BET Inhibitors Treatment of Myelofibrosis

BET inhibitors appears promising for treatment of Myelofibrosis when used in combination with Jakafi-ASCO 2024 Update

Charles H. Weaver, MD
3–4 minutes
Home » Non Hodgkins Lymphoma Treatment » BET Inhibitors Treatment of Myelofibrosis

Bromodomain and extra-terminal domain (BET) proteins regulate key cancer causing pathways which are important drivers of pro-inflammatory cytokine expression and bone marrow fibrosis implicated in myelofibrosis. BET inhibitors suppress the cytokine production, promote erythroid (red blood cell) differentiation and normalize megakaryocytic (platelet) differentiation.1 Preclinical studies suggest that a combination of a BET inhibitor and Jakafi may result in synergistic reduction of splenomegaly and bone marrow fibrosis.2 Several BET inhibitors are currently in clinical development and early trial results look promising. 

Pelabresib (CPI-0610)

The MANIFEST clinical trial is evaluating the role of Pelabresib (CPI-0610), a BET inhibitor in combination with Jakafi (ruxoltinib) in patients with myelofibrosis (MF).  Myelofibrosis is characterized by the presence of bone marrow fibrosis, increased cytokine production and inflammation, over activation of the JAK-STAT pathway, and aberrant erythroid and megakaryocytic differentiation. 

Pelabresib was evaluated alone and in combination with Jakafi in MF patients who were refractory/intolerant or had an inadequate initial response to Jakafi. Results of the first 48 patients enrolled in the Phase 2 MANIFEST clinical trial were released at ASH.

  • Spleen volume reduction was observed in 94% of patients.
  • An increase in hemoglobin by 1.5 mg/dL post-baseline was observed with both CPI-0610 monotherapy and CPI-0610 + Jakafi.
  • Improvement in bone marrow fibrosis was reported in 58% of evaluable patients.

At ASCO updates on the combination of Pelabresib combined with Jakafi were updated in 2 groups.

Intermediate or higher risk myelofibrosis with no prior JAK inhibitor therapy 

  • The primary objective of spleen volume reduction by 35% (SVR35) at week 24 was achieved in 67% of patients.
  • Total symptom score improved with a more than 50% reduction in symptoms (TSS50) reported in 57% of patients.
  • Hemoglobin increase was noted among patients particularly those with baseline less than 10 g/dl.
  • One third of the patients demonstrated at least one grade improvement in bone marrow fibrosis.3,5

MF Patients with suboptimal response or progression on Jakafi

  • 20% experienced reduction in splenomegaly at week 24
  • Majority had improvement in hemoglobin and 16% were converted from transfusion dependent to independent
  • 36% experienced a reduction in symptoms.3

Data continue to indicate that CPI-0610 combined with Jakafi is generally well-tolerated and provides clinical benefits in MF patients with inadequate responses or who are refractory to Jakafi. Improvement in bone marrow fibrosis and anemia responses indicate the potential for meaningful disease modification.

BMS-986158

Treatment with the BET inhibitor BMS-986158 plus Jakafi or Inrebic resulted in a reduction in splenic volume and tolerable side effects according to study results presented at the European Hematology Society 2023 Annual Meeting.

BMS-986158 is an orally administered selective small molecule BET inhibitor that is currently being evaluated alone and in combination with the JAK inhibitors Jakafi and Inrebic patients with myelofibrosis. A reduction in splenic volume was reported among all patients treated with the combination and continued to improve through week 24 of treatment.4

References

  1. MANIFEST, a Phase 2 Study of CPI-0610, a Bromodomain and Extraterminal Domain Inhibitor (BETi), As Monotherapy or “Add-on” to Ruxolitinib, in Patients with Refractory or Intolerant Advanced Myelofibrosis
  2. ash.confex.com/ash/2019/webprogram/Paper127119.html
  3. Mascarenhas J, Kremyanskaya M, Patriarca A, et al. BET inhibitor pelabresib (CPI-0610) combined with ruxolitinib in patients with myelofibrosis – JAK inhibitor-naïve or with suboptimal response to ruxolitinib – preliminary data from the MANIFEST study. Presented at: 2022 EHA Congress; June 9-12, 2022; Vienna, Austria. Abstract S198.
  4. Ayala R, Lopez N, Abulafia AS, et al. BMS-986158, a potent BET inhibitor, as monotherapy and in combination with ruxolitinib or fedratinib in intermediate- or high-risk myelofibrosis (MF): results from a phase 1/2 study. Presented at the 2023 European Hematology Association Congress; Frankfurt, Germany. June 8-11, 2023. Abstract S213.

  5. Rampal. ASH 2024. Abstr 6502.

, , , , ,

You May Be Interested In