Advancing the outcomes of AML out of antecedent MPN by targeting mutated IDH1

Abstract

Outcomes of myeloproliferative neoplasms (MPN)‐associated acute leukaemias are dismal with conventional therapy. Approximately 20% of MPN‐associated acute leukaemias have mutations in isocitrate dehydrogenase (IDH). Olutasidenib, and inhibitor of IDH1, demonstrates important clinical benefits in MPN‐associated leukaemia with IDH1 mutation.

Commentary on: Botton et al. Olutasidenib demonstrates significant clinical activity in mutated IDH1 acute myeloid leukemia arising from a prior myeloproliferative neoplasm. Br J Haematol 2025; 206:1121‐1128.

Acute myeloid leukaemia (AML) arising in the setting of antecedent myeloproliferative disorders has historically had outcomes among the worst with standard cytarabine‐based chemotherapy. The study of novel‐targeted therapies in this subset has been hampered by exclusion from most de novo AML trials with novel agents. In their paper, De Botton et al. ¹ describe the clinical activity of the novel isocitrate dehydrogenase 1 (IDH1) inhibitor olutasidenib in a cohort of patients with IDH1 R132 mutations. These data highlight the importance of reassessment of molecular drivers at the time of progression and the clinical utility of a novel‐targeted IDH1 agent in an AML/myeloproliferative neoplasms (MPN) subset with encouraging results.

Advances in the treatment in recent years of AML based on the use of small molecule inhibitors of BCL‐2, FLT3, IDH1/2 and Menin have led to significant improvements over conventional cytotoxic therapies. One area where novel therapies have little prospective data are in patients who have developed accelerated or acute transformations of myeloproliferative disorders. This is largely because most late‐phase studies exclude these patients based on historical challenges with meeting conventional count recovery response criteria for acute myeloid leukaemia. To illustrate the futility of conventional cytotoxic chemotherapy, patients with AML that arise in the setting of prior myelofibrosis have a 41% response rate (all regressing to prior chronic phase MPN and not meeting conventional Complete Remission (CR) criteria for AML) but only a 9% 1‐year survival. ² Consortium of clinicians interested in capturing clinically meaningful therapies in this field has proposed alternative end‐points, ³ but few trials have used these end‐points as primary disease assessments to date. Regulatory hurdles with conclusions drawn from older high intensity therapy trials have left CR with full count recovery as the only surrogate for overall survival that the FDA will routinely consider for novel AML therapies. ⁴ Despite this limitation, in molecular targeted therapies, achievement of disease regression and elimination of blast phase disease can allow for allogeneic stem cell transplantation with curative intent.

Isocitrate dehydrogenase(IDH) 1 and 2 are mutated in approximately 20% of newly diagnosed AML with similar rates found in AML in the setting of antecedent MPN. ⁵ The pathophysiology of mutations in IDH1 and IDH2 is driven by neomorphic enzyme activity of the respective IDH proteins to generate an oncometabolite 2‐Hydroxygluterate(2‐HG). ⁶ 2‐HG is a competitive inhibitor of several dioxygenases including several well‐known to influence leukaemogenesis (TET2, ⁷ and histone demethylases ⁸ ). The production of 2‐HG leads to epigenic changes associated with a specific hypermethylation pattern leading to impaired differentiation and ultimately leukaemogenesis. ⁷ Small molecule inhibitors of the neomorphic activity of the cytosolic version (IDH1) ⁹ and mitochondrial (IDH2) ¹⁰ have been developed and the antitumour activity of these agents are thought to primarily relate to suppression of oncometabolite 2‐hydroxygluterate (2‐HG) and subsequent reversal of the epigenetic modifications trigged by 2‐HG. Inhibitors of both IDH1 and IDH2 have been approved for marketing based largely on the clinical utility of these agents in either front‐line or relapsed acute myeloid leukaemia.

In their paper, De Botton et al. ¹ describe the clinical outcomes of a subset of patients with IDH1‐mutated AML after prior MPN using the second‐generation IDH1 inhibitor olutasidenib. Olutasidenib was approved by the FDA in December 2022 for the treatment of relapsed or refractory AML with IDH1 mutations based on the larger olutasidenib phase I/II trial. ¹¹ Unlike many trials of novel agents in AML, this study enrolled post‐MPN cases, and the cohort of post‐MPN cases described in this study represents an area of unmet clinical needs as outlined above. Therapy consisted of olutasidenib alone at the approved dose of 150 mg twice daily or in combination with azacitidine at standard doses. The authors report a remarkable compete response rate of 40% (6/15 cases) who met conventional remission criteria with full count recovery. Of note, 10 of the 15 patients had received some form of prior anti‐leukaemia therapy and were refractory. Notable adverse effects leading to discontinuation in three patients include two patients with evidence of hepatotoxicity (elevated GGT and elevated liver function tests) which will need to be taken into account with monitoring patients on treatment. Responses appear durable, particularly in those who achieved CR, with a median duration of response of 24.8 months. Overall response rate was reported at 60% (9/15 patients) and in that larger group of responders, the median overall survival was 20.9 months with a median follow‐up of 55.3 months. Two patients in the cohort pursued allogeneic transplant in CR. The utility of the addition of azacitidine to olutasidenib is unclear as three of six patients on monotherapy achieved CRc and five of nine on the doublet achieving CRc. Co‐mutations with MPN driver genes JAK2, MPL and CALR were demonstrated in responders and non‐responders in the cohort which is reassuring in consideration of future applicability of these results. One concern would be the presence of only one patient with TP53 in the cohort, with the knowledge that the acquisition of TP53 mutations is routine at the time of progression to accelerated or blast‐phase MPN.

While the results of this cohort are promising, responses are not uniform and we are left with the intriguing question of the possibility of synergy of olutasidenib with inhibitors of BCL2 such as venetoclax. A recent case series of patients with triplet therapy of a venetoclax/IDHi/DMNTi combination report remarkable clinical activity in AML not associated with MPN ¹² as evidenced by almost uniform high‐quality responses (CRc:100% and MRD neg CR 90%). In select series of MPN in accelerated or blast phase, the utility of venetoclax and DMNTi appears to show limited activity in line with conventional induction chemotherapy (Median OS of 0.71 vs. 0.68 years respectively). ¹³ Based on these competing outcomes, and the unmet clinical need, future efforts in MPN‐associated leukaemias with IDH1 mutations will need to carefully evaluate addition of venetoclax to olutasidenib‐based therapy with particular attention to the myelosuppression often seen in venetoclax‐based therapies. In the interim, for those with MPN‐associated leukaemia with IDH1 mutation, the combination of olutasidenib with azacitidine appears as a welcome addition to our previously limited therapeutic options.

Pratz KW. Advancing the outcomes of AML out of antecedent MPN by targeting mutated IDH1 . Br J Haematol. 2025;206(4):1250–1252. 10.1111/bjh.19959