JAK Inhibition for the Management of Primary Myelofibrosis - Episode 2

Prognostic Classification Systems in Myelofibrosis

Rami S. Komrokji, MD:After establishing the diagnosis, the most important step is risk stratification for patients. The risk stratification helps establish 2 goals. One is to provide a prognosis for the patient and their family. The second is really to tailor therapy based on the risk of the disease.

Most of the time we are thinking of allogeneic stem cell transplant, especially in younger patients, because it’s the only curative option. However, the procedure itself is risky. It is associated with mortality and morbidity. One weighs the benefit and the risk of the procedure. So the disease risk has to be high enough to justify a risky procedure.

There are several scoring systems used for myelofibrosis that evolved over time. The original IPSS, international prognostic scoring system, weighs mostly on clinical variables such as age of the patient, presence of constitutional symptoms, leukocytosis, anemia, and presence of circulating blasts. The patients are staged into 4 groups, from low to high risk, and survival could vary from more than 10 years, or less than 2 years.

This has evolved further. There is a model called dynamic IPSS [DIPSS], where we weigh a little bit more on the importance of the anemia because anemia is one of the most important clinical prognostic factors in myelofibrosis. This has evolved further to where we consider other factors such as thrombocytopenia. There’s DIPSS-plus. That also accounts for the thrombocytopenia as well as the karyotype.

More recently we started incorporating molecular data as we have learned about somatic mutations and acquisition in myeloproliferative diseases. So we look at the presence ofJAK2, calreticulin,MPLmutations. The absence of those mutations, which we call triple-negative disease, actually carries a worse outcome. So there are new models that are based on the molecular data. There is the GIPSS, the genetically inspired prognostic scoring system, that’s mainly based on molecular data; and there is the MIPSS70 [mutation-enhanced international prognostic scoring system for transplant-age patients] and MIPSS70-plus, which is a newer version of MIPSS70. Those are a combination of clinical variables as well as molecular variables.

The MIPSS70, particularly, was developed to really assess the patients going to transplant. The purpose of it to risk stratify patients below an age of 70 takes out the age component, so the decision to proceed to transplant is based on the disease risk itself. We still weigh on the clinical variables such as anemia, thrombocytopenia, presence of circulating blasts, constitutional symptoms. We account for the fibrosis in the bone marrow, but then we incorporate the molecular data. There are certain mutations we identify as high-risk mutations, such as presence of anASXL1mutation,SRSF2mutation,EZH2orIDHmutation, and more recently added to that, aU2AF1Q157 mutation.

Then also, the cytogenetics are refined. They are a little bit different from the original DIPSS-plus, where we put patients into a very high-risk cytogenetic group, or unfavorable risk group.

Based on the scoring, it’s a sum score of those variables where we assign the patient into a group—typically 1 out of 4 groups. Again, patients with a low-risk disease have a median survival of typically more than 10 years. For patients with high-risk disease, the median survival is 1 to 2 years.

So really, there are several systems. I think one should become familiar with 1 or 2 and use those. But the idea is really looking at clinical variables, molecular data, and cytogenetics when trying to estimate the risk of the disease. There are cases where there is some discrepancy between those models, and it seems that the genetically inspired model, or the MIPPS70, predicts better outcomes for patients.

Transcript edited for clarity.

Case: 66-Year-Old Man Diagnosed With Primary Myelofibrosis

January 2019

  • A 66-year old man presents to primary care physician with complaints of fatigue, headache, and abdominal discomfort when taking deep breaths
  • PMH: depression
  • PE: Splenomegaly ~7 cm below left costal margin
  • Lab values:
    • HGB: 9.2 g/dL
    • Platelets: 242 x 109/L
    • WBC: 26.2 x 109/L
    • Serum LDH: 1400 U/L
    • Serum EPO: 10.9 mU/mL
  • Bone Marrow Biopsy:
    • MF-3
    • Circulating blasts, 1.1%
    • JAK V617Fmutation; trisomy 8
  • Peripheral Blood Smear: leukoerythroblastosis
  • Diagnosis: Primary myelofibrosis