Navitoclax Overcomes Ruxolitinib Resistance for Myelofibrosis

Jacqueline S. Garcia, MD

The addition of navitoclax to ruxolitinib (Jakafi) showed clinically meaningful spleen responses and improvements in symptoms for patients with primary or secondary myelofibrosis, following the development of resistance to frontline ruxolitinib, according to findings from a phase II study presented at the 2019 ASH Annual Meeting.

In the single-arm study, spleen volume response of ≥35% (SVR35) was achieved by 30% of patients at week 24. Additionally, 53% of patients had resolution of palpable splenomegaly. Sixty-five percent of patients experienced a reduction in symptoms, and 35% of patients experienced a ≥50% reduction in total symptom score (TSS).

"With the addition of navitoclax to ruxolitinib, we were able to observe that there are meaningful spleen responses and improvements in symptom scores," Jacqueline S. Garcia, MD, Department of Medical Oncology, Dana-Farber Cancer Institute, said during a presentation of the findings. "The addition of navitoclax overcomes resistance in patients with uncontrolled myelofibrosis, despite prior prolonged ruxolitinib exposure."

Navitoclax is a small molecule inhibitor of BCLXL, BCL2, and BCLW, which has shown signs of activity in myeloproliferative neoplasm cell lines, including in myelofibrosis. In preclinical models, the combination of JAK2, BCLXL, and BCL2 inhibition was able to synergistically overcome JAK2 mutations and resistance to JAK2 inhibitors.

The phase II study enrolled 34 patients with primary myelofibrosis (n = 16), post-essential thrombocythemia myelofibrosis (n = 5), and post-polycythemia vera myelofibrosis (n = 13). All patients had received ruxolitinib for ≥12 weeks prior to first dose of navitoclax, with no wash out period prior to the start of the trial. The dose of navitoclax was escalated from 50 mg daily to 300 mg daily over the course of the study.

Of those available for baseline testing, more than half had high molecular risk (52%). The most common mutations identified were JAK2 (79%) and CALR (21%). Overall, 47% of patients at high-risk had 2 or more mutations. The duration of prior ruxolitinib therapy was 21 months (range, 4-71) and the baseline spleen volume was 1665 cm³.

The best achieved SVR35 was 43% for the combination. Additionally, 25% of patients saw a reduction in bone marrow fibrosis compared with baseline. There was a 1 grade reduction for 13% of patients and a 2 grade improvement for 13% of patients.

The mean white blood cell count at week 24 was 25.8 x 10⁹/L. Two patients entered the study with transplant dependence, with 1 becoming transplant independent following the addition of navitoclax. Seven patients entered the study receiving ≥1 unit of packed red blood cells within the past 12 weeks. Of these patients, 57% were transplant-free for ≥12 weeks following treatment with the combination. Platelet counts stabilized during the study, going from 232 x 10⁹/L at baseline to a nadir of 95 x 10⁹/L by week 8.

"Although very early transient thrombocytopenia was observed immediately after dosing, as expected, it was manageable with a slow weekly dosing ramp up," said Garcia. "The time frame of the 8-week nadir is similar to what we initially observed with ruxolitinib alone."

The median duration of navitoclax treatment was 330 days, and 68% were able to achieve the maximum tolerated dose of 300 mg. Most patients entered the trial on ruxolitinib doses >10 mg twice daily (BID) but most were able to reduce their dose to 10 mg BID during the study (88%).

A quarter of patients discontinued navitoclax during the study (27%), due to adverse events (AEs; 9%), progressive disease (6%), and other causes (12%). Grade ≥3 AEs of any cause were experienced by 79% of patients receiving the combination. The most common grade ≥3 AEs were thrombocytopenia (44%), anemia (27%), diarrhea (6%), and vomiting (3%). Eight patients experienced a serious AE (24%). There was 1 grade 5 case of pneumonia that was deemed unrelated to navitoclax.

The phase II study is still ongoing to further assess navitoclax alone or in combination with ruxolitinib for patients with myelofibrosis (NCT03222609). Additionally, outside of the United States, an expanded access program is available to gain access to navitoclax (NCT03592576).

Harrison CN, Garcia JS, Mesa JA, et al. Results from a phase 2 study of navitoclax in combination with ruxolitinib in patients with primary or secondary myelofibrosis. Presented at: 2019 ASH Annual Meeting; December 7-10, 2019; Orlando, FL. Abstract 671. bit.ly/343YuBX.

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