John O. Mascarenhas, MD, discusses with <em>Targeted Oncology </em>the recent advancements being made in the treatment of patients with advanced myelofibrosis and highlights some of the unmet needs that still exist within this space.
John O. Mascarenhas, MD
Ruxolitinib (Jakafi) is currently the only FDA-approved treatment option for patients with myelofibrosis (MF). For patients who relapse on or are refractory to this drug, there are limited options available.
Median survival for the general population of patients with MF is 5 to 6 years. However, in those who fail ruxolitinib, their median survival is only about 12 months. Data presented at the 2018 ASH Annual Meeting suggests imetelstat, a telomerase inhibitor, could fulfill this unmet need.
Based on prior data from a pilot trial in which imetelstat was associated with complete pathologic responses and molecular responses, investigators initiated a global randomized phase II study evaluating 2 dose levels of this agent in patients with advanced MF, the majority of which had failed ruxolitinib.
“It was a really sick patient population and the fact that we saw this survival advantage, or what appeared to be a survival advantage, in the high-dose arm, was quite remarkable, particularly in the subset population of triple-negative patients who lack discernable driver mutations,” said lead study author John O. Mascarenhas, MD.
In an interview withTargeted Oncology, Mascarenhas, an associate professor of hematology and oncology at the Icahn School of Medicine at Mount Sinai, discussed the recent advancements being made in the treatment of patients with advanced MF and highlighted some of the unmet needs that still exist within this space.
TARGETED ONCOLOGY: What does the current treatment landscape of MF look like?
Mascarenhas:It’s really trying to address the goals of the patient, the goals of care. We risk stratify patients, usually by DIPSS, the Dynamic International Prognostic Scoring System, and categorize patients into low-, intermediate 1-, 2-, and high-risk disease. Patients with the lowest risk can often be followed expectedly and not treated necessarily, particularly if they feel okay. If they don’t feel okay and are having symptoms of MF such as bone pains or spleen-related complaints, then ruxolitinib, which is the only approved therapy, can be used. That really holds true for continuing on other patients as well. In the intermediate 1-, 2-, and high-risk patients, in general, they should be considered for upfront ruxolitinib. Particularly if they have constitutional symptoms: fevers, night sweats, weight loss, spleen-related complaints.
For patients with anemia, we can use an algorithm. If their erythropoietin level is low, we give them a prominent form of erythropoietin. If the erythropoietin levels are elevated, we give them danazol, which is a male synthetic antigen. These 2 types of approaches in 20% to 40% of patients can improve hemoglobin levels and help patients stay out of the transfusion suite. If those don’t work, then it’s really clinical trial options because ruxolitinib, although it is a drug for addressing spleen-related symptoms, doesn’t improve hemoglobin, and in many ways, it can worsen it.
TARGETED ONCOLOGY: What are some of the areas of unmet need that still exist in MF?
Mascarenhas:For anemic patients or any patients with significant thrombocytopenia, which is an unmet need and a poor prognostic marker, ruxolitinib is not really an adequate drug, and those patients really tend to run available clinical trial options. Ruxolitinib, even in patients who are potentially transplant eligible, is often the first-line of therapy, regardless, in order to optimize them for transplant. These aren’t always mutually exclusive options.
Because of what I do with my focus on clinical trials, we are trying to evaluate experimental therapies that can be used either upfront in patients who are not eligible for ruxolitinib or patients who have failed ruxolitinib. By that, I mean patients who have had a response and maybe lost a response, never had a response, or have progressive disease on the drug. The median time to discontinuation on ruxolitinib is about 3 years, so there are multiple different areas of unmet needs that exist in this space.
TARGETED ONCOLOGY: Are there any recent data aiming to solve these challenges?
Mascarenhas:One thing for MF that I presented at the ASH meeting on behalf of our coinvestigators was the trial of imetelstat, which is a telomerase inhibitor. It’s a small molecular inhibitor on the enzyme telomerase that actually targets chromosomes and has been shown to be upregulated in malignancies in general, but specifically in MF. It’s a therapeutic target.
In a pilot study that was published in theNew England Journal of Medicinea couple of years ago as a single-institution study at Mayo Clinic, this was a drug that was associated with complete pathologic responses and molecular responses. It looks very promising, so we embarked on a global randomized phase II study looking at 2 different dose levels of this infusion drug in patients with advanced MF, the majority of which had failed ruxolitinib. It was a very sick patient population. Actually, not the majority of patients, but all of them had failed ruxolitinib by stringent criteria.
TARGETED ONCOLOGY: What results have you seen with this research?
Mascarenhas:What we saw in the interim analysis which was made public more than a year ago now was that the low dose was ineffective, so it was stopped. However, in the high dose, there was a clear advantage if you looked at the survival curves in terms of survival of these patients when comparing it to the low dose, suggesting that there was clinical activity seen but not necessarily preceded by the standard response assessment of the bone marrow and spleen symptom response. These patients were garnering some benefit to the drug in terms of improved survival.
That’s important because the median survival with MF is about 5 to 6 years. If you fail ruxolitinib, which was this patient population, the median survival is about 12 months. We had a [subset] in this study that was enriched for patients with advanced disease who were molecularly poor-risk. It was a really sick patient population and the fact that we saw this survival advantage, or what appeared to be a survival advantage, in the high-dose arm, was quite remarkable, particularly in the subset population of triple-negative patients who lack discernable driver mutations. Those patients did just as well as patients who didn’t have a driver mutation, which is not what you would expect. I think that was a step forward, and it’s a drug that I think should be evaluated further, maybe in a randomized phase III study in MF.
Tefferi A, Lasho TL, Begna KH, et al. A pilot study of the telomerase inhibitor imetelstat for myelofibrosis.N Engl J Med.2015;373:908-919. doi: 10.1056/NEJMoa1310523.