THE TWO GUIDING principles that I learned during my medical training were that (1) disease presentations are heterogeneous and (2) therapy must be “individualized.” The article by Harrison et al1 in this issue of BLOODaddresses both of these issues by carefully defining the incidence of clonal and nonclonal hematopoiesis in patients given the clinical diagnosis of essential thrombocythemia (ET).

ET is one of the four myeloproliferative disorders (MPDs; with chronic myelogenous leukemia [CML], polycythemia vera [PV], and myelofibrosis [MF] constituting the others), but unlike CML, there is no cytogenetic or molecular abnormality that definitively establishes its diagnosis. Rather, the diagnosis of ET is made when a patient has an elevated platelet count, increased numbers of megakaryocytes in the bone marrow, no identifiable underlying abnormality known to cause thrombocytosis, and the absence of findings suggestive of a different MPD (see Table 1 for the current diagnostic criteria of the Polycythemia Vera Study Group).

Table 1.

Diagnostic Criteria: Essential Thrombocythemia

I.  Platelet count >600,000/μL 
II.  Hematocrit <40, or normal RBC mass (males <36 mL/kg, females <32 mL/kg) 
III.  Stainable iron in marrow or normal serum ferritin or normal RBC mean corpuscular volume* 
IV.  No Philadelphia chromosome or bcr/abl gene rearrangement 
V.  Collagen fibrosis of marrow 
 A. Absent or 
 B.  <13 of biopsy involved and neither marked splenomegaly nor a leukoerythroblastic reaction 
VI.  No cytogenetic or morphologic evidence for a myelodysplastic syndrome 
VII. No cause for reactive thrombocytosis 
I.  Platelet count >600,000/μL 
II.  Hematocrit <40, or normal RBC mass (males <36 mL/kg, females <32 mL/kg) 
III.  Stainable iron in marrow or normal serum ferritin or normal RBC mean corpuscular volume* 
IV.  No Philadelphia chromosome or bcr/abl gene rearrangement 
V.  Collagen fibrosis of marrow 
 A. Absent or 
 B.  <13 of biopsy involved and neither marked splenomegaly nor a leukoerythroblastic reaction 
VI.  No cytogenetic or morphologic evidence for a myelodysplastic syndrome 
VII. No cause for reactive thrombocytosis 
*

If these measurements suggest iron deficiency, PV cannot be excluded unless a trial of iron therapy fails to increase the RBC mass into the polycythemic range.

Modified and reprinted with permission.12 

The treatment of ET is designed to prevent or reduce the risk of its complications, which are most commonly related to vaso-occlusion or hemorrhage and are often neurologic. There are no predictive tests to determine who will develop hemostatic complications, but the risk varies according to age, platelet count, duration of disease, prior symptoms, and the presence or absence of other medical conditions.2 The treatment of ET can vary from no treatment (ie, observation) or low-dose aspirin for low-risk patients, to treatment with hydroxyurea, α-interferon, or Anagrelide, often in combination with aspirin, for patients with intermediate-risk or high-risk disease.3 ET can evolve into myelofibrosis and, rarely, into acute leukemia (in roughly 3% to 5% of cases).4 

Myeloproliferative disorders such as ET are generally thought to be stem cell disorders, yet clonality has not been universally found in several analyses of ET patients. Clonality restricted to the megakaryocytic lineage has been reported,5 but clonality can be difficult to demonstrate for a variety of reasons, as discussed in Harrison et al.1 Methodologies used to assess clonality have included analysis of G6PD isoenzymes, X-linked polymorphisms, and DNA methylation patterns of X-linked genes.

In the report by Harrison et al,1 the investigators examined X-chromosome inactivation patterns to assess clonality in a population of 46 female patients with an elevated platelet count, in whom secondary causes of thrombocythemia had been ruled out. This group, and others, have previously shown that skewing of XCIPs occurs commonly in females more than 65 years of age (by comparing the XCIP pattern in neutrophils v T cells).6,7 Of the 46 patients with ET, they found 23 that were suitable for XCIP clonality analysis. Ten of these patients (43%) clearly demonstrated clonal hematopoiesis, whereas 57% had polyclonal disease, illustrating the heterogeneity of patients given a clinical diagnosis of ET. The incidence of clonality was not related to the age of the patient, the platelet count, or the duration of disease. No patients in this series developed acute myelogenous leukemia (AML), but 2 patients, both with clonal disease, developed myelofibrosis. The incidence of thrombotic, but not hemorrhagic, events appeared to be less in patients with polyclonal hematopoiesis.

This report raises many important issues about the management of patients with ET, and future studies will hopefully address whether patients with clonal disease should be treated differently than those with nonclonal disease. Studies of patients with familial ET suggest that clonality is not required for the development of hemostatic complications, although it may increase the risk of such events. The risk of developing AML, and myelofibrosis, is probably higher in patients with clonal disease; thus, the presence of clonal abnormalities may guide the choice of cytoreductive treatment, avoiding agents with leukemogenic potential.

Molecular abnormalities in the thrombopoietin (TPO) gene have recently been found in several families with an autosomal dominant form of hereditary thrombocythemia, suggesting at least one mechanism for nonclonal ET. TPO is a major regulator of platelet production, and the circulating level of TPO generally varies inversely with the number of platelets in the blood and megakaryocytes in the bone marrow. In two families with hereditary thrombocythemia (HT), abnormalities in the 5′ UTR of the TPO gene were detected in affected but not unaffected individuals, which generate aberrantly spliced TPO mRNAs and overproduction of TPO. Affected individuals have an elevated platelet count and an elevated TPO level.8,9 Elevated TPO levels have also been found in nonfamilial ET and in reactive thrombocytosis,10 but there has been only a limited search for molecular defects in these individuals. Neither of these studies examined hematopoietic progenitor cell clonality in HT, but a third study has demonstrated polyclonal hematopoiesis in affected members of an HT family.11 Recurrent hemostatic abnormalities have been reported in some, but not all HT families; however, the clonality of the hematopoietic progenitors in these instances was not described. Although TPO administration itself does not appear to activate platelets in vivo, hemostatic abnormalities could occur as a result of chronic, persistent thrombocytosis and possibly the presence of other risk factors.

Further study of patients with ET is necessary to confirm the findings in Harrison et al1 and to address some of the questions raised in Table 2. This disorder remains a diagnosis of exclusion, but someday it should be possible to identify subgroups of patients who are particularly at risk for thrombotic or hemorrhagic complications or progression to AML or MF, so that specific algorithms can be applied to patient management. We may soon be able to refer to thrombocytosis that is clonal as thrombocythemia vera and consider all nonclonal disorders (whether due to increased TPO production, iron deficiency, etc) as secondary thrombocythemia. Further efforts to define the clonality and molecular abnormalities of ET and the other MPDs will allow us to better understand their heterogeneity and better individualize therapy.

Table 2.

Clonal Versus Nonclonal ET: Some Remaining Questions

1.  Can nonclonal ET progress to clonal disease? 
2.  What is the incidence of megakaryocyte restricted clonality? 
3.  How common are mutations in the TPO gene? 
4.  Are patients with clonal disease the only ones at risk for transformation to AML? 
5.  Does the incidence of thrombotic complications vary depending on clonality? 
6.  Should clonality affect the choice of cytoreductive therapy? 
7.  When will we be able to routinely distinguish thrombocythemia vera from secondary thrombocythemia? 
1.  Can nonclonal ET progress to clonal disease? 
2.  What is the incidence of megakaryocyte restricted clonality? 
3.  How common are mutations in the TPO gene? 
4.  Are patients with clonal disease the only ones at risk for transformation to AML? 
5.  Does the incidence of thrombotic complications vary depending on clonality? 
6.  Should clonality affect the choice of cytoreductive therapy? 
7.  When will we be able to routinely distinguish thrombocythemia vera from secondary thrombocythemia? 

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Author notes

Address reprint requests to Stephen D. Nimer, MD, Division of Hematologic Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, Box 575, New York, NY.