Integrating Prognostic Risk Score into the Diagnosis and Treatment of Patients With MPNs

Aaron T. Gerds, MD, MS

For decades, the understanding behind the molecular markers and their ability to aid in the diagnosis and treatment of myeloproliferative neoplasms (MPNs) has grown. A more novel area of research, however, is how mutational status can be prognostic of outcomes in these patients.

During the NCCN 2021 Congress: Hematologic Malignancies, Aaron T. Gerds, MD, MS, assistant professor, Department of Medicine, and School of Medicine member, Developmental Therapeutics Program, Case Comprehensive Cancer Center, explained the risk stratification tools used in patients with MPNs, and how studies have shown that using certain molecular markers as stratification factors can predict overall survival (OS), and leukemia-free survival (LFS). Gerds’ focus was 5 parameter systems, including the widely used Dynamic International Prognostic Scoring System (DIPSS).¹

“Historically we use clinical factors readily available to understand an individual's prognosis. The international prognostic scoring system or the IPSS used age, constitutional symptoms, and blood counts to determine prognosis, things that are readily available, and likewise the DIPSS did the same thing. And the DIPSS being dynamic, meaning you could use it at any time during the disease course, this is really helpful because we always know what a patient's age is, we can ask them what their constitutional symptoms are, and they're getting regular blood draws, so we can use DIPSS anytime and it's still a very valuable tool, said Gerds, during his presentation. “But we know if we add in mutation analysis, such as calreticulin mutation status and other high-risk mutations, we can improve our ability to predict what may happen to that patient in the future.”

The International Working Group for Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) introduced DIPSS in 2010 as a dynamic prognostic model that can be used for the prediction of survival in patients with myelofibrosis (MF).²

DIPSS

Point allocation in the DIPSS parameter range from 0 to 2. These points are combined to determine an overall risk score. Looking at age, patients ≤ 65 years of age have a score of 0 and those > 65 years had a score of 1. If constitutional symptoms are absent in a patient, the DIPSS is 0, and if present, it is 1. Patients with anemia ≥ 10 g/dL have a DIPSS of 0 and those with anemia < 10 g/dL have a DIPSS of 2. Those who have leukocytosis are score at DIPSS of 0 if their condition is ≤ 25 10⁹/L, and scored at a 1 if the leukocytosis is > 25 10⁹/L. Finally, those with circulating blasts < 1% have a DIPSS of 0, and those with circulating blasts ≥ 1% had a DIPSS of 1.¹

Patients with 0 DIPSS points are considered low risk, with 1 to 2 points, patients are intermediate-1 risk, 3 to 4 points is an intermediate-2 risk, and 5 to 6 points is high-risk disease. Based on the initial study by the IWG-MRT, survival among the 4 risk groups was significantly different (P < .001).

The study included 525 patients with MF who were followed for a median of 3.3 years (range, 0.6-24). Forty-nine percent of patients were younger than 65 years of age, 27% had constitutional symptoms, 36% were anemic with a lower than 10 g/dL, and 27% had peripheral blast cells greater than 1%.²

The median anemia-free survival was 7.6 years in the overall population, but observing the results based on risk factors, patients were more likely to be anemic if they had advanced age (P =.014), higher leukocyte count (P =.019), and lower hemoglobin level (P <.001).

The cumulative incidence of leukocytosis was 21.6% at the 15-year mark. Results showed that advanced age (P = .032) and higher leukocyte count (P < .001) were independent prognostic factors for the development of leukocytosis. Also at 15 years, the cumulative incidence of blast excess was 38.7%, and higher leukocyte count (P = .01) and lower platelet count (P = .01) were identified as independent prognostic indicators. Finally, constitutional symptoms had a 22.2% cumulative incidence at 15 years, and age (P = .03) was an independent prognostic factor associated with constitutional symptoms.

The proposed risk factors were used as time-dependent covariates, and the analysis showed that all variables including age (HR, 2.6; 95% CI, 2.04-3.45; P <. 001), peripheral blood blasts (HR, 3.55; 95% CI, 2.77-4.56; P < .001), and constitutional symptoms (HR, 3.03; 95% CI, 2.60-4.20; P < .001), and hemoglobin (HR, 6.74; 95% CI: 4.93-9.21; P < .001) retained statistical significance on survival.

“This tool, even though it doesn't include mutations is still very valuable and does a pretty good job separating out patients,” Gerds stated.

In addition to these prognostic indicators, karyotype, namely JAK-STAT pathway activating mutation found in all MPNs was considered to be prognostic of survival, and therefore was added in a parameter known as DISPSS-Plus.¹

DIPSS-Plus

The JAK/STAT activating mutations include JAK2 V617F, JAK2 Exon 12, MPL, and CALR. JAK/MPL/CALR unmutated karyotype is also found in the JAK/STAT pathway. Research shows that CALR exon 9, JAK2 V617F, and MPL exon 10 mutations impact survival outcomes in patients with polycythemia vera (PV), essential thrombocytopenia (ET), and MF.³

Gerds said: “JAK/STAT activating mutations are not the end of the story. There are lots of other mutations that we observe in this disease often. You might recognize some of the mutations, such as IDH1 and IDH2 from other diseases like acute myeloid leukemia because these are not only important for prognosis, but we now have therapeutics targeted against this. So, the role of mutations is only increasing over time for diagnosis, prognosis, and perhaps treatment in the future.”

Gerds further explained that factoring mutation into prognosticating survival in patients with MPNs has become so important that there has been a shift toward using more in-depth prognostication parameters like MIPSS70.

MIPSS70

“Models like the MIPS70 have come to the forefront of determining prognosis in patients. So, MIPS 0 is a model that includes molecular markers in patients with myelofibrosis under the age of 70. And in addition to blood counts and constitutional symptoms and things that we often use in other models,” explained Gerds.

In addition to the 4 indicators seen in DIPSS, the MIPSS70 parameter looks at bone marrow fibrosis grade of < MF‐2 for low-risk patients ≥ MF‐2 for intermediate-risk patients, and whether or not patients have a CALR type 1/like mutation, high‐molecular risk (HMR) mutations, and ≥ 2 HMR mutations.

In a study of 805 patients with primary MF age ≤ 70 years, use of the MIPSS70 or the MIPSS70-Plus, which includes karyotype, determined that hemoglobin < 100 g/L, leukocytes > 25 × 10⁹/L, platelets < 100 × 10⁹/L, circulating blasts ≥ 2%, bone marrow fibrosis grade ≥ 2, constitutional symptoms, absence of CALR type-1 mutation, presence of high–molecular risk mutation were all predictive of overall survival (OS).

Combining the risk factors into categories of low- to high-risk disease with MIPSS70, the study showed that at 5 years, the OS rate was 95% in the low-risk population, 70% in the intermediate-risk population, and only 29% in the high-risk population. The median OS among patients with low-risk primary MF was 27.7 years (95% CI, 22-34). In the intermediate-risk population, the median OS was 7.1 years (95% CI, 6.2-8.1), and in the high-risk group, the median OS was 2.3 years (95% CI, 1.9-2.7).

When investigators utilized the MIPSS70-Plus parameter to assess the same risk factors, the OD at 5 years was 91% for low-risk patients, 66% for those with intermediate-risk, and 42% for those with high-risk primary MF. In the very high-risk category, the 5-year OS was a mere 7%.⁴

Since showing the ability to offer prognostic information in primary MF, MIPSS is in the process of being integrated into prognosticating patients with PV and ET.¹

MIPSS-PV and MIPSS-ET

SRSF2 mutations in patients with PV have been shown to negatively impact survival outcomes, according to a study of 906 molecularly annotated patients, 404 of whom were diagnosed with PV. Further, SRSF2, SF3B1, U2AF1, or TP53 mutations are indicative of poor survival outcomes in patients with ET, according to the same study.⁵

Among the patients with PV in the study, the risk factors determined to be prognostic for poorer survival were having adverse mutations (HR, 7.8, 95% CI, 3.1-17.0), being aged > 67 years (HR, 5.4; 95% CI, 3.6-8.1), having leukocytosis ≥ 15 × 10^9/l (HR, 2.8, 95% CI, 1.8-4.2) and having a history of thrombosis (HR, 2.0, 95% CI, 1.4-2.9).

In the ET population, the risk factors determined to be prognostic for poorer survival were having adverse mutations (HR 2.4; 95% CI, 1.6-3.5), being aged >60 years (HR, 6.6, 95% CI, 4.6-9.7), being male (HR, 1.8; 95% CI, 1.3-2.4), and having leukocytosis ≥ 11 × 10⁹/l (HR, 1.7, 95% CI, 1.1-2.2).

“These 2 models have been proposed and are in the process of being validated and hopefully will have validation in the near future, and we will be able to use them more readily in the clinic, but again mutation analysis is important for PV and ET when determining prognosis,” said Gerds.¹

Investigators continue to identify prognostic indicators of survival in patients with MPNs. The novel MIPSS70+ v2.0 and MYSEC‐PM are being evaluated as prognostic tools for survival and long-term survival.^6,7

_REFERENCES:

_{1. Gerd AT. Mutational landscape in myeloproliferative neoplasms: implications on prognosis and clinical management. Presented at: NCCN 2021Virtual Congress: Hematologic Maligancies; October 14-16, 2021.}

_{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. Grinfeld J, Nangalia J, Baxter J, et al. Classification and personalized prognosis in myeloproliferative neoplasms. N Engl J Med. 2018;379(15):1416-1430. doi: 10.1056/NEJMoa1716614.}

_{4. Gugliemelli 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}

_{5. Tefferri A, Gugliemelli P, Lasho TL, et al. Mutation-enhanced international prognostic systems for essential thrombocythaemia and polycythaemia vera. Br J Haemtol. 2020;189(2):291-302. doi: 10.1111/bjh.16380}

_{6. Ali H, Aldoss I, Yang D, et al. MIPSS70+ v2.0 predicts long-term survival in myelofibrosis after allogeneic HCT with the Flu/Mel conditioning regimen. Blood Adv. 2019;3(1): 83-95. doi: 10.1182/bloodadvances.2018026658}

_{7. Passamonti F, Giorgno T, Vannucchi AM, 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.}