Ruxolitinib Stands Out Among JAK2 Inhibitors for Myelofibrosis

In this virtual tumor board discussion, experts review the case of a 68-year-old woman diagnosed with primary myelofibrosis. The discussion focuses on recent data and emerging insights to guide clinical decision-making and explore the latest advances in treatment strategies for this challenging disease.

Prithvira J. Bose, MD: What are the first steps you would take for this patient, and how do you view multidisciplinary collaboration?

Julie Huynh-Lu, PA-C: Specific to [The University of Texas] MD Anderson [Cancer Center], the role of the physician assistant or nurse practitioner in the leukemia department is to evaluate the patient. Aside from doing a review of systems, I go over the myeloproliferative neoplasms [MPN] questionnaire with the patients to review any changes in their score. Whether they have started therapy or not, [we determine whether they] need to be on therapy based on their answers.

I do a physical assessment of the patient checking their spleen. We don’t order ultrasounds or CT scans on patients unless we’re unable to palpate due to pain in that area. I’ll measure the spleen size every time the patient comes in with a tape measure.

Having a second set of eyes evaluating the patient [is key] because some questions that I may ask, someone else may not—or the physician may ask questions that I may not know [to ask]. Collaboration among nurses, physician assistants or nurse practitioners, and physicians in compiling patient information ensures the best care for the patient.

We are lucky to have the MPN10 form in the Epic system on our flow sheet, and patients can fill out this form before they check in for their appointment. If they were unable to fill it out, I can go into that flow sheet, ask those questions, and fill it out with them. Then, the score [generates] for each patient.

Bose: This patient chose not to go to transplant and was given ruxolitinib. Do you agree with this?

Rami Komrokji, MD: First, to verify the diagnosis, [I ask myself whether] the patient meets the criteria. In some cases, we get surprised when a patient was [incorrectly] labeled with myelofibrosis and [yet] they do not have myelofibrosis. In this case, there are enough features with the bone marrow, [which is] a clonal marker [and a] clinical scenario that fits [the diagnosis of myelofibrosis].

The risk is somewhat intermediate to higher. I would have had the discussion about transplant with the patient up front. When it comes to treatment, the patient’s spleen measures 6 to 7 cm, and [they do] have some fatigue. I was not sure to what extent this patient needed immediate treatment. [For instance,] is the splenomegaly symptomatic, and is the patient anemic as well? That is a consideration.

Because this patient is not going to transplant, I’m not sure about the timing of starting the treatment. In the past, I never treated patients unless they were symptomatic from [the] spleen. Over time, I have developed respect for splenomegaly. For instance, if the spleen grows substantially over time, you’ll start [to] see complications. If the spleen is very large, I may start treatment a little bit earlier. I take all those factors [into consideration].

Ruxolitinib is a reasonable option if the main indication is for fatigue and splenomegaly. The aspect we must keep in mind as we start this treatment is regarding the borderline hemoglobin. We may be leading this patient toward transfusion dependency down the road and must maintain that balance. I may have [opted to] wait a little more if the magnitude or burden of symptoms is not enough to justify treatment. Ruxolitinib is one of the options if we are conscious [of the fact] that this will worsen the anemia and probably not improve it.

Primary myelofibrosis cells in blood flow: © LASZLO - stock.adobe.com

What are the factors you would consider when starting ruxolitinib?

Claire Harrison, MD: I would want to explore with this patient more about why she does not want a transplant. Sometimes, patients will come to see us having been told they cannot have a transplant because they are too old or they have a fixed view. Looking at this patient, she will be 68 in a few years. She may not be fit enough [for transplant]. [Regardless], it’s still a good option.

It’s our only curative option. The patient does not need to rush. I would always encourage them to have a consult with a transplant clinician. This patient is going to die from myelofibrosis almost certainly at some point, and yet the symptoms are not that impressive, I agree. However, we have learned more about early vs late treatment. The data from [the phase 3] COMFORT-I trial [NCT00952289] show that patients treated within 12 months of diagnosis have a better outcome in terms of the spleen.¹

I also have respect for the spleen that I did not have before. It was great to hear how [the spleen] is measured with a tape measure rather than fingers, as we were taught in medical school. We put added guidance on that in the UK guidelines.²

Right now, in the UK, we could use momelotinib [Ojjaara] for this patient. I do not want to assume that this patient is anemic because of their myelofibrosis. I would want to check [to confirm] that they are not iron, [vitamin] B₁₂ , or folate deficient and have good renal function and so on. However, I’m reassured that our processes are not too different. That’s great.

Bose: In the COMFORT-I trial, ruxolitinib [was evaluated] against placebo, and in the [phase 3] COMFORT-II trial [NCT00934544], led by Harrison et al, ruxolitinib was evaluated against best available therapy.³ In both [trials], patients had platelet [counts] of 100,000 or greater and had to be IPSS intermediate-2 or high. Spleen and symptoms were the main readouts. These trials have shown a survival benefit for ruxolitinib; however, the trials were not specifically designed to show that but a later analysis instead. In COMFORT-I, the benefit was shown at 1 year and then at 5 years. For COMFORT-II, the benefit emerged at 3 years and again at 5 years.

There was a pooled analysis done where the median survival for ruxolitinib was 5.3 years, and the median survival for the comparator arms was 3.8 years, which is a 30% improvement. This is despite crossover. If corrected for crossover, there is an even more accentuated difference between the 2 arms.

If you look at the COMFORT-II population and stratify them by less than 12 months from diagnosis vs 12 or more months from diagnosis, not only [with] response rates, but also [with] survival [rates], there was an advantage for those who began ruxolitinib early.

That said, there was a survival benefit to starting early, which showed better response rates. This is practical and important in everyday practice as we see patients. The spleen response to ruxolitinib is dose dependent, and the spleen responds with increasing doses.

This is not necessarily the case with symptoms where [a dose of] 10 mg at 2 times per day may suffice. For the most part, 10 mg at 2 times per day suffices for symptoms. However, the spleen response is dose dependent. This is important because the better the spleen responds, the better the survival.

Regarding the spleen response, in the COMFORT-I trial at 24 weeks, data showed 35% or greater reduction in spleen volume on imaging (42% with ruxolitinib vs 0.7% with placebo). For the COMFORT-II trial at the 48-week readout, the reduction in spleen volume on imaging was 28% for ruxolitinib and 0% for placebo, and 32% at 24 weeks.

Ruxolitinib can cause cytopenia, the most prominent adverse event (AE). There are rates of anemia and thrombocytopenia in both trials side by side with the comparator arm. The cytopenia are most prominent during the first 12 to 24 weeks, and then they get a little better; however, these AEs do not usually come back to baseline.

What are your impressions on the COMFORT-I and COMFORT-II data?

Harrison: It’s been a huge privilege to have been practicing when we started using JAK inhibitors, and it’s been important to see the benefit these drugs can bring to patients with this disease. It’s interesting and remarkable how similar the data between the 2 studies were, and it plays out as we look at real-world data and see patients [treated] in our clinic. It has made me a lot more aware and respectful of the spleen and more aware of the symptoms that patients [can] have.

Regarding the blunt, non–disease-specific tools that we had to use in the COMFORT-II study, now we have the 10-point or whichever version of a myelofibrosis symptom assessment form that is used, and we also have more educated patients. This changes the way we manage the disease; however, the only cure is still transplantation. Since then, we have been trying to improve it and have learned more by looking back at the data, for instance, to treat within 12 months.

Bose: How do you approach the cytopenia observed?

Komrokji: These medications change the way we practice and treat our patients. I believe those agents derive survival advantages for patients in the right context. I always tell patients that if someone is asymptomatic, low grade, low risk, you are not going to tell them, “Take this medication because this improves your survival.” However, in the right context of how the trials were done, if patients have symptoms and you prescribe those medications, compared to the controls, those medications do improve survival for patients. We have seen that in practice over many years now.

The challenge has been the toxicity of cytopenia. It is very predictable, and the hemoglobin [level] drops 2 g by week 8, and patients develop thrombocytopenia [more so] than neutropenia. Other than this, the toxicity is very manageable. Some headaches, dizziness, and recurrent urinary tract infections [are observed as well]. Nowadays, I tell my patients to get [the] shingles vaccine because there is herpes zoster reactivation with the cytopenia.

This is changing with the availability of other JAK2 inhibitors…. [O]ur threshold of the expected toxicity is changing a bit, and this depends on the goal. If I’m aiming for symptom improvement, many times you can get by with lower dosing, and the patient’s fatigue and constitutional symptoms improve. You are not going to be pushing the patient toward transfusion dependency. However, if you are going for a spleen response, it is a matter of dose dependency. In the past, in the absence of other agents, we either accepted that and compared which was worse, the spleen symptoms vs the cytopenia, and we pushed the dosing, or we tried to adjust it.

Most of the time, when patients have borderline blood counts, we do not start with the 20-mg or 15-mg [dose]. Most of us will start at [a] lower dose for the first 8 weeks and manage the cytopenia, which does not become life-threatening with that approach. But did we get the optimal spleen and symptom responses with that dose titration? Not necessarily in every patient. Dose [adjustments] of ruxolitinib are one approach. Then, sometimes, we’ve used other approaches, such as for people who have used erythropoietin-stimulating agents on and off to help mitigate anemia. There were studies with sotatercept [Winrevair] a few years ago, and now luspatercept [Reblozyl] is going into phase 3 as adjunctive therapy for anemia.^4,5 I know people have used thalidomide [Contergan, Thalomid] and other agents in combination. There is no doubt that ruxolitinib is an effective treatment, but once you get particularly [entrenched] in that borderline group, cytopenia is going to be the main challenge.

Bose: Considering cytopenia, how do you walk a patient through those first weeks of ruxolitinib treatment?

Huynh-Lu: Specific in our clinic, whenever we prescribe a patient ruxolitinib, we tell them that the process can be lengthy with insurance, etc. The day [the patients are] prescribed the medication, we fill out a consent form with them, going over the potential risk factors or AEs that can occur. [With] every patient, I tell them [that in the f irst 8 to 12 weeks, their blood counts should drop]. I don’t want them to worry as hemoglobin dropping 1 or 2 g is expected.

Once the treatment is started, I [inform] them [that they will] come back every 2 weeks to reevaluate their blood counts until they stabilize. If they don’t stabilize, and the hemoglobin or platelets are dropping too much, we will conduct dose adjustments dependent on blood levels.

I always inform patients that once they receive the medication, they are going to contact me or the primary team to let them know they received it. That way we can set up every-2-week laboratory checks in what we call fast track and review, which is run by the advanced practice provider group in our leukemia department. We also suggest the shingles vaccine for the patients, and sometimes we initiate prophylactic valacyclovir [Valtrex].

Bose: For patients who declined transplant, would you reevaluate and discuss this with the patient?

Komrokji: That is an important question. I tell patients that if they are eligible for a transplant, it’s a matter of the optimal timing of the transplant rather than whether they need a transplant. The only curative option we have for these patients is transplant, and we are always trying to weigh the benefit and the risk. For instance, “Do I have enough risk of the disease to justify the transplant-related mortality and morbidity at this point of the disease?”

For patients at higher risk, this is justifiable early on. Sometimes, if I’m not sure, such as with intermediate risk, then I tell the patients, let us observe the disease kinetics over the coming year and how the disease is going to progress.

If someone has progressed, it depends on the pattern of progress. For instance, if a patient is going into an accelerated phase such as MPN or adrenomyeloneuropathy, this becomes a more difficult situation for transplant. The patient must understand that the outcomes are going to be inferior. However, if the pattern of progression is failure of response to therapy, such as the cytopenia getting worse, this is partly salvageable, and you can revisit the option of the transplant and proceed with it.

Harrison: Often, patients will not tell me the reason why they will not have one, but they might tell another member of the team. Sometimes, it is about sitting down with a patient and talking to them about [the] prognosis. With these prognostic scores, like the MIPS score or the predicted blood score, you can give patients a picture of what will likely happen over time.

There is plenty of time to have a discussion with this patient because she seems to have indolent disease. The only drawback is that she is a bit older, and her hemoglobin is borderline. However, the spleen is not massive, palpable but not enormous. I would rather take a patient to transplant at the peak of their first response than wait for them to have lost that response or to progress to [an] accelerated phase.

REFERENCES:

1. Mesa RA, Gotlib J, Gupta V, et al. Effect of ruxolitinib therapy on myelofibrosis-related symptoms and other patient-reported outcomes in COMFORT-I: a randomized, double-blind, placebo-controlled trial. J Clin Oncol. 2013;31(10):1285-1292. doi:10.1200/JCO.2012.44.4489

2. McMullin MF, Harrison C. Experience of myeloproliferative neoplasms guidelines in the United Kingdom: perspective and international context. J Natl Compr Canc Netw. 2016;14(12):e1626-e1631. doi:10.6004/jnccn.2016.0171

3. Harrison CN, Vannucchi AM, Kiladjian JJ, et al. Long-term findings from COMFORT-II, a phase 3 study of ruxolitinib vs best available therapy for myelofibrosis. Leukemia. 2016;30(8):1701-1707. doi:10.1038/leu.2016.148

4. Bose P, Masarova L, Pemmaraju N, et al. Final results of a phase 2 study of sotatercept (ACE-011) for anemia of MPN-associated myelofibrosis. Blood. 2021;138(suppl 1):144. doi:10.1182/blood-2021-150908

5. Hatzimichael E, Timotheatou D, Koumpis E, Benetatos L, Makis A. Luspatercept: a new tool for the treatment of anemia related to β-thalassemia, myelodysplastic syndromes and primary myelofibrosis. Diseases. 2022;10(4):85. doi:10.3390/diseases10040085