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 (bone marrow is progressively replaced with fibers, a process that progressively leads to cytopenias (low counts of the three main blood cell types) and ultimately failure of the bone marrow to produce blood (Figure 1a and top right panel in Figure 2 depicted below). MF is the most aggressive MPN, whereas PV and ET constitute more indolent (i.e., benign) subtypes. Myelofibrosis (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. Please see below the separate section and our article 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 (middle right panel in Figure 2 depicted below) and harbor the JAK2 V617F mutation. Essential thrombocythemia is the most indolent MPN and is characterized by a high number of platelets (cells that control bleeding); bottom right panel in Figure 2 depicted below. For a comprehensive presentation of MPNs, please review our book chapter: Bose P, Masarova L, Amin HM, Verstovsek S. Philadelphia Chromosome-Negative Myeloproliferative Neoplasms (Chapter 6), In: The MD Anderson Manual of Medical Oncology, Kantarjian HM, Wolff RA, Rieber AG., Eds., 4^th edition, McGraw Hill, 2022.

"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 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

Systemic mastocytosis is an atypical hematologic neoplasm that is characterized by uncontrolled proliferation and accumulation of mast cells in the internal tissues and organs of the body other than the skin, for example, bone marrow, liver, and gastrointestinal track. Mast cell is a type of white blood cell that our body’s immune system uses as an alarm under certain conditions. During allergic and inflammatory reactions, mast cells are activated and release certain chemicals, such as histamine, cytokines, and growth factors from small sacs; these chemicals activate the body’s response to allergens (for example, certain foods, insect venoms, 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, 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.  On May 22, 2023, avapritinib was approved as a treatment for patients with indolent systemic mastocytosis and symptoms.

Advanced systemic mastocytosis comprises 3 subtypes: aggressive systemic mastocytosis, systemic mastocytosis with an associated hematologic neoplasm, and mast cell leukemia. 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. The most common type of advanced systemic mastocytosis is systemic mastocytosis with an associated hematologic neoplasm. In patients who have this disease, two 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 (about 95%) who have systemic mastocytosis harbor a mutation in the KIT gene (called 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 the recently approved treatments (midostaurin, avapritinib) and others in clinical development for systemic mastocytosis.

Approved Treatments and Investigational Medications in Systemic Mastocytosis

• Tyrosine kinase inhibitors (TKIs) transformed the treatment landscape of systemic mastocytosis. For an overview on current and emerging therapies for 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 for patients with advanced systemic mastocytosis on April 28, 2017.
• Avapritinib (formerly BLU-285), a potent and highly selective tyrosine kinase inhibitor (TKI) targeting KIT D816V, 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 indolent systemic mastocytosis based on the results of the PIONEER trial (Gotlib J. et al., N. Engl. J. Med. Evid., 2023). 
• Bezuclastinib (formerly CGT-9486) and Elenestinib (formerly BLU-263) are two highly selective and potent investigational TKI inhibitors targeting KIT D816V with minimal penetrance of the blood-brain barrier. The MD Anderson Cancer Center has opened two phase 2 clinical trials that are enrolling patients to evaluate bezuclastinib in indolent or smoldering mastocytosis (SUMMIT trial, NCT05186753; MD Anderson protocol #2021-0880) and advanced systemic mastocytosis (APEX trial, NCT04996875; MD Anderson protocol #2021-0587); and one phase 2/3 clinical trial to evaluate elenestinib in patients who have indolent systemic mastocytosis (HARBOR trial, NCT04910685; MD Anderson protocol #2022-0072).
• TL-895 (potent, selective inhibitor of Bruton tyrosine kinase) is being investigated in patients with symptomatic indolent systemic mastocytosis in a phase 2 clinical trial (NCT04655118; MD Anderson Protocol #2020-0738).

MPN Tissue Bank at the MD Anderson Cancer Center

A unique aspect of our MPN Research Program is the establishment of the largest central MPN tissue bank and the corresponding clinical database worldwide. Our MPN tissue bank comprises specimens and clinical data (including bone marrow biopsies and mutations) for more than 3,700 patients. Retrospective studies of bone marrow specimens and blood samples from MPN patients are crucial in assessing new medications. Specimens collected before and during treatment can be used to understand prognosis and response to treatment. In addition, our tissue bank is used to conduct translational research studies and explore the pathophysiology of myelofibrosis; and, in certain cases, the underlying mechanism of transformation to AML.