MPN Overview and Pathogenetic Features

Myeloproliferative neoplasms (MPNs) are a group of chronic cancers of the bone marrow that can become worse over time, especially if left untreated. The major MPN subtypes are primary myelofibrosis (PMF), polycythemia vera (PV) and essential thrombocythemia (ET).

MPNs are characterized by myeloproliferation — uncontrolled growth of the blood stem cells in the bone marrow and increase of one or more of the three blood cell types in the circulation, namely red and white blood cells and platelets — specific morphologic features (i.e., appearance) in the bone marrow, such as fibrosis (scarring of the bone marrow), hypercellularity (presence of excess cells in the bone marrow) and certain genetic mutations (abnormalities in specific genes present in malignant cells), among others.

The three classic MPNs present different clinical phenotypes (observable characteristics) and a range of morphologic/molecular features. PMF is characterized by bone marrow fibrosis: the bone marrow is progressively replaced with fibers (Figure 1a and top right part in Figure 2 depicted below), a process that progressively leads to cytopenias (low blood cell counts, for example, red blood cells or platelets) and ultimately failure of the bone marrow to produce blood. Myelofibrosis (MF) is the most aggressive MPN, whereas PV and ET constitute more indolent (i.e., benign) subtypes. MF is also characterized by progressive splenomegaly, anemia, extramedullary hematopoiesis (occurring outside the bone marrow), and several constitutional symptoms that can be debilitating, such as fatigue, low-grade fevers, night sweats, early satiety, bone pain, pruritus, abdominal discomfort, and unintentional weight loss among others. Below, please see the journal cover of our featured article in Cancers (Basel) on myelofibrosis phenotypes.

Myelofibrosis can occur as the primary disease — primary MF — or evolve from PV or ET to the fibrotic phase (secondary MF). Patients with polycythemia vera typically have an elevated count of red blood cells (please see the middle right part in Figure 2 depicted below) and harbor the JAK2 V617F mutation in the vast majority of cases. Essential thrombocythemia is the most indolent MPN and is characterized by a high number of platelets (blood cells that control bleeding); please see bottom right part in Figure 2 depicted below. 

"Driver" Mutations in MPNs

In 2005, the landmark discovery of the JAK2 V617F mutation and its involvement in MPN biology was reported. The JAK2 mutation is nearly ubiquitous in PV patients (95%), and it is detected in about 50-60% of PMF or ET patients. CALR is another mutation detected in the bone marrow/blood cells of MF and ET patients (25-30% in MF, and 20-25% in ET). In addition, a gene called MPL is mutated in 10-20% of ET and MF patients. These three mutations in the genes JAK2, CALR and MPL typically are mutually exclusive; they are called “driver” mutations because they activate signaling that makes affected cells grow without control (this is called the JAK-STAT pathway inside the bone marrow/blood cells). Notwithstanding the fact that JAK2, CALR and MPL are not the cause of MPN, clinical and experimental findings clearly support the critical impact of these mutations in the manifestation of a specific MPN phenotype. 

MPN Transformation to Post-MPN Acute Myeloid Leukemia (AML)

MPNs can transform to post-MPN AML or MPN in the blast phase in 20-25% of the cases. AML is a disease where “baby” bone marrow cells called blasts start to grow without control (comprising more than 20% of the bone marrow cells) and do not go through the maturation process. Progression of the MPNs (primarily myelofibrosis) to MPN-BP (blasts ≥ 20% in the bone marrow) transitions through MPN in the accelerated phase (MPN-AP); in MPN-AP, blasts in the bone marrow are in the range ≥10-19%. A few “non-driver” mutations (mutations in genes that are not directly related to activation of the JAK-STAT pathway) or “triple-negative” status for the three driver mutations (no JAK2, CALR, and MPL mutations) may play a role in transformation of MF to AML. For example, IDH1 and IDH2 mutations are detected in about 20% of the patients with MPN in transformation to AML. In our recent article "Outcome of patients with IDH1/2-mutated post-MPN AML in the era of IDH inhibitors" that was published in Blood Advances (2020), we report the promising clinical efficacy of IDH1/2-inhibitor based combinations in a small cohort of IDH1/2-mutated patients with MPN in the blast phase. Bone marrow biopsies, molecular studies (determination of specific mutations in the bone marrow/blood cells), and cytogenetic testing (morphology of chromosomes) are important for diagnostic and prognostic assessment of advanced phase MPN; and evaluation of response to treatment and progression to post-MPN AML. For a comprehensive review regarding mutations in MPNs (in chronic phase) that increase the risk of transformation to MPN in the blast phase, please read our comprehensive book chapter "Mutational landscape of blast phase myeloproliferative neoplasms (MPN-BP) and antecedent MPN" that was published in the International Review of Cell and Molecular Biology (2022). Please read our review "Accelerated phase of myeloproliferative neoplasms" that was published in Acta Haematologica (2021) for a comprehensive overview of MPN in the accelerated phase.

Systemic mastocytosis is an atypical hematologic neoplasm that is characterized by uncontrolled proliferation and accumulation of mast cells (Figure 1b) in the internal tissues and organs of the body other than the skin (for example: bone marrow, liver and gastrointestinal track). Mast cells are a type of white blood cell that our body’s immune system uses as an alarm under certain conditions. During allergic and inflammation responses, mast cells (Figure 1b) are activated and release certain chemicals, such as histamine, cytokines and growth factors from small sacs (Figure 1b); these chemicals activate the body’s response to allergens (for example: certain foods, insect venoms and pollen), medications or pathogens. Mast cells are found in connective tissues throughout the body, especially under the skin, near blood vessels and lymph vessels, in the bone marrow, the lungs, the spleen and liver and the lining of the stomach and intestines.

The vast majority of patients who have systemic mastocytosis are diagnosed with either indolent (i.e., benign) systemic mastocytosis or advanced systemic mastocytosis. Indolent systemic mastocytosis is much more common; it does not affect organ function, but it may cause many symptoms and poor quality of life. In general, indolent systemic mastocytosis does not affect life expectancy and rarely progresses to an advanced form. Symptoms may include skin swelling, hives, flushing, headaches, low blood pressure, itching, nausea, fainting, shortness of breath and body aches, among many others. Most cases of indolent systemic mastocytosis can be treated with antihistamines and avoidance of dietary and environmental triggers. Prednisone, cromolyn sodium (mast cell stabilizer) or other types of anti-allergic medications may help control the symptoms. 

Advanced systemic mastocytosis comprises three subtypes:

• Aggressive systemic mastocytosis is characterized by infiltration of internal organs by neoplastic mast cells, resulting in organ dysfunction and damage (usually the liver, bone marrow or bones); this may significantly affect life expectancy. 
• Systemic mastocytosis with an associated hematologic neoplasm is the most common type of advanced systemic mastocytosis. In patients who have this disease, two different neoplasms are detected in the bone marrow: mastocytosis and another form of non-mast cell hematologic neoplasm, including any type of myeloproliferative neoplasms, for example. 
• Mast cell leukemia is a very rare entity, which is suspected when abnormal mast cells are found not only in the bone marrow but also in the blood. Mast cell leukemia is very aggressive and is associated with a very shortened survival. For an overview of systemic mastocytosis and similar entities, please read our review article: "Systemic mastocytosis and other entities involving mast cells: A practical review and update" (Cancers 2022).

KIT Mutations in Systemic Mastocytosis

The vast majority of patients (approximately 90 to 95%) who have systemic mastocytosis harbor a mutation in the KIT gene (KIT D816V mutation), encoding a tyrosine kinase (an enzyme). Mutated tyrosine kinase is an abnormal protein in malignant mast cells, driving their growth and proliferation. Detection of the KIT D816V mutation in the bone marrow or other extracutaneous organs is a hallmark of the disease and is considered a minor diagnostic criterion for systemic mastocytosis (other criteria need to be met for diagnosis of the disease). Mutated KIT D816V in malignant mast cells is the target of KIT inhibitors (e.g., avapritinib) and others in clinical development (e.g., bezuclastinib, elenestinib) for systemic mastocytosis.

Approved Treatments in Systemic Mastocytosis

• Tyrosine kinase inhibitors (TKIs) transformed the landscape of systemic mastocytosis treatment and significantly improved the patients' outcomes and survival. For an overview on current and emerging therapies in systemic mastocytosis, please read our comprehensive review article, "SOHO State of the Art Update and Next Questions: Current and Emerging Therapies for Systemic Mastocytosis", Chifotides HT, Bose P. Clinical Lymphoma Myeloma & Leukemia, 2024.
• Midostaurin is a TKI that inhibits multiple kinases, including the wild-type KIT and mutated KIT D816V. Midostaurin was approved by the FDA as a treatment for patients with advanced systemic mastocytosis on April 28, 2017.
• Avapritinib (formerly BLU-285) is a potent and highly selective tyrosine kinase inhibitor (TKI) targeting KIT D816V. Avapritinib received regulatory approval as a treatment for patients with advanced systemic mastocytosis on June 16 2021 based on the results of the EXPLORER trial (DeAngelo DJ. et al., Nature Med. 2021) and the PATHFINDER trial (Gotlib J. et al., Nature Med., 2021). On May 22, 2023, avapritinib was also approved as a treatment for patients with symptomatic indolent systemic mastocytosis based on the results of the PIONEER trial (Gotlib J. et al., N. Engl. J. Med. Evid., 2023).

Investigational Agents in Systemic Mastocytosis

• Bezuclastinib (formerly CGT-9486) is a highly selective and potent investigational TKI inhibitor targeting KIT mutations, including KIT D816V, with minimal penetrance of the blood-brain barrier. At the MD Anderson Cancer Center, bezuclastinib is being evaluated in two phase 2 clinical trials in symptomatic indolent systemic mastocytosis and smoldering systemic mastocytosis (SUMMIT trial, NCT05186753; MD Anderson protocol #2021-0880) and advanced systemic mastocytosis (APEX trial, NCT04996875; MD Anderson protocol #2021-0587). The results of the registrational phase 2 clinical trial SUMMIT demonstrated that bezuclastinib was safe and rapidly reduced markers of disease burden (mast cells in the bone marrow, tryptase levels, KIT D816V variant allele burden) while also improving symptoms in patients with nonadvanced systemic mastocytosis. The FDA announced Breakthrough Therapy Designation for bezuclastinib in nonadvanced systemic mastocytosis, in October 2025.
• Elenestinib (formerly BLU-263) is another highly selective and potent investigational TKI inhibitor targeting KIT D816V with minimal penetrance of the blood-brain barrier. Elenestinib is being evaluated in a phase 2/3 clinical in patients who have symptomatic indolent systemic mastocytosis (HARBOR trial, NCT04910685; MD Anderson protocol #2022-0072).
• TL-895 is a potent, selective inhibitor of Bruton tyrosine kinase that is being investigated in patients with symptomatic indolent systemic mastocytosis in a phase 2 clinical trial (NCT04655118; MD Anderson Protocol #2020-0738).

A unique aspect of our MPN Research Program is the establishment of the largest central, single site MPN Tissue Biobank and the corresponding clinical database worldwide. Our MPN Tissue Biobank is a comprehensive repository of biospecimens, including peripheral blood samples (78%) and bone marrow aspirates (22%) from thousands of patients who were treated at MD Anderson since 2006 when the MPN Tissue Biobank was established. As of September 1, 2024, our MPN Tissue Biobank has specimens and clinical data from more than 4,700 patients. The biospecimens were sourced from patients with MPNs, including myelofibrosis (50%), polycythemia vera (15%), essential thrombocythemia (10%), systemic mastocytosis (6%) and other rarer MPN subsets (19%) at various stages of treatment. The MPN Tissue Biobank also includes biospecimens from patients who progressed from MPNs to AML (MPN in the blast phase), which currently lacks approved treatments. The biospecimens are collected and cryopreserved (frozen at extremely low temperatures).

Our MPN Tissue Biobank provides extensive biological materials for diverse research applications in MPNs. The corresponding database includes pathology and laboratory data, molecular profiles, cytogenetics, treatment details, and survival outcomes. By linking molecular and cellular alterations in the biospecimens to patient outcomes, we aim to explore the pathophysiology of myelofibrosis and identify the mechanism(s) that drive the disease, response and resistance to treatment, and the genomic profiles (mutations) of the patients over time; these and other factors contribute to progression of the disease, including transformation to AML. Retrospective studies on the bone marrow aspirates and peripheral blood samples from MPN patients are also crucial in assessing new medications. Biospecimens collected before and during treatment can be used to understand prognosis and response to treatment. This information is critical to develop new therapeutic strategies and improve existing treatments, thereby advancing the field of MPNs and improving our patients' quality of life and outcomes.

Left Panel. Top part: healthy bone marrow. Middle and bottom parts: normal blood cell counts.

Right Panel. Top part: abnormal bone marrow in primary myelofibrosis. Middle part: high red blood cell count in polycythemia vera. Bottom part: high platelet count in essential thrombocythemia.