Roundtable Discussion: Ali and Participants Indicate How They Diagnose and Treat Myelofibrosis

Haris Ali, MD

Haris Ali, MD, associate clinical professor, Division of Leukemia, Department of Hematology & Hematopoietic Cell Transplantation at the City of Hope, discussed the diagnosis and treatment of myelofibrosis with a group of physicians during a Targeted Oncology^TM Case-Based Roundtable event.

ALI: Do you rely on hematopathology and/or do you use the diagnostic criteria to diagnose myelofibrosis?

SHAHIDI: The diagnosis is made by a hematopathologist who stains the [bone] marrow for fibrosis and [grades the findings on a scale of 0 to 3; a grade of ≥ 2 is the cutoff used] to diagnose myelofibrosis.1 Clinically, the presence of splenomegaly and hypercatabolic symptoms [are used to diagnose myelofibrosis].

ALI: So, basically, you use the World Health Organization criteria to diagnose myelofibrosis by relying on both [hematopathology findings] and clinical criteria?2

SHAHIDI: Yes.

ALI: What challenges do you face in making a diagnosis of myelofibrosis?

SHAHIDI: Most of the time [the diagnosis is] clear-cut, but sometimes it is not, [in which case we may make a diagnosis of prefibrotic myelofibrosis, although] I’m not familiar with how to treat that. But [usually the diagnosis of] myelofibrosis is straightforward.

BEHL: The main thing [in diagnosing myelofibrosis] is to determine whether it is primary myelofibrosis or secondary myelofibrosis evolving from a preexisting myeloproliferative condition, such as essential thrombocythemia [ET]. That’s where the challenge sometimes [arises], although it doesn’t make that much of a difference in management. Sometimes in JAK2-negative myelofibrosis, I order myeloid next-generation sequencing [NGS], and that tells me [whether the myeloproliferation] is a clonal process.

Sometimes [the diagnosis can be] confusing when the patient has other fibrotic conditions [that cause] proliferative conditions in the bone marrow. Sometimes, the pathologist’s report is also [ambiguous]; for example, when there is a bone marrow infiltration, such as granulomatous disease accompanied by a lot of fibrosis, [where the fibrosis is the result of] inflammation.

ALI: As you said, evidence of clonal disease and the presence of fibrosis [are cardinal] features of myelofibrosis and mutational analysis helps [to make the diagnosis].

In addition to testing for a JAK2 mutation, what other mutational analysis would you perform in your patients with myelofibrosis?

BEHL: We routinely [do molecular testing for] JAK2 V617F mutations with additional testing for MPL and CALR [if the JAK2 test is negative].1 Sometimes we’ll order a myeloid NGS if all these tests are negative.

AMBIKA: We must do [myeloid] NGS to calculate the [score for the MIPSS70 (Mutation-Enhanced International Prognostic Scoring System)].^3,4 I think NGS has become universal nowadays for risk assessment of myelofibrosis.

I’ve seen cases of Hodgkin [disease in which there is] a lot of bone marrow fibrosis. A few months ago, I had a patient with a lot of liver infiltration. [Repeated liver] biopsies were negative, but a bone marrow biopsy showed myelofibrosis. [The patient was diagnosed with Hodgkin disease], and he rapidly declined. So, some of these lymphomas can also cause myelofibrosis.

ALI: If [the results of] a mutation analysis and/or cytogenetics are available, we can assess the patient with the latest prognostic scores [using] the MIPSS-70 or the MIPSS- 70-Plus.3,5 If we just have clinical variables, we can use the [International Prognostic Scoring System (IPSS)], [the Dynamic IPSS (DIPSS)], or the DIPSS-Plus.^6-9

Given the multiple risk assessment tools for myelofibrosis, how do you choose among them?

SHAHIDI: All of them are equally good. As long as you use one of them, you’re OK.

AMBIKA: I use the MIPSS-70 because the website is very helpful. You just plug in the numbers [to determine the patient’s prognosis]; the website even provides information about the high-risk mutations, for example del(17q) mutations.⁴

ALI: Based on your experience, what are the survival outcomes for patients [categorized as having] low, intermediate, and high risk, and what percentage of your patients have high-risk disease?

SUPERFIN: I use most of these prognostic scores, but I usually use MIPSS-70. Usually around 20% of my patients have high-risk disease.

ALI: Which patients are at highest risk for transformation to AML?

SUPERFIN: I think patients with more blasts [in the bone marrow and peripheral blood] and patients who progress [to myelofibrosis] from polycythemia vera [PV] or from

ALI: What is the trigger to initiate therapy for a patient with myelofibrosis?

RASILA: I [would initiate therapy] if the patient had significant cytopenias, required blood transfusion, had symptomatic splenomegaly, or had any profound symptoms [such as] fatigue or symptoms [resulting from] abnormal blood counts.

ALI: What is the timing to start JAK inhibitor therapy, and how do you choose between [the 2 JAK inhibitors that are currently available]?

RASILA: I use ruxolitinib [Jakafi] because that’s what I’m used to; I have not used the other JAK inhibitor, fedratinib [Inrebic].

ALI: Do the nature and the burden of symptoms influence your decision to initiate therapy?

RASILA: Yes. First, I want to know whether the patient is a candidate for a bone marrow transplant. If the patient is not a candidate [for a transplant] and is symptomatic, [then I consider] treatment options. If the patient just has anemia and low erythropoietin, sometimes I will try growth factors such as danazol before I initiate ruxolitinib. But if the patient has a large spleen or constitutional symptoms, then I would start the patient on ruxolitinib.

ALI: How important is it to initiate therapy early?

RASILA: I think it’s reasonable to monitor patients [who are asymptomatic and have] low-risk or intermediate-1 disease, [based on a prognostic risk score], because you don’t want to commit someone to treatment if they don’t need it. But, if the patient is symptomatic and has intermediate-2 or high-risk disease, I would be more likely to initiate therapy.

ALI: When would you consider clinical trial enrollment for a patient?

RASILA: I think, if one is available, always.

AMBIKA: To be thorough and diligent about [monitoring] the severity of myelofibrosis symptoms you can use the MPN10 [symptom assessment] score.¹⁰

ALI: How would you monitor therapy in this patient?

ROBLES: Simple things like a complete blood count, symptom assessment, and physical exams make it simple to monitor patients [such as the one presented here].

ALI: What is the importance, in the long term, of controlling symptoms in patients [with myelofibrosis]?

ROBLES: For constitutional symptoms, the JAK2 inhibitors are great, but then you run into countervailing symptomatic anemia.

ALI: How do you use platelet counts [to guide decision-making about use of a] JAK inhibitor or any other treatment?

ROBLES: For ruxolitinib, the recommended starting dose is based on the platelet count. [Findings from the] EXPAND study [NCT01317875] demonstrated that you can try to escalate the dose; [for example], patients with very low platelet counts [50-74 × 10⁹/L] [can start at a dose as high as 10 mg twice daily].11 But in patients with low platelet counts, my experience has been that you’re balancing dose, symptom response, spleen response, platelet count, and anemia all at once.

FANG: I had a patient with long-standing PV, and biopsy findings showed that he had progressed to myelofibrosis. The patient had thrombocytopenia and had been treated with ruxolitinib for about 18 months. His white blood cell count gradually rose to about 100 × 10⁹/L, and his platelet count fell to about 40 × 10⁹/L. We thought he [might have] progressed to acute leukemia, so we did a bone marrow biopsy [and found] he still had myelofibrosis.

We switched this patient to the second-generation JAK inhibitor, fedratinib, and his [leukocytosis improved and] thrombocytopenia resolved with treatment. If the thrombocytopenia is from a disease, you should treat with a tyrosine kinase inhibitor.

ALI: That’s very good. Has anyone else seen a similar response in a patient after [switching from ruxolitinib to] fedratinib?

AMBIKA: Not really. [Dr Fang,] in this patient, did the spleen shrink [a lot and did] that help with the platelet [count]?

FANG: No. We used ultrasound to measure his spleen, [and found that sometimes it was larger], sometimes smaller. So, it’s difficult to say it was shrinking, [but] the main thing [is that the patient’s platelet count] improved; he got better.

ALI: How do age and frailty factor into [your decision-making for] treatment?

FANG: I treated a patient who was 72 years old and not high functioning, and he tolerated the medication [well]. So, I wouldn’t [withhold treatment just because the patient is elderly].

ALI: Agreed. Some patients look weak and have a poor performance status, [but this] may just be the effect of the myelofibrosis. If you treat the [myelofibrosis], their performance status might improve, [sometimes so much so] that they become a candidate for transplant.

_References:

_{1. NCCN. Clinical Practice Guidelines in Oncology. Myeloproliferative neoplasms,
version 1.2021. Accessed July 15, 2021. https://bit.ly/2Wcczfa}

_{2. Swerdlow SH, Camp E, Harris NL, et al, eds. WHO classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. International Agency for Research on Cancer; 2017.}

_{3. Guglielmelli P, Lasho TL, Rotunno G, et al. MIPSS70: Mutation-Enhanced International Prognostic Score System for transplantation-age patients with primary myelofibrosis. J Clin Oncol. 2018;36(4):310-318. doi:10.1200/JCO.2017.76.4886}

_{4. MIPSS70 Score. Accessed July 15, 2021. https://bit.ly/2W1vlcg}

_{5. Tefferi A, Guglielmelli P, Lasho TL, et al. MIPSS70+ version 2.0: Mutation and Karyotype-Enhanced International Prognostic Scoring System for Primary Myelofibrosis. J Clin Oncol. 2018;36(17):1769-1770. doi:10.1200/JCO.2018.78.9867}

_{6. Bose P, Verstovsek S. The evolution and clinical relevance of prognostic classification systems in myelofibrosis. Cancer. 2016;122(5):681-692. doi:10.1002/ cncr.29842}

_{7. Cervantes F, Dupriez B, Pereira A, et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood. 2009;113(13):2895-2901. doi:10.1182/blood-2008-07-170449}

_{8. Passamonti F, Cervantes F, Vannucchi AM, et al. A dynamic prognostic model to predict survival in primary myelofibrosis: a study by the IWG-MRT (International Working Group for Myeloproliferative Neoplasms Research and Treatment). Blood. 2010;115(9):1703-1708. doi:10.1182/blood-2009-09-245837}

_{9. Gangat N, Caramazza D, Vaidya R, et al. DIPSS plus: a refined Dynamic International Prognostic Scoring System for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status. J Clin Oncol. 2011;29(4):392-397. doi:10.1200/JCO.2010.32.2446}

_{10. Mesa R, Miller CB, Thyne M, et al. Myeloproliferative neoplasms (MPNs) have a significant impact on patients’ overall health and productivity: the MPN Landmark survey. BMC Cancer. 2016;16:167. doi:10.1186/s12885-016-2208-2}

_{11. Vannucchi AM, Te Boekhorst PAW, Harrison CN, et al. EXPAND, a dose-finding study of ruxolitinib in patients with myelofibrosis and low platelet counts: 48-week follow-up analysis. Haematologica. 2019;104(5):947-954. doi:10.3324/ haematol.2018.204602}