diagnosed FLT3mut+ AML ineligible for intensive chemotherapy. Blood 2022;140:1845-57. [Crossref] [PubMed]
10. Döhner H, Wei AH, Appelbaum FR, et al. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood 2022;140:1345-77. [Crossref] [PubMed]
11. Dombret H, Seymour JF, Butrym A, et al. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood 2015;126:291-9. [Crossref] [PubMed]
12. DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia. N Engl J Med 2020;383:617-29. [Crossref] [PubMed]
13. Chen TT, Lin CC, Lo WJ, et al. Venetoclax Plus Azacitidine as a Bridge Treatment to Allogeneic Stem Cell Transplantation in Unfit Patients with Acute Myeloid Leukemia. Cancers (Basel) 2024;16:1082. [Crossref] [PubMed]
14. Lichtenberg FR. The Relationship Between Pharmaceutical Innovation and Cancer Mortality in Spain, From 1999 to 2016. Value Health 2023;26:1711-20. [Crossref] [PubMed]
15. Dohner H, Pratz KW, DiNardo CD, et al. ELN risk stratification is not predictive of outcomes for treatment-naïve patients with acute myeloid leukemia treated with venetoclax and azacitidine. Blood 2022;140:1441-4. [Crossref]
16. Pallavicini I, Frasconi TM, Catozzi C, et al. LSD1 inhibition improves efficacy of adoptive T cell therapy by enhancing CD8(+) T cell responsiveness. Nat Commun 2024;15:7366. [Crossref] [PubMed]
17. Jen WY, Kantarjian H, Kadia TM, et al. Combination therapy with novel agents for acute myeloid leukaemia: Insights into treatment of a heterogenous disease. Br J Haematol 2024;205:30-47. [Crossref] [PubMed]
18. Seo HJ, Kim SY, Lee YJ, et al. RoBANS 2: A Revised Risk of Bias Assessment Tool for Nonrandomized Studies of Interventions. Korean J Fam Med 2023;44:249-60. [Crossref] [PubMed]
19. Pabst T, Papayannidis C, Demirkan F, et al. Cusatuzumab plus azacitidine in newly diagnosed acute myeloid leukaemia ineligible for intensive chemotherapy (CULMINATE): part one of a randomised, phase 2, dose optimisation study. Lancet Haematol 2023;10:e902-12. [Crossref] [PubMed]
20. Garcia-Manero G, Kazmierczak M, Wierzbowska A, et al. Pracinostat combined with azacitidine in newly diagnosed adult acute myeloid leukemia (AML) patients unfit for standard induction chemotherapy: PRIMULA phase III study. Leuk Res 2024;140:107480. [Crossref] [PubMed]
21. Zeidan AM, Boss I, Beach CL, et al. A randomized phase 2 trial of azacitidine with or without durvalumab as first-line therapy for older patients with AML. Blood Adv 2022;6:2219-29. [Crossref] [PubMed]
22. Hojjatipour T, Ajeli M, Maali A, et al. Epigenetic-modifying agents: The potential game changers in the treatment of hematologic malignancies. Crit Rev Oncol Hematol 2024;204:104498. [Crossref] [PubMed]
23. Liu HM, Zhou Y, Chen HX, et al. LSD1 in drug discovery: From biological function to clinical application. Med Res Rev 2024;44:833-66. [Crossref] [PubMed]