Oncology

Myelofibrosis

Advertisment

Initial Evaluation and Overall Approach to the Management of Myelofibrosis

expert roundtables by John Mascarenhas, MD; Raajit K. Rampal, MD, PhD; Michael Savona, MD
Overview

There are many illnesses that overlap with myelofibrosis, and the presentation is variable. Therefore, a thorough evaluation based on disease and patient characteristics is important to establish the diagnosis and to accurately determine an individual patient’s risk stratification.

QUESTION:
How would you summarize key aspects of the diagnosis and evaluation of myelofibrosis, and how does your initial workup inform your treatment plan?
“. . . there are nuances in the diagnosis of myelofibrosis using bone marrow histopathology, and it really does require expert hematopathology review to distinguish myelofibrosis from other diagnoses. . . . Another component that is integral to the diagnostic process is genomic profiling with next-generation sequencing. . . . profiling a patient's mutational status is important from both a prognostic and a therapeutic standpoint.”
— John Mascarenhas, MD

The diagnosis of myelofibrosis is one that requires bone marrow histopathologic confirmation. Sometimes I see misdiagnosis occur when a biopsy is done and read by an outside hematopathologist. There is a long list of illnesses, both malignant and nonmalignant, that can be associated with bone marrow fibrosis and reactive processes, and, because there are overlapping syndromes, sometimes you may see an incorrect diagnosis. For example, there may be patients who do have myelofibrosis but had been previously misdiagnosed with polycythemia vera or even essential thrombocythemia. And then there may be patients with myelofibrosis who, by the time a diagnosis is accurately made, are already in progression to an accelerated or even blast phase disease. So, there are nuances in the diagnosis of myelofibrosis using bone marrow histopathology, and it really does require expert hematopathology review to distinguish myelofibrosis from other diagnoses.

 

Another component that is integral to the diagnostic process is genomic profiling with next-generation sequencing. Beyond identifying the oncogenic driver mutation, which includes JAK2, MPL, or CALR, we can look at other mutations that can provide prognostic information that may be informative for patient risk modeling or treatment decisions. For example, identifying IDH2 mutations, which do not occur at a very high frequency but can occur in both chronic and blast phase disease, may be beneficial because patients with these mutations can be treated with IDH inhibitors in combination with other therapies. Thus, profiling a patient’s mutational status is important from both a prognostic and a therapeutic standpoint. It can help you rule out other potential conditions, and it allows the application of risk stratification to optimize a risk-adapted therapeutic approach.

“It is important to assess the patient’s symptom burden and how those symptoms can impact their risk stratification. This information can be obtained through a careful history and through the use of validated instruments. . . . In addition, it is important to assess the patient’s blood counts because the prognoses for patients with low blood counts and for those with high blood counts may be very different.”
— Raajit K. Rampal, MD, PhD

Once we get the diagnosis of myelofibrosis from histopathology, we then have to think about how to stratify patients by their risk level. Molecular genetic testing is becoming increasingly important in risk stratification, and it certainly does have a prognostic value in most settings, although there is still more to be learned in this field. In addition, cytogenetic testing, which should be performed on a bone marrow sample, also continues to play an important role in determining a more accurate patient prognosis.

 

In addition, understanding patient-centered factors is important for determining the prognosis for a patient with myelofibrosis. It is important to assess the patient’s symptom burden and how those symptoms can impact their risk stratification. This information can be obtained through a careful history and through the use of validated instruments such as the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score. In addition, it is important to assess the patient’s blood counts because the prognoses for patients with low blood counts and for those with high blood counts may be very different. For example, knowing whether the patient has anemia or thrombocytopenia and whether the patient has progressed to needing red blood cell transfusions can factor into their prognosis. All of these individual assessments are important adjuncts to the use of molecular genetics and bone marrow histopathology in assessing a patient’s prognosis.

“. . .we want to treat people and intervene where we can to prevent disease progression, especially when we know that they have high-risk features or a limited time period in which they qualify for a given therapy, such as stem cell transplant. However, since patients in the prodromal phase may have a fairly good quality of life for an extended period, we may be hesitant to expose them to the risks that are associated with transplant, including increased risks of morbidity and mortality.”
— Michael Savona, MD

Whether and when to take a patient with myelofibrosis to stem cell transplant are probably some of the more difficult decisions that we make as oncologists. When we are deciding whether to recommend transplant for a patient, we often will use the same types of information that we gather for making the diagnosis and for risk stratifying patients.

 

If a patient with myelofibrosis lives long enough, they will ultimately develop sclerotic disease and bone marrow failure, and a significant number (around one-third) will go on to develop acute leukemia, which is extremely difficult to manage and is largely incurable in this patient population. Thus, we want to treat people and intervene where we can to prevent disease progression, especially when we know that they have high-risk disease features or a limited time period in which they qualify for a given therapy, such as stem cell transplant. However, since patients in the prodromal phase may have a fairly good quality of life for an extended period, we may be hesitant to expose them to the risks that are associated with transplant, including increased risks of morbidity and mortality.

 

There are also clinical considerations with respect to decisions surrounding ablative conditioning in patients with proliferative disease. Those with more proliferative disease may do better with a myeloablative conditioning regimen before allogeneic transplant, which means that they have to be treated with the conditioning regimen while they can still physically handle it. For many institutions, the age cutoff is somewhere between 55 and 65 years. Thus, making the decision of whether to go to transplant for someone who is aged 55 years and is actively working and doing okay but has proliferative disease and high-risk genetics is difficult, and we continue to strive to find greater guidance for how to treat such people and make these decisions.

References

Ajufo HO, Waksal JA, Mascarenhas JO, Rampal RK. Treating accelerated and blast phase myeloproliferative neoplasms: progress and challenges. Ther Adv Hematol. 2023;14:20406207231177282. doi:10.1177/20406207231177282

 

Arber DA, Orazi A, Hasserjian RP, et al. International Consensus Classification of myeloid neoplasms and acute leukemias: integrating morphologic, clinical, and genomic data. Blood. 2022;140(11):1200-1228. doi:10.1182/blood.2022015850

 

Combaluzier S, Quessada J, Abbou N, et al. Cytological diagnosis of classic myeloproliferative neoplasms at the age of molecular biology. Cells. 2023;12(6):946. doi:10.3390/cells12060946

 

Devlin R, Gupta V. Myelofibrosis: to transplant or not to transplant? Hematology Am Soc Hematol Educ Program. 2016;2016(1):543-551. doi:10.1182/asheducation-2016.1.543

 

Lee Y-C, Hsieh C-C, Lee Y-L, Li C-Y. Molecular markers and prognosis of myelofibrosis in the genomic era: a meta-analysis. Clin Lymphoma Myeloma Leuk. 2018;18(9):558-568. doi:10.1016/j.clml.2018.06.004

 

McLornan DP, Godfrey AL, Green A, et al; BSH Committee. Diagnosis and evaluation of prognosis of myelofibrosis: a British Society for Haematology Guideline. Br J Haematol. 2024;204(1):127-135. doi:10.1111/bjh.19164

 

Szuber N, Tefferi A. Driver mutations in primary myelofibrosis and their implications. Curr Opin Hematol. 2018;25(2):129-135. doi:10.1097/MOH.0000000000000406

 

Tefferi A, Alkhateeb H, Gangat N. Blast phase myeloproliferative neoplasm: contemporary review and 2024 treatment algorithm. Blood Cancer J. 2023;13(1):108. doi:10.1038/s41408-023-00878-8

 

Tefferi A. Primary myelofibrosis: 2023 update on diagnosis, risk-stratification, and management. Am J Hematol. 2023;98(5):801-821. doi:10.1002/ajh.26857

John Mascarenhas, MD

Professor of Medicine, Division of Hematology/Oncology
Member, The Tisch Cancer Institute
Icahn School of Medicine at Mount Sinai
New York, NY

Raajit K. Rampal, MD, PhD

Associate Member
Clinical Director, Leukemia Service
Director, Myeloproliferative Neoplasms Program
Memorial Sloan Kettering Cancer Center
New York, NY

Michael Savona, MD

Beverly and George Rawlings Director of Hematology Research
Professor of Internal Medicine and Cancer Biology
Division of Hematology & Oncology, Department of Medicine
Vanderbilt-Ingram Cancer Center and Vanderbilt University School of Medicine
Nashville, TN

Advertisment