CASE
- A 68-year-old man presented to his physician with symptoms of fatigue, drenching night sweats, abdominal pain, and intermittent fevers lasting 4 months. He also reported increased bruising.
- Medical history: type 2 diabetes and atrial fibrillation, both controlled with medication
- Spleen palpable 10 cm below the left costal margin
- CT scan of the abdomen/pelvis showing splenomegaly with spleen length of 30.3 cm
- ECOG performance status: 2
Targeted Oncology: What are the recommendations from the National Comprehensive Cancer Network (NCCN) guidelines in high-risk myelofibrosis?
KISHTAGARI: According to the NCCN guidelines, the symptom assessment score, based on the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score [MPN-SAF TSS], is an important objective tool, which I always [use] in my practice to assess the symptom burden. Then you risk stratify these patients based on the platelet count. With a platelet count of less than 50,000/μL, we can treat with pacritinib [Vonjo], and the other option is a clinical trial.
Every patient with myelofibrosis needs to have a transplant evaluation. If a patient is a transplant candidate, they need to proceed with allogeneic hematopoietic cell transplant. With a platelet count of at least 50,000/μL, we can consider ruxolitinib [Jakafi] or fedratinib [Inrebic].1 One thing I want to highlight, which is something the NCCN guidelines have clearly stated, is that if a patient [experiences progression] on ruxolitinib or fedratinib [and] is intolerant to [either], you can consider pacritinib even if the platelet count is 50,000/μL or more.1 Even though it is only approved for patients with a platelet count of less than 50,000/μL in the front-line setting,2 in the second-line setting, you can consider it for patients with a platelet count of 50,000/μL or more.1
What therapeutic agents are approved by the FDA for the management of myelofibrosis?
Three agents are FDA approved for [managing] myelofibrosis. All 3 are JAK inhibitors, and there are slight differences in the way they work. The JAK2 mutation was discovered in this disease in 2005, and then there was a focus on inhibiting this mutation, and that led to the development of ruxolitinib. This was FDA approved in 2011 for the [management] of intermediate- or high-risk primary or secondary myelofibrosis.3
The recommended starting dosage of ruxolitinib, if the platelet count is more than 200,000/μL, is 20 mg twice a day. For a platelet count in the range of 100,000/μL to 200,000/μL, you initiate at 15 mg twice a day. For a platelet count in the range of 50,000/μL to less than 100,000/μL, it is recommended to initiate at 5 mg twice daily.4 This is something I do not recommend at all; 5 mg twice daily has never been shown to control symptom burden. I think these are patients for whom we need to consider [alternative] therapies. You can initiate it, but I have never seen any improvement at such a low dose of ruxolitinib. You need to monitor the complete blood count [every] 2 to 4 weeks until the dose is stabilized and then as clinically indicated.
What we struggle with in the clinic whenever we see these patients is [this]: If there is a drop in the platelet count, we decrease the dose of ruxolitinib. I do not recommend abruptly interrupting ruxolitinib because there is something called ruxolitinib withdrawal syndrome. Whenever you are trying to mitigate the thrombocytopenia, I think you need to reduce dose. That is probably a better strategy than stopping ruxolitinib altogether.
Fedratinib was approved in 2019 for intermediate-2 or high-risk primary or secondary myelofibrosis.5 It is approved for use at a dosage of 400 mg once a day for patients with a baseline platelet count of at least 50,000/μL. That platelet count was chosen because the patients with a platelet count of less than 50,000/μL had severe thrombocytopenia, [which] led to hemorrhage in the clinical trial.
That is the reason why only patients with a platelet count of at least 50,000/μL [should] get fedratinib. There are some dose reductions [recommended for patients who take strong CYP3A inhibitors] or who have renal impairment.6
Recently, pacritinib was FDA approved in 2022 for intermediate-or high-risk primary or secondary myelofibrosis in patients with a platelet count of less than 50,000/μL at a dosage of 200 mg twice a day,2 with or without food.7
What symptoms of ruxolitinib withdrawal should physicians watch for?
The most important symptoms [are similar to those observed] when you suddenly stop steroids. Patients develop hypotension, severe rebound symptoms of their myelofibrosis, and a sudden drop in blood counts. All these point toward ruxolitinib withdrawal syndrome.
How do these 3 agents compare with each other?
Pacritinib, ruxolitinib, and fedratinib have slight differences in their mechanisms of action. The main thing I want to highlight is how pacritinib is different from the other 2 medications. Pacritinib does not inhibit JAK1; it only targets JAK2, in contrast with other medications.8-10 It preferentially affects the JAK2 V617F mutation but does not affect JAK1,10 and JAK1 has been shown to play an important role in megakaryopoiesis.11
One of the main reasons why this medication does not [cause a] drop in blood count is that it spares JAK1. Interestingly, it also inhibits IRAK1,10 and right now there is lot of clinical interest, [with respect to] myeloid [malignant tumors], to develop IRAK1 inhibitors because IRAK1 plays an important role in cytokine regulation. By inhibiting both JAK2 and IRAK1, pacritinib has a unique mechanism of action where it can control the symptom and help with the platelet count.
What clinical trials have examined the use of pacritinib in the management of cytopenic myelofibrosis?
There were 2 clinical trials: PERSIST-1 [NCT01773187] and PERSIST-2 [NCT02055781]. PERSIST-1 involved a 2:1 randomization to pacritinib at 400 mg once a day vs the best available therapy [BAT], and the classic primary end point was spleen volume reduction [SVR]. PERSIST-2 included patients [receiving either] first-line or second-line therapy, and they only included patients with a platelet count of no more than 100,000/μL. These were all patients with cytopenic myelofibrosis, an aggressive phenotype, and they were randomly assigned [1:1:1] to receive 400 mg once a day, 200 mg twice a day, or the BAT. This study had the classic end points of SVR at week 24 and the symptom assessment score based on the MPN-SAF TSS at week 24.12
What were the results of the PERSIST-2 trial?
In this clinical trial, there was a good distribution of patients who had already received ruxolitinib [45% in the control arm]. Additionally, some patients had received watch-and-wait [monitoring; 19%], some had received hydroxyurea [19%], and some had received steroids or other agents. There was a good distribution of both intermediate- and high-risk [disease] based on the Dynamic International Prognostic Scoring System classification [approximately 70% and 30%, respectively]. The majority of patients in the clinical trial had thrombocytopenia, and approximately 40% of patients had a platelet count of less than 50,000/μL. These patients were equally distributed between the twice-daily pacritinib arm and the BAT arm.12 The SVR had a 35% cutoff at week 24. Pacritinib 200 mg twice a day improved the SVR compared with the BAT [SVR of at least 35% occurred in 18% vs 3% of patients in the twice-daily experimental arm and control arm, respectively].7,12
Pacritinib also improved the total symptom [score and the individual symptom score]. These are the different measures we use in all clinical trials with myelofibrosis. [These are] based on the MPN-SAF TSS. Pacritinib decreased the symptom burden compared with the BAT arm [Patient Global Impression assessment scores of “much improved” or “very much improved” were observed in 57% vs 28% of the twice-daily experimental arm and control arm, respectively].12
The transfusion burden is very important clinically. Pacritinib 200 mg twice a day improved the transfusion burden by week 24 [among transfusion-dependent patients; the percentage of patients that experienced a reduced burden was 22% in the twice-daily experimental arm vs 9% in the control arm]. Pacritinib also [improved] hemoglobin levels and stabilized the transfusion burden if it was not improved.
What were the adverse events observed in this trial?
The most important adverse event I want to highlight is diarrhea, which was observed in 48% of patients in the twice-daily arm, but rarely was this grade 3 or higher [4%]. Whenever a patient experiences diarrhea, in my practice at least, they respond very well with a single dose of loperamide [Imodium]. You can try that, and if the patient has persistent diarrhea despite the medication, then you need to reduce dose. But in the clinical trial, rarely was the dose reduced.7,12
Additionally, there was a good percentage of patients with thrombocytopenia [34% for all grades; 32% for grade 3 or higher] and anemia [24% for all grades; 22% for grade 3 or higher], but the majority of patients in the clinical trial had thrombocytopenia and anemia to begin with. For example, if a patient had a platelet count of 56,000/μL at the time of enrollment and they dropped to a platelet count of 49,000/μL, we know that is not clinically significant. However, the clinical trial would capture it as grade 3 thrombocytopenia.