Ruxolitinib Safely Explored As Peri-Transplant Therapy for Myelofibrosis

Haris Ali, MD

A maximum dose of 10 mg of ruxolitinib (Jakafi) given pre-transplant is not only safe, but also decreases the risk of graft versus host disease (GvHD) in patients with myelofibrosis undergoing hematopoietic cell transplantation (HCT), according to data presented at the 2021 Transplantation and Cellular Therapy Meetings.

Usually, ruxolitinib is stopped prior to transplantation. However, this can sometimes cause ruxolitinib withdrawal syndrome, which can cause renal failure. Data from the prospective pilot trial (NCT02917096) found that it is safe and feasible to continue therapy peri-transplantation.

The trial enrolled 18 patients, 6 of whom were given 5 mg of ruxolitinib and 12 who were given 10 mg of ruxolitinib twice daily for 100 days, starting 3 days prior to transplant. Every patient achieved engraftment with neutrophil recovery. Patients in the lower-dose arm achieved engraftment within 19 days and patients in the higher dose group achieved it in 16 days.

The regimen was also well-tolerated. Seventeen percent of patients developed grade 2 to 4 GvHD (95% CI, 6%-47%). The overall survival rate at 1 year was 77% (95% CI, 50%-91%), and the progression-free survival rate was 71% (95% CI, 44%-87%). Over the course of the study, 4 patients died. Causes of death included 2 cases of GvHD, 1 of which was refractory GvHD of the patient’s liver, cardiac arrest, and respiratory failure.

In an interview with Targeted Oncology, Haris Ali, MD, a hematology oncologist at the City of Hope Cancer Center, discussed the efficacy of ruxolitinib in patients with myelofibrosis, the impact of mutations on ruxolitinib treatment, and the use of the agent in the peri-transplant setting.

TARGETED ONCOLGY: How has ruxolitinib shaped the treatment landscape of myelofibrosis over the recent years? 

ALI: [Ruxolitnib] is currently the only treatment along with fedratinib (Inrebic) that's approved for the treatment of myelofibrosis. For the longest period of time, we did not have any drug that was FDA approved for the treatment of myelofibrosis that could significantly improve the survival of the patients. However, ruxolitinib was approved in 2011 and since then, it has really changed the treatment landscape for myelofibrosis by not only improving the symptoms [and] prolonging the survival, but also reducing the spleen size, which is a big problem in these patients. Now, we are looking into various additions to this backbone ruxolitinib to improve the outcomes of a patient's myelofibrosis.

In your opinion, what research about ruxolitinib has been the most impactful to the way hematological oncologists treat patients today?

The original studies, COMFORT-1 (NCT00952289) and COMFORT-2 (NCT00934544), which were in myelofibrosis, showed very good responses in these patients when it was compared to best available treatment or other supportive treatment. Subsequently, how it actually improves is beneficial for patient polycythemia vera. Most recently, ruxolitinib was approved for the treatment of acute GvHD, and it's looking very promising in chronic GvHD. It has a very unique mechanism of improving inflammation, which is the main driver in these patients, both in myelofibrosis, other myeloproliferative neoplasms (MPNs), and GvHD. It has really improved outcomes for these patients, and that has been a game changer in both MPNs and GvHD.

What was the rationale for administering ruxolitinib as peri-transplant treatment for patients with myelofibrosis?

Normally, most of these patients are on the JAK inhibitors ruxolitinib or fedratinib. These are currently the only agents that are approved for the treatment of myelofibrosis. However, when these patients are in need of transplant, either because of progression, or because of high-risk disease, previously, we used to stop the ruxolitinib prior to the transplant. What we saw was that stopping it abruptly was associated with a very serious adverse event, called ruxolitinib withdrawal syndrome, which would manifest as a shock like picture where patients can have circulatory shock and renal failure. The purpose to continue ruxolitinib was actually to prevent that withdrawal syndrome and to add to the beneficial effects of ruxolitinib during the transplant. This had the potential to decrease the risk of GvHD and hopefully improve the engraftment growth after the transplant.

What end points did you explore in this study and why was it important to look at these outcomes for this specific patient population?

We were the first ones to actually do this. The main end point was safety and feasibility and we found it that it was safe and feasible. The secondary end points were improving the survival, evaluating the survival, and to evaluate for GvHD. What we found out was that it is very safe and feasible, and it actually reduces the risk for GvHD without affecting the engraftment, which is the big concern in these patients with myelofibrosis.

What were rhe key findngs from this study?

What we presented was the safety and efficacy. We found it to be safe for the majority of the patients. There was low-grade toxicity, mainly grade 1, and very few patients had grade 3 or grade 4 AEs. There was 1 patient who had a renal failure, 1 patient had cardiac arrest, which was not related to the drug. What we saw that the rate of high-grade GVHD very low only 12%, and grade 2 to 4 was 17%. Basically, our hypothesis, which was to make sure that it is safe, it actually has a lower rate of GVHD disease without affecting the engraftment. That is what we saw on the trial.

There were a number of patients in the study with driver mutations, aside from JAK2, do you see these mutations impacting survival in these patients in a later phase of this study? And what does research say about these driver mutations?

The most common driver mutations are JAK mutations, others are CALR and FTL mutations. JAK2 is more of a high-risk mutation. Among the driver mutations, it's a slightly higher risk. We did not see any impact of mutations on the study. However, this is actually a small study, we definitely need to expand it to a larger number of patients. We are collaborating with other institutions to look at the impact of mutation in a large population to see if these mutations have any impact on the transplant outcomes in patients with myelofibrosis.

This is a study with 18 patients where we saw a very positive response. There is a signal that 10 milligrams twice a day is a good dose in these patients. We are planning to expand it into more randomized trials in the future where we can definitely show the impact and can improve the outcomes of a transplant in patients with myelofibrosis.