Peri-Transplant Administration of Ruxolitinib Safe and Feasible in Myelofibrosis


Ruxolitinib is one of only 2 treatments for MF that significantly improved the survival of patients. Still oncologists see opportunity to prolong survival in these patients even more.

Haris Ali, MD

Haris Ali, MD

Myelofibrosis (MF) is commonly treated with ruxolitinib (Jakafi), an FDA-approved JAK inhibitor.

Ruxolitinib is one of only 2 treatments for MF that significantly improved the survival of patients. Still oncologists see opportunity to prolong survival in these patients even more.

The survival benefit of ruxolitinib was demonstrated in the COMFORT-1 (NCT0095228) and COMFORT-2 (NCT00934544)clinical trials. In COMFORT-1, which had primary endpoints of response durability, changes in symptom burden and overall survival, 41.9% of patients who received ruxolitinib achieved durable responses. In the placebo group, only 0.7% achieved had durable responses. 

In COMFORT-2, which looked at the drug’s effect on spleen reduction, 28% of patients in the ruxolitinib group saw at least a 35% reduction in spleen volume. By week 48, compared to 0% who received the best available therapy. The median duration of response was not reached as 80% of patients were stilling have a response at the 12-month median follow-up.

To further improve outcomes for patients with myelofibrosis, investigators conducted a prospective pilot trial (NCT02917096) of ruxolitinib as a peri-transplant treatment for patients with MF. The goal of the study was to identify the maximum tolerated dose of ruxolitinib and its safety in this novel treatment strategy

In an interview with Targeted Oncology following the 2021 Transplantation and Cellular Therapy (TCT) Meetings, Haris Ali, MD, associate clinical professor, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California, discusses the prospective study of peri-transplant ruxolitinib as treatment of patients with MF.

TARGETED ONCOLOGY: How has ruxolitinib shaped the treatment landscape of MF over the recent years?

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

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

ALI: The original studies the COMFORT-1 and COMFORT-2 studies which were for MF ensured very good responses in this patient when it was compared to best available treatment or other supportive treatment and subsequently, how it actually improved. It's beneficial for a patient with polycythemia vera. Most recently, sunitinib (Sutent) got approved for treatment of acute graft-versus-host disease (GvHD), and it's looking very promising in chronic GvHD. It has a very unique mechanism of improving the inflammation, which is the main driver in these patients, both in MF other myeloproliferative neoplasms (MPNs) and in GvHD. It has really improved the outcome of this patient population, and that has been really a game changer in both these MPNs and GvHD.

TARGETED ONCOLOGY: What was the rationale for administering ruxolitinib as peri-transplant treatment for patients with MF?

ALI: Normally, most of these patients are on the ruxolitinib or fedratinib, which is another JAK inhibitor as part of the treatment of the MF. These are only currently two agents that are approved for treatment of MF. However, when these patients are in need of transplant, either because of progression, or because of high-risk disease, we previously used to stop the sunitinib prior to the transplant. We saw that stopping it abruptly was associated with very serious side effects, which were called ruxolitinib withdrawal syndrome, which would manifest as a shock like picture where a patient can have circulatory shock and renal failure. So, the purpose of continuing sunitinib was actually to prevent that withdrawal syndrome and to add to the beneficial effects of ruxolitinib during the transplant of making the transplant decrease the risk for GvHD and hopefully improving the engraftment after the transplant.

TARGETED ONCOLOGY: What endpoints did you explore in this study and why was it important to look at these outcomes for this specific patient population?

ALI: This has not been done before. We were the first to actually do this. The main endpoint was safety and feasibility, and we found it that it was a safe and feasible and the secondary endpoints were improving the survival to evaluate this survival, and to evaluate the GvHD. And if so, what we found out that actually it is very safe and feasible, and it actually reduces the risk for GvHD. And also, without affecting the engraftment, which is the big concern in these patient’s in myelofibrosis. So, so these were the outcomes that we saw the trial.

TARGETED ONCOLOGY: What did you present regarding this study during the 2021 TCT Meetings?

ALI: What I presented was the safety and efficacy. It was very safe and the majority of the patients had low-grade toxicity. Many were grade 1, and very few patients had grade 3 or grade 4 adverse events, which were mainly one patient had a renal failure, one patient had cardiac arrest. And which was not related to the drug. What we saw that the rate of GvHD, grades 3 to 4, which is a high grade was actually very low, only 12% and grade 2 to 4 was 17%. Our hypothesis, which was to make sure that it is safe, and it actually has a lower rate of GvHD without affecting the engraftment, was shown in the trial.

There were a number of patients in the study with driver mutations, aside from JAK-2. Do you see these mutations impacting survival in these patients in a later phase of this study?

ALI: The most common driver mutations in this study was the JAK2 mutation. The others were MAPL and CALRmutations. JAK-2 is more much of a high risk [mutation]. We did not see any impact of mutation on this study. However, this is actually a small study. We definitely need to expand it on a larger number of patients, and we are collaborating with another institute to look at the impact of mutations on a large population to see if these mutations have any impact on the transplant outcomes in patients with MF.

TARGETED ONCOLOGY: Is there anything you'd like to add about this abstract?

ALI: This is a study with 18 patients, and we saw a very positive response. There is also a signal that 10 milligrams twice a day is a good dose [of peri-transplant ruxolitinib to use] in these patients. We are going to hopefull expand it into a more randomized trial in the future where we can definitely show the impact and can improve the outcomes of a transplant in patient MF.

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