MD2B - Myeloproliferative Disorders

The term "myeloproliferative disorders" was first coined by William Dameshek in 1951.

This heterogeneous group consists of four diseases, all featuring chronic, acquired, monoclonal proliferation of either pluripotential or more differentiated hematopoietic stem cells. The four types of myeloproliferative disorders are named for the predominant cell type involved, and are frequently associated with biochemical and chromosomal abnormalities, as discussed below. These disorders have been linked by shared mutations which provide further insight into the genetic events resulting in “myeloproliferation.”

Chronic Myelocytic Leukemia (CML)

Characterized by severe granulocytosis (with higher-than-average proportion of immature cells), anemia, thrombocytosis, and splenomegaly.

Epidemiology, Etiology and Pathogenesis [1]

• Lifetime risk of CML is 1 in 526 [2].
• Occurs predominantly in the middle-aged and is slightly more common in males (1.4 to 1).
• Associated with ionizing radiation exposure.
• Progenitor cell involved gives rise to granulocytes (neutrophils, eosinophils, basophils), monocytes, erythrocytes, platelets and possibly some B- and T- lymphocytes.
• Pathognomonic “Philadelphia chromosome (Ph)” 9;22 translocation, present in >90% patients, results in the formation of the BCR::ABL1 fusion protein.
• BCR: ABL1 has constitutive tyrosine kinase activity which results in continuous cell replication and growth.
• In the chronic phase, additional molecular and chromosomal abnormalities are acquired because of increased marrow proliferation; over years hematopoietic differentiation is impaired and acute leukemia (blast crisis) develops.

Clinical Presentation

• History: Fatigue, hypermetabolic symptoms, abdominal discomfort, and early satiety from splenomegaly, or asymptomatic and detected by routine blood tests (up to half of patients) [4].
• Physical exam: Splenomegaly, sternal tenderness from marrow expansion.
• Labs: WBC count (granulocytosis often >50,000 cells/mL) and differential (granulopoiesis and left shift, meaning there is an increase in the number of immature cells) usually diagnostic, anemia, and thrombocytosis [4].
• Basophilia is present in all CML patients’ blood smears, and eosinophilia is very common.
• Peripheral smear shows granulocytes, with a predominance of mature cells and late precursors (polyps, bands, metamyelocytes, myelocytes) but few primitive cells; also see eosinophils and basophils.
• Molecular testing confirms diagnosis with detection of Philadelphia chromosome, BCR::ABL1 protein, or BCR::ABL1 mRNA in peripheral blood or bone marrow [4].

Natural Course

• Chronic Phase: First 1-5 years are usually asymptomatic and very amenable to achieving remission with targeted therapy.
• Accelerated Phase: Increasing WBC immaturity, difficulty in controlling WBC counts, anemia, worsening splenomegaly, fever.
• "Blast Crisis:" Medullary/acute leukemia or extra-medullary/ "chloromas", with patient survival measured in months at this stage.

Treatment 

• Both treatment and prognosis are dependent on disease phase.
• Imatinib, approved in 2001, is a molecular inhibitor of BCR::ABL1. It has revolutionized CML treatment and serves as a model for molecular targeted therapy. A landmark clinical trial showed patients treated with imatinib demonstrated a mortality rate like the overall population [4,5].
• Chronic Phase: imatinib is first-line therapy with excellent rates of remission. After 5 years of imatinib as initial therapy, 98% of patients had hematological remission, 87% had complete cytogenetic remission, 7% had progression to accelerated/blast phase, and overall survival was 89% [6].
• Accelerated/Blast Crisis: tyrosine kinase inhibitor and/or allogeneic hematopoietic stem cell transplant [7, 8].
• Imatinib Failure: options include allogeneic stem-cell transplantation if young (potentially curative in 40-60%) and imatinib or dasatinib (targeted inhibitors of imatinib-resistant BCR-ABL mutants) [4].
• Cytogenetic and molecular response after imatinib should be monitored by FISH and RT-PCR. A combination cytogenetic and molecular response is strongly predictive of long-term treatment success [6].

Polycythemia Vera (PV)

Characterized monoclonal proliferation of trilineage, with disproportionate expansion of RBCs and platelets, leading to a clinical picture of hyperviscosity, hemorrhage and thrombosis.

Epidemiology, Etiology and Pathogenesis [9]

• Incidence is 2/100,000 population, usually middle-aged to older patients [10].
• Mutations in the JAK2 tyrosine kinase are found in nearly all (>95%) and are believed to be central to pathogenesis.
• JAK2 mutations activate the JAK-STAT pathway, resulting in cytokine-independent growth and transformation of hematopoietic progenitor cells.
• Erythroid cells undergo transformation through interactions between the erythropoietin receptor and the constitutively active JAK2 kinase mutant protein.

Clinical Presentation

• History: Majority of cases are asymptomatic and discovered incidentally, but symptoms can include headaches, dizziness, visual changes, tinnitus, erythromelalgia, pruritis, gout, hemorrhagic events in 25% of patients (nose/GI bleeds) and thrombotic events in 33% (strokes, MI, hepatic vein thrombosis in 10%).
• Physical Exam: Plethoric, distended fundal veins, mild-moderate splenomegaly and hepatomegaly, hypertension.
• Labs: Chronically elevated Hgb, elevated RBC mass (to exclude relative polycythemia), normal arterial oxygen saturation; thrombocytosis, leukocytosis, normal LAP score, elevated vitamin B12 level, hyperuricemia.
• Diagnosis (by major WHO criteria): Hgb >18.5males/16.5females, JAK2 mutation [11].

Natural Course

• Polycythemic Phase: 5-20 years, 10-20% patients die of thrombotic events and 5% die of hemorrhage.
• Stable Phase: RBC mass stabilizes with treatment.
• Postpolycythemic Myeloid Metaplasia: 15-20% of cases, with anemia, leukoerythroblastic smear, leukopenia, thrombocytopenia, marrow fibrosis and massive hepatosplenomegaly.
• Acute Leukemia/ AML: 1% of cases, therapy resistant.

Treatment

• The primary goal of treatment is to decrease thrombotic complications (cardiac, PE, venous) while limiting treatment side effects (acute leukemia).
• Low thrombotic risk (age <60, no previous thrombosis).
• Phlebotomy (goal Hct<45) and Aspirin [12].
• In a randomized trial aspirin reduced major thrombotic events, however, did not improve mortality [13].
• High thrombotic risk (age >60, history of thrombosis).
• Myelosuppressive therapy (hydroxyurea)
  • Hydroxyurea shown to decrease thrombotic complications. Pegylated IFN-alpha is the agent of choice for younger patients (<40) and in pregnant women [12,14].
  • The leukemogenic potential of hydroxyurea as monotherapy is controversial: most data indicate no increased risk of leukemia however no direct randomized comparison has been done.
• Ruxolitinib is a JAK inhibitor that can help with symptom management, but its long-term effects are not well understood. It is currently reserved for patients who failed to respond to other treatments [15].

Essential Thrombocytosis (ET)

Also features clonal trilineage hematopoiesis, but with prominent megakaryocytic hyperplasia, increased platelet counts and risk for thrombosis.

Epidemiology, Etiology and Pathogenesis

• 6,000 new cases per year in the US (less common than PV).
• Median age at diagnosis is 60 years old, more common in females 2:1 [16].
• Associated with iron deficiency, chronic inflammatory disease, solid tumors, splenectomy).
• JAK2 mutations are found in 41-72% of ET resulting in clonal hematopoeisis. Pathogenesis, including myeloproliferation in JAK2 negative patients, is incompletely understood [9].
• Other common mutations include those upstream in the JAK-STAT pathway including CALR or MPL [17].

Clinical Presentation

• History: Most cases are asymptomatic and discovered incidentally, but can present with nosebleeds, headache, bruises, macrovascular or microvascular obstruction.
• Physical Exam: Mild, palpable splenomegaly in 50%.
• Labs: Platelets > 45,0000/microliter, mild anemia, leukocytosis below 50,000, normal or elevated LAP score, hyperuricemia less common, pseudohyperkalemia.
• Peripheral smear shows abnormal platelet morphology, with large and small (anisocytosis), bizarre and agranular forms (poikilocytosis) on peripheral smear, but absent or minimal collagen fibrosis of the marrow.
• Diagnosis (by Major WHO Criteria): platelets >450,000/microliter, bone marrow biopsy, JAK2, CALR or MPL mutation [18, 19].

Natural Course

• Majority have normal expectancy.
• Thrombotic risk increased with advance age, leukocytosis, and JAK2 mutation [19, 20].
• Hemorrhagic risk highest with platelet count >1,500,000 [19].
• Rare myelofibrosis (4%) and AML (2%) in an Italian cohort (15-year risk) [21].
• Patients have a higher risk for pregnancy loss than the general population.

Treatment [16]

• Many require no therapy (young, no previous thrombosis).
• Cytoreductive therapy in high risk (age >65, thrombotic event, CV risk factors), options include hydroxyurea, anagrelide, and pegylated IFN-alpha.
• Hydroxyurea has emerged as treatment of choice due to proven efficacy (reduction of thrombosis in randomized prospective trials), good tolerability, and minimal leukemogenic potential [22].
• Aspirin is useful for relief of pain, neurologic, and ocular symptoms of microvascular ischemia. Combination Aspirin + cytoreductive therapy is often prescribed in high-risk patients, but prospective studies have not been done.

Myelofibrosis/ Myeloid Metaplasia (MMM)

The rarest of the myeloproliferative disorders, MMM is characterized by a triad of 1) leukoerythroblastic peripheral blood smear, 2) extramedullary hematopoiesis and 3) collagen fibrosis of the marrow. This increase in marrow fibroblasts is a polyclonal response to ineffective megakaryocyte production and subsequent release of fibrogenic growth factors. These factors lead to fibroblast proliferation, collagen secretion and collagenase activity. The extramedullary hematopoiesis usually occurs in the liver and spleen, probably from progenitor cells that have landed in these organs after leaking out from the damaged marrow.

Epidemiology, Etiology and Pathogenesis

• Rare, usually presents in late middle-aged patients.
• No specific chromosomal or molecular genetic abnormality, although karyotypes are abnormal in one-third of patients.

Clinical Presentation

• History: Majority present symptomatically with weight loss, fatigue, dyspnea from anemia, pruritis, early satiety and abdominal discomfort from splenomegaly.
• Physical exam: 100% with splenomegaly, 66% with hepatomegaly, lymphadenopathy.
• Labs: Modest leukocytosis with a few myeloblasts, mild anemia, variable platelet count, hyperuricemia, elevated or normal LAP score (but low in 10%), high numbers of CD34+ hematopoietic stem cells circulating in peripheral blood.
• Peripheral smear shows "teardrop" RBC's, nucleated RBC's, immature granulocytes, large platelets, and megakaryocyte fragments.
• Marrow aspiration yields "dry tap" and biopsy shows marked megakaryocytic hyperplasia, bizarre-looking cells, and marked reticulin and collagen fibrosis.
• Radiographic studies: plain bone x-rays with osteosclerosis in 50% of cases.
• Diagnosis (Major WHO criteria): bone marrow biopsy, not meeting criteria for other MPDs, clonal marker (JAK2, CALR, MPL, or another clonal marker) [11].
• In addition to minor criteria (2) - leukoerythroblastosis, serum LDH, splenomegaly, anemia [23].

Natural Course [24]

• Usually indolent (median survival of 5 years) and variable.
• Poorest survival in >60yo, hemoglobin <10, WBC <4,000 or WBC >30,0000 [25].
• Eventually develop multifactorial anemia, massive splenomegaly with infarctions, compression, portal hypertension, thrombosis (40%), symptomatic tumors from extramedullary hematopoiesis, transformation to acute leukemia (5%).

Treatment [25,26]

• No therapy for asymptomatic low-risk patients, otherwise direct therapy to symptoms and complications as follows:
• Painful splenomegaly: Splenic irradiation or splenectomy (up to 30% mortality rate from post-operative portal vein thrombosis or sepsis) [27,28].
• Hypermetabolism and thrombosis: Hydroxyurea or alpha interferon (30-50% hematologic response rates) [29]. Low dose thalidomide + prednisone being explored (70% hematologic response in a small study) [30].
• Thrombosis: Aspirin controversial as in ET.
• Symptomatic extramedullary tumors: Radiation therapy.
• Potential curative approach for younger patients involves allogeneic peripheral stem cell or bone marrow transplantation if a suitable sibling donor is available with 30% treatment related mortality and 50% 5-year survival.
• Ruxolitinib can be used pre-transplant to increase the odds of successful engraftment [31].
• Other JAK inhibitors such as momelotinib, fedratinib, and pacritinib can help control symptoms but are generally not associated with superior survival [32].