Talha Badar, Assistant Professor at Mayo Clinic Comprehensive Cancer Center shared a thread on Twitter/X:

“Myelofibrosis after failure of Ruxolitinib.

JAK inhibitors are incorporated into management for splenomegaly and improved quality of life from symptom improvement. 50% of patients discontinue treatment at 3 years and 75% at 5 yrs, as per data from COMFORT-I and II trial.

No consensus definition of Ruxolitinib failure in clinical trials; lack of response, intolerance, or disease progression? Transplant is the only potential curative option, but high rates of morbidity and mortality limit eligibility.

Outcome after JAKi failure.

Median OS after Jakafi failure reported is around 14 mo; ranging from 4 months to a little over 2 years, dependent on the phase of disease at the time of progression .
Acquisition of new mutation (e.g. ASXL1), clonal evolution associated with inferior outcome. Read the the supporting paper here.

Fedratinib in MF previously treated with Ruxolitinib (JAKARTA-2).

Of 83 assessable patients, 55% achieved a spleen response. Common grade 3-4 adverse events were cytopenias. Seven (7%) patients died during the study, but none of the deaths was drug related. Suspected cases of Wernicke’s encephalopathy in other fedratinib trials led to study termination.
Read the supporting paper here.

PERSIST-2 trial: Pacritinib vs Best Available Therapy (including ruxolitinib), crossover allowed after 24 weeks/progressive disease.

The benefit of pacritinib in terms of SVR and TSS reduction was observed in patients with baseline platelet count less than 50 × 109/L and those with prior ruxolitinib treatment (comprising >40% of patients). There was a trend for better OS with pacritinib.
Read the supporting paper here.

SIMPLIFY2 trial: Momelotinib vs Best Available Therapy in patients with MF previously treated with ruxolitinib.

24-week spleen response were not different between momelotinib and BAT groups. Total symptom score and transfusion independence favored momelotinib.
Read the supporting paper here.

Ongoing promising trial exploring novel drugs for management of MF after JAKi failure.

Imetelstat, a telomerase inhibitor, evaluated in phase 3 trials for patients with MF who are refractory to JAKi treatment. The comparator arm of this randomized phase 3 trial is Best Available Therapy.

Navitoclax + Ruxolitinib vs Best Available Therapy as second-line treatment in suboptimal responders to ruxolitinib monotherapy.
Read the supporting paper here.”

Source: Talha Badar/X

Dr. Talha Badar, MD, is a specialist in Hematology Oncology based in Mayo Clinic, Jacksonville, Florida. His primary areas of expertise include Leukemia, particularly Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS), Acute Lymphoblastic Leukemia (ALL), and Bone Marrow Transplantation. Over his career, he has actively contributed to clinical research and clinical trials.