Navitoclax Plus Jakafi Improves Spleen Volume Reductions in Myelofibrosis

The combination of navitoclax with Jakafi (ruxolitinib) reduced spleen volume by 35% or more at week 24 when being compared with Jakafi in combination with placebo for patients with myelofibrosis, according to findings from the phase 3 TRANSFORM-1 study that were presented at the 2023 American Society of Hematology (ASH) Annual Meeting and Exposition.

After a median follow-up of 14.9 months, navitoclax and Jakafi resulted in a spleen volume reduction of 35% or more by week 24 for 63.2% of patients compared with 31.5% for placebo plus Jakafi, marking a significant overall difference of 31%. At week 24, there was an average -9.7 change in TSS (total symptom score) with navitoclax/ Jakafi from baseline compared with a change of -11.1 for placebo plus Jakafi, which was not statistically significant.

“The spleen volume reduction was doubled and highly statistically significant. There’s no question there, but for the secondary end point, the total symptom score, both groups have the reduction, but it was not statistically significant,” said lead investigator Dr. Naveen Pemmaraju, Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston. “There may be multiple reasons for that. (Jakafi) alone is a nice drug for symptom improvement, but when you add in a second drug, you're improving the outcomes for the patient but maybe introducing a bit more toxicity. The statistical significance may not have come out because of that.”

Oral Jakafi is a drug that inhibits certain proteins (BCL-XL, BCL-2 and BCL-W), which may impart unique efficacy for myeloproliferative neoplasms (MPN).

“It turns out in MPN and myelofibrosis that the BCL-XL pathway appears to be a bit more important than the BCL-2,” said Pemmaraju. “In myelofibrosis, BCL-XL appears to be upregulated and so in vitro studies showed that either the Jakafi by itself or even better in combination with the Jakafi can overcome JAK resistance and add benefit.”

The median TSS in the combination arm was 21 compared with 24 in the control group. A minority of patients were transfusion dependent at baseline, at 4% in the combination group and 3% in the control arm. The most common risk score was intermediate-2, at 83% in the combination group and 87% in the control. JAK2 V617F was the most common driver mutation, with approximately two-thirds having this mutation in each group. Nearly half of patients had mutations associated with high molecular risk. “These high molecular risk mutations are very important,” said Pemmaraju. “Earlier studies may not have captured this, and we were fortunate to capture this in the majority of patients.”

There was a significantly higher rate of spleen volume reduction of 35% or more with the combination at all time points throughout the study. Across the full-time scale of the study, 76.8% of those in the combination arm experienced a spleen volume reduction of at least 35% compared with 41.7% with Jakafi in combination with placebo, which was a meaningful 34.6% reduction.

The median time to first spleen volume reduction of 35% response was similar between groups, at 12.3 vs 12.4 weeks, for the combination and control arms, respectively. Fewer patients lost spleen volume reduction of 35%, in the combination group (18.8%) compared with the control arm (26.4%). Nearly three-fourths of patients had a 12-month duration of spleen volume reduction of 35% in each arm (76.7% vs 76.9%, combination and control, respectively).

The rate of any-grade side effect was similar between arms, with more patients in the combination arm having a grade 3 or higher side effect (85% vs 70%). The most common grade 3 or higher side effects in the combination vs control arms, respectively, were thrombocytopenia (51% vs 15%), anemia (46% vs 39%) and neutropenia (38% vs 4%). For all grade events, diarrhea was more commonly seen with the combination vs control (34% vs 14%). Serious side effects were less common with the combination at 26% compared with 32% for the control arm. Side effects that led to dose reduction or dose interruption were twice as common in the combination arm.

“Importantly, dose reductions and interruptions were mostly due to the thrombocytopenia, but importantly none of those were due to clinical bleeding,” said Pemmaraju.

In 2022, AbbVie, the company developing navitoclax noted plans for a submission to the FDA in 2023, pending pivotal study results.

At this time, the agent is not approved.

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