MANIFEST trial update: Pelabresib monotherapy for high-risk HU refractory or intolerant ET

During the European Hematology Association (EHA) 2023 Hybrid Congress, preliminary results from arm 4 of the phase II MANIFEST trial were reported.¹ The MANIFEST trial is an ongoing 4-arm global study investigating pelabresib, an oral inhibitor of bromodomain and extra-terminal for the treatment of patients diagnosed with myelofibrosis and essential thrombocythemia (ET).¹

Arm 4 of the study is currently evaluating pelabresib as a monotherapy for patients with high-risk ET who are refractory or intolerant to hydroxyurea treatment.¹ We summarize the key preliminary findings from this treatment arm in the article below. For more recent developments in myeloproliferative neoplasms presented at the EHA 2023 Hybrid Congress, check out our list of hot abstracts here.

Study design

• Patients diagnosed with high-risk ET
• Refractory or intolerant to hydroxyurea
• At least two symptoms of average score ≥3 or a total symptom score ≥15
• Platelet count >600 × 10⁹/L
• 225 mg of pelabresib once daily for 14 days in 21-day cycles
• Primary endpoint was complete hematologic response at any time

Results

• The total number of patients in arm 4 was 21.
• The full list of baseline patient characteristics is shown in Table 1.

Table 1. Baseline patient characteristics*

Hgb, hemoglobin; MF, myelofibrosis; TSS, total symptom score; WBC, white blood cell. *Adapted from Seymour.1
Characteristic, % (unless otherwise stated)	All patients (N = 21)
Median age, years	64
Sex
Female	60
Male	40
Median Hgb, g/dL	13
Median platelet count, × 109/L	722
Median WBC count, × 109/L	7.9
Median spleen volume, cc	402
Median TSS	32.7
Median prior hydroxyurea duration, months	103
Patients with ≥2 prior lines of therapy	60
Prior thrombosis	15
High-risk MF	20
Driver mutations
JAK2	45
CALR	40
ASXL1	15
MPL	5

Efficacy

• The median blood counts at Week 12 were as follows:
  • Median platelet count, 446 × 10⁹/L
  • Median white blood count, 8.2 × 10⁹/L
  • Hemoglobin, 13.0 g/dL
• The median percentage change in platelet counts at Week 12 was 40%.
• The median change in white blood cell counts at Week 12 was 8.2 × 10⁹/L.
• The median hemoglobin remained stable at 13.4 g/dL by Week 24.
• A total of 14 patients showed a 50% reduction in total symptom score at any time.
• By Week 12 the median total symptom score had reduced by 31%.
• Patients experienced an ∼40% reduction in nuclear factor kappa B-driven cytokine levels.
• Interleukin-8 gene expression was also reduced posttreatment.

Safety

• Serious adverse events (AEs) occurred in 3 patients.
• Treatment-emergent AEs were experienced by a further 3 patients, which led to treatment discontinuation.
• No Grade 5 AEs were reported.
• The only reported hematologic AE was leukopenia, which was reported in 10% of patients.
• The most commonly experienced non-hematologic AEs were:
  • Nausea (60%)
  • Diarrhea (35%)
  • Dysgeusia (35%)
  • Constipation (30%)
  • Abdominal pain (25%)
  • Vomiting (25%)
• Hemorrhagic and thromboembolic events included:
  • Grade 3 pulmonary embolism (5%)
  • Deep vein thrombosis of any grade (5%)
  • Acute myocardial infarction of any grade (5%)
  • Grade 3 hemorrhagic diarrhea (5%)
  • Grade 3 eyelid bleeding (5%)
  • Hematoma of any grade (5%)
  • Hematuria of any grade (5%)
  • Petechia of any grade (5%)
• Thromboembolic events and eyelid bleeding were not associated with treatment.

Conclusion

Preliminary results from this study highlight hematologic responses and symptom improvements among patients with high-risk ET. Treatment was tolerable and showed potential changes in biomarkers posttreatment. These results continue to support the evidence of a potential rationale for the use of pelabresib therapy for patients with ET.