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MANIFEST-2: Pelabresib + ruxolitinib for the treatment of JAKi-naïve MF

By Jennifer Reilly

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Jan 4, 2024

Learning objective: After reading this article, learners will be able to cite the safety and efficacy data associated with the use of pelabresib for the treatment of Janus kinase inhibitor-naïve myelofibrosis.


Test your knowledge! Take our quick quiz before and after you read this article to find out if you improved your knowledge. Results help us to improve content and continually provide open-access education.

Question 1 of 2

In the pelabresib + ruxolitinib arm at Week 24, what ≥35% reduction in spleen volume rate was observed?

A

B

C

D

Pelabresib, a bromodomain and extra-terminal motif inhibitor, is currently under investigation in Janus kinase inhibitor (JAKi) naïve patients with myelofibrosis (MF) as part of the phase III MANIFEST-2 trial (NCT04603495).1

This trial was selected by the MPN Hub Steering Committee  as a top abstract at the 65th American Society of Hematology (ASH) Annual Meeting and Exposition. Rampal presented the latest data from the MANIFEST-2 clinical trial of pelabresib + ruxolitinib for the treatment of JAKi-naïve myelofibrosis. Here, we summarize the key points.

Study design1

  • In this double-blind trial, 430 patients were randomized 1:1 to either the experimental arm, receiving pelabresib 125 mg plus ruxolitinib; or a control arm, receiving placebo plus ruxolitinib, over 21-day cycles.
  • The primary endpoint of MANIFEST-2 was ≥35% reduction in spleen volume ≥35% (SVR35) at Week 24.
  • Secondary endpoints were Total Symptom Score (TSS) change, ≥50% reduction in TSS (TSS50) rate, and adverse events of any grade.

Key eligibility criteria included:

  • patients with JAKi-naïve MF (primary of post-essential thrombocytosis/polycythemia vera);
  • Dynamic International Prognostic Scoring System intermediate-1 or above;
  • splenomegaly of ≥450 cm3; and
  • TSS ≥10.

Results1

At Week 24, the rate of SVR35, TSS50, and absolute change in symptom scores were recorded. Overall, the rate of SVR35 and TSS50 was higher in the experimental arm, with a higher mean spleen volume reduction (SVR) across the whole cohort (Figures 1 and 2).

Figure 1.  SVR35 and TSS50 at Week 24* 

SVR35, ≥35% reduction in spleen volume ; TSS50, ≥50% reduction in Total Symptom Score.
*Adapted from Rampal.1

  • The mean SVR for pelabresib + ruxolitinib was −50.6%
  • The mean SVR for placebo + ruxolitinib was −30.6%

Figure 2. Incidence of SVR35 and TSS50 in combination and isolation* 

RUX, ruxolitinib; SVR35, ≥35% reduction in spleen volume ; TSS50, ≥50% reduction in Total Symptom Score.
*Adapted from Rampal.1

 In each measure of TSS, pelabresib + ruxolitinib resulted in a larger mean change in symptom score from baseline to Week 24 (Figure 3). The highest recorded symptom decrease was observed in itching and pain under the left rib vs night sweats and pain under the left rib in the pelabresib arm vs the placebo arm, respectively.

Figure 3. Mean change in TSS by domain from baseline to Week 24* 

RUX, ruxolitinib.
*Adapted from Rampal.1

 Safety1

Overall, the safety profile was comparable for the pelabresib and ruxolitinib alone groups (Table 1). A decreased incidence of anemia was observed, which is particularly beneficial for the treatment of MF where anemia is common.

Table 1. Treatment-emergent adverse events*

AE, adverse event; SAE, serious adverse event.
*Adapted from Rampal.1

Treatment-emergent adverse event, % (unless otherwise specified)

Pelabresib + ruxolitinib
(n = 212)

Placebo + ruxolitinib
(n = 214)

Any grade AE

96.7

97.2

Grade ≥3 AE

49.1

57.5

SAE

29.7

29.4

Hematologic

 

 

              Anemia

43.9

55.6

              Thrombocytopenia

32.1

23.4

              Decreased platelet               count

20.8

15.9

Non-hematologic

 

 

              Diarrhea

23.1

18.7

              Dysgeusia

18.4

3.7

              Constipation

18.4

24.3

              Nausea

14.2

15.0

              Cough

12.7

11.2

              Fatigue

11.8

16.8

              Dizziness

11.3

8.9

              Headache

11.3

10.7

              COVID-19

11.3

15.9

              Dyspnea

9.0

13.1

Conclusion

Overall, treatment with pelabresib + ruxolitinib resulted in a higher incidence of SVR35 and significantly reduced splenomegaly in JAKi-naïve patients with MF compared with ruxolitinib + placebo. The combination also produced a significantly higher rate of dual SVR35 and TSS50, with a higher rate of improved individual symptom scores. The safety profile was comparable with ruxolitinib monotherapy, with a lower incidence of anemia. The results of MANIFEST-2 highlight pelabresib as a potential treatment option for JAKI-naïve MF for extended investigation in clinical trials.

References

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