JAK Inhibitor Therapy in the Myeloproliferative Neoplasm Population

Ruxolitinib’s Role for Symptoms and Survival Benefit in Myelofibrosis

During a Targeted Oncology case-based roundtable event, Rami Komrokji, MD, discussed data supporting the use of ruxolitinib and what role it may play in improving long-term outcomes for patients with myelofibrosis. This is the second of 2 articles based on this event.

Targeted OncologyTM: What do the National Comprehensive Cancer Network (NCCN) guidelines recommend for patients with higher-risk myelofibrosis?

RAMI KOMROKJI, MD: [Based on the guidelines, for] higher risk, we consider [stem cell] transplant.1 In patients who are not candidates to transplant or bridge to transplant, the NCCN guidelines now separate the choice of JAK2 inhibitors based on the platelet count. If patients are not thrombocytopenic, ruxolitinib [Jakafi] or fedratinib [Inrebic]. If patients are thrombocytopenic, then pacritinib [Vonjo]. The NCCN cutoff is 50×109/L, which is based on the FDA label approval for pacritinib.2 Some people use the 100×109/L, what the PERSIST-2 study [NCT02055781] was based on.

Could you give an overview of the trials that led to the use of ruxolitinib for treatment of myelofibrosis?

Ruxolitinib is approved based on 2 trials; COMFORT-I [NCT00952289] done in the United States, COMFORT-II [NCT00934544] done in Europe. In the United States, the comparison was placebo; in Europe, it was best available therapy. But all those myelofibrosis studies have 2 primary end points in general. [The first is] spleen volume reduction which on trials they use MRI because in the phase 1/2, a 50% reduction by physical exam correlated to that 35% volume reduction by MRI, so it became the gold standard in clinical trials. In real life, I go by physical exam. If it is difficult to assess the spleen by exam, I will get an ultrasound.

The other end point of those trials is total symptom score improvement. This is a symptom score that Ruben Mesa, MD, and his group developed years ago and validated, called MPN-SAF [Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score]. We try to do it in every patient, which is always informative [since we often] either over or underestimate the burden of the disease. But what’s considered relevant is 50% or more reduction in the total symptom score and it has different domains.

What benefit does ruxolitinib have for treating symptoms of myelofibrosis?

With ruxolitinib, around 30% to 40% of the patients will achieve a spleen response. In reality, almost all the patients will have some spleen reduction. It’s that 30% or 40% who achieve this primary end point of spleen volume reduction of 35% or more.

When you look at the symptom response, [it is] the same thing. Around 40% to 50% of the patients achieved that 50% total symptom score reduction. Again, the majority of the patients will have some improvement in their symptom score.

What effect do JAK inhibitors have on survival and long-term disease outcomes?

[Researchers] always debate the role of the JAK2 inhibitors. Do they improve [overall survival (OS)] for those patients or not? The COMFORT-I and COMFORT-II [trials] were not powered to detect OS and they both allowed crossover, but post hoc analysis did show survival advantage.3 I always tell patients, if somebody is lower risk, doesn’t have splenomegaly and constitutional symptoms, there is no indication to start a JAK2 inhibitor to improve their OS. But, if patients were intermediate or higher risk with splenomegaly and constitutional symptoms, they do derive survival advantage from ruxolitinib, at least from the COMFORT-I and COMFORT-II compared with hydroxyurea [Hydrea]. So those patients will benefit the treatment.

Most of the time it’s not changing the transformation to AML [acute myeloid leukemia], and no reversing to fibrosis. It’s probably reversing some of the longstanding complications of splenomegaly like portal hypertension and cirrhosis. And by improving the patient’s general performance, preventing cachexia, that’s how I think it alters the natural history of the disease.

How does spleen response to ruxolitinib impact outcomes for patients?

There have been several studies looking at that; at the bottom line, I think most of the studies suggest if you have a 25% or more reduction in the spleen size, you do see correlation with OS. Why is that? I think part of that is reversing some of those complications. Over time, as I follow those patients, as they get into the massive splenomegaly, they start having portal hypertension and ascites. I’ve seen some patients ending with cirrhosis. I think part of it is that, and part of it is the improvement in the symptoms. But there is correlation between spleen response and OS.

There have been studies recently looking at the prediction of the durability of response with ruxolitinib. We did a study along with the Italian group [where we used] a new model called RR6 [Response to Ruxolitinib After 6 Months] looking at [patients after] 6 months and seeing the response.4 They look at 3 things: the dose of ruxolitinib, the transfusion dependency, and the spleen response, and you divide the patients into 3 groups. If somebody achieved all those points—had a meaningful dose of the ruxolitinib, are not transfusion dependent, and spleen is shrinking—those patients are going to enjoy long survival and long duration of response to ruxolitinib. If some patients are transfusion dependent, you are not able to push the ruxolitinib dose, and there is no spleen response, those patients will probably have very short response to ruxolitinib. The discussion now is that an indication to change the treatment at 6 months, similar to what we do in chronic myeloid leukemia with some of the tyrosine kinase inhibitors where you have milestones of green, yellow, or red.

What issues are there with the dosing of ruxolitinib?

The [concern] with the ruxolitinib is getting to a meaningful dose. I look at this from 2 different points. You probably could achieve symptom improvement at 10 mg dosing or more. The spleen response is definitely dose dependent. Most of the time we are not going to see a spleen response with below 10 mg, and most of the time you need 15 mg. It takes 3 to 4 months to see the spleen response, while within a week or 2, you will see the symptom improvement.

The cytopenia that happens early on that [cause] you to adjust the dosing. When patients have borderline cytopenia, it’s hard to push the dose to get a meaningful response in those patients. There are different school of thoughts on this. Sometimes I start one dose level less but I escalate quickly if the patient is tolerating it. The group from [The University of Texas MD Anderson Cancer Center], for example, starts with a higher dose, even if they render the patient transfusion dependent and then they back off later on because they think that an earlier response does correlate with better outcome.

Cytopenias are very predictable. You rarely see neutropenia…anemia, or thrombocytopenia. The nadir usually is around week 8, so in 2 months. With hemoglobin you expect almost a 2 g/dL drop. So, if somebody’s hemoglobin is 12 g/dL, I think that’s reasonable, and they would be feeling better. If somebody’s hemoglobin 8 g/dL or 9 g/dL, you probably could [take] them on transfusion. Usually [that is] the way that the numbers improve after 2 months. In my experience, it’s more backing off the dose and the dose adjustment rather than that the counts are going to improve spontaneously.

The original studies with ruxolitinib required platelets above 100 ×109/L. There were some studies looking at 50 ×109/L to 100×109/L. In reality, it’s very difficult in this group to get a meaningful dose for spleen reduction, particularly if you are going after the spleen. It’s tough, in my experience, to get to the desired dose of ruxolitinib.

References

1. NCCN. Clinical Practice Guidelines in Oncology. Myeloproliferative neoplasms, version 3.2022. Accessed December 9, 2022. https://bit.ly/2E77tIB

2. Vonjo. Prescribing information. CTI BioPharma Corp; 2022. Accessed December 9, 2022. https://bit.ly/3Y7J1y2

3. 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. 2017;10(1):156. doi:10.1186/s13045-017-0527-7

4. Maffioli M, Mora B, Ball S, et al. A prognostic model to predict survival after 6 months of ruxolitinib in patients with myelofibrosis. Blood Adv. 2022;6(6):1855-1864. doi:10.1182/bloodadvances.2021006889