NPM1: the ultimate target in AML Free

In this issue of Blood, Arellano et al report the first clinical evidence that a menin inhibitor induces complete remissions in acute myeloid leukemia (AML) with an NPM1 mutation, validating the latter as a new therapeutic target in AML alongside FLT3, IDH1/2, and KMT2A.¹ 

Since the discovery of NPM1 mutations (NPM1m) in more than 30% of de novo AML by Falini et al in 2005, the role of NPM1m has been the subject of intense clinical and basic research, justifying the identification of AML with NPM1m as a distinct genetic entity in the 2016 and 2022 World Health Organization classifications.² Clinically, this entity is synonymous with sensitivity to genotoxic agents and BCL-2 inhibitors and with a favorable prognosis, although the comutational environment also impacts the prognosis. In the ELN2022 risk classification, AML with NPM1m belongs to the favorable or intermediate group, depending on the presence of FLT3-ITD mutation. Additionally, NPM1m is a reliable marker of measurable residual disease (MRD), guiding transplantation indications in first remission or early therapeutic interventions in case of MRD relapse. However, NPM1m had not yet been validated as a therapeutic target.

The role of NPM1m in leukemogenesis has also been extensively studied.³ Due to the nature of the mutation creating an additional nuclear export signal, mutant NPM1 is predominantly delocalized in the cytoplasm, and its leukemogenic role was initially studied in this context. However, although cytoplasmic mutant NPM1 has an important role in leukemogenesis, a significant piece was missing, specifically its role in self-renewal capacities and stemness. More recently, it has been shown that a portion of the nuclear mutant NPM1 can interact with the menin-KMT2A complex, allowing stem-cell programs to remain constitutively active.⁴ This discovery paved the way for the development of menin-KMT2A interaction inhibitors in NPM1m AML, in addition to AML with KMT2A rearrangements. The first-in-class menin inhibitor, revumenib, was recently approved for the treatment of relapsed or refractory (R/R) KMT2A-rearranged AML.

In this study, investigators of the AUGMENT-101 study reported the results of a phase 2 trial evaluating revumenib in R/R NPM1m AML. The primary objective was achieved with a complete remission (CR) or CR with incomplete hematologic recovery rate of 23% (overall response rate, 47%) in heavily pretreated patients who were largely preexposed to venetoclax. Some responses were durable, and a significant proportion of patients were bridged to transplantation. Although the sample size is insufficient to draw definitive conclusions, patients with IDH1 or IDH2 comutations showed a fairly impressive response rate. Conversely, patients preexposed to venetoclax or FLT3 inhibitors showed lower response rates. This study confirmed that QTc prolongation and differentiation syndrome are the 2 adverse effects of revumenib to be closely monitored. Given the very poor prognosis of NPM1m AML beyond the first relapse, it is hoped that revumenib will be approved for this indication.

Certain aspects of this study are interesting to discuss. First, primary refractory disease in NPM1m AML treated with intensive chemotherapy is extremely rare. In patients who achieve complete remission, the first relapse does not have the same negative connotation as with other categories of AML, as intensive chemotherapy salvage results in a second remission in over 50% of relapsed patients.⁵ Venetoclax in combination with intensive or less intensive therapies has further improved the salvage rate of these patients.⁶ The very unfavorable prognosis thus concerns first refractory relapses or beyond, a situation where patients may benefit from menin inhibitors.

Second, since patients with NPM1m AML patients are closely monitored with NPM1m MRD, more and more patients are now treated with venetoclax-based low-intensity therapies for MRD relapse with promising results in terms of safety, response, transition to transplant, and overall survival.⁷ The role of menin inhibitors in MRD relapses remains to be clarified and could be the subject of specifically designed clinical trials.

Third, the response rate obtained in patients with IDH1 or IDH2 comutations is intriguing and should stimulate basic research to explore the mechanisms of this possible synergy. For example, it has been shown that the IDH1 mutation regulates granulomonocytic transcription factors favoring the action of another differentiating agent, all-trans retinoic acid.⁸ 

Finally, and most importantly, the clinical development of menin inhibitors in first-line treatment is a logical evolution. Phase 1b/2 trials evaluating several menin inhibitors in intensive (7 + 3 chemotherapy) or less intensive (hypomethylating agent + venetoclax) triplet combinations have shown the safety of such approaches and high response rates, allowing for the launch of phase 3 trials.⁹ However, most of these phase 3, placebo-controlled trials will include 2 very different patient populations: a minority population with adverse prognosis (KMT2Ar) and a majority population with favorable prognosis (NPM1), and determining a primary objective in this situation is a challenge. Indeed, although increasing the overall survival of KMT2Ar patients remains a reasonably achievable goal, it may be very difficult to achieve in NPM1m AML where median survival with intensive chemotherapy is not reached in most recent series. MRD event-free survival in NPM1m patients could be a relevant end point, the goal being to demonstrate that menin inhibitors can contribute to curing more patients from first-line therapy without the need for transplantation or second-line treatment. Furthermore, NPM1m AML are frequently associated with already targetable mutations such as FLT3 (∼50%) or IDH1/2 (∼30%).¹⁰ A phase 3 trial evaluating ivosidenib or enasidenib in combination with intensive chemotherapy has been recently completed (NCT03839771). The therapeutic landscape could therefore change very soon in AML with IDH1 or IDH2 mutations. Venetoclax, which is particularly effective in NPM1m AML, is also in the pipeline (NCT04628026). All these points will be important to consider for the interpretation of phase 3 trial results evaluating menin inhibitors. Moreover, 4-drug regimens may be necessary in AML with NPM1 and FLT3 comutations (NCT06313437). Thus, enthusiasm is high, but the road ahead is long before menin inhibitors are fully approved for first-line treatment in NPM1m AML.

In AML more than anywhere else, the contribution of genetics to therapeutic management has been crucial for clinicians. PML::RARA has long exemplified everything that molecular biology can bring: a robust prognostic marker, a relevant therapeutic target, and a reliable marker of MRD. NPM1 is becoming a new example with the advent of menin inhibitors.

Conflict-of-interest disclosure: C.R. declares a consulting or advisory role with AbbVie, Amgen, Astellas, Bristol-Myers Squibb (BMS), Boehringer, Daiichi-Sankyo, Jazz Pharmaceuticals, Janssen, and Servier; has received research funding from AbbVie, Amgen, Astellas, BMS, Daiichi-Sankyo, Iqvia, and Jazz Pharmaceuticals; and has received support for attending meetings and/or travel from AbbVie, Daiichi-Sankyo, Novartis, and Servier.