JAK Inhibitors Can Impact Transplant Outcomes in Patients With Myelofibrosis

David S. Snyder, MD

David S. Snyder, MD

Although the FDA granted approval to fedratinib (Inrebic), a JAK inhibitor, for the treatment adult patients with intermediate-2 or high-risk primary or secondary myelofibrosis (MF) in August 2019, the JAK2 inhibitor is not a curative therapy for patients with MF. However, fedratinib joins ruxolitinib (Jakafi) as the second JAK inhibitor approved for the treatment of patients with MF and the second treatment to be approved in this space after nearly a decade.

The only curative option for patients with MF at this time remains allogenic stem cell transplant (SCT). JAK inhibitors like fedratinib and ruxolitinib, however, can help provide patients the opportunity to become candidates for transplant in cases where they would not ordinarily be eligible.

“Patients who are treated with those [JAK inhibitors] may have reduction in the size of their spleen, improvement in the performance status,” said David S. Synder, MD. “and those are things that could help their outcomes after transplant.”

In an interview withTargeted Oncology, Snyder, associate director at the City of Hope Cancer Center discussed the treatment approaches for patients with MF who are candidates for SCT, as well as prognostic scoring systems that can help determine a patient’s likelihood of response to transplant.

TARGETED ONCOLOGY: Could you discuss the evolution of transplant outcomes in patients with MF?

Snyder:We all know that allogenic SCT is the only curative option available for patients with MF. What we are all trying to develop are better tools to help us select the appropriate candidates for transplant, to improve the outcomes after transplant, and to predict who is likely to do well after transplant. There are new prognostic scoring systems that are being developed. DIPSS and DIPSS Plus were the original systems, but now there are systems that incorporate molecular and karyotypic information. MIPSS and MIPSS70 Plus Version 2.0 are the latest versions. They do help to stratify patients in terms of prognosis, survival, not necessarily after transplant, but overall with general treatment. The question then is do those prognostic scoring systems help you predict what the outcomes will be like after transplant? They may help you decide which patients should be considered for transplant, but they do not necessarily help you predict what the outcome will be after transplant. That is something that patients are looking for.

TARGETED ONCOLOGY: How is transplant being used with agents like ruxolitinib and fedratinib?

Snyder:The drugs that are available, ruxolitinib was first and now fedratinib was just recently approved by the FDA. Those are effective at helping to control systemic symptoms and to help control splenomegaly. They don’t cure the disease, and they don’t change the natural history of the disease, so they are not substitutes for transplant. However, they may help pave the way toward transplant. Patients who are treated with those drugs may have reduction in the size of their spleen, improvement in the performance status, and those are things that could help their outcomes after transplant.

TARGETED ONCOLOGY: What is your advice to oncologists who are determining what treatment to give their patients with myelofibrosis?

Snyder:I think it is important in the beginning to make an assessment of whether a patient is a potential candidate for transplant or not and to focus on that goal as part of their treatment plan. That is expanding, as far as who could be considered for transplant. We used to go up to age 50 to 55, but now with the use of what is called a “reduced intensity conditioning regimen,” we can go up to 70 or 75, or even beyond, and even with patients who have other comorbidities. It broadens the pool.

The other issue is the availability of donors. We don’t have to rely just on a fully matched sibling donor because those are harder to find these days, but we can expand it to either a fully matched unrelated donor or a partially mismatched unrelated donor. Now, other options including cord blood and even haplo-identical donors, so there are quite a few patients who are candidates. I think it is important to identify that patient group and look at the available donors for that patient, then start them on a JAK2 inhibitor. We must then figure out with the patient when the right time is to move ahead to transplant. That’s the challenge. I talk about not going too soon nor too late, and again, the question is whether these new prognostic scoring systems can help us to make that decision.

TARGETED ONCOLOGY: How are these new prognostic scoring systems impacting the field?

Snyder:The new systems incorporate new data such as molecular mutations. We know there are 3 main driver mutations—JAK2,CALR, andMPL—but there are a number of other mutations, some of which are considered high molecular risk mutations, and also karyotypic cytogenetic changes that may impact prognosis. Those features are being incorporated into prognostic scoring systems, and it allows you to stratify patients in an even more finely tuned way so you can have very low-risk patients who have very long survival predicted, all the way down to very high-risk patients who have very short survivals. That can help in decision-making in terms of proceeding to transplantation.

Transplantation is the only curative option, but on the other hand, it has some other risks associated with it, including the risk of early mortality. That’s the key, to try to select who is the right candidate. Some of what our data have shown is that patients who are considered to be intermediate-risk, by the MIPSS70 Plus 2.0, have excellent outcomes in terms of survival after transplant, up to 90% at 5 years. However, the question is if that is the right patient to offer transplant to because patients at intermediate risk may be feeling fairly well, may be quite functional, and they may not be thinking about transplant at that time. On the other hand, in terms of a long-term strategy, that might be the best time for them to achieve the best outcome.

TARGETED ONCOLOGY: How are you currently using ruxolitinib in light of the recent approval of fedratinib in patients with MF?

Snyder:Fedratinib was just approved as first- and second-line for salvage after ruxolitinib. I have to say that since fedratinib was just approved, I don’t have much direct experience using it, but from what I understand, the toxicity profiles are fairly similar in terms of risk of myelosuppression. Fedratinib may have more in the way of gastrointestinal toxicity. I certainly have more familiarity with ruxolitinib at this point, so I would tend to go to that drug as first-line choice, but certainly, there are many patients who do not respond adequately to ruxolitinib or do respond but then start to break through. It is good to know that there is an option for those patients as well.

As I said, I am always thinking about whether a patient is potentially a candidate for transplant, and if so, it would be good to treat them with a JAK inhibitor to which they are responding to help reduce their spleen size, control their systemic symptoms, improve their performance status, which we think would help improve their outcomes ultimately after transplant.

TARGETED ONCOLOGY: Is there anything else important to highlight in this space?

Snyder:It’s interesting thinking about the MIPSS70 Plus 2.0 scoring system and how well it can predict outcomes after transplant. It’s clear that the risk stratification of that system is useful, so intermediate-risk patients definitely do better than high-risk or very high-risk patients. Interestingly, the so-called high-risk molecular mutations to find in that system do not pan out as predictors of poor outcomes after transplant, so that is something to be aware of.

On the other hand, there are a couple of mutations, 1 being theDNMT3Aand another,U2AF1orCBL