Myeloproliferative Neoplasms

GENERAL PRINCIPLES

MPNs are a group of hematologic malignancies characterized by clonal expansion of a hematopoietic stem cell resulting in overproduction of mature, largely functional cells.

DIAGNOSIS

Diagnostic Criteria

• PV

î Criteria for the diagnosis of PV have been updated in the WHO 2016. The diagnosis of PV requires meeting either all three major criteria, or the first two major criteria and the minor criterion²¹ (Table 21-5).

TABLE 21-5

WHO 2016 DIAGNOSTIC CRITERIA FOR POLYCYTHEMIA VERA

Major Criteria

1. Hgb gt;16.5 g/dL in men and Hgb gt;16.0 g/dL in women

Or

Hct gt;49% in men and Hct gt;48% in women

Or

Increased red cell mass more than 25% mean normal predicted value

2. BM biopsy showing Mypercellularity for age with trilineage growth (panmyelosis) including prominent erythroid, granulocytic, and megakaryocytic proliferation with pleomorphic, mature megakaryocytes (differences in size)

3. Presence of JAK2 V617F mutation or JAK2 exon 12 mutation

Minor Criteria

Subnormal serum erythropoietin level

Diagnosis of PV requires meeting either all three major criteria or the first two major criteria and the minor criterion

BM, bone marrow; Hct, hematocrit; Hgb, hemoglobin; PV, polycythemia vera; WHO, World Health Organization.

Reprinted from Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia.

• PMF

î The WHO 2016 diagnostic criteria for PMF are listed in Table 21-6.²¹ The updated classification has divided PMF into pre-PMF and overt PMF. For both pre-PMF and overt PMF, all three major criteria and at least one minor criterion need to be met for the diagnosis.

TABLE 21-6

WHO 2016 DIAGNOSTIC CRITERIA FOR PRIMARY MYELOFIBROSIS (PMF)

Pre-PMF Criteria

Major Criteria

1. Megakaryocytic proliferation and atypia, without reticulin fibrosis gt;grade 1, accompanied by increased age-adjusted BM cellularity, granulocytic proliferation, and often decreased erythropoiesis

2. Not meeting the WHO criteria for BCR-ABLl CML, PV, ET, MDS, or other myeloid neoplasms

3. Presence of JAK2, CALR, or MPL mutation or in the absence of these mutations, presence of another clonal marker, or absence of minor reactive BM reticulin fibrosis

Minor Criteria

Presence of at least one of the following, confirmed in two consecutive determinations:

a. Anemia not attributed to a comorbid condition

b. Leukocytosis #8805;11 ? 10⁹#8725;L

c. Palpable splenomegaly

d. LDH increased to above upper normal limit of institutional reference range

Diagnosis of pre-PMF requires meeting all three major criteria and at least one minor criterion

Overt PMF criteria

Major Criteria

1. Presence of megakaryocytic proliferation and atypia, accompanied by either reticulin

and/or collagen fibrosis grades 2 or 3

2. Not meeting WHO criteria for ET, PV, BCR-ABLl CML, MDS, or other myeloid neoplasms

3. Presence of JAK2, CALR, or MPL mutation or in the absence of these mutations, presence of another clonal marker, or absence of reactive myelofibrosis

Minor Criteria

Presence of at least one of the following, confirmed in two consecutive determinations:

a. Anemia not attributed to a comorbid condition

b. Leukocytosis #8805;11 ? 10⁹#8725;L

c.

d. LDH increased to above upper normal limit of institutional reference range

e. Leukoerythroblastosis

Diagnosis of overt PMF requires meeting all three major criteria and at least one minor criterion

BM, bone marrow; CML, chronic myelogenous leukemia; ET, essential thrombocythemia; LDH, lactate dehydrogenase; MDS, myelodysplastic syndrome; PV, polycythemia vera; WHO, World Health Organization.

Reprinted from Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391-2405. Copyright © 2016 Elsevier. With permission.

Diagnostic Testing

• Patients with PV typically present with an elevated Hct but may also have elevations in WBC or platelet count. The JAK2V617F mutation is present in gt;95% of patients. A low EPO level is often present. PV patients who do not have a JAK2V617F mutation may have a JAK2 exon 12 mutation.

• Patients with PMF may present with leukocytosis or cytopenias (i.e., anemia) and may have mutations in JAK2 (50%), MPL (10%), or calreticulin (CALR) (40%). Immature granulocytes, tear drop cells, and nucleated RBCs may be seen on the peripheral blood smear (leukoerythroblastic smear).

DIAGNOSTIC PROCEDURES

A BM biopsy should be included in the diagnostic workup of PMF, including reticulin stain, to evaluate for fibrosis. A BM biopsy may not be required for PV in cases with sustained absolute erythrocytosis defined as an Hgb gt;18.5 g/dL in men or gt;16.5 g/dL in women. Cytogenetic studies should be performed and have a significant impact on prognosis in PMF.²²

TREATMENT

• PV: The main goal of treatment is to decrease the risk of thrombotic complications by maintaining the Hct lt;45.²³ All patients are recommended to be on aspirin 81 mg/d in the absence of bleeding contraindications.

î In patients with low risk for thrombosis (age lt;60 years, no history of thrombosis): serial phlebotomy to keep goal Hct lt;45% in men and lt;42% in women.

î Patients with high risk for thrombosis (age gt;60 years, prior thrombosis) should be treated initially with serial phlebotomy and hydroxyurea, with the ultimate goal of maintaining Hct lt;45% in men and lt;42% in women on hydroxyurea without the need for phlebotomy.

î Ruxolitinib 10 mg twice a day, a JAK inhibitor first approved for treatment of myelofibrosis, is approved by the FDA for the treatment of PV in patients who fail hydroxyurea therapy. Ruxolitinib

has been shown to improve pruritus.²⁴

î Ropeginterferon alfa-2b is an emerging therapy for patients with PV and demonstrated noninferiority to hydroxyurea in inducing hematological responses.²⁵

• PMF: Patients are risk-stratified based on several prognostic scoring systems and treatment depends on the risk category.²² Treatment may not be needed for low-risk patients.

î Low-dose aspirin should be started to decrease the risk of thrombosis in the absence of significant thrombocytopenia.

î Cytoreductive agents such as hydroxyurea have been used historically to improve leukocytosis but do not significantly improve constitutional symptoms or splenomegaly and can cause myelosuppression.

î Allogeneic hematopoietic SCT is the only curative therapy and should be considered for high-risk patients.

î JAK inhibitors such as ruxolitinib and fedratinib are approved for the treatment of patients with intermediate- and high-risk myelofibrosis. They are effective in improving constitutional symptoms and splenomegaly.^26,27

î Splenectomy may be considered for painful splenomegaly in patients intolerant to or not responsive to the JAK inhibitor; however, it is associated with an increased risk for thrombosis and infections.

î Involved-field radiotherapy may also offer symptomatic relief for drug-refractory splenomegaly or sites of extramedullary hematopoiesis; however, the effects are usually transient.