Jaktinib Further Improves Spleen Volume in Myelofibrosis

Jaktinib, a novel JAK/ACVR1 inhibitor, significantly improved rates of spleen volume reductions at 24 weeks in patients with intermediate or high-risk myelofibrosis compared with hydroxyurea, according to findings from a phase 3 study.

Findings from the ZGJAK016 study were presented at the 2023 EHA Congress.

Results from the analysis of the study showed that the 24-week spleen-volume reduction of at least 35% rate was 72.3% in the jaktinib group (47 patients) compared with 17.4% in the hydroxyurea arm (23 patients). Additionally, the best spleen response rates were 80.9% versus 26.1%, respectively. Of note, myelofibrosis may cause an enlarged spleen, also known as splenomegaly.

“Three small molecule JAK inhibitors have been approved for myelofibrosis by the FDA, including ruxolitinib (Jakafi), fedratinib (Inrebic) and pacritinib (Vonjo),” Dr. Jie Jin, professor of medicine in the department of hematology at The First Affiliated Hospital of Zhejiang University School of Medicine in Hangzhou, China, said during the presentation.

ZGJAK016 was a multicenter trial that enrolled adults with intermediate- or high-risk myelofibrosis. Patients were randomly assigned either jaktinib plus a hydroxyurea placebo or hydroxyurea plus a jaktinib placebo. At week 24, patients who achieved spleen-volume reduction of at least 35% remained on their initially assigned treatment and those who did not received jaktinib.

The primary focus of the study was spleen-volume reduction of at least 35% at week 24, measured by MRI or CT imaging. Other areas of interest for researchers included spleen-volume reduction of at least 35% at week 24, best spleen response rate (defined as achieving spleen-volume reduction of at least 35% at any time), proportion of patients with symptom reduction of at least 50%, anemia-related improvements and safety.

Most patients in the jaktinib arm completed 24 weeks of treatment (89.4%) and entered the extension period (83%). In the control arm, these rates were 69.6% and 69.6%, respectively. Four patients died on the jaktinib arm compared with one on the hydroxyurea arm; no death was determined to be treatment related.

Additional findings from the study showed that the spleen-volume reduction of at least 35% benefit was observed with jaktinib over hydroxyurea across all prespecified subgroups. The greatest differences in spleen-volume reduction of at least 35% rate in favor of jaktinib were observed among patients with a high symptom burden (72%), those with intermediate myelofibrosis (66.2%) and those whose disease harbored a JAK2 V617F mutation (63.4%).

More patients in the jaktinib arm experienced a reduction in symptom score from the beginning of the study compared with the hydroxyurea group at every time point examined in the analysis. This included week 6 (55.3% versus 34.8%), week 12 (59.6% versus 43.5%), week 18 (66% versus 39.1%) and week 24 (63.8% versus 43.5%).

Hemoglobin levels were increased in the jaktinib arm and decreased in the hydroxyurea arm. Among the seven patients who received jaktinib and required a red blood cell transfusion, five patients achieved a decreased in red blood cell transfusion unit of at least 50% by week 24 compared with two patients who received hydroxyurea and required a transfusion.

Safety findings demonstrated that nearly all patients in the jaktinib and hydroxyurea arms experienced an any-grade treatment-emergent side effects, at 97.9% and 100%, respectively. Most patients in both arms experienced a treatment-emergent side effect considered severe or worse (51.1% versus 60.9%).

Serious treatment-emergent side effects were present in 27.7% of patients in the jaktinib arm compared with 47.8% in the hydroxyurea arm. Treatment-emergent side effects leading to dose reduction or interruption (23.4% versus 34.8%), as well as those leading to treatment discontinuation (8.5% versus 17.4%), were reported in both arms.

In the jaktinib arm, the most common any-grade treatment-emergent side effects included thrombocytopenia (low number of platelets in blood; 40.4%), anemia (38.3%), respiratory tract infections (21.3%), leukopenia (low levels of white blood cells called leukocytes; 14.9%), fever (12.8%) and reduced blood bilirubin (what forms when red blood cells are broken down; 12.8%). Common severe or worse treatment-emergent side effects consisted of anemia (25.5%), thrombocytopenia (17%), leukopenia (2.1%), neutropenia (low number of a white blood cell called neutrophils; 2.1%) and decreased lymphocyte count (a type of white blood cell formed in bone marrow; 2.1%).

Comparatively in the hydroxyurea arm, the most common any-grade treatment-emergent side effects included thrombocytopenia (52.2%), anemia (52.2%), leukopenia (30.4%), neutropenia (26.1%), decreased lymphocyte count (26.1%) and decreased blood bilirubin (26.1%). Severe or worse treatment-emergent side effects included anemia (43.5%), thrombocytopenia (39.1%), leukopenia (21.7%), neutropenia (21.7%) and decreased lymphocyte count (13.0%).

“At the time of this prespecified interim analysis, jaktinib has demonstrated an improved trend in symptom response versus hydroxyurea,” Jin said. “(Additionally), there were (fewer) cytopenias in the jaktinib group than the hydroxyurea (arm). Our interim results demonstrate that jaktinib could be a new treatment option for patients with myelofibrosis (who are) DIPSS intermediate-2 or high-risk.”

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