The Bethesda Handbook of Clinical Oncology

Yogen Saunthararajah

INTRODUCTION

Chronic myeloproliferative neoplasms (MPNs) are clonal diseases of myeloid precursors that stand out clinically because of an increase in at least one peripheral blood count or a substantial increase in bone marrow fibrosis. The World Health Organization (WHO) recognizes the following entities (Table 26.1):

1.Chronic myelogenous leukemia (CML), BCR-ABL positive

2.Chronic neutrophilic leukemia (CNL)

3.Polycythemia vera (PV)

4.Primary myelofibrosis (PMF)—PMF, prefibrotic early stage; PMF, overt fibrotic stage

5.Essential thrombocythemia (ET)

6.Chronic eosinophilic leukemia, not otherwise specified (NOS)

7.MPN, unclassifiable

TABLE 26.1The 2016 World Health Organization Classification Scheme for Myeloid Neoplasms (Sub-types of AML and MDS Not Shown)

1.Myeloproliferative neoplasms (MPN)

3.1Chronic myeloid leukemia (CML), BCR-ABL⁺

3.2Polycythemia vera (PV)

3.3Essential thrombocythemia (ET)

3.4Primary myelofibrosis (PMF)PMF, prefibrotic/early stage; PMF, overt fibrotic stage

3.5Chronic neutrophilic leukemia (CNL)

3.6Chronic eosinophilic leukemia, not otherwise specified (NOS)

3.7MPN, unclassifiable

2.MDS/MPN

4.1Chronic myelomonocytic leukemia (CMML)

4.2Juvenile myelomonocytic leukemia

4.3Atypical chronic myeloid leukemia (aCML), BCR-ABL^-

4.4MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T)

4.5MDS/MPN unclassifiable

3.Myeloid neoplasms associated with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1

5.1Myeloid neoplasms associated with PDGFRA rearrangement

5.2Myeloid neoplasms associated with PDGFRB rearrangement

5.3Myeloid neoplasms associated with FGFR1 rearrangement (8p11 myeloproliferative syndrome)

4.Myelodysplastic syndromes (MDS)

5.Acute myeloid leukemia (AML)

CML is discussed in Chapter 25 because of its unique treatment paradigm. This chapter is limited to a discussion of the three “classical” and more common MPNs: PV, ET, and PMF. These three neoplasms share clinical characteristics, including propensities to thrombosis and hemorrhage, splenomegaly, debilitating systemic symptoms, cytopenias of some lineages, and a risk of leukemic transformation. The overlap in clinical features, which sometimes confounds attempts at disease classification, reflects overlap at the level of causative mutations, illustrated by a common high frequency of the JAK2 V617F mutation. Common biologic strands are revealed also by evolution of both PV and ET into PMF in some patients, and a common risk for transformation into acute myeloid leukemia (AML). Overlap can also occur with myelodysplastic syndromes (MDS), and MDS/MPN overlap neoplasm is a classification recognized by the WHO.

PATHOPHYSIOLOGY AND DIAGNOSIS

Molecular Mechanism

The MPNs are clonal diseases driven by combinations of molecular abnormalities, most of which can be found in all the MPN subtypes, although individual mutations do have specific clinicopathologic associations. For example, the JAK2 mutation that substitutes phenylalanine for valine at position 617 (V617F) causes cytokine-independent (constitutive) activation of downstream messengers through the JAK-STAT, PI3K, and AKT pathways and is found in 95% of patients with PV and 50% to 60% with ET or idiopathic myelofibrosis. Mutated JAK2 is found in >50% of patients with Budd-Chiari syndrome suggestive of a masked myeloproliferative disorder. The CSF3R mutation is strongly linked with CNL. Inactivating mutations in EZH2 (a polycomb repressor complex component which is also deleted by chromosome 7q loss) are more evenly distributed, but do have an association with increased platelet counts. Inactivating mutations in another polycomb repressor component ASXL1 are highly associated with PMF, and interestingly, with transformation of PV or ET into PMF. Thus, the improving knowledge regarding the molecular basis of MPNs is useful for diagnosis and prognosis (Table 26.2), and hopefully increasingly useful in guiding therapy. Testing for the JAK2 V617F mutation by different techniques (polymerase chain reaction, restriction enzyme digestive pyrosequencing) is sensitive and specific, and readily available as a diagnostic tool.

TABLE 26.2WHO Diagnostic Criteria for Polycythemia Vera (PV), Essential Thrombocythemia (ET), and Primary Myelofibrosis (PMF)

PV (Requires all 3 Major, or First 2 Major and the Minor Criterion

ET (Requires All 4 Major Criteria, or First 3 Major and the Minor Criterion)

PMF (Requires All 3 Major and at Least 1 Minor Criteria)

Major criteria

1. Hgb >16.5 g/dL (men), >16.0 g/dL (women) OR Hematocrit >49% (men), >48% (women) OR increased red cell mass >25% above mean normal predicted value

2. BM biopsy showing hypercellularity for age with trilineage growth (panmyelosis) including prominent erythroid, granulocytic, and megakaryocytic proliferation with pleiomorphic, mature megakaryocytes

3. Presence of JAK2V617F or JAK2 exon 12 mutation

1. Platelet count ≥450 × 10⁹/L

2. BM biopsy showing proliferation mainly of megakaryocytes with large and mature morphology; no significant increase or left shift in neutrophil or erythroid proliferation, and very rarely minor (grade 1) increase in reticulin fibers.

3. Not meeting WHO criteria for BCR-ABL⁺CML, PV, PMF, MDS, or other myeloid neoplasms

4. Presence of JAK2, CALR, or MPL mutation

1. Megakaryocyte proliferation and atypia (pre PMF=without reticulin fibrosis>grade1; overt PMF=reticulin and/or collagen fibrosis ≥grade2), accompanied by increased age-adjusted BM cellularity, granulocytic proliferation, and often, decreased erythropoiesis

2. Not meeting WHO criteria for BCR-ABL⁺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

1. Subnormal serum erythropoietin level

1. Presence of a clonal marker or absence of evidence for reactive thrombocytosis

1. Anemia, not attributed to comorbidity

2. Leukocytosis ≥11 x 10⁹/L

3. Palpable splenomegaly

4. LDH above upper limit of normal

5. Leukoerythroblastosis (criterion for overt PMF)

Diagnosis and Distinguishing between the MPNs

The clinical presentation of MPNs can be with incidentally noted abnormal blood counts with patterns that vary depending on the particular MPN (Table 26.3). Distinctive clinical features relate to these lineage changes and splenomegaly.

TABLE 26.3Distinguishing Clinical Features of the Myeloproliferative Neoplasms

	CML	PV	ET	PMF
Hematocrit	N or ↓	↑↑	N	↓
WBC count	↑↑↑	↑	N	↑ or ↓
Platelet count	↑ or ↓	↑	↑↑↑	↑ or
Splenomegaly	++++	+	+	++++
Cytogenetic abnormality	Ph chromosome	±	−	±
LAP score^a	↓	↑↑	N or ↑	N or ↑
Marrow fibrosis	±	± or ↓	±	++++ (Dry tap)
Marrow cellularity	↑↑↑ Myeloid	↑↑	↑↑ Megakaryocytes	N or ↓
Basophils ≥2%	+	±	±	Usually +

a See Chapter 24.

CML, chronic myeloid leukemia; PV, polycythemia vera; ET, essential thrombocytopenia; MF, myelofibrosis; N, normal; WBC, white blood cell; LAP, leukocyte alkaline phosphatase; MPN, myeloproliferative neoplasm.

Symptoms and Signs: Increased red blood cell (RBC) mass and thus viscosity in PV can produce symptoms such as headaches, vertigo, tinnitus, and blurred vision, as well as arterial or venous thrombotic events. Another characteristic of PV in some patients is pruritus (histamine release) aggravated by hot water. Increased number of abnormal platelets in ET can cause arterial thrombotic events such as cerebrovascular ischemia, digital ischemia/erythromelalgia, and spontaneous abortions. Anemia in patients with MF may cause fatigue and shortness of breath, and splenomegaly can cause abdominal discomfort or early satiety. Hypermetabolic symptoms such as weight loss and sweating can be seen in MF but also in the other MPNs. Symptom burden can be semi-quantified using the MPN Symptom Assessment form for 20 items (MPN-SAF). Obviously prior transfusion and treatment history is highly pertinent information.

Bone marrow aspirate and biopsy: Morphologic examination should incorporate trichome and reticulin stains. Standard metaphase karyotyping can be supplemented with fluorescence in situ hybridization (FISH) especially if BCR-ABL⁺ CML is in the differential diagnosis.

Molecular testing: For JAK2 V617F mutation, and if negative, for CALR and MPL mutations if clinical impression is of ET or MF, and for JAK2 Exon 12 mutations if clinical impression is of PV.

Other relevant labs: Besides complete blood counts with differentials and peripheral smear, reticulocyte counts, LDH and D-dimer levels can be useful parameters to assist with evaluation and tracking of tumor burden and risks over-time. Serum erythropoietin levels and iron studies are pertinent also to diagnosis and management. Finally, human leukocyte antigen (HLA) testing and evaluation by a stem cell transplant team is appropriate for patients with PMF who might be stem cell transplant candidates.

Risk stratification is discussed below in the context of management.

Diagnosis summary As outlined earlier, there is overlap in the molecular underpinnings of MPNs, and thus, not surprisingly, in clinical behaviors. Nonetheless, the various MPN individual diagnoses do have differing types of complication, risks of complication, and prognoses. For example, prefibrotic (early) PMF, distinguishable from ET on the basis of BM morphology, has a higher risk of progressing to overt PMF or AML and has poorer survival than ET. Thus, there is clinical and treatment value in establishing a best-fit specific diagnosis. CML should be ruled out by performing a FISH analysis for BCR-ABL in JAK2 mutation-negative thrombocytosis or bone marrow fibrosis. Even with a positive JAK2 mutation or other clinical and peripheral blood observations to favor a particular MPN classification, bone marrow biopsy with cytogenetic analysis is recommended, to not miss a diagnosis of CML or MDS with accompanying prognostic and treatment implications. Platelet function tests or bleeding times are of little use in diagnosing or in guiding the management of MPNs.

PROGNOSIS

Median Survivals

Patients with PV have a median survival of 1.5 to 13 years. In a recent multicountry prospective study of 1,638 patients with PV, the 5-year event-free survival was 82%, with a relatively low risk of death from cardiovascular disease and a high risk of death from noncardiovascular causes (mainly hematologic transformations).

Patients with ET have a median survival of more than 10 years.

Patients with MF have a median survival between 3 and 5 years.

Rate of Transformation to Acute Leukemia

The estimated incidence of acute leukemia in 1,638 patients with PV prospectively followed in the European collaboration study on low-dose aspirin in polycythemia (ECLAP) study was 1.3%, with an estimated annual incidence of 0.5 per 100,000 per year. Older age and exposure to P32, busulfan, or pipobroman were independent risk factors.

The cumulative rate of transformation for patients with ET is 2% to 4%, respectively, at 10 and 20 years from diagnosis.

The cumulative rate of transformation for patients with MF is 10% at 10 years (please also see discussions on treatment regarding transformation risk).

Transformation of PV or ET into PMF

Both PV and ET may progress to post-PV PMF or post-ET PMF, previously referred to as the spent phase, which clinically resembles PMF and is characterized by progressive cytopenias, splenomegaly, and marrow fibrosis. The cumulative rate of transformation is 5% and 10% at 10 to 20 years, respectively, for ET, and 10% to 20% for the same time line for PV.

Risk Factors for Thrombosis

In two prospective studies, the ECLAP study and the MRC-PT1, the cumulative rate of cardiovascular events in patients with PV ranged from 2.5% to 5% per patient-year and from 1.9% to 3% per patient-year for patients with ET. Arterial thrombosis accounts for 60% to 70% of the events, and is the major cause of death.

In PV, older age (>60), a hematocrit ≥45%, and a previous history of thrombosis are risk factors. Surgery should be avoided in patients until a hematocrit <45% has been maintained for more than 2 months.

In ET, age over 60 years and the presence of other cardiovascular risk factors (e.g., smoking and previous thrombosis) increase the risk for thrombosis.

In ET, an association between platelet count and thrombosis has not been established, but platelet cytoreduction on treatment with hydroxyurea (HU) has been associated with a reduced risk.

Risk Factors for Hemorrhage

In ET, a platelet count >2 × 10⁶/µL is a risk factor for hemorrhage (please also see the recommendations regarding treatment).

TREATMENT

As a general principle, treatment for PV, ET, PMF, or overlaps thereof is aimed at (i) alleviating the particular symptoms present in the individual patient (e.g., symptoms from splenomegaly, pruritus, cytopenias) and (ii) anticipating and preventing potential life-threatening complications or risks such as thrombosis or hemorrhage. Accordingly, management is guided by formal assessments of risk as described below. Bone marrow transplantation is a potentially curative option that should be considered for some patients with PMF. Following is a definition of risk categories and recommended treatments, with an overview provided in Table 26.4.

TABLE 26.4Current Management Depending on Risk Stratification in PV, ET, and MF

Risk Category	PV	ET	PMF
Low	Low-dose aspirin (81–100 mg/day) + phlebotomy to maintain hematocrit <45% (consider <42% for females or if symptoms persist or progress)	Observation or low-dose aspirin (also for very low risk)	Individualize per predominant symptoms (e.g., anemia, splenomegaly, constitutional). Managing patients with both splenomegaly and cytopenias is where difficulties arise—consider pegylated IFN-α or DNMT1-depleting drugs (decitabine or 5-azacytidine) in such subjects. Please see text
Intermediate		Low-dose aspirin ± hydroxyurea	Consider stem cell transplant in transplant eligible intermediate-2 or high-risk subjects.
High	Low-dose aspirin + phlebotomy + hydroxyurea. Alternative to hydroxyurea for cytoreduction are IFN-α or ruxolitinib	Low-dose aspirin + hydroxyurea Alternative to hydroxyurea for cytoreduction is IFN-α especially for patients <60 years old

PV, polycythemia vera; ET, essential thrombocytopenia; PMF, myelofibrosis.

Polycythemia Vera

Low risk: Age <60 years and no personal history of vascular events, and who do not have additional risk factors for cardiovascular disease. Recommended treatment: phlebotomy alone (target hematocrit <45%) with or without low-dose aspirin (81–100 mg/day).

High risk: Age ≥60 years and/or a prior history of thrombosis. Recommended treatment: HU (with or without concomitant phlebotomy) and low-dose aspirin.

Maintaining a hematocrit <45% dramatically decreases the incidence of thrombotic complications. This is important, since in PV, 35% of initial thrombotic events are fatal. A randomized study of 518 patients with PV has shown that treatment with low-dose aspirin (100 mg per day) lowers the risk of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. For females, a lower threshold of <42% can be considered, especially if there are persistent or progressive symptoms.

Post-PV/ET PMF: Please see PMF management.

Pruritus: Intractable pruritus responds to IFN-α in up to 81% of patients. In low-risk patients in whom IFN-α is not indicated, paroxetine, a selective serotonin reuptake inhibitor, can alleviate symptoms in most cases.

Hyperuricemia: Allopurinol should be started before chemotherapy to decrease the risk of urate nephropathy (300 mg per day given orally; dose reduction needed in renal insufficiency).

Essential Thrombocythemia

Treatment is primarily directed at preventing thrombosis and/or hemorrhage, and risk stratification is mostly a means to guide the use of cytoreductive treatments, to avoid potential risks of triggering more aggressive transformation of disease by unnecessary early application of cytotoxic/cytostatic treatment with hydroxyurea. Other cardiovascular risk factors should be concurrently managed.

Very Low risk: Age ≤60 years, no JAK2 mutation, no history of thrombosis.

Recommended treatment: observation or low-dose aspirin, especially if there are symptoms or cardiovascular risk factors (e.g., smoking). Cytoreductive therapy is not an upfront consideration, but could be needed for progressive increase in platelet counts to ≥1,500 x10⁹/L. In this instance, also consider possibility of acquired von Willebrand’s disease (ristocetin cofactor activity <30%). Other reasons to consider cytoreductive therapy are symptomatic splenomegaly or thrombocytosis, B-symptoms, new thrombosis or hemorrhage, or progressive thrombocytosis or leukocytosis. If cytoreductive treatment needed, consider IFN-α rather than hydroxyurea in these younger patients.

Low risk: As above but with JAK2 mutation.

Recommended treatment: As above.

Intermediate risk: Age >60 years, no JAK2 mutation, no history of thrombosis.

Recommended treatment: Aspirin 81–100 mg. In addition, cytoreductive therapy with hydroxyurea or IFN-α could be an upfront consideration.

High risk: Age >60 years and/or a previous history of thrombosis.

Recommended treatment: Aspirin 81–100 mg/day and in addition, cytoreduction with hydroxyurea or IFN-α.

A randomized trial of hydroxyurea versus placebo in 114 high-risk patients showed a significant reduction of thrombotic events in the treatment arm (3.6% vs. 24%). The hydroxyurea dose was adjusted to achieve a platelet count of <600 × 10⁹/L. Anagrelide is a nonmutagenic orally active agent that produces selective platelet cytoreduction by interfering with megakaryocyte maturation. In a randomized study of 809 patients with high-risk ET, hydroxyurea plus low-dose aspirin was superior to anagrelide plus low-dose aspirin. IFN-α can also effectively cause platelet cytoreduction and is preferred in younger patients. The therapeutic target platelet count in this trial was <400 × 10⁹/L. Plateletpheresis is used as an emergency therapy when ongoing thrombosis cannot be adequately managed with chemotherapy and antithrombotic agents.

Myelofibrosis

Risk stratification by the Dynamic International Prognostic Scoring System Plus (DIPSS Plus) determines whether a patient should be considered upfront for stem cell transplant if they are a transplant candidate (for DIPSS intermediate-2 or high-risk patients). Otherwise, for low risk or intermediate-1 risk patients, or non-transplant candidate higher risk patients, management is directed toward relieving symptoms caused by splenomegaly or cytopenias, and decreasing risk of further progression.

Risk stratification by DIPSS Plus: one point each for age >65 years, white blood cell count >25 × 10⁹/L, circulating blast cells ≥1%, presence of constitutional symptoms, unfavorable karyotype, platelet count <100 × 10⁹/L, and transfusion dependence, and two points for hemoglobin <10 g/dL.

Low risk: 0 points, median survival 20 years. Intermediate risk-1: 1 point, median survival 6.5 years. Intermediate risk-2: 2 to 3 points, median survival 2.9 years. High risk: 4 to 6 points, median survival 1.7 years.

Anemia: Androgens (e.g., danazol) combined with prednisone (prednisone is tapered after a few weeks) is an option, with the caution that danazol can potentially exacerbate thrombotic risk. There is some data to support use of lenalidomide (especially if there is a 5q– chromosome abnormality) or thalidomide combined with prednisone, although again, possible increase in thrombotic risk should be considered with thalidomide, and results have been mixed. Erythropoietin replacement is a consideration in patients with inappropriately low erythropoietin levels (<500 mU/mL in the setting of anemia can be considered as inappropriately low). DNMT1-depleting drugs (decitabine or 5-azacytidine) that are approved for treatment of MDS can also alleviate anemia and thrombocytopenia in PMF, and can be considered, although the optimal doses and regimens to use, especially for decitabine, are still being evaluated, with lower dose, more frequent administration likely to be more rational based on mechanism of action (5-azacytidine and decitabine are both pro-drugs that are metabolized differently and it is possible that decitabine could have more activity than 5-azacytidine in the context of PMF cellular metabolism). Transfusion needs may diminish after splenectomy (see below). Iron chelation may be indicated for transfusion-dependent patients.

Splenomegaly: Options include JAK2 inhibitor (ruxolitinib) if there is no significant anemia and platelets are >50 x10⁹/L, although the currently approved dosages may be unnecessarily high, and it may be appropriate to start with lower than standard dosages with an escalation if necessary. The main cautions are that ruxolitinib has a high chance of lowering platelet and hemoglobin levels, which is why it may be appropriate to sometimes start at lower than approved doses in the package insert, and for rebound disease growth and inflammatory symptoms if the drugs are discontinued abruptly (dosage should be tapered off rather than abruptly discontinued). Lenalidomide can be considered if there is a 5q– abnormality. HU can be considered, with dose modifications depending on cytopenias. Difficulties arise when confronted with symptomatic splenomegaly and clinically significant anemia or thrombocytopenia. Other treatment options to consider in this circumstance, with an eye to ongoing clinical trials, are pegylated IFN-α or DNMT1-depleting drugs (decitabine or 5-azacytidine). Splenectomy is an option to alleviate pain and early satiety, depending on local surgical experience and thus surgical risk. Secondary progressive hepatomegaly is a potential long-term complication of splenectomy. Increasing white blood cell counts and platelet counts after splenectomy may necessitate HU therapy. Also a possible consideration depending on local expertize is splenic artery embolization via interventional radiology. Analgesia may be required for splenic infarct pain, whether or not a patient has splenic artery embolization.

Curative therapy: Allogeneic transplantation should be considered for intermediate-2 or high risk patients who are transplant candidates. Five-year survivals with a related or an unrelated matched transplant have been reported at 54% and 48%, respectively, by the European Group for Blood and Marrow Transplantation (EBMT). A recommendation for transplantation is not clear-cut in lower risk patients because the median survival in this group is >14 years with non-transplant therapy. In other words, risk classification should be considered, and although the outcome with transplantation is adversely affected by risky characteristics, risk factors such as hemoglobin level <10 g/dL; white blood cell count <4 × 10³/µL or >30 × 10³/µL; more than 10% of circulating blasts, promyelocytes, or myelocytes; or abnormal cytogenetics should prompt consideration for transplantation. Pretransplantation splenectomy, although not necessary in every patient, is associated with faster engraftment and can be considered in those with massive splenomegaly. Marrow fibrosis is reversible with transplantation.