EHA 2021: updates in myeloid malignancies

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KOMET-001: TARGETING MENIN-KMT2A IN AML NARSOPLIMAB FOR TA-TMA MYF2001: IMETELSTAT FOR MDS IMERGE: IMETELSTAT FOR LR-MDS JAKARTA & JAKARTA2: FEDRATINIB IN MYELOFIBROSIS

KOMET-001: targeting menin-KMT2A in AML

The treatment and management of patients with acute myeloid leukemia (AML) characterized by histone-lysine-N-methyltransferase 2A (KMT2A) gene mutations presents an unmet clinical need, due to aggressive disease and poor prognosis with standard chemotherapy. The KMT2A gene plays an essential role in the regulation of the homeobox gene family and MEIS1 genes, as well as having a role in the epigenetic dysregulation of co-mutations including NPM1, IDH1/2 and FLT3. Between 5 and 10% of patients with AML have KMT2A mutations.¹

In the past couple of years, preclinical studies have indicated that inhibitors targeting the menin-KMT2A gene complex may show promise in patients with KMT2A-mutant AML. Now, two menin inhibitors, KO-539 and SNDX-5613, are being investigated in Phase I/II trials for the treatment of KMT2A-mutated and NPM1-mutated AML.²

In this video, Eunice Wang, MD, of the Roswell Park Comprehensive Cancer Center, Buffalo, NY, gives an update on the KOMET-001 trial (NCT04067336), a Phase I/II first-in-human dose-escalation trial of KO-539. Phase I of the KOMET-001 trial has been designed to examine the safety and tolerability of KO-539, and to recommend a Phase II dose for patients with relapsed/refractory AML.¹

In the Phase II KOMET-001 trial, the safety, tolerability and efficacy of the recommended Phase II dose will be investigated in AML patients with NPM1 and KMT2A rearrangements. Efficacy assessment outcomes will include complete remission, complete remission with incomplete hematologic recovery, drug-free survival, overall survival and transfusion independence. Exploratory biomarkers will also be examined to determine possible predictors of efficacy.

Dr Wang also notes that preliminary data³ presented at ASH 2020 indicated clinical activity of KO-539, saying “Out of eight evaluable patients there was some evidence of clinical activity in six out of the eight patients, including CR in two patients, one of which had a target NPM1 mutation, and the other one who did not.”

Further updates on escalation of the trial and the recommended Phase II dose are expected to be presented at the next ASH meeting in Atlanta Georgia, or virtually, taking place from December 11-14, 2021.

Narsoplimab increases platelets and decreases LDH in TA-TMA

Transplant-associated thrombotic microangiopathy (TA-TMA) is an endothelial damage syndrome which is a complication of autologous and allogeneic hematopoietic stem cell transplantation, and is associated with high morbidity and mortality due to permanent renal injury. TA-TMA is caused by a cycle of activation of endothelial cells, antigen-presenting cells and lymphocytes, as well as the formation of microthrombi.⁴

Complement is a complex network of circulating and membrane-associated proteins that initiate inflammatory and cytolytic immune responses to bacterial infections, and has recently emerged as a major contributor of TA-TMA. Thus, inhibition of the complement cascade is being considered as a therapeutic target.⁴

In this video, Eleni Gavriilaki, MD, PhD, of the National and Kapodistrian University of Athens in Greece, shares an update on the single-arm Phase II pivotal trial (NCT02222545) of narsoplimab (previously OMS721) in adult TA-TMA patients. Narsoplimab is a novel monoclonal antibody which targets mannan-binding lectin-associated serine protease-2 (MASP-2), thus inhibiting the complement pathway.⁵

Dr Gavriilaki reports that treatment with narsoplimab in this trial achieved increased platelet counts and decreased LDH levels in adult TA-TMA patients, as well demonstrating a good tolerability profile. Dr Gavriilaki concludes that the results seen so far demonstrate the safety and efficacy of complement inhibitors in adult TA-TMA and show promise for their future use in routine clinical practice.

The safety profile of imetelstat in myeloid malignancies

Although current treatments for myeloproliferative neoplasms (MPNs) achieve some clinical benefits, their efficacy and durability are limited. For example, Janus kinase (JAK) inhibitors fail to target the cause of the diseases itself⁸ and long-term administration of erythropoiesis-stimulating agents (ESAs) often results in resistance.⁹ As such, novel therapies are required. Recently, the novel telomerase inhibitor imetelstat, which selectively affects malignant megakaryopoiesis, has come under investigation for the treatment of MPNs.

In this video, John Mascarenhas, MD, from the Icahn School of Medicine at Mount Sinai, New York, NY, discusses the tolerability and safety findings of two recent studies of imetelstat in patients with myeloid malignancies: the MDS3001 study (NCT02598661) and the MYF2001 study (NCT02426086).

The MDS3001 study investigated imetelstat in patients who were refractory to prior ESA therapy with low- or intermediate-risk myelodysplastic syndromes (MDS). The MYF2001 study, investigated imetelstat for patients with intermediate- or high-risk myelofibrosis relapsed/refractory (R/R) after JAK inhibitor therapy. Imetelstat was administered at 7.5mg/kg every four weeks in the MDS population and at 9.4mg/kg every 3 weeks in the myelofibrosis population.¹⁰

Dr Mascarenhas reports that imetelstat demonstrated efficacy in both studies, with benefits in symptom and spleen responses, reduced bone marrow fibrosis and signals for improved survival.

Dr Mascarenhas also gives an overview of the observed safety profile, with incidences of grade 3/4 neutropenias and thrombocytopenias being between 30% and 60%. These cytopenias were reversible and led to discontinuation of treatment in less than 5% of the patient population. Liver toxicity was not a significant adverse effect and there were no signals for liver injury.

Imetelstat in heavily-transfused lower-risk R/R MDS

Treatment options for relapsed/refractory patients with lower risk myelodysplastic syndromes (MDS) who are heavily transfusion-dependent are currently limited; however, high telomerase activity and human telomerase reverse-transcription expression in clonal hematopoietic cells have emerged as therapeutic targets for patients with MDS.¹¹ Based on these findings, the activity of imetelstat, a first-in-class telomerase inhibitor, is being explored as a novel treatment for MDS.

At the 26th Congress of the European Hematology Association (EHA 2021), Uwe Platzbecker, MD, University of Leipzig, Leipzig, Germany, provides an update on the findings of the Phase II/III IMerge study (NCT02598661) investigating the efficacy of imetelstat in inducing transfusion independence for heavily transfusion-dependent patients with lower-risk MDS who were relapsed/refractory to erythropoiesis stimulating agents. The subgroup analysis presented at EHA 2021 aimed to determine the impacts of molecular subtypes on the efficacy of imetelstat in this group of patients.

The most common genetic mutations were in SF3B1, DNMT3A, KIT and RUNX1. Prof. Platzbecker reports that favorable response rates were achieved, regardless of differing baseline characteristics such as mutations and transfusion burden. No specific mutation or cytogenic abnormality was found to be associated with lower response rates.¹² Prof. Platbecker also comments that the data indicated that imetelstat had a disease-modifying effect, whereby the allelic burden of SF3B1 was reduced with imetelstat treatment in some responders.

Prof. Platzbecker concludes that imetelstat results in a meaningful transfusion independence rate, and comments that these findings will be further explored in the Phase III portion of the trial.

JAKARTA and JAKARTA2: OS and PFS analysis of fedratinib in myelofibrosis

The Phase III JAKARTA (NCT01437787) and Phase II JAKARTA2 (NCT01523171) trials both investigated the role of fedratinib, a JAK2 inhibitor, as a frontline therapy for the treatment of patients with myelofibrosis. JAKARTA enrolled myelofibrosis patients who had previously received ruxolitinib, and JAKARTA2 enrolled patients with intermediate-2 and high-risk myelofibrosis.

The US Food and Drug Administration (FDA) placed fedratinib on a clinical hold between 2013 and 2017, when 8 out of 608 patients in the two trials developed symptoms of Wernicke encephalopathy. After further investigation it was concluded that there was no evidence that fedratinib induces Wernicke encephalopathy, although risk factors were identified, and the trials resumed.¹³

In 2019, based on the findings of the JAKARTA and JAKARTA2 trials, fedratinib received FDA approval for the treatment of adults with intermediate-2 or high-risk myelofibrosis, with the primary endpoints being met in 35-40% of patients in the JAKARTA trial and in 25-30% of patients in JAKARTA2.

In this video, John Mascarenhas, MD, from the Icahn School of Medicine at Mount Sinai, New York, NY, discusses the findings of survival analysis at the 26th Congress of the European Hematology Association (EHA 2021).

Dr Mascarenhas reports that with a median follow-up of 19 months, the median overall survival (OS) in the JAKARTA and JAKARTA-2 studies was not reached. In the JAKARTA study, the one-year OS rate was 92% and in JAKARTA2 the one-year OS rate was 84%.¹⁴