Myeloproliferative Disorder Overlap Syndrome: How Should it be Approached?

Myeloproliferative Disorder Overlap Syndrome: How Should it be Approached?

Comprehensive Review Myelodysplastic/Myeloproliferative Disorder Overlap Syndrome: How Should it be Approached? Mark R. Litzow Abstract The chronic my...

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Comprehensive Review Myelodysplastic/Myeloproliferative Disorder Overlap Syndrome: How Should it be Approached? Mark R. Litzow Abstract The chronic myeloid disorders are typically divided into myelodysplastic syndromes (MDS) and myeloproliferative disorders (MPD). However, there are a group of disorders with overlapping features of MDS and MPD. The World Health Organization has recently reclassified hematologic disorders and included a category of MDS/MPD overlap syndromes, which include chronic myelomonocytic leukemia, atypical chronic myelogenous leukemia, juvenile myelomonocytic leukemia, and MDS/MPD unclassifiable, which includes the provisional entity refractory anemia with ringed sideroblasts associated with marked thrombocytosis (RARS-T). These latter 4 disorders remain largely enigmatic in their pathogenesis, have a poor prognosis, and limited therapeutic options. However, the JAK2-V617F mutation has recently been discovered in a large majority of patients with RARS-T and might have future therapeutic implications. The approach to the management of these MDS/MPD overlap syndromes largely relies on extrapolation from the management of other MDS and MPD disorders that are similar to the MDS/MPD overlap syndromes. Clinical Leukemia, Vol. 1, No. 2, 95-100, 2006 Key words: JAK2, Myeloid neoplasms, Nosology, Thrombocytosis

Introduction The science of nosology of diseases remains an important mechanism by which physicians and scientists classify, diagnose, communicate, research, and ultimately treat disease. However, such classification systems have inherent limitations related to ongoing ignorance of the causes and mechanisms of disease. These classification schemes sometimes artificially limit clinicians’ thinking about particular patients or groups of patients whose clinical presentation does not fit into one of the described categories. These opportunities and limitations certainly exist in the diseases characterized as chronic myeloid disorders. In 1951, William Dameshek made seminal observations linking the chronic myeloproliferative disorders (MPDs) together.1 Currently, “classical” MPDs are considered to be chronic myelogenous leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis with myeloid metaplasia (MMM).2 The prescient nature of Dameshek’s observation came to fruition in 2005 with the identification of an activating somatic point mutation of the Janus tyrosine kinase 2 (JAK2) gene that was frequently found in patients with PV, thrombocythemia, and MMM (discussed in detail herein).3

French-American-British Classification In the same year that Dameshek proposed his classification of the myeloproliferative syndromes came the first description of the myelodysplastic syndromes (MDSs).4 The classification of these syndromes was, however, not uniform for many years after this initial observation, and difficulty ensued in communicating about and understanding these disorders. Mayo Clinic College of Medicine, Rochester, MN Submitted: September 21, 2006; Revised: October 28, 2006; Accepted: November 3, 2006 Address for correspondence: Mark R. Litzow, MD, Mayo Clinic College of Medicine, Department of Hematology, 200 First St SW, Rochester, MN 55905 Fax: 507-266-4972; e-mail: [email protected] Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1931-6925, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.


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Myelodysplastic/Myeloproliferative Disorder Overlap Syndrome

Table 1

World Health Organization Classification of Chronic Myeloid Neoplasms9

Myeloproliferative Diseases Chronic myelogenous leukemia, Philadelphia chromosome–positive (t[9;22][q34;q11], bcr-abl) Chronic neutrophilic leukemia Chronic eosinophilic leukemia/hypereosinophilic syndrome Chronic idiopathic myelofibrosis

in situ hybridization, and polymerase chain reaction (PCR), were shown to identify subtypes of acute leukemia and chronic myeloid disorders with distinct clinicopathologic features and natural histories.7 A history of cytotoxic therapy for another disease and/or an antecedent history of a MDS were also shown to have a significant impact on the natural history and sometimes on the morphologic features of subtypes of acute leukemia and myelodysplastic disorders.8 It was also recognized that other atypical MPDs had not been incorporated into a uniform classification scheme.

Polycythemia vera

World Health Organization Classification

Essential thrombocythemia

On the basis of these advances and the limitations noted previously, the Society for Hematopathology and the European Association for Hematopathology jointly developed a classification of hematologic neoplasms for the World Health Organization (WHO; Table 1).9 In the MDSs, many of the components of the FAB classification scheme were retained, including the categories of RA, RARS, and RAEB. The category of RAEB in transformation was eliminated because studies demonstrated a survival pattern for patients with 20%-30% blasts that was similar to patients with  30% blasts in the BM.10 The category “refractory cytopenia with multilineage dysplasia” was added to recognize patients with > 5% blasts in their BM who have significant dysplasia involving the megakaryocytic and granulocytic cell lines. These patients appear to have a poorer prognosis than patients without multilineage dysplasia.11 The identification of an interstitial deletion in the long arm of chromosome 5 in a group of patients with unique morphologic features and its association with a relatively good prognosis justified the inclusion of a distinct entity of MDS in the WHO classification known as the (del)5q syndrome.12,13 The WHO also defined a MDS that had < 5% blasts in the BM, the presence of neutropenia or thrombocytopenia, but with dysplasia restricted to the neutrophil or megakaryocytic cell line and, therefore, could not be categorized within the other designated MDSs and was referred to as MDS, unclassified.14 Within the WHO classification of the chronic MPDs, the classic disorders of CML (Bcr-Abl positive), PV, thrombocythemia, and MMM (referred to as chronic idiopathic myelofibrosis) were retained.15 The rarer, chronic neutrophilic leukemia, was added and defined.16,17 The disorder chronic eosinophilic leukemia/hypereosinophilic syndrome was also added as a distinct entity.18-20 Finally, as in myelodysplasia, the disorder “chronic myeloproliferative disease, unclassifiable” was acknowledged.9 Patients with this disorder were believed to represent those who lack a bcr-abl gene rearrangement and were in the initial stages of PV, thrombocythemia, or MMM in which the characteristic features of the disease had not yet fully developed, or were in an advanced late stage of a chronic MPD that could include myelofibrosis and osteosclerosis but in which the underlying disorder was obscure.21 In 2005, the discovery of an activating mutation in exon 12 of the JAK2 at position 617, substituting a phenylalanine for a valine, was described by 5 groups nearly simultaneously. This activating mutation in JAK2 was found frequently in patients with the classic Bcr-Abl–negative MPDs in anywhere from two thirds up to nearly 100% of patients with PV and in one third to one half of patients with thrombocythemia or MMM.22-27 The frequency of this mutation in

Myeloproliferative disorder, unclassifiable Myelodysplastic/Myeloproliferative Diseases Chronic myelomonocytic leukemia Atypical chronic myelogenous leukemia Juvenile myelomonocytic leukemia Myelodysplastic/myeloproliferative disease, unclassifiable Provisional entity: refractory anemia with ringed sideroblasts–thrombocytosis Myelodysplastic Syndromes Refractory anemia With ringed sideroblasts Without ringed sideroblasts Refractory cytopenia with multilineage dysplasia Refractory anemia with excess blasts (del)5q syndrome Myelodysplastic syndrome, unclassifiable Adapted with permission from Harris et al. World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee Meeting-Airlie House, Virginia, November 1997. J Clin Oncol 1999; 17:3835-3849.

They were, however, often referred to, as “pre-leukemias” because the bone marrow (BM) biopsy specimens of patients with these disorders contained a higher percentage of blast cells than normal, although not a sufficient number to fulfill the diagnosis of acute leukemia. Further clarification ensued after the proposed classification of the acute leukemias by the French-American-British (FAB) Cooperative Group in 1976.5 In 1982, the FAB Group further refined and delineated subcategories of MDSs and characterized 5 categories, including (1) refractory anemia (RA), (2) RA with ring sideroblasts (RARS), (3) RA with excess blasts (RAEB), (4) RAEB in transformation, and (5) chronic myelomonocytic leukemia (CMML).6 This study defined the cutoff for a diagnosis of acute myelogenous leukemia (AML) to be  30% BM blasts. This classification scheme, like its counterpart for the acute leukemias, became the standard among hematopathologists and hematologists for the classification of the MDSs in the ensuing years. However, as with any classification scheme, the limitations of the FAB classification schemas became more apparent with time. In particular, it was recognized that patients with morphologic features of MDS in their BM who had other cytopenias besides anemia did not fit into the proposed classification schema well. The widespread use of genetic assays, including cytogenetics, fluorescence


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Mark R. Litzow the classic Bcr-Abl–negative MPDs has important diagnostic and classification implications for our understanding of the MPDs and will likely have therapeutic implications in the future, as has been recently summarized.28,29 The presence of this activating mutation in other chronic myeloid disorders, such as the MDSs or MDS/MPDs, has been relatively uncommon.30-32

Myelodysplastic/Myeloproliferative Diseases The WHO classification scheme acknowledged that there are a group of disorders that share features of proliferation and prominent dysplasia and categorized them as MDS/MPD. Within this category were placed CMML, atypical CML, juvenile myelomonocytic leukemia (JMML), and myelodysplastic/myeloproliferative diseases, unclassifiable (Table 1).33

that of classic Bcr-Abl–positive CML.45 Patients typically present with anemia and/or thrombocytopenia but can also often have splenomegaly.45-48 The prognosis of these patients is poor with median survival times < 20 months.45,47 Significant anemia and thrombocytopenia are poor prognostic factors, and one quarter to one third of patients have disease that will evolve to acute leukemia, whereas the remainder can die of marrow failure.47,48 As anticipated, imatinib is ineffective in the treatment of these patients.49 Patients with atypical CML are in a similar situation to patients with CMML. Those with poor prognostic features have a poor outcome with conventional therapy, and allogeneic BMT should be considered for any patient with this disorder who is a BMT candidate, although experience in this setting is small.50

Juvenile Myelomonocytic Leukemia Chronic Myelomonocytic Leukemia In recognition that some patients with CMML have an increased white blood cell count and splenomegaly, CMML was reclassified from the old FAB classification as a MDS into this hybrid entity.9 Chronic myelomonocytic leukemia remains an enigmatic entity despite this reclassification. Patients with CMML are subject to many of the challenges faced by other patients with MDS and MPS in that there is no well-defined genetic abnormality underlying the disease, the clinical presentation is heterogeneous, and many patients are elderly and not candidates for intensive therapy that can sometimes bring, at least temporarily, disease control.34 Rare cases of CMML have a fusion gene linking TEL to the platelet-derived growth factor receptor–,35,36 which can render them responsive to imatinib therapy.37 The JAK2-activating tyrosine kinase mutation described previously is also a rare event in patients with CMML.30,38 The prognosis of most patients with CMML remains poor, and risk assessment can be done using any one of several scoring schemas as outlined by Germing et al.39 Therapeutic options in CMML remain limited with no known therapies definitively shown to extend survival, and thus, treatment options are directed toward supportive care and control of myeloproliferation.34 Oral chemotherapy can control blood counts and symptoms.40 A recent study described 18 patients with CMML in whom a 50% complete response rate with a 67% objective response was achieved with intravenous decitabine in a 5-day schedule. The estimated 18-month survival rate was 57%.41 Patients who are not candidates for BM transplantation (BMT) or who might be in the rare category of having a good prognosis could be considered for other therapies such as decitabine or experimental therapy. For younger or older patients who are candidates, allogeneic blood or BMT is a therapeutic option, albeit one carrying high risk.42,43

The third disease category in the myelodysplastic/myeloproliferative diseases section of the WHO classification is JMML. As indicated, this is a childhood disorder that is characterized by proliferation of monocytic and granulocytic precursors, although erythroid and megakaryocytic abnormalities are also frequently present, suggesting that JMML also arises from a multipotent early BM progenitor.51 Juvenile myelomonocytic leukemia is seen in up to 20%-30% of patients aged < 14 years with myeloproliferative or myelodysplastic disorders. Three quarters of the cases occur in children aged < 3 years, and boys are affected twice as often as girls.52-55 The clinical presentation involves constitutional symptoms, including fever and malaise with infection, particularly bronchitis or tonsillitis along with evidence of bleeding, seen in almost half of cases at initial presentation.54-56 Diagnostic criteria for JMML include a peripheral blood monocytosis > 1 × 109/L, < 20% blasts (including promonocytes in the blood or BM), lack of evidence of bcr-abl gene rearrangement, and  2 of the following: increased hemoglobin F level, immature granulocytes in the peripheral blood, a white blood cell count > 10 × 109/L, a clonal chromosomal abnormality, and granulocyte-macrophage colony-stimulating factor hypersensitivity of myeloid progenitors in vitro.57 In 30%-40% of patients, cytogenetic abnormalities are noted, including monosomy 7, but none of these cytogenetic abnormalities are specific for JMML.55 The prognosis of patients with JMML, although variable, is generally poor. For 30% of patients, the disease can progress rapidly with death occurring within a year from the time of onset. The younger the age, the better the prognosis. Progression to acute leukemia is uncommon. Blood and marrow transplantation remains the only therapy known to significantly prolong survival.52,54-56

Myelodysplastic and Myeloproliferative Disorders Atypical Chronic Myeloid Leukemia The second hybrid myelodysplastic/myeloproliferative disorder characterized in the WHO classification was atypical CML. This was defined as a disorder demonstrating myelodysplastic as well as myeloproliferative features with principal involvement of the neutrophil series manifested by a leukocytosis composed of immature and mature neutrophils that are dysplastic. Multilineage dysplasia is common, and these patients must not express the bcr-abl fusion gene.44 Atypical CML is observed in a frequency of only 1%-2%

The final disorder in the MDS/MPD overlap group is “myelodysplastic/myeloproliferative diseases, unclassifiable,” which is selfevidently the least well characterized. Clinical cases falling within this category have features of MDS and MPDs but do not meet the criteria for any of the other disorders included in the MDS/MPD category. In the WHO description of these disorders, it was indicated that  1 of the myeloid lineages has ineffective hematopoiesis/ dysplastic changes or both of these abnormalities and, at the same time, has “effective proliferation” with or without dysplasia in  1 of

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Myelodysplastic/Myeloproliferative Disorder Overlap Syndrome

Figure 1

Typical Colonies Observed in ET and in RARS with ET Features75





Ringed Sideroblasts Associated with Marked Thrombocytosis


Colonies are shown after May-Grünwald-Giemsa staining of collagen gels and are typical of (A-C) ET or of (D-E) RARS with ET features. (A) Endogenous megakaryocytic colony grown without serum or cytokine. (B,D) Erythroid colonies grown in the presence of cytokines; (D) note the small size of the RARS colony. (C) Detail of erythroblasts of the colony shown in panel B. (E) Detail of erythroblasts of the colony shown in panel D; note extensive cell death. Images were obtained using a Leica microscope equipped with a 10×/0.8 numeric aperture (A,B,D) or a 100×/0.8 numeric aperture (C,E) objective. Images were acquired using a Sony Power HAD DXC-950P camera and Tribun ICS/Thunder 17 acquisition software. Reproduced with permission from Boissinot et al. The JAK2-V617F mutation and essential thrombocythemia features in a subset of patients with refractory anemia with ring sideroblasts (RARS). Blood 2006; 108:1781-1782.


the other myeloid lineages.58-60 Inclusion of patients in this disease category requires exclusion of Bcr-Abl–positive CML and should not be used for patients with a well-defined previous myeloproliferative disorder who are now in transformation to a more aggressive phase and develop dysplastic features. It was recognized that some patients in this category might have had a previous MPD that was not clinically apparent and are in transformation with myelodysplastic features at the time of diagnosis. Drug treatment effects on the marrow also need to be taken into account in deciding whether a patient should be included in this category.58 Within this MDS/MPD unclassifiable category, the WHO included a provisional entity known as “MDS/MPD, unclassifiable RARS associated with marked thrombocytosis” (RARS-T). This entity has been described in the literature as early as 1971.61-64 These patients meet the criteria for a diagnosis of RARS, have increased ring sideroblasts in their BM, and also have a platelet count > 600 × 109/L.62-64 The marrow biopsy specimens of these patients have the typical features of RARS with > 15% ring sideroblasts but concomitantly demonstrate megakaryocytic proliferation. The megakaryocytes are often normal or enlarged and have been reported to have an appearance similar to that seen in ET.58 It is important to distinguish patients with RARS-T from patients with the (del)5q syndrome. Although they might resemble patients with the (del)5q syndrome,65 if the (del)5q chromosome abnormality is present, they should be classified as having (del)5q syndrome if they otherwise meet the criteria for that diagnosis.66 Another group of rare patients that might present with a chronic myeloid disorder and thrombocytosis are patients with abnormalities of chromosome 3q21q26. The marrow of these patients often contains micromegakaryocytes, and these patients should be classified as having AML if > 20% bone marrow blasts are present or in the respective MDS category that most morphologically fits with their disorder if they have < 20% blasts.67-69 There, however, remains a spectrum of patients with MDS who can present with increased platelet counts, and until recently, this entity remained relatively ill defined.70 Some have suggested that some of these patients might have the “coincidental occurrence of essential thrombocythemia and RARS.”71

Because of these findings, it is of great interest to note the reports of 3 groups describing JAK2-V617F mutations in patients with RARS-T.72-74 In the study by Szpurka et al, blood or BM from 270 patients with MDS, MDS/MPD, AML that had transformed from MDS, CML-PV, thrombocythemia, or MMM were studied for the presence of the JAK2-V617F mutation using PCR, sequencing, and melting curve analysis.72 Only 2 of 89 patients with typical forms of MDS had a JAK2-V617F mutation. In the 35 patients with MDS/MPD, unclassifiable, 9 had the mutation, with most of these patients having RARS-T. Among the 9 patients with RARS-T, 6 showed the presence of JAK2-V617F mutation. One of the 3 patients without the mutation had aberrant positive phosphorylated signal transducer and activator of transcription 5 (STAT5) staining that is frequently present only in association with a JAK2-V617F mutation.

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Mark R. Litzow In the study by Boissinot and colleagues, 16 patients with RARS-T had genomic DNA extracted, and quantitative PCR was performed.75 In 5 of the 16 patients, the JAK2-V617F mutation was found. For 1 patient, the JAK2-V617F mutation was also amplified from a BM biopsy performed 5 years before. At that time, the patient’s platelet count was normal. Of these 16 patients, 8 had features in the marrow of ET. The other 8 did not. In the 8 patients with features of ET that were found, 5 of the patients had JAK2-V617F–positive disease. None of these patients had evidence of myelofibrosis. In 4 of the 5 patients with JAK2-V617F–positive disease, endogenous megakaryocyte colony formation, which is present in 85% of patients with typical thrombocythemia, was not seen. An additional observation was that cell death was frequently seen in the erythroid colonies grown from these patients in the presence of cytokines (Figure 1).75 This finding is more typically seen in MDS than in thrombocythemia. Thus, in this series, 50% of the patients with RARS with high platelet counts presented with features of thrombocythemia, and 31% carried the JAK2-V617F mutation. Finally, in the series by Remacha et al, all 3 cases studied with RARS-T had the JAK2-V617F mutation detected. None of 16 patients with typical RARS had the mutation. In a group of 21 typical patients with thrombocythemia, 13 demonstrated the mutation. They concluded that RARS-T represented the coexistence of 2 disorders, with erythropoiesis showing the characteristics of RARS and megakaryocytes showing those of thrombocythemia.74

Prognosis The approach to the treatment of patients with MDS/MPD overlap syndromes remains problematic because of the relative rarity of these disorders and the lack of effective therapies to significantly prolong survival short of the use of allogeneic BMT. It is also difficult to extrapolate the use of the International Prognostic Scoring System described by Greenberg et al76 or the more recently described WHO Prognostic Scoring System77 to patients with the MDS/MPD overlap syndromes. However, features of these scoring systems, including adverse cytogenetics, increased blasts, cytopenias, and transfusion requirements, can all intuitively suggest a poorer prognosis for patients with MDS/MPD overlap syndromes. Thus, patients with multiple adverse prognostic features are likely to have a shorter survival and increased risk of transformation to AML and should be considered for allogeneic BMT if they are suitable candidates and a suitable donor can be found. The Markov analysis by Cutler et al demonstrated that, in patients with typical MDS in a low-risk category, proceeding to allogeneic BMT can reasonably be delayed until their disease progresses without compromising their overall survival. For patients with high-risk MDS, proceeding expeditiously to allogeneic BMT is the most favorable course of action. Although these results are not directly applicable to patients with the MDS/MPD overlap syndrome, it is likely that similar guidelines for deciding when to proceed to BMT could also apply.78

Conclusion The close cooperation between clinician and hematopathologists is crucial in characterizing patients with the uncommon MDS/MPD overlap syndromes. The appropriate incorporation

of molecular studies for inclusion or exclusion of patients into the MDS/MPD overlap syndromes is essential to categorize these patients correctly. When a diagnosis is established, careful monitoring and follow-up are important to look for signs of transformation and to determine appropriate therapy based on risk factors extrapolated from similar disorders.

Acknowledgement The author thanks Denise P. Chase for her careful transcription of the articles.

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Clinical Leukemia • December 2006