Disease progression in myelofibrosis (MF) can take many forms, as detailed in this review published in the SOHO 2019 Meeting Proceedings Supplement in Clinical Lymphoma, Myeloma and Leukemia.
The most dismal complication in MF patients is transformation to acute myeloid leukemia (AML) – a malignancy that carries a grim prognosis and where therapies are still lacking. Long-term survivors of AML tend to be patients who can attain complete remission and proceed to allogeneic hematopoietic cell transplantation.
In one study, comprised of 370 consecutive patients with primary MF (PMF), transformation to AML was almost always preceded by an accelerated phase of the disease, defined by the presence of one or more of the following: platelets <50 x109/L, ≥10% blood or bone marrow blasts and chromosome 17 aberrations
A recent study from the Mayo Clinic identified IDH1, SRSF2 and ASXL1 mutations, “very high risk” karyotype with patients 70 years and older, who are males, and with the presence of moderate or severe anemia, and with circulating blasts or constitutional symptoms presenting as predictors of leukemic transformation within five years of diagnosis.
To combat disease progression, researchers have devoted increased efforts into developing Janus kinase (JAK), which as studies have observed, can prolong the survival of patients with intermediate-2 or high-risk myelofibrosis in comparison to placebo or best available therapy (BAT). In a phase 2, open-label, JAKARTA-2 study of the JAK2 inhibitor fedratinib, patients were only required to have received the JAK ruxolitinib for at least 14 days. There was also a required washout from ruxolitinib for at least 14 days, during which time splenomegaly and symptoms of MF could have worsened prior to fedratinib initiation.
Recently, a re-analysis of this study found the rate of ≥35% spleen volume reduction (SVR) at 24 weeks to be 30%, instead of 55% as previously reported. Besides newer JAK inhibitors, as the study author wrote, “there is also considerable enthusiasm for testing agents with novel mechanisms of action in the “ruxolitinib failure” setting. Recently released results from an ongoing study of the telomerase inhibitor imetelstat are intriguing in that the median survival of patients in the higher dose arm (9.4 mg/kg IV every 3 weeks) was 29.9 months.”
The author also wrote that a “concept that has been rapidly gaining ground has been that of a “sub-optimal” response to ruxolitinib, with a variety of different agents, representing multiple drug classes, being tested in “add-on” fashion, in hopes of resurrecting a response to ruxolitinib through synergy,” adding that, as with ruxolitinib, “there is also no uniformly accepted definition of sub-optimal response to ruxolitinib, and various criteria are in use.”