Kishtagali on Myelofibrosis Risk Assessment and Treatment Options

Dr. Ashwin Kishtagari

Assistant Professor of Medicine

Department of Hematology and Oncology

Vanderbilt University Medical Center

Nashville, Tennessee


  • A 68-year-old man presented to a physician with symptoms of malaise, drenching night sweats, abdominal pain, and intermittent fevers lasting four months. He also reported increased bruising.
  • History: Type 2 diabetes and atrial fibrillation, both controlled by medication
  • Spleen palpable 10 cm below left rib cage
  • A CT scan of the abdomen/pelvis shows splenomegaly with a spleen length of 30.3 cm.
  • ECOG performance status: 2

Targeted Oncology: What are the recommendations of the National Comprehensive Cancer Network (NCCN) guidelines in high-risk myelofibrosis?

Kari Kishida: According to NCCN guidelines, the symptom assessment score is based on the total symptom score of the Myeloproliferative Neoplasms Symptom Assessment Form. [MPN-SAF TSS]is an important objective tool and I use it all the time [use] My practice assesses symptom burden. Second, there is the risk of stratifying these patients based on platelet count. If the platelet count is less than 50,000/mcL, it can be treated with pacritinib. [Vonjo]another option is a clinical trial.

All patients with myelofibrosis should undergo a transplant evaluation. If the patient is a transplant candidate, allogeneic hematopoietic cell transplantation should be pursued. Ruxolitinib can be considered if the platelet count is at least 50,000/μL. [Jakafi] or fedratinib [Inrebic].1 One thing I would like to emphasize is that the NCCN Guidelines clearly state that patients [experiences progression] On ruxolitinib or fedratinib [and] intolerant [either]The use of pacritinib can be considered even if the platelet count is ≥50,000/μL.1 Approved only for patients with platelet counts <50,000/μL in frontline settings2 A second-line setting can be considered for patients with platelet counts ≥50,000/μL.1

What therapeutic agents have been approved by the FDA for the management of myelofibrosis?

Three drugs have been approved by the FDA. [managing] Myelofibrosis. All three are JAK inhibitors and differ slightly in their action.of JAK2 A mutation was discovered in this disease in 2005, and the subsequent interest in blocking this mutation led to the development of ruxolitinib. This he was approved by the FDA in 2011. [management] Intermediate- or high-risk primary or secondary myelofibrosis.3

The recommended starting dose of ruxolitinib for platelet counts >200,000/μL is 20 mg twice daily. For platelet counts between 100,000/μL and 200,000/μL, start at 15 mg twice daily. For platelet counts in the range of 50,000/μL to less than 100,000/μL, it is recommended to start at 5 mg twice daily.Four I do not recommend this at all. 5 mg twice daily has not been shown to control symptom burden.I think these are the patients we need to consider [alternative] Treatment. You can start, but I have never seen improvement with ruxolitinib at such a low dose.A complete blood count should be monitored [every] It takes 2-4 weeks for the dose to stabilize and then as clinically indicated.

What we struggle with every time we see these patients in our clinic is [this]: Decrease the dose of ruxolitinib if there is a low platelet count. Sudden discontinuation of ruxolitinib is not recommended due to something called ruxolitinib withdrawal syndrome. I think that whenever you try to reduce thrombocytopenia you need to reduce the dose. It is probably a better strategy than discontinuing ruxolitinib altogether.

Fedratinib was approved in 2019 for intermediate 2 or high-risk primary or secondary myelofibrosis.Five It is approved for use at a dose of 400 mg once daily in patients with a baseline platelet count of at least 50,000/μL. This platelet count was chosen because patients with platelet counts <50,000/μL had severe thrombocytopenia. [which] Caused bleeding in clinical trials.

This is why only patients with platelet counts >50,000/μL are eligible. [should] Get fedratinib.Although there is some weight loss [recommended for patients who take strong CYP3A inhibitors] Or those with renal impairment.6

Pacritinib was recently approved by the FDA in 2022 at a dose of 200 mg twice daily for intermediate- or high-risk primary or secondary myelofibrosis in patients with platelet counts <50,000/mcL. rice field.2 With or without food.7

What symptoms of ruxolitinib withdrawal should a doctor look for?

most important symptoms [are similar to those observed] When you stop taking steroids abruptly. Patients develop hypotension, severe rebound symptoms of myelofibrosis, and a sudden drop in blood counts. All of these are indicative of ruxolitinib withdrawal syndrome.

How do these three agents compare?

Pacritinib, ruxolitinib, and fedratinib have slightly different mechanisms of action. The main point I want to emphasize is how pacritinib is different from her other two drugs. Pacritinib does not inhibit her JAK1. Unlike other drugs, it only targets JAK2.8-10 Priority is given to JAK2 The V617F mutation had no effect on JAK1,10, and JAK1 has been shown to play an important role in megakaryopoiesis.11

One of the main reasons why this drug doesn’t work is [cause a] This is because low blood counts spare JAK1. Interestingly, it also inhibits IRAK1.Ten And now there is a lot of clinical interest. [with respect to] myeloid [malignant tumors]Since IRAK1 plays an important role in cytokine regulation, we aim to develop IRAK1 inhibitors. Pacritinib has a unique mechanism of action that helps control symptoms and increase platelet count by inhibiting both JAK2 and IRAK1.

What clinical trials have investigated the use of pacritinib in the management of cytopenic myelofibrosis?

There were two clinical trials: PERSIST-1 [NCT01773187] and permanent-2 [NCT02055781]. PERSIST-1 randomized 2:1 to pacritinib 400 mg once daily versus best available therapy. [BAT]the classical primary endpoint was splenic volume reduction [SVR]. Patients included in PERSIST-2 [receiving either] Only patients with platelet counts <100,000/μL were included. These were all patients with an aggressive phenotype, cytopenic myelofibrosis, and were randomly assigned. [1:1:1] Administer 400 mg once daily, 200 mg twice daily, or BAT. In this study, the classic endpoint of SVR was set at week 24 and the MPN-SAF TSS-based symptom rating score was set at week 24.12

What were the results of the PERSIST-2 trial?

The trial had a good distribution of patients who had already received ruxolitinib [45% in the control arm].In addition, some patients were followed up [monitoring; 19%]some were receiving hydroxyurea [19%], some had been given steroids and other drugs.Both medium and high risk were well spread [disease] Based on Dynamic International Prognostic Scoring System classification [approximately 70% and 30%, respectively]. The majority of patients in clinical trials had thrombocytopenia, with approximately 40% of patients having platelet counts below her 50,000/μL. These patients were evenly distributed between the twice-daily pacritinib and BAT groups.12 SVR had a 35% cutoff at week 24. Pacritinib 200 mg twice daily improved SVR compared with 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 overall symptoms [score and the individual symptom score]. These are the different measures we use in all myelofibrosis clinical trials. [These are] Based on MPN-SAF TSS.Pacritinib reduced symptom burden compared with BAT group [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

Transfusion burden is of great clinical importance.Pacritinib 200 mg twice daily improved 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].Also pacritinib [improved] Hemoglobin levels declined and, if not improved, stabilized the transfusion load.

What adverse events were observed in this trial?

The most important adverse event I would like to highlight is diarrhea. Although this was observed in his 48% of patients in the twice-daily dosing group, it was rarely grade 3 or greater. [4%]. If a patient experiences diarrhea, he responds very well to one dose of loperamide, at least in my practice. [Imodium]. If you give it a try and the patient continues to have diarrhea despite taking the medication, the dose should be reduced. However, clinical trials have rarely reduced doses.7,12

In addition, a significant proportion of patients had thrombocytopenia [34% for all grades; 32% for grade 3 or higher] and anemia [24% for all grades; 22% for grade 3 or higher]However, the majority of patients enrolled in clinical trials originally had thrombocytopenia and anemia. For example, if a patient had a platelet count of 56,000/μL at enrollment, but her platelet count dropped to 49,000/μL, we would know it was not clinically significant. However, in clinical trials it would be seen as grade 3 thrombocytopenia.


1.NCCN. Clinical Practice Guidelines in Oncology. Myeloproliferative neoplasms, version 3.2022. Accessed 10 March 2023.

2. FDA approves drug for adults with rare form of bone marrow disease. FDA. March 1, 2022. Accessed 11 March 2023.

3. Mascarenhas J, Hoffman R. Ruxolitinib: First FDA-approved therapy for myelofibrosis. clinical cancer treatment. 2012;18(11):3008-3014. Doi: 10.1158/1078-0432.CCR-11-3145

4. Jakafi. Prescribing Information. Insight. 2023. Accessed 11 March 2023.

5. FDA Approves Fedratinib for Myelofibrosis. FDA. August 16, 2019. Accessed 11 March 2023.

6. Inrevic. Prescribing Information. Bristol-Myers Squibb Company. 2022. Accessed 11 March 2023.

7. Vonjo. Prescribing Information. CTI Biopharma; 2022. Accessed 11 March 2023.

8. Mascarenhas JO, Talpas M, Gupta V, et al. Primary analysis of a phase II open-label study of the selective JAK1 inhibitor INCB039110 in patients with myelofibrosis. Haematologica. 2017;102(2):327-335. Doi:10.3324/haematol.2016.151126

9. Pardanani A, Lasho T, Smith G, Burns CJ, Fantino E, Tefferi A. Selective JAK1/JAK2 inhibitor CYT387: in vitro assessment of kinase selectivity and polycythemia vera patient-derived cell lines and primary cells. Preclinical studies using leukemia. 2009;23(8):1441-1445. Doi: 10.1038/leu.2009.50

10. Singer J, Al-Fayoumi S, Ma H, Komrokji RS, Mesa R, Verstovsek S. A non-myelosuppressive JAK2 kinase inhibitor in phase 3 development in primary and post-ET/PV myelofibrosis. Comprehensive Kinase Profile of a Pacritinib. blood. 2014;124(21):1874. doi:10.1182/blood.V124.21.1874.1874

11. Jarocha DJ, Gadue P, Tong W, Newton RC, Poncz M. Janus kinase (Jak) 1 inhibition affects both megakaryopoiesis and plateletogenesis. blood. 2018;132(suppl 1):2559. Doi: 10.1182/blood-2018-99-115407

12. Mascarenhas J, Hoffman R, Talpas M, et al. Best Available Therapies Including Pacritinib and Ruxolitinib in Patients With Myelofibrosis: A Randomized Clinical Trial. JAMA Ongol. 2018;4(5):652-659. Doi: 10.1001/jamaoncol.2017.5818

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