Aaron T. Gerds, MD, MS
Aaron T. Gerds, MD, MS, Associate Professor of Medicine, Deputy Director for Clinical Research at the Cleveland Clinic Taussig Cancer Institute and Medical Director of the Case Comprehensive Cancer Center Clinical Research Office, found the MANIFEST-2 findings to be highly noteworthy.
He cited a favorite quote to reflect his perspective on treating myelofibrosis today.As Charlie Mackesy wrote in The Boy, the Mole, the Fox and the Horse: “‘We have a long way to go,’ sighed the boy. ‘Yes, but look how far we’ve come,’ said the horse.”1
Drawbacks of JAK Inhibition
As Dr. Gerds explained, in myelofibrosis JAK inhibitors are the mainstay of treatment and are featured predominantly in algorithms and guidelines; however, “they are not perfect, even at the start of treatment,” he pointed out. In the COMFORT-I and COMFORT-II studies, ruxolitinib resulted in spleen responses (SVR35) in 42% (COMFORT-1) and 29% (COMFORT-II) of JAK inhibitor–naive patients.2 “This means that upward of 60% of patients will not have this sizable improvement in splenomegaly.”
Moreover, a consistent side effect of JAK inhibition is myelosuppression, leading to anemia and thrombocytopenia in a disease already burdened with ineffective hematopoiesis, he added.
Lastly, targeting the Janus kinase in myelofibrosis is not the same as targeting BCR- ABL1 in chronic myeloid leukemia, he further noted. Although ruxolitinib has shown a survival advantage over the control arms in pooled analyses of the COMFORT studies,3 there is no plateau in the survival curve “as it persistently marches to zero,” he observed. “This is why we need to respond with a relentless attack—developing new, innovative treatments for myelofibrosis, because ‘we have a long way to go.’”
Promising Results With BET Inhibitors
“That is why BET inhibition is a development we are watching with anticipation,” Dr. Gerds continued. For more than 20% of patients in whom ruxolitinib did not work or stopped working, CPI-0610 used as an “add-on” strategy resulted in a spleen volume reduction of at least 35%. In addition to symptom responses, 35% of transfusion-dependent patients had a restoration of erythropoiesis.
Moreover, he said, in arm 3 of the MANIFEST study, the combination of ruxolitinib and CPI-0610 resulted in spleen volume responses of 67% in JAK inhibitor–naive patients. “This level of response is beyond what we would expect from ruxolitinib alone based on the results of the COMFORT studies.”
But we also can’t ignore “how far we’ve come,” Dr. Gerds emphasized. In addition to the survival advantage seen with single-agent ruxolitinib in the context of clinical trials, real-world analyses have shown improvements in overall survival in patients diagnosed after ruxolitinib approval compared with before.3
Dr. Gerds continued: “Now, as other agents move along in development, we will need to contend with questions of sequencing, as we have with other cancers. If the response rate of the combination of ruxolitinib and CPI-0610 is 60% to 70%, but we can get similar response rates sequencing single-agent ruxolitinib followed by combination therapy, which is better? Should we start off with combination therapy, or reserve it for those who do not have an optimal response on a JAK inhibitor alone?”
“That is why it is exciting to see CPI-0610 move on to randomized phase III studies that will be able to evaluate not only spleen and symptom responses, but long-term outcomes such as progression-free and overall survival. With this information, we will really be able to move the needle forward for our patients,” Dr. Gerds remarked.
DISCLOSURE: Dr. Gerds has served as a consultant or advisor to AstraZeneca/MedImmune, CTI, and Incyte; and has received research funding from Celgene, CTI, Gilead Sciences, Incyte, Pfizer, and Roche/Genentech.
REFERENCES
1. Mackesy C: The boy, the mole, the fox and the horse. New York, NY: HarperOne, 2019.
2. Verstovsek S, Gotlib J, Mesa RA, et al: Long-term survival in patients treated with ruxolitinib for myelofibrosis: COMFORT-I and -II pooled analyses. J Hematol Oncol 10:156, 2017.
