Ask the Hematologist November-December 2009

Myelofibrosis with myeloid metaplasia, or simply myelofibrosis (MF), is also known as chronic idiopathic myelofibrosis, according to the World Health Organization system for classification of myeloid neoplasms. MF is currently classified with polycythemia vera (PV) and essential thrombocythemia (ET) as a BCR-ABL-negative classic myeloproliferative disorder (MPD). Pathogenetic mechanisms in MF include i) stem cell-derived clonal myeloproliferation, ii) reactive bone marrow stromal changes including collagen fibrosis, and iii) extramedullary hematopoiesis. However, the primary transforming event(s) has not been identified, although much attention has been given to recently described gain-of-function mutations involving the JAK2 tyrosine kinase (JAK2V617F) and thrombopoietin receptor (MPLW515L/K).

A 55-year-old woman presented with fatigue and dyspnea on exertion. Over the last three months, she had developed left upper quadrant discomfort, early satiety, night sweats, and weight loss despite good appetite. Physical examination revealed pallor and marked splenomegaly. Complete blood count disclosed anemia, thrombocytosis, and left-shifted leukocytosis. Peripheral blood smear examination showed myelophthisis (i.e., presence of nucleated red blood cells, immature granulocytes, and dacryocytes). Bone marrow examination yielded a “dry tap” and biopsy was read out as showing myelofibrosis. How should the clinician approach the patient, henceforth?

Neither myelophthisis nor bone marrow fibrosis is specific to MF and one has to entertain and exclude other conditions that could mimic MF in their clinical presentation. In this regard, the therapeutically most relevant distinction is between MF and chronic myeloid leukemia. Therefore, cytogenetic studies and/or fluorescent in situ hybridization/RT-PCR for BCR-ABL are highly recommended during the initial evaluation of MF. I also recommend mutation screening for JAK2V617F as part of the initial workup. The presence of JAK2V617F excludes the possibility of reactive bone marrow fibrosis associated with infections, inflammatory processes, lymphoid disorders, or metastatic cancer. However, JAK2V617F is detected in only ~ 50 percent of patients with MF and can also occur in other myeloid disorders, including myelodysplastic syndrome and atypical MPD. Therefore, bone marrow histological review by an experienced clinical pathologist is required to distinguish MF from the latter disorders.

Survival in MF is substantially affected by the presence or absence of risk factors that have been used to construct several prognostic scoring systems (PSS). At my institution, we use a modified Dupriez PSS, henceforth referred to as the Mayo PSS, that considers four adverse prognostic features: a platelet count of < 100 x 10⁹/L, hemoglobin level of < 10 g/dL, leukocyte count of < 4 or > 30 x 10⁹/L, and an absolute monocyte count of > 1 x 10⁹/L. In the absence of any of these four poor prognostic indicators (low-risk category), median survival in patients younger than 60 years of age approaches 15 years as opposed to five years in the intermediate-risk category (presence of one adverse feature) and two years in the high-risk category (presence of two or more adverse features). Within each of these risk groups, the presence of cytogenetic abnormalities other than 13q- and 20q- portend a worse prognosis.

Current drug therapy in MF is unlikely to either cure the disease or prolong life and is utilized primarily for palliative purposes. Such palliative care is also accomplished, when appropriate, by involved field radiation or splenectomy. Similarly, although potentially curative, allogeneic stem cell transplant (ASCT) is marred by a high risk of treatment-related mortality and morbidity. Therefore, recognizing the fact that the goal of therapy in cancer is not necessarily to “cure,” but to secure a long productive life with quality, one must be careful in selecting the right patients for a particular treatment modality.

At present, watchful waiting is the treatment of choice for low-risk patients, regardless of age. I believe that the risk of procedure-related death and chronic morbidity is too high to justify ASCT in this group of patients. On the other hand, ASCT is a reasonable treatment option in the presence of high-risk disease. Unfortunately, the majority of patients with MF are not good transplant candidates because of either advanced age or presence of co-morbidities. In general, I prefer experimental therapy over ASCT for both high-risk older patients (age > 60 years) and intermediate-risk patients of all ages. When transplant is indicated, the choice between myeloablative and reduced-intensity conditioning (RIC) ASCT is currently based not on controlled evidence but one’s interpretation of the limited literature on the subject matter. My current preference is the former for patients younger than age 45 years and the latter otherwise. Finally, based on recent observations, presence of del(5)(q31) warrants a therapeutic trial with lenalidomide, regardless of risk category.