Promising research sheds light on treating deadly bone-marrow disorder

Researchers are beginning to understand more about how to treat a rare but deadly type of blood cancer known as Philadelphia chromosome-negative (Ph-negative) myeloproliferative neoplasms (MPNs). These stem cell disorders occur when white or red blood cells or platelets are overproduced in the bone marrow. This results in a variety of signs and symptoms, such as fatigue, blood clots, weight loss, enlarged spleen and shortness of breath.

The outlook for MPNs is very poor, especially once the disease progresses to the accelerated or "blast" phase (MPN-AP/BP). Most patients survive fewer than six months following treatment with conventional chemotherapy options.

For this aggressive blood cancer, new and better treatments that extend life are badly needed. Therapeutic options, including intensive chemotherapy, have limited effectiveness in patients with MPNs in the blast phase, and the outcome is uniformly poor. Although stem-cell transplantation may cure the disease, only a minority of patients are eligible for such a transplant.

Ideally, treatment options should take into account the variability of the disease; this could be addressed by a personalized approach to therapy. Ongoing research into MPNs focuses on the molecular signals that allow the disease to advance to the blast phase, which can then be targeted, using drugs such as inhibitors to treat the disease.

IDH2 is an enzyme, or protein that speeds up a reaction, involved in cellular metabolism. IDH2, along with the metabolic enzyme IDH1, is mutated in approximately 20% of patients with myeloproliferative neoplasms in the blast phase. Early treatment options targeting IDH2 include the inhibitor enasidenib, which has recently shown promise in treating IDH2-mutated acute myeloid leukemia (AML), another form of blood cancer.

In order to determine if the inhibitor could also be effective in patients suffering from Ph-negative MPNs, researchers at the University of Chicago Medicine, led by Olatoyosi Odenike, MD, took a close look at using it in patients with IDH-mutated MPN-AP/BP.

Patients listed on the University of Chicago Next-Generation Sequencing (NGS) database between 2009 and 2019 with IDH-mutated MPN-AP/BPs who had been given an IDH inhibitor were included in the analysis. This resulted in a cohort of eight patients, with all eight patients having IDH2 mutations. Of this cohort, six patients received enasidenib (50–100 mg once daily) as initial treatment, whereas the other two patients received enasidenib after their disease had come back.

Although follow up was relatively short, the authors observed median survival was not reached with enasidenib. There were patients whose survival exceeded two years, with the longest being over four years. As median survival for this disease is fewer than six months, this represents an incredible extension and suggests that enasidenib or other IDH inhibitors have potential for responses that extend beyond the historically poor survival rate associated with MPN progression.

The authors also found, even at the time of best response, that the slower-progressing stages of disease persisted in all of the patients. This suggests that combination therapies may be necessary when using IDH inhibitors so as to target both the acute (fast) and the chronic (slow) phases of MPNs. Future studies are still needed to address this.

For patients, this study provides promising preliminary data that IDH inhibitors may be beneficial for treating IDH-mutated MPN-AP/BPs. However, Odenike cautioned, “The major limitations of the study are its retrospective nature and the small sample size.”

Nevertheless, these results help inform future research efforts. “Prospective IDH inhibitor-based therapeutic clinical trials focused on this patient population are needed and are in development,” said Odenike.

The study, “Clinical outcomes of IDH2-mutated advanced-phase Ph-negative myeloproliferative neoplasms treated with enasidenib,” was published July 2020 in the British Journal of Haematology. First authors include Anand A. Patel and Kirk Cahill. Additional authors include Angella Charnot-Katsikas, Hongtao Liu, Sandeep Gurbuxani, Michael Thirman, Satyajit Kosuri, Richard A. Larson, Wendy Stock, and Jeremy Segal from the University of Chicago, and Andrew A. Artz from the University of Chicago and City of Hope National Medical Center.