Risk Assessment and Treatment Approaches for Myelofibrosis

Pankit Vachhani, MD (Moderator)

Assistant Professor

Department of Medicine

Hematologist/Oncologist

O’Neal Comprehensive Cancer Center

University of Alabama at Birmingham

Birmingham, AL

CASE SUMMARY

A 68-year-old woman presented to her physician with symptoms of fatigue and abdominal pain lasting 4 months. She also reported increased bruising and unexplained weight loss. Her spleen was palpable 8 cm below the left costal margin. Genetic testing showed a JAK2 V617F mutation. A bone marrow biopsy showed megakaryocyte proliferation and atypia with evidence of reticulin fibrosis. Blood smear revealed leukoerythroblastosis.

DISCUSSION QUESTIONS

• Given the multiple risk-assessment tools for myelofibrosis (MF), how do you choose between them?
• Based on your experience, what are the survival outcomes for patients with low-, intermediate-, and high-risk disease?
  • What percentage of your patients are high risk?

PANKIT VACHHANI, MD: [Would you] pick the Dynamic International Prognostic Scoring System [DIPSS] for one patient but some other tool for another patient?

KHALEEL K. ASHRAF, MD, MBBS, DMRD: I’ve been using the DIPSS Plus. It helps us decide when to [send] patients to referral centers for transplant and so on and also when to start treatment.

In community practice, this is not a very common disease. You stick with one [risk-assessment tool]. I don’t use all of them. I have not used the Mutation-Enhanced [International Prognostic Scoring System in Adults 70 and Younger (MIPSS70)], even though I’m sure it must have its place. I have been using DIPSS Plus for a good while.

KEVIN M. GALLAGHER, MD: I use the DIPSS Plus [because] this is what I have used historically, so I'm comfortable with it. I stick with the same method for each patient. [As to] the question of how [often the patients are] high risk, the numbers are very small, maybe 1 per year.

VACHHANI: The IPSS risk-stratification schema was the first schema that came out in modern times. The IPSS incorporates 5 different points: age, hemoglobin level, white blood cell count, peripheral blood blast count, and constitutional symptoms.¹

I don't use IPSS anymore. That system was only supposed to be used at the time of diagnosis. I don’t think it’s wrong to use it, but I think that there are better risk-stratification schemas that you could use. This brings us to the DIPSS.²

The difference [between DIPSS and IPSS] is that with DIPSS, more weight is given to anemia.^1,2 For example, a hemoglobin level of less than 10 g/dL gets 2 points with the DIPSS and only 1 with the IPSS. [Additionally,] the D in DIPSS, which stands for “dynamic,” means that you can use this risk-stratification schema at any time [during] a patient’s journey.²

The DIPSS Plus includes 3 additional things. [This schema] incorporates karyotype information. It also gives additional weight to anemia; [not only does] anemia feature in the risk calculation, but also, if the patient is transfusion dependent, they get an extra point. [Finally,] with the DIPSS Plus, a platelet count of less than 100 × 10⁹/L is recognized as a prognostic factor.³

[There are some circumstances in which] you would not use the DIPSS Plus. If you don't have the karyotype information for some reason—if a prior physician saw the patient and bone marrow [biopsy] was never done, or [if the biopsy] was done, but you couldn’t get the karyotype information—DIPSS Plus won’t be [very] helpful. In those scenarios, DIPSS would be the better thing to use.

[For patients stratified according to the DIPSS, an analysis showed] the median survival of low-risk patients [was not reached]. The median survival of intermediate-1–risk patients was approximately 14 years, and the median survival of intermediate-2–risk patients was approximately 4 years. The high-risk patients’ median survival, which was the worst, was 1.5 years.²

All these schemas were made for patients who had primary MF. If your patient has secondary MF, you could use one of these schemas. We did it for a long time, and we still do it [occasionally]. But there is another risk-stratification schema: the MF Secondary to PV and Essential Thrombocythemia [ET]–Prognostic Model [MYSEC-PM], which was made specifically for those patients.⁴

According to the latest version of the National Comprehensive Cancer Network guidelines, if you have a patient with primary MF, [the preferred options are] the MIPSS70 or MIPSS70 Plus [version 2.0] schemas, which incorporate some additional molecular results like U2AF1 and ASXL1.^5-7 

In routine practice, if you were not seeing many different patients with MF and you had to pick just one [schema] that could be applied to almost every patient without knowing the patient’s karyotype or genetic mutation profile beyond JAK2, MPL, and CALR, maybe the single schema to remember would be DIPSS. The key here is that we should risk stratify every patient if possible.

DISCUSSION QUESTIONS

• What is the trigger to initiate therapy for a patient with MF?
  • What is the timing to start Janus kinase (JAK) inhibitor therapy, and how do you choose?
  • How does the nature and burden of symptoms influence your decision to initiate JAK inhibitor therapy?
• How important is it to initiate therapy early?
• When do you consider clinical trial enrollment?

JOSÉ L. MENDOZA, MD: Typically, these patients with MF are symptomatic, and they need a diagnosis in order to be able to treat the symptoms. I would say that as soon as you have a diagnosis, if the patient is symptomatic [with] splenomegaly, cytopenias, or both, that is an indication to initiate therapy in most cases.

ASHRAF: I agree. Most patients, by the time I see them, have symptoms, and JAK inhibition quickly improves their symptoms.

VACHHANI: Is there anyone who [uses a JAK inhibitor] for patients whose risk status is high or intermediate-2 but not intermediate-1? Does that [factor into your decision], or is [your decision based] purely on symptoms and spleen?

DAVID YOUNG KAHN, MD: Often if the patient has splenomegaly, I like to start JAK inhibitor therapy. In terms of what to choose, [although] I hate to say it, it often depends on cost, insurance, and what’s on the patient’s formulary.

MENDOZA: My response was a general [one] but was applicable to higher-risk patients. But in the lower-risk situation, it’s more likely that you [will find yourself diagnosing] an asymptomatic patient, [so] you will have more time to plan your strategy. I would probably wait [to treat] unless there were issues like cytopenias or organomegaly. If a low-risk patient does develop high-bulk disease, I still treat, but the treatment [might] be a little different. [In this situation,] I think you might have a chance to try treatments that you wouldn’t use in a higher-risk population.

VACHHANI: The pivotal studies that led to the approval [of JAK inhibitor therapy] were done with intermediate-2 and high-risk patients, although there are data for intermediate-1–risk patients as well.⁸ In fact, recent data have shown that starting patients [on treatment] earlier led to better outcomes.⁹

DISCUSSION QUESTIONS

• Have you used fedratinib (Inrebic)? If so, what line have you used it in?
• How does it compare with your use of ruxolitinib (Jakafi)?

CANDICE BALDEO, MD: I haven’t had the chance [to use] fedratinib yet. My patients have been doing well on ruxolitinib.

VACHHANI: Is there a reason that you would not use fedratinib? Does anything concern you?

BALDEO: I think the risk of encephalopathy scares my patients.

QUILLAN HUANG, MD: I haven’t [used fedratinib]. I’ve seen my colleagues use it in the second-line setting after ruxolitinib failure.

VACHHANI: Is that because you just haven’t [found yourself in] that scenario, or is there any other reason?

HUANG: I think fedratinib is a very reasonable choice in the second line. I just haven’t had that situation yet.

VACHHANI: Personally, I restrict fedratinib use to the second-line setting or beyond if I cannot get someone on a clinical trial.

_REFERENCES

_{1. 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}

_{2. 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}

_{3. Gangat N, Caramazza D, Vaidya R, et al. DIPSS plus: a refined DynamicInternational 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}

_{4. Passamonti F, Giorgino T, Mora B, et al. A clinical-molecular prognostic model to predict survival in patients with post polycythemia vera and post essential thrombocythemia myelofibrosis. Leukemia. 2017;31(12):2726-2731. doi:10.1038/leu.2017.169}

_{5. NCCN. Clinical Practice Guidelines in Oncology. Myeloproliferative neoplasms, version 3.2022. Accessed September 13, 2022.https://bit.ly/2E77tIB}

_{6. 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}

_{7. 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}

_{8. Mascarenhas J, Hoffman R. Ruxolitinib: the first FDA approved therapy for the treatment of myelofibrosis. Clin Cancer Res. 2012;18(11):3008-3014. doi:10.1158/1078-0432.CCR-11-3145}

_{9. Palandri F, Tiribelli M, Benevolo G, et al. Efficacy and safety of ruxolitinib in intermediate-1 IPSS risk myelofibrosis patients: results from an independent study. Hematol Oncol. 2018;36(1):285-290. doi:10.1002/hon.2429}