The clinical issues confronting patients with myelofibrosis have changed little with time. Clinical manifestations related to anemia, thrombocytopenia, extramedullary hematopoiesis, constitutional symptoms, and leukemic transformation remain the primary sources of morbidity and mortality in myelofibrosis patients. The disease course can also vary greatly from survival measured in decades to just several months. In the pre-JAK2 inhibitor era, nontransplant options included immunomodulatory agents, hydroxyurea, erythropoiesis-stimulating agents, androgenic steroids, and transfusions. Most myelofibrosis patients with anemia are primarily managed using immunomodulatory agents (lenalidomide or thalidomide ± prednisone), androgenic steroids (danazol), steroids, erythropoiesis-stimulating agents, and pegylated interferon. When constitutional symptoms and symptoms related to extramedullary hematopoiesis are present, hydroxyurea, immunomodulatory agents, splenectomy, and splenic irradiation are considered with only marginal and temporary success. The possibility of cure in myelofibrosis patients remains limited to a small subset of patients who are eligible to undergo allogeneic hematopoietic stem cell transplant (Allo-HSCT). However, there are several challenges encountered with this type of treatment approach including the limited number of suitable donors, presence of multiple comorbidities usually as a function of advanced age, difficulty in deciding at which time point during the disease course is it best to perform Allo-HSCT and lastly the choice of conditioning regimen.
Various prognostic scoring schemes have been developed to help stratify patients into specific risk groups with designated estimates of their survival outcomes and also risk for acute myelogenous leukemia (AML) transformation to help provide guidance on when to initiate more intensive therapies that includes Allo-HSCT. The most commonly used risk scoring system in MF is the International Prognostic Scoring System (IPSS) which takes into account 5 different clinicopathologic parameters namely age >65 years old, presence of constitutional symptoms, hemoglobin level <10 g/dl, white blood cell count >25 × 109
/l, and presence of circulating peripheral blood blasts. The IPSS, which is used at the time of diagnosis, has since undergone further refinements. The Dynamic IPSS was developed and allows for prognosis prediction at any time during the disease course. Finally, the Dynamic IPSS-plus takes into account three additional adverse prognostic factors, including unfavorable cytogenetic abnormalities, platelet counts <100 × 109
/l and red blood cell transfusion dependence. The higher the score, the worse the risk groupings and associated outcomes. The prevailing expert opinion and clinical data support the potential benefit of Allo-HSCT in myelofibrosis patients whose disease are classified as either intermediate-2 or high risk, transfusion dependent, and those who have unfavorable cytogenetics [McLornan et al. 2012
]. Data supporting Allo-HSCT in low-risk and intermediate-1-risk myelofibrosis patients are less established ().
Given the high number of myelofibrosis patients who are ineligible for Allo-HSCT and who remain symptomatic despite conventional therapies, there was a need for novel therapies that can produce greater efficacy while targeting important disease-relevant pathophysiologic pathways. The similarity in clinical characteristics of the BCR-ABL1
-negative MPN patients along with the prevalence of the JAK
mutation in this population provided a strong rationale for the development of a new class of pharmacologic inhibitors of the JAK-STAT pathway. The optimism was further emphasized when taking into consideration the success that imatinib and other BCR-ABL1
(Philadelphia chromosome) directed agents have made in CML, with a hope that JAK inhibitors would have analogous effects in BCR-ABL1
-negative patients [Kumar et al. 2009
]. Although JAK2
mutations, in conjunction with other genetic/epigenetic abnormalities, can contribute to the initiation and progression of MPNs, it is very important to mention that recent evidence has shown that none of the JAK-STAT activating mutations (including JAK2
V617F) in MPNs can be considered a causal event [Tefferi, 2010
], in contrast to the role of BCR-ABL1
mutation in CML (see and ).
General description of JAK inhibitors.
Description of JAK inhibitor trials.