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The safety and efficacy of the four JAK inhibitors in patients with myelofibrosis

Aug 31, 2021
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The approval of ruxolitinib for the treatment of myeloproliferative neoplasms (MPN) has been transformative. Newer Janus Kinase (JAK) inhibitors are now starting to come on to the market with the US Food and Drug Administration (FDA) and European Commission’s approval of fedratinib for first- and second-line therapy after ruxolitinib failure. In addition, momelotinib, a JAK1 and 2 inhibitor, and pacritinib, a JAK-2 inhibitor, are in phase III development for the treatment of patients with myelofibrosis (MF).

A recent meta-analysis has been performed by Sureau, et al. to examine the comparative safety and efficacy of the four different JAK inhibitors (JAKis) and the MPN Hub is happy to provide a summary of this.1

Study design

A search was performed for head-to-head randomized control trials that were placebo-controlled to be included in this meta-analysis. The keywords ‘myelofibrosis’ and ‘JAK inhibitor’ were used.

Primary endpoint examined was spleen volume reduction (SVR) >35% after 24 weeks of treatment.

Secondary endpoints included reduction of the total symptom score (TSS) using MF Symptom Assessment Form 2.0 and adverse events due to hematologic toxicity, specifically Grade 3 or 4 anemia and Grade 3 or 4 thrombocytopenia over the 24 weeks of treatment.

Table 1. JAK2 inhibitor trials*

Trial name

Number of
patients
enrolled

Primary
endpoint

Previous
Rux
exposure

Platelets
count at
baseline

Minimum
treatment
period,
weeks

Results

COMFORT-1

Rux (n = 155)

SVR

 

No

≥ 100x109/L

24

Rux > placebo for spleen response (p < 0.001).

Placebo
(n = 154)

COMFORT-2

Rux (n = 146)

SVR

No

≥ 50x109/L

48

Rux > BAT for spleen response (p < 0.001).

BAT (n = 73)

JAKARTA

Fedratinib 400 mg/day
(n = 96)

SVR

No

≥ 50x109/L

24

Fedratinib (all arms) > placebo for spleen response (p < 0.001).

Fedratinib 500 mg/day
(n = 97)

Placebo
(n = 96)

PERSIST-1

Pacritinib
(n = 220)

SVR

No

Not specified

24

Pacritinib > BAT including watchful waiting for spleen response
(p = 0.0003).

BAT (excluding anti JAK
(n = 107)

PERSIST-2

Pacritinib 400 mg
(n = 104)

SVR, Reduction of TSS

Previous rux exposure or not

Must be < 100x109/L

24

Pacritinib (all arms) > BAT including rux for spleen response
(p = 0.001) and for symptom response
(p = 0.08).

Pacritinib 200 mg§
(n = 107)

BAT
(n = 100)

SIMPLIFY-1

Momelotinib
(n = 215)

SVR

No

≥ 50x109/L

24

Momelotinib was noninferior to rux for SVR (p = 0.011) but not for

symptom response (p = 0.98). Momelotinib

was associated with a reduced

transfusion requirement (p < 0.019).

Rux (n = 217)

SIMPLIFY-2

Momelotinib
(n = 104)

SVR

Yes, after rux exposure

Not specified

24

Momelotinib

< BAT for spleen

response (p = 0.90) but > symptom response (p = 0.0006).

BAT (n = 52)

BAT, best available therapy; rux, ruxolitinib; SVR, spleen volume response; TSS, total symptom score.
*Data from Sureau, et al.
Data available at 24 weeks.
Once daily.
§Twice daily.

Results

In total, 162 articles were found referring to clinical trials from which seven studies were included in the meta-analysis, they are summarized in Table 1. Only two trials included patients with previous exposure to ruxolitinib; PERSIST-2 and SIMPLIFY-2. Fedratinib was only examined in the JAKARTA trial. All other JAKis had two trials included in the meta-analysis.

Overall, 1,953 adults were included. Within this group, 58.3% had MF, 25.4% had post-polycythemia vera, and 16.2% had post-essential thrombocythemia MF (diagnosis was missing for 0.1%).

Table 1. JAK2 inhibitor trials*

Efficacy

When assessing the primary endpoint of SVR, SIMPLIFY-2 and PERSIST-2 were excluded as they included patients treated as second-line. The analysis included 1,576 patients from five studies where fedratinib, ruxolitinib, and momelotinib were shown to be significantly associated with improved SVR compared with the placebo. Ruxolitinib and momelotinib treatment resulted in a significant increase in SVR compared with pacritinib. The same was not true for fedratinib. However, there was not a statistically significant difference in SVR achieved between ruxolitinib, fedratinib, and momelotinib.

A sensitivity test was used to assess the first- and second-line patients and showed that pacritinib demonstrated greater efficacy than ruxolitinib, though the difference was not significant. The results for fedratinib, momelotinib, and BAT were the same as the main analysis.

TSS reduction was analyzed, a reduction being defined as a decrease of at least 50% at 24 weeks; however, only the JAKARTA-1 and the COMFORT-1 studies were included as they used the MF Symptom Assessment Form 2.0. Ruxolitinib and fedratinib were associated with a significant reduction in TSS compared with the placebo. There was no significant difference when the improvement in symptoms by ruxolitinib was compared with that of fedratinib.

Safety

When looking at adverse events across the studies (1,953 patients in seven studies), momelotinib use was associated with significantly less Grade 3/4 anemia compared with the 3 other JAKis. There was no significant difference between ruxolitinib, pacritinib, and fedratinib.

Grade 3/4 thrombocytopenia incidence over 24 weeks of JAKi therapy was also assessed. Fedratinib showed a decreased incidence of thrombocytopenia compared with ruxolitinib, pacritinib, and momelotinib. This was confirmed in studies using first-line only.

Conclusion

The results of this meta-analysis showed that ruxolitinib is well placed as the reference JAKi. Fedratinib was shown to be a close second with respect to SVR and improving symptom score. These results suggest that the type of JAKi could be selected based on the line of treatment and the risk of severe anemia and/or thrombocytopenia onset. Momelotinib appeared to be a good option for patients with anemia whereas fedratinib might be preferable for patients with thrombocytopenia. Pacritinib is a valuable second-line agent after previous exposure with a JAK inhibitor. Ideally further trials should be undertaken to ascertain the relative benefits of each of these 4 JAKis.

  1. Sureau L, Orvain C, Ianotto JC, et al. Efficacy and tolerability of Janus kinase inhibitors in myelofibrosis: a systematic review and network meta-analysis. Blood Cancer J. 2021;11(7):135. DOI: 1038/s41408-021-00526-z

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