Promising Antileukemic Activity of Bleximenib in Combination Therapy for Acute Myeloid Leukemia

Analysis reveals significant industry trends and economic implications

Release Date

2025-06-13

Category

Clinical Trial Event

Reference

Source

Breakthrough Clinical Results

Johnson & Johnson announced positive Phase 1b data for bleximenib, a menin inhibitor, in combination with venetoclax and azacitidine for acute myeloid leukemia (AML). The study, NCT05453903, included patients with newly diagnosed, intensive chemo-ineligible AML and relapsed/refractory AML harboring KMT2A gene rearrangements or NPM1 gene mutations. Results showed high overall response rates (ORR) of 82% in relapsed/refractory AML and 90% in newly diagnosed, chemo-ineligible AML at the recommended Phase 2 dose. The safety profile was favorable, with a low rate of differentiation syndrome and no QTc prolongation. These findings suggest potential for bleximenib as a combination therapy for AML.

Key Highlights

  • High overall response rates (ORR) of 82% in relapsed/refractory AML and 90% in newly diagnosed, chemo-ineligible AML patients at the recommended Phase 2 dose.
  • Favorable safety profile with low differentiation syndrome rate and no QTc prolongation.
  • Bleximenib targets a key oncogenic interaction between menin and KMT2A fusion proteins, disrupting a pathway that drives leukemic cell growth.
  • Further Phase 2 and 3 trials are currently enrolling patients to explore bleximenib's potential as a monotherapy and in combination with standard of care.

Incidence and Prevalence

Acute myeloid leukemia (AML) Global Incidence and Prevalence Trends:

Incidence:

  • Increasing Trend: The incidence of AML has been steadily rising globally. One study using data from the Global Burden of Disease (GBD) 2021 study reported an increase from 79,372 cases in 1990 to 144,645 cases in 2021. Another study, using the GBD 2017 database, also noted a gradual increase in AML incidence from 1990 to 2017. A third study, analyzing SEER data from 1980-2017, also observed an increasing trend in AML incidence over these four decades.
  • Age and Sex: AML disproportionately affects males and the elderly. Several studies confirm that incidence increases with age, with one study reporting a median age at diagnosis of 68 years in the US.
  • Geographic Variation: Developed nations generally exhibit higher age-standardized incidence rates than developing nations. However, the burden of AML is increasing in both developed and developing countries, with a positive correlation between AML burden and the socio-demographic index (SDI).

  • Specific Numbers:

  • In 2019, there were an estimated 21,450 new AML cases and 10,920 deaths in the United States.

  • In 2019, the 60-89 age group reported 61,559 new AML cases globally, with 53,620 deaths and 990,656 DALYs.

  • The age-adjusted incidence of AML is approximately 4.3 per 100,000 annually in the United States.

Prevalence:

Prevalence data for AML on a global basis is not directly provided in the given abstracts. However, the increasing incidence rates, coupled with relatively short survival times (5-year survival of 24% reported in one study), suggest that the prevalence is also likely increasing. It's important to note that prevalence is influenced by both incidence and survival rates. As incidence rises and survival times remain relatively short, the number of people living with AML at any given time is likely to increase. More research is needed to quantify the global prevalence of AML.

Key Factors Influencing Incidence:

  • Aging Population: The increasing global population of older adults contributes significantly to the rising incidence of AML, as age is a major risk factor.
  • Risk Factors: Smoking, high body mass index, and occupational exposure to benzene and formaldehyde are identified as major risk factors for AML. The prevalence of these risk factors varies by region, with smoking and high BMI more prevalent in developed countries and occupational exposure to carcinogens more prevalent in developing countries.

Overall, the available data indicates a concerning trend of increasing AML incidence globally, particularly among older males in developed nations. Further research is needed to fully understand the global prevalence and to develop effective prevention and treatment strategies.

Key Unmet Needs and Targeted Populations in Acute Myeloid Leukemia (AML) Research (Based on Recent PubMed Publications):

1. Effective and Less Toxic Treatments:

  • Many AML patients, particularly older adults, are ineligible for standard induction chemotherapy due to its toxicity. This highlights the urgent need for less toxic yet effective therapies. Research focuses on developing novel agents and treatment strategies, including targeted therapies and immunotherapies, to address this need. Low-intensity therapies, such as hypomethylating agents (HMAs) combined with venetoclax, are emerging as a new standard of care for older/unfit patients.

2. Relapse Prevention:

  • AML is characterized by high relapse rates, making relapse prevention a critical area of research. Strategies to reduce relapse include optimizing existing treatment regimens, developing maintenance therapies, and exploring novel approaches such as immunotherapy and targeted therapies against minimal residual disease (MRD).

3. Improved Quality of Life (QoL):

  • Disease- and therapy-related toxicities significantly impact AML patients' QoL. Research aims to develop less toxic treatments and supportive care strategies to improve QoL. Studies have identified younger age, female gender, and lower income as factors associated with poorer QoL, emphasizing the need for tailored support strategies. Social functioning and psychosocial support are also crucial aspects of QoL that require attention.

4. Targeted Therapies for Specific AML Subsets:

  • Research focuses on developing targeted therapies for specific AML subsets based on their unique molecular and genetic profiles. This personalized approach aims to improve treatment outcomes and minimize toxicities. Examples include FLT3 and IDH inhibitors for patients with these mutations.

5. Addressing Economic Burden:

  • AML treatment poses a substantial economic burden due to hospitalization, stem cell transplantation, and medication costs. Research explores ways to reduce costs, such as shifting towards oral and outpatient therapies. However, the increasing availability of novel, often expensive, therapies may also drive up overall costs, requiring careful consideration by payers.

6. Older/Unfit Patients:

  • This population represents a significant challenge due to their inability to tolerate intensive chemotherapy and the presence of poor cytogenetics and genetic anomalies. Research focuses on developing less toxic and more effective treatment options for this group, such as low-intensity therapies and targeted therapies.

7. Relapsed/Refractory AML:

  • Patients with relapsed/refractory AML have limited treatment options and poor outcomes. Research aims to develop more effective therapies for this group, including targeted therapies, immunotherapies, and novel combinations.

8. Measurable Residual Disease (MRD) Monitoring:

  • Incorporating MRD assessment into longitudinal risk assessments is a key area of research. This allows for dynamic risk stratification and personalized treatment decisions based on the presence of minimal residual disease.

9. Supportive Care:

  • Optimizing supportive care is crucial for managing treatment-related toxicities and improving patient outcomes. Research focuses on developing strategies to prevent and manage infections, anemia, and bleeding, as well as providing psychosocial support.

10. Region-Specific Recommendations:

  • Developing region-specific recommendations for AML management, considering local resources and challenges, can enhance patient outcomes. This includes adapting international guidelines to the specific needs of different regions.

Drug used in other indications

Bleximenib (JNJ-75276617) is currently being investigated primarily for Acute Myeloid Leukemia (AML). The provided texts do not mention other indications for which it is being trialed.

Venetoclax, in combination with azacitidine, is primarily used for treating AML, particularly in patients ineligible for intensive chemotherapy. It has also shown activity in other hematological malignancies:

  • Relapsed/Refractory AML: Venetoclax-based chemotherapy has shown activity with CR/CRi rates of 33-46%.
  • High-Risk Myelodysplastic Syndromes (MDS): Venetoclax has shown a CR of 39% in treatment-naive patients and 5-14% in HMA failure patients.
  • Blast-Phase Myeloproliferative Neoplasm (MPN): Venetoclax has demonstrated a CR of 25%.
  • Chronic Lymphocytic Leukemia (CLL): Venetoclax has been approved for the treatment of both first-line and relapsed/refractory CLL.

The intervention models for trials involving venetoclax often include combination regimens. For AML, the most common combination is with hypomethylating agents (HMAs) like azacitidine or decitabine, or with low-dose cytarabine. Trials also explore venetoclax in combination with intensive chemotherapy, in the post-transplant setting, or as a maintenance strategy. The specific intervention model depends on the disease and patient characteristics.

Clinical Trial Information for Venetoclax Combinations:

  • NCT02993523 (VIALE-A): This phase 3 trial compared venetoclax plus azacitidine to azacitidine plus placebo in newly diagnosed AML patients ineligible for intensive chemotherapy. It demonstrated improved overall survival and remission rates with the venetoclax combination.
  • NCT03941964: This study evaluated the efficacy and safety of venetoclax plus HMA in a US community-based outpatient setting for newly diagnosed AML patients ineligible for intensive chemotherapy.

It's important to note that the information provided focuses on the use of venetoclax in combination with azacitidine, and other venetoclax-based combinations may be used for different indications or with different intervention models.