Management of Myeloproliferative Disorders and Chronic Myeloid Leukemia

Ayalew Tefferi

The myeloproliferative neoplasms (MPN) are considered separate from the myelodysplastic syndromes (MDS) and are further classified into classic and nonclassic MPN (Table 46-1).¹ MPN represent stem cell-derived clonal myeloproliferation, and the disease initiating mutation has been defined in some but not all cases. The current chapter will focus on the classic MPN: essential thrombocythemia (ET), polycythemic vera (PV), primary myelofibrosis (PMF), and chronic myelogenous leukemia (CML).

ESSENTIAL THROMBOCYTHEMIA

ET is currently a diagnosis of exclusion and represents an acquired nonreactive thrombocythemic state that is not accounted for by another myeloid malignancy. The World Health Organization (WHO) diagnostic criteria requires evaluation of a bone marrow (BM) biopsy to establish a morphologic diagnosis of ET.² Approximately 60% of patients with ET carry the JAK2V617F mutation, which is a reliable clonal marker and thus can distinguish ET from reactive/secondary thrombocytosis.³ However, the particular mutation cannot distinguish ET from another MPN.

Diagnosis

A clinical diagnosis of ET first requires the exclusion of conditions that are associated with reactive thrombocytosis. Often, these are obvious and include iron deficiency anemia, surgical or functional asplenia, metastatic cancer, trauma (surgical or otherwise), acute bleeding or hemolysis, and a variety of infectious or inflammatory conditions (Table 46-2).⁴

When a cause for reactive thrombocytosis is not readily apparent, demonstration of increased acute-phase reactants (C-reactive protein, fibrinogen, and sedimentation rate) can be used as evidence for the presence of an occult inflammatory process. Once reactive thrombocytosis is considered to be an unlikely cause, a BM examination with cytogenetic studies, JAK2 mutation analysis, and fluorescence in situ hybridization (FISH) or RT-PCR for BCR-ABL1 is recommended to confirm the presence of an underlying MPN (as opposed to reactive thrombocytosis) and distinguish ET from CML, cellular phase PMF, MDS, and other myeloid malignancies (Fig. 46.1). Characteristic, but not diagnostic, BM features of ET include megakaryocyte hyperplasia and clustering without overt cellular dysplasia or granulocyte proliferation.

Clinical Aspects

The incidence of ET is estimated to be 2.5 per 100,000.⁵ Because life expectancy is near normal,⁶ the prevalence of the disease is severalfold higher. Several studies have reported a female preponderance in ET by approximately 2-fold compared with males.⁷ The median age at diagnosis is approximately 55 years, and as many as 20% of patients may be younger than 40 years. The disease is rare in children. One-fourth to one-third of the patients with ET may be totally asymptomatic at presentation; the remainder may report “vasomotor” symptoms or manifest thrombohemorrhagic complications. In addition, one-third to one-half may present with palpable splenomegaly.

Vasomotor symptoms occur in one-third of patients and include headache, lightheadedness, syncope, atypical chest pain, acral paresthesia, visual disturbances, livedo reticularis, and erythromelalgia. The last-named disorder refers to burning pain of the hands or feet associated with erythema and warmth. These events are usually controlled by treatment with low or standard doses of acetylsalicylic acid (ASA) (40 to 325 mg per day).⁸ Reported incidence rates of thrombosis and hemorrhage at diagnosis range from 9% to 22% and 3% to 37%, respectively.⁹ After diagnosis, these events occur in 7% to 17% and 8% to 14% of patients, respectively.

In the Mayo Clinic experience, transformation of the disease into PV, PMF, and acute myeloid leukemia (AML), in the first decade, was observed in 2.7%, 4%, and 1.4%, respectively.⁷ Reported incidence figures of leukemic conversion range from 0.6% to 5%.¹⁰ Leukemic conversion in ET has also occurred in the absence of previous therapy,¹¹ suggesting that the event may be a natural sequela of the disease that depends more on disease biology and duration than on specific therapy.

Prognosis

In a previously reported case-control study, the overall risk of thrombotic episodes in patients with ET was 6.6% per patient-year compared with 1.2% per patient-year in the control group.¹² A history of thrombosis (31.4% per patient-year) and age >60 years (15.1% per patient-year) were significantly associated with a high risk of thrombosis. The experience of many other investigators supports the above observations (Table 46-3).¹⁰ The lack of a significant correlation between platelet count and the risk of thrombosis has been consistently observed.¹³ Bleeding manifestations at initial presentation of ET have been significantly associated with extreme thrombocytosis (platelet counts >1 to 2 million per µl) and with the use
of antiplatelet therapy.¹⁴ On the other hand, the risk of major bleeding episodes during the clinical course of the disease is very low (<5%).¹³

Table 46-1 WHO Classification of Chronic Myeloid Malignancies

1.	MPN
	▪	Classic MPN
		CML, BCR-ABL1 positive PV PMF ET
	▪	Nonclassic MPN
		Chronic neutrophilic leukemia Chronic eosinophilic leukemia not otherwise specified Mastocytosis MPN, unclassifiable
2.	MDS
	▪	Refractory cytopenia with unilineage dysplasia
		— Refractory anemia — Refractory neutropenia — Refractory thrombocytopenia
	▪	Refractory anemia with ring sideroblasts
	▪	Refractory cytopenia with multilineage dysplasia
	▪	Refractory anemia with excess blasts
	▪	MDS with isolated del(5q)
	▪	MDS, unclassifiable
	▪	Childhood MDS
	▪	Refractory cytopenia during childhood
3.	MDS/MPN
	▪	Chronic myelomonocytic leukemia
	▪	Atypical chronic myeloid leukemia, BCR-ABL1 negative
	▪	Juvenile myelomonocytic leukemia
	▪	MDS/MPN, unclassifiable
	▪	Refractory anemia with ring sideroblasts and thrombocytosis
4.	Myeloid and Lymphoid Neoplasms Associated with Eosinophilia and Genetic Abnormalities
	▪	Myeloid and lymphoid neoplasms associated with PDGFRA rearrangement
	▪	Myeloid neoplasms associated with PDGFRB rearrangement
	▪	Myeloid and lymphoid neoplasms associated with FGFR1 abnormalities

Treatment

In one study, low-risk patients with ET were prospectively followed and evaluated for thrombohemorrhagic events.¹⁵ The incidence of thrombosis in the study patients (1.9 per 100 patient-years) was not significantly different from that of an age- and sex-matched control population (1.5 cases per 100 patient-years). Similarly, bleeding episodes occurred rarely (1.12 cases per 100 patient-years). Our experience with young women with ET was similar,¹⁶ and these data support the practice of observation alone, without cytoreductive therapy, in low-risk patients with ET. In addition, these patients are strongly advised to avoid the use of tobacco and high doses of ASA. However, low-dose aspirin is probably useful based on indirect evidence from a recently published randomized study in PV.¹⁷

The risk of recurrent thrombosis is unacceptably high in high-risk patients. In the only randomized study that evaluated the benefit of cytoreductive therapy in ET, hydroxyurea therapy was compared with no treatment in high-risk patients.¹⁸ At a median duration of follow-up of 27 months, the incidence of recurrent thrombosis was significantly lower in the hydroxyurea group (3.6% vs. 24%). Furthermore, in a head-to-head comparative study, hydroxyurea displayed overall therapeutic superiority over anagrelide in terms of both prevention of arterial thrombosis and drug tolerance.¹⁹ Therefore, cytoreductive therapy with hydroxyurea is recommended for high-risk patients with ET.

Some investigators are concerned about the potential leukemogenicity that is associated with the long-term use of hydroxyurea. However, reported incidence rates of acute leukemia in ET when this agent is used alone (0% to 5%) are not significantly different from the previously cited general incidence figures.¹⁰ Furthermore, recently published large studies in both ET¹¹ and PV²⁰ do not support an increased leukemic transformation rate associated with the use of single agent therapy with hydroxyurea. In women of childbearing age, interferon alpha (IFN-α) is considered to be the safest of the available agents.²¹

ET patients with platelet counts that are >1.5 million per µl might be at risk for bleeding because of an acquired von Willebrand syndrome (AvWS) associated with MPN with extreme thrombocytosis.²² It is therefore currently recommended that such patients be screened for AvWS, and ASA be held if there is a clinically significant presence of AvWS.

POLYCYTHEMIA VERA

PV is a clonal stem cell disease characterized by an increased red cell mass.²³ Erythrocytosis in PV is independent of the erythroid growth factor, erythropoietin (Epo). In 2005, a novel gain-of-function JAK2 mutation (JAK2V617F) was identified in almost all patients with PV, and the precise pathogenetic role of the specific mutation is currently under investigation.²⁴
The incidence of PV is estimated to be 2.3 per 100,000 per year, and the median age at diagnosis is approximately 60 years.²⁵ The disease affects both men and women equally but is rare in children.

Table 46-2 Causes of Thrombocytosis

Primary Thrombocytosis

Reactive Thrombocytosis

▪ ET

▪ PV

▪ Myelofibrosis with myeloid metaplasia (overt)

▪ Myelofibrosis with myeloid metaplasia (cellular phase)

▪ Chronic myeloid leukemia

▪ MDS

▪ Acute leukemia

▪ Infection

▪ Tissue damage

▪ Chronic inflammation

▪ Malignancy

▪ Rebound thrombocytosis

▪ Renal disorders

▪ Hemolytic anemia

▪ Post-splenectomy

▪ Blood loss

From Tefferi A, Barbui T. bcr/abl-negative, classic myeloproliferative disorders: diagnosis and treatment. Mayo Clin Proc. 2005;80:1220-1232.

Diagnosis

In the pre-JAK2V617F era, diagnosis in PV was based on consensus criteria that relied primarily on either measured variables (e.g., red cell mass, hematocrit [Hct], platelet count, and serum Epo level) or subjective technologies (e.g., BM histology); the two internationally recognized diagnostic criteria in this regard were fostered by the Polycythemia Vera Study Group (PVSG) and the WHO.²⁶^,²⁷ The WHO recently revised its diagnostic criteria for classic BCR-ABL1-negative MPN including PV, based primarily on the recognition that JAK2V617F is present in >95% of patients with PV (Table 46-4).

Figure 46.1 Diagnostic algorithm for ET. (From Tefferi A, Barbui T. bcr/abl-negative, classic myeloproliferative disorders: diagnosis and treatment. Mayo Clin Proc. 2005;80:1220-1232 with permission.)

Over 95% of patients with PV carry JAK2V617F.²⁸ Therefore, I recommend the incorporation of peripheral blood
mutation screening for JAK2V617F during the initial evaluation of a patient with suspected PV (Fig. 46.2). However, at the present time, the possibility of JAK2V617F-negative PV cannot be excluded, and therefore, I encourage the concomitant measurement of serum Epo level to minimize the chances of both false negative and false positive results from mutation screening alone (Fig. 46.2). JAK2 exon 12 mutation screening is appropriate in the presence of a subnormal serum Epo level and in the absence of JAK2V617F.

Table 46-3 Risk Stratification in ET and PV

Low Risk

Age <60 y

No history of thrombosis

High Risk

Age ≥60 y, or

Previous history of thrombosis

Clinical Aspects

Approximately 20% of patients with PV present with thrombotic events, including strokes, transient ischemic attacks, retinal artery or venous occlusions, coronary artery ischemia, pulmonary embolism, hepatic or portal vein thrombosis, deep vein thrombosis, and digital ischemia.⁹ The incidence of recurrent thrombosis depends on age, history of thrombosis, and the particular form of therapy. Bleeding complications are less frequent and less serious and have been significantly associated with the use of ASA.

Figure 46.2 A diagnostic algorithm for PV.

Leukemic conversions occur in <5% of patients with PV that is treated with phlebotomy alone. Treatment with certain agents, especially alkylating agents, increases the risk of acute leukemia. In contrast, specific therapy may or may not modify the risk of fibrotic transformation, which occurs in 10% to 30% of patients with PV who are followed for 10 to 25 years. Aquagenic pruritus (postbath) is a characteristic manifestation of PV that is difficult to treat.

Prognosis

Age and history of previous thrombosis are the most powerful predictors of recurrent thrombosis in PV.²⁹ Neither the degree of thrombocytosis nor the presence of platelet function abnormalities has been correlated with thrombotic risk. Patients with PV, similar to those with ET, can be stratified into defined risk groups that are managed differently (Table 46-3).

Treatment

In untreated patients, survival in PV is severely compromised (a median of <2 years) by fatal thrombotic complications. Thrombotic complications in PV are significantly reduced at Hct levels below 45%. Accordingly, with adequate phlebotomy alone (Hct <45% in males, <42% in females), the median survival in PV has been extended to >12 years.³⁰ However, recent data suggest that in ASA-treated patients with PV, Hct
levels of as high as 50% might be safe.³¹ To date, no other or additional therapy has been shown to offer a survival advantage over treatment with phlebotomy alone. Instead, when either chlorambucil or phosphorus 32 was added to phlebotomy, survival was significantly compromised because of an increased incidence of acute leukemia. The incidence of acute leukemia over 13 to 19 years was 1.5%, 9.6%, and 13.2% for phlebotomy alone, phlebotomy and phosphorus 32, and phlebotomy and chlorambucil, respectively.³⁰

Treatment of PV with phlebotomy alone is associated with an increased rate of early thrombosis, however. In a nonrandomized study by the PV Study Group, treatment with hydroxyurea was associated with a lower incidence of early thrombosis and also acute leukemia (5.9% after a median follow-up of 8.6 years).³⁰ Therefore, hydroxyurea treatment (starting dose 500 mg orally two times a day) is added in the presence of increased thrombohemorrhagic risk (Table 46-3). In addition, low-dose ASA (100 mg per day) has been shown to benefit all patients with PV in the absence of contraindications to ASA therapy.¹⁷

Table 46-4 World Health Organization Diagnostic Criteria for PV, ET, and PMF

2008 WHO Diagnostic Criteria
	Polycythemia Vera^a	Essential Thrombocythemia^a	Primary Myelofibrosis^a
Major criteria	Hgb >18.5 g/dl (men) >16.5 g/dl (women) or^b Presence of JAK2V617F or JAK2 exon 12 mutation	Platelet count ≥450×10⁹/L Megakaryocyte proliferation with large and mature morphology Not meeting WHO criteria for CML, PV, PMF, MDS, or other myeloid neoplasm Demonstration of JAK2V617F or other clonal marker or no evidence of reactive thrombocytosis	Megakaryocyte proliferation and atypia^c accompanied by either reticulin and/or collagen fibrosis, or^d Not meeting WHO criteria for CML, PV, MDS, or other myeloid neoplasm Demonstration of JAK2V617F or other clonal markeror no evidence of reactive marrow fibrosis
Minor criteria	BM trilineage myeloproliferation Subnormal serum Epo level EEC growth		Leukoerythroblastosis Increased serum LDH level Anemia Palpable splenomegaly
^aPV diagnosis requires meeting either both major criteria and one minor criterion or the first major criterion and two minor criteria. ET diagnosis requires meeting all four major criteria. PMF diagnosis requires meeting all three major criteria and two minor criteria. ^bHgb or Hct >99th percentile of reference range for age, sex, or altitude of residence or red cell mass >25% above mean normal predicted or Hgb >17 g/dl (men)/>15 g/dl (women) if associated with a sustained increase of ≥2 g/dl from baseline that cannot be attributed to correction of iron deficiency. ^cSmall to large megakaryocytes with aberrant nuclear/cytoplasmic ratio and hyperchromatic and irregularly folded nuclei and dense clustering. ^dIn the absence of reticulin fibrosis, the megakaryocyte changes must be accompanied by increased marrow cellularity, granulocytic proliferation, and often decreased erythropoiesis (i.e., pre-fibrotic PMF).
Key: EEC, endogenous erythroid colony; LDH, lactate dehydrogenase.