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 tests showed a JAK2 V617F mutation. A bone marrow biopsy showed megakaryocyte proliferation and atypia with evidence of reticulin fibrosis. Blood smear revealed leukoerythroblastosis.
- Given the multiple risk assessment tools for myelofibrosis (MF), how do you choose between them?
- In 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] choose International Dynamic Forecast Scoring System [DIPSS] for one patient but some other tool for another patient?
KHALEEL K. ASHRAF, MD, MBBS, DMRD: I have been using the DIPSS Plus. It helps us decide when [send] patients to transplant referral centers and so on, and also when to start treatment.
In community practice, this is not a very common disease. you keep one [risk-assessment tool]. I don’t use all of them. I have not used Mutation-Enhanced [International Prognostic Scoring System in Adults 70 and Younger (MIPSS70)], though I’m sure it should have its place. I have been using DIPSS Plus for a long time.
KEVIN M. GALLAGHER, MD: I use the DIPSS Plus [because] this is what I’ve used historically, so I’m comfortable with that. I follow 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 scheme was the first scheme to emerge in modern times. The IPSS incorporates 5 different items: age, hemoglobin level, white blood cell count, peripheral blood blast count, and constitutional symptoms.1
I no longer use IPSS. 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 there are better risk stratification schemes you could use. This brings us to DIPSS.two
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 scores 2 points on the DIPSS and only 1 on the IPSS. [Additionally,] the D in DIPSS, which stands for “dynamic,” means you can use this risk stratification scheme at any time [during] a patient’s journey.two
The DIPSS Plus includes 3 additional things. [This schema] incorporates karyotype information. It also gives additional weight to anemia; [not only does] anemia in the risk calculation, but also, if the patient is transfusion dependent, they get an extra point. [Finally,] with DIPSS Plus, a platelet count of less than 100 × 109/L is recognized as a prognostic factor.3
[There are some circumstances in which] I wouldn’t use the DIPSS Plus. If you don’t have the karyotype information for some reason, if a previous doctor saw the patient and the bone marrow [biopsy] was never done, or [if the biopsy] was done, but could not obtain the karyotype information: DIPSS Plus was not [very] Useful. In those scenarios, DIPSS would be the best thing to use.
[For patients stratified according to the DIPSS, an analysis showed] the median survival of low-risk patients [was not reached]. Median survival for intermediate-risk 1 patients was approximately 14 years, and median survival for intermediate-risk 2 patients was approximately 4 years. The median survival of high-risk patients, which was the worst, was 1.5 years.two
All of these schemes were performed for patients who had primary MF. If your patient has secondary MF, one of these schedules might be used. We did it for a long time, and we still do it. [occasionally]. But there is another risk stratification scheme: MF Secondary to PV and Essential Thrombocythemia [ET]–Prognostic model [MYSEC-PM]that 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] schemes, which incorporate some additional molecular results such as U2AF1 Y ASXL1.5-7
In routine practice, if you don’t see many different MF patients and have to choose just one [schema] that could be applied to almost all patients without knowing the patient’s karyotype or genetic mutation profile beyond JAK2, MPLY HEAT, perhaps the only scheme to remember would be DIPSS. The key here is that we must risk stratifying each patient if possible.
- What is the trigger to start therapy for a patient with MF?
- When is the time to start Janus kinase (JAK) inhibitor therapy and how to choose?
- How does the nature and burden of symptoms influence your decision to start JAK inhibitor therapy?
- How important is it to start therapy early?
- When do you consider enrolling in a clinical trial?
Dr. JOSE L. MENDOZA: Typically, these MF patients are symptomatic and need a diagnosis in order to treat the symptoms. I would say that as soon as I have a diagnosis, if the patient is symptomatic [with] splenomegaly, cytopenias, or both, which is an indication to initiate therapy in most cases.
ASHRAF: I agree. Most patients, when I see them, have symptoms, and JAK inhibition rapidly improves their symptoms.
VACHHANI: There is someone who [uses a JAK inhibitor] for patients whose risk status is high or intermediate-2 but not intermediate-1? He does that [factor into your decision]or is it [your decision based] purely on the symptoms and the spleen?
DAVID YOUNG KAHN, MD: Often, if the patient has splenomegaly, I like to start JAK inhibitor therapy. As for what to choose, [although] I hate to say it, it often depends on cost, insurance, and what is on the patient’s formulary.
MENDOZA: my answer was general [one] but it was applicable to higher risk patients. But in the lowest risk situation, you are more likely to [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 problems such as cytopenias or organomegaly. If a low-risk patient develops high-volume disease, I still treat them, but treatment [might] be a little different. [In this situation,] I think I might have an opportunity to try treatments that I wouldn’t use in a higher risk population.
VACHHANI: The fundamental studies that led to the approval [of JAK inhibitor therapy] were performed with intermediate-2 and high-risk patients, although there are also data for intermediate-1 risk patients.8 In fact, recent data has shown that patients starting [on treatment] earlier led to better results.9
- Have you used fedratinib (Inrebic)? If so, what line have you used it on?
- How does it compare to your use of ruxolitinib (Jakafi)?
CANDICE BALDEO, MD: I have not had the chance [to use] fedratinib yet. My patients have done well with ruxolitinib.
VACHHANI: Is there a reason you wouldn’t use fedratinib? Something is bothering you?
Washdown: I think the risk of encephalopathy scares my patients.
QUILLAN HUANG, MD: I have not [used fedratinib]. I have seen my colleagues use it in second-line settings after the ruxolitinib failure.
VACHHANI: Is it because you just haven’t [found yourself in] that scenario, or is there some other reason?
HUANG: I think fedratinib is a very reasonable second line option. I just haven’t had that situation yet.
VACHHANI: Personally, I restrict the use of fedratinib to the second-line setting or more if I can’t get someone to participate in a clinical trial.
1. Cervantes F, Dupriez B, Pereira A, et al. New prognostic scoring system for primary myelofibrosis based on a study by the International Task Force for Research and Treatment of Myelofibrosis. 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 for predicting survival in primary myelofibrosis: an IWG-MRT (International Working Group for Research and Treatment of Myeloproliferative Neoplasms) study. 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 Scoring System for Transplant-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: Karyotype and Mutation 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 patients with IPSS intermediate-1 risk myelofibrosis: results of an independent study. Hematol Oncol. 2018;36(1):285-290. doi:10.1002/hon.2429