Medical School · Year 2 · Hematology Oncology · includes a quiz and discussion video

Lecture 12: Myeloproliferative Neoplasms

Unit 2.9: Hematology/Oncology

Learning Objectives

By the end of this lecture, students will be able to:

1. Describe the classification and pathophysiology of MPNs
2. Explain the diagnosis and management of polycythemia vera
3. Describe essential thrombocythemia and its management
4. Explain primary myelofibrosis and its treatment
5. Describe the myelodysplastic syndromes
6. Explain the relationship between MDS and AML

Lecture Outline

I. Myeloproliferative Neoplasms Overview

Myeloproliferative neoplasms are clonal stem cell disorders characterized by increased production of mature blood cells, distinguishing them from myelodysplastic syndromes where hematopoiesis is ineffective. The key feature of these neoplasms is effective hematopoiesis, meaning that the clonal proliferation results in mature, functional cells accumulating in the peripheral blood rather than immature blasts or dysplastic cells that fail to function normally. The classic Philadelphia-negative MPNs include polycythemia vera, essential thrombocythemia, and primary myelofibrosis, while chronic myeloid leukemia represents the Philadelphia-positive MPN defined by the BCR-ABL1 fusion gene. Understanding this distinction between Philadelphia-positive and Philadelphia-negative disease is fundamental because CML has a unique molecular pathogenesis and targeted therapy, whereas the Philadelphia-negative MPNs share overlapping driver mutations and clinical features.

The World Health Organization classification of myeloproliferative neoplasms categorizes these disorders based on the primary cell line that is expanded. Chronic myeloid leukemia is characterized by granulocyte proliferation driven by the BCR-ABL1 oncoprotein. Polycythemia vera primarily involves erythrocyte overproduction, leading to elevated red cell mass and hematocrit. Essential thrombocythemia manifests as platelet overproduction from expanded megakaryocyte populations. Primary myelofibrosis involves abnormal megakaryocyte proliferation that drives reactive bone marrow fibrosis through cytokine release. Additional less common entities in this category include mastocytosis, chronic eosinophilic leukemia, and unclassifiable MPNs, though the four major entities account for the vast majority of clinical cases.

The discovery of recurrent driver mutations has transformed the understanding and diagnosis of Philadelphia-negative MPNs. The JAK2 V617F mutation, located in exon 14 of the JAK2 gene, is present in approximately 95 percent of polycythemia vera cases and roughly 55 percent of both essential thrombocythemia and primary myelofibrosis. Calreticulin (CALR) mutations are found in approximately 25 percent of ET and 25 percent of PMF cases. MPL mutations affecting the thrombopoietin receptor account for about 5 percent of ET and 5 percent of PMF. The remaining 15 percent of ET and PMF cases that lack all three driver mutations are termed triple-negative and generally carry a less favorable prognosis, though some harbor mutations in other genes detectable by next-generation sequencing.

The JAK2 signaling pathway is central to normal hematopoietic regulation and understanding its dysregulation explains the proliferative phenotype of MPNs. Under normal circumstances, JAK2 is activated through cytokine receptor signaling, requiring ligand binding for kinase activation and subsequent downstream signaling through the JAK-STAT pathway. The V617F point mutation in JAK2 results in constitutive activation of the kinase, meaning the enzyme is continuously active regardless of cytokine binding. This cytokine-independent proliferation drives uncontrolled expansion of the affected hematopoietic lineage, explaining the elevated blood counts characteristic of these disorders. The recognition of this constitutive signaling has provided the rationale for therapeutic targeting with JAK inhibitors such as ruxolitinib in the management of myelofibrosis and refractory polycythemia vera.

<image>Panel A: WHO classification of myeloproliferative neoplasms showing CML, polycythemia vera, essential thrombocythemia, and primary myelofibrosis. Panel B: Driver mutation distribution with JAK2 V617F in 95% of PV and 55% of ET/PMF, CALR in 25%, and MPL in 5%. Panel C: JAK2 signaling pathway showing normal cytokine-dependent activation versus constitutive activation with V617F mutation. Panel D: Comparison of Philadelphia-positive CML versus Philadelphia-negative MPNs with diagnostic and therapeutic implications.</image>

II. Polycythemia Vera

Polycythemia vera is a clonal myeloproliferative neoplasm characterized primarily by erythrocyte overproduction, though it frequently involves proliferation of all three myeloid lineages. The JAK2 V617F mutation is the driver in approximately 95 percent of cases, while JAK2 exon 12 mutations account for an additional 4 percent and are typically seen in younger patients who may present with lower white blood cell counts than those harboring the V617F variant. A hallmark laboratory finding is a low or suppressed serum erythropoietin level, which distinguishes clonal polycythemia from secondary causes of erythrocytosis such as chronic hypoxia, erythropoietin-secreting tumors, or high-altitude residence where EPO levels are characteristically elevated.

The WHO 2016 diagnostic criteria for polycythemia vera require three major criteria or two major criteria plus the minor criterion. The first major criterion is hemoglobin greater than 16.5 g/dL in men or greater than 16 g/dL in women, or alternatively hematocrit greater than 49 percent in men or greater than 48 percent in women. The second major criterion is bone marrow biopsy demonstrating hypercellularity with trilineage growth and pleomorphic mature megakaryocytes varying in size. The third major criterion is the presence of JAK2 V617F or JAK2 exon 12 mutation. The minor criterion is a subnormal serum erythropoietin level. Diagnosis can be established by meeting all three major criteria, or by meeting the first and third major criteria along with the minor criterion, allowing diagnosis in some cases without bone marrow biopsy when the hemoglobin or hematocrit threshold is clearly exceeded and the mutation is present with a low EPO.

The clinical presentation of polycythemia vera reflects the consequences of increased red cell mass and blood viscosity. Hyperviscosity produces symptoms including headache, blurred vision, and dizziness that improve with phlebotomy. Thrombosis, both arterial and venous, represents the leading cause of morbidity and mortality, with events ranging from stroke and myocardial infarction to deep vein thrombosis and pulmonary embolism. Aquagenic pruritus, a distinctive symptom triggered by contact with warm water such as after a shower, is reported by a substantial proportion of patients and can be extremely distressing. Erythromelalgia manifests as burning pain in the extremities, particularly the hands and feet, caused by microvascular platelet aggregation and is characteristically responsive to aspirin therapy. Splenomegaly is common due to extramedullary hematopoiesis and increased red cell sequestration, while paradoxical bleeding may occur in patients with very high platelet counts due to acquired von Willebrand disease. Hyperuricemia from increased cell turnover can produce gout.

Several distinctive clinical findings are particularly associated with polycythemia vera and should raise diagnostic suspicion. Budd-Chiari syndrome, defined as hepatic vein thrombosis, is a characteristic complication that presents with abdominal pain, ascites, and hepatomegaly, and PV should be considered in any patient presenting with this condition. Splanchnic vein thrombosis involving the portal, mesenteric, or splenic veins is another hallmark thrombotic complication that may be the first presentation of underlying PV. Physical examination often reveals a ruddy or plethoric complexion resulting from the increased red cell mass, giving the face and skin a characteristically reddish appearance. Conjunctival injection, manifesting as prominent redness of the eyes, may also be observed and contributes to the overall plethoric appearance that can suggest the diagnosis on visual inspection alone.

<image>Panel A: WHO 2016 diagnostic criteria showing hemoglobin/hematocrit thresholds, bone marrow findings, JAK2 mutation, and low EPO as minor criterion. Panel B: Clinical features including hyperviscosity symptoms, aquagenic pruritus, erythromelalgia with burning extremity pain, and ruddy plethoric complexion. Panel C: Budd-Chiari syndrome as hepatic vein thrombosis with liver congestion, ascites, and abdominal pain in PV patients. Panel D: Splanchnic vein thrombosis sites including portal, mesenteric, and splenic veins with diagnostic considerations.</image>

III. PV - Treatment and Prognosis

Risk stratification in polycythemia vera guides treatment intensity and is based on two primary factors that predict thrombotic risk. Low-risk disease is defined as age less than 60 years with no prior history of thrombosis, identifying patients whose risk of vascular events is sufficiently low to manage with phlebotomy and aspirin alone. High-risk disease is defined as age 60 years or older or any prior history of thrombosis, indicating patients who require the addition of cytoreductive therapy to reduce their elevated thrombotic risk. This straightforward two-tiered system has proven clinically useful in directing therapeutic decisions, though ongoing research continues to refine risk assessment by incorporating additional variables such as cardiovascular risk factors, JAK2 allele burden, and leukocytosis.

Treatment of polycythemia vera follows a risk-stratified approach in which all patients receive phlebotomy and low-dose aspirin, while high-risk patients additionally receive cytoreductive therapy. Phlebotomy is performed to achieve and maintain a target hematocrit below 45 percent, a threshold established by the CYTO-PV trial demonstrating that maintaining hematocrit below this level significantly reduces cardiovascular events compared with a more lenient target. Low-dose aspirin at 81 to 100 milligrams daily is administered to all patients unless contraindicated, as the ECLAP trial demonstrated that aspirin reduces the combined risk of nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death without a significant increase in major bleeding.

For high-risk patients requiring cytoreductive therapy, hydroxyurea is the first-line agent, effectively reducing blood counts and thrombotic risk with a generally favorable tolerability profile. Ruxolitinib, a JAK1/JAK2 inhibitor, is approved for patients who are resistant to or intolerant of hydroxyurea, and it is particularly effective at controlling splenomegaly, pruritus, and constitutional symptoms. Pegylated interferon alfa is an emerging option especially attractive for younger patients because it does not carry the theoretical leukemogenic risk associated with hydroxyurea and has demonstrated the ability to achieve molecular remissions in some patients, reducing the JAK2 V617F allele burden over time.

The prognosis of polycythemia vera is generally favorable compared with other myeloproliferative neoplasms, with a median survival of approximately 14 years. However, the disease carries risks of transformation to other hematologic conditions over time. Transformation to myelofibrosis (post-PV myelofibrosis) occurs in approximately 15 to 20 percent of patients at 15 years, manifesting with progressive cytopenias, splenomegaly, and marrow fibrosis that fundamentally alters the disease course. Transformation to acute myeloid leukemia occurs in approximately 5 to 10 percent of patients at 15 years and carries a very poor prognosis. Risk factors for disease transformation include leukocytosis, older age at diagnosis, and an abnormal karyotype, and these features should prompt closer monitoring and consideration of more aggressive therapeutic approaches.

<image>Panel A: Phlebotomy procedure demonstrating removal of 450-500 mL blood to achieve target hematocrit below 45%. Panel B: Risk stratification algorithm with low risk defined as age under 60 without thrombosis history versus high risk requiring cytoreduction. Panel C: Treatment approach showing phlebotomy plus aspirin for all patients with addition of hydroxyurea or other cytoreduction for high-risk. Panel D: Survival curves and transformation rates to myelofibrosis at 15-20% and AML at 5-10% over 15 years.</image>

IV. Essential Thrombocythemia

Essential thrombocythemia is a clonal myeloproliferative neoplasm characterized by sustained platelet overproduction resulting from megakaryocyte proliferation in the bone marrow. The driver mutation landscape includes JAK2 V617F in approximately 55 percent of cases, CALR mutations in 25 percent, MPL mutations in 5 percent, and triple-negative status in the remaining 15 percent. The specific driver mutation has prognostic significance, with CALR-mutated ET carrying the best prognosis, characterized by lower thrombotic risk and a more favorable overall survival compared with JAK2-mutated or triple-negative disease. This molecular heterogeneity underlies the variable clinical behavior observed among ET patients and increasingly informs risk stratification and treatment decisions.

The WHO 2016 diagnostic criteria for essential thrombocythemia require fulfillment of all four major criteria, or the first three major criteria plus the minor criterion. The first major criterion is a sustained platelet count of 450,000 per microliter or greater. The second major criterion requires bone marrow biopsy demonstrating megakaryocyte proliferation with enlarged, mature morphology and hyperlobulated nuclei, without significant increase in other lineages. The third major criterion is that the findings do not meet diagnostic criteria for other myeloproliferative neoplasms, myelodysplastic syndromes, or other myeloid neoplasms. The fourth major criterion requires demonstration of a JAK2, CALR, or MPL mutation. The minor criterion, applied when the fourth major criterion is not met, requires evidence of a clonal marker or the absence of evidence for reactive thrombocytosis, thereby helping to distinguish clonal disease from secondary causes of elevated platelets.

The clinical presentation of essential thrombocythemia is often asymptomatic, with the elevated platelet count discovered incidentally on routine blood work. When symptoms occur, thrombosis is the predominant complication, with arterial events more common than venous thrombosis, manifesting as stroke, transient ischemic attack, myocardial infarction, or peripheral arterial occlusion. Microvascular symptoms are characteristic and include erythromelalgia presenting as burning pain and redness in the extremities, digital ischemia, and visual disturbances from ocular microvascular compromise. Paradoxically, bleeding can occur in patients with very high platelet counts exceeding 1 million per microliter due to acquired von Willebrand disease, where extreme thrombocytosis leads to adsorption and clearance of high-molecular-weight von Willebrand factor multimers. Splenomegaly is mild or absent in most patients, distinguishing ET from other MPNs where organomegaly is more prominent.

Distinguishing essential thrombocythemia from reactive thrombocytosis is a critical diagnostic task, as secondary causes of elevated platelets are far more common than clonal disease. Reactive thrombocytosis occurs in settings of iron deficiency, active infection, chronic inflammation, malignancy, and post-surgical states, where the elevated platelet count represents an appropriate physiologic response rather than a clonal process. Acute phase reactants such as C-reactive protein and ferritin are typically elevated in reactive thrombocytosis but normal in ET. Iron studies may reveal deficiency as the underlying cause of reactive elevation. The presence of JAK2, CALR, or MPL mutations, found in approximately 85 percent of ET cases, strongly supports a clonal diagnosis, while their absence requires careful exclusion of reactive causes before invoking the diagnosis of triple-negative ET.

<image>Panel A: WHO 2016 diagnostic criteria with platelet count 450,000 or greater, characteristic megakaryocyte morphology, exclusion of other MPNs, and driver mutation positivity. Panel B: Bone marrow biopsy showing enlarged mature megakaryocytes with hyperlobulated nuclei characteristic of ET. Panel C: Erythromelalgia clinical photograph demonstrating red, painful extremities with burning sensation relieved by aspirin. Panel D: Comparison of reactive thrombocytosis versus clonal ET with acute phase reactants, iron studies, and mutation testing.</image>

V. ET - Treatment and Prognosis

Risk stratification in essential thrombocythemia uses the International Prognostic Score for ET (IPSET-thrombosis), which categorizes patients into four risk groups based on age, thrombosis history, and JAK2 mutation status. Very low risk is defined as age less than 60 with no thrombosis history and JAK2 negativity. Low risk applies to patients under 60 without prior thrombosis who are JAK2 positive. Intermediate risk includes patients 60 years or older without thrombosis history who are JAK2 negative. High risk encompasses any patient with a history of thrombosis or those who are both 60 years or older and JAK2 positive, reflecting the synergistic effect of age and JAK2 positivity on thrombotic risk.

Treatment of essential thrombocythemia is guided by risk category, with the primary goal of reducing thrombotic and hemorrhagic complications. Patients in the very low and low risk categories may be managed with observation alone, with or without low-dose aspirin depending on the presence of microvascular symptoms and cardiovascular risk factors. Intermediate-risk patients are generally treated with aspirin for thrombotic prophylaxis. High-risk patients require the combination of cytoreductive therapy and aspirin to adequately control their elevated thrombotic risk, with the goal of reducing the platelet count and thereby decreasing vascular events.

The pharmacologic options for cytoreduction and thrombotic prevention in ET each carry specific considerations. Low-dose aspirin is the cornerstone of antithrombotic therapy, though it should be used cautiously or avoided in patients with very high platelet counts where acquired von Willebrand disease may increase bleeding risk. Hydroxyurea is the first-line cytoreductive agent, effective at controlling platelet counts with a well-established safety profile. Anagrelide is an alternative that specifically reduces platelet production by inhibiting megakaryocyte differentiation, though it carries increased bleeding risk and should be used with awareness of its cardiac side effects including palpitations and fluid retention. Pegylated interferon alfa is preferred in younger patients and during pregnancy due to its favorable safety profile and lack of teratogenic risk. The therapeutic platelet count target generally ranges from 400,000 to 600,000 per microliter, though the primary treatment goal is prevention of thrombosis rather than achieving a specific number.

The prognosis of essential thrombocythemia is the most favorable among the myeloproliferative neoplasms, with near-normal life expectancy in many patients. Transformation to myelofibrosis occurs in approximately 5 to 10 percent of patients at 15 years, a rate lower than that observed in polycythemia vera. Transformation to acute myeloid leukemia occurs in approximately 2 to 5 percent of cases, representing a relatively low but clinically significant risk. Among the molecular subtypes, CALR-mutated ET carries the best prognosis with the lowest rates of thrombosis and transformation, while triple-negative disease may carry a somewhat higher risk of adverse outcomes. Overall, the indolent nature of ET allows most patients to maintain excellent quality of life with appropriate risk-adapted management.

<image>Panel A: IPSET-thrombosis risk stratification from very low through high risk based on age, thrombosis history, and JAK2 status. Panel B: Treatment algorithm by risk category with observation for very low/low, aspirin for intermediate, and cytoreduction plus aspirin for high risk. Panel C: Aspirin considerations including low-dose for prevention but avoidance with very high platelet counts due to acquired von Willebrand disease risk. Panel D: Survival curves showing near-normal life expectancy with transformation rates to myelofibrosis and AML lower than PV.</image>

VI. Primary Myelofibrosis

Primary myelofibrosis is a clonal myeloproliferative neoplasm characterized by progressive bone marrow fibrosis that replaces normal hematopoietic tissue and drives extramedullary hematopoiesis. The fibrosis is a reactive process mediated by non-clonal fibroblasts responding to cytokines released by abnormal clonal megakaryocytes, with transforming growth factor-beta (TGF-beta) and platelet-derived growth factor (PDGF) being the principal profibrotic mediators. This distinction is important: the fibroblasts themselves are not part of the malignant clone but rather are stimulated by the clonal megakaryocyte population to deposit excessive collagen and reticulin in the marrow space. The driver mutation landscape mirrors that of essential thrombocythemia, with JAK2 V617F present in approximately 55 percent, CALR mutations in 25 percent, MPL mutations in 5 percent, and triple-negative status in 15 percent of cases.

The WHO 2016 diagnostic criteria for primary myelofibrosis establish three major criteria and several minor criteria. The first major criterion requires megakaryocyte proliferation and atypia accompanied by reticulin or collagen fibrosis on bone marrow biopsy. The second major criterion stipulates that the findings do not meet diagnostic criteria for other myeloproliferative neoplasms, myelodysplastic syndromes, or other myeloid neoplasms. The third major criterion requires demonstration of a JAK2, CALR, or MPL mutation, or in the absence of these mutations, evidence of another clonal marker or exclusion of reactive fibrosis. Minor criteria include unexplained anemia, leukocytosis with a white blood cell count above 11,000 per microliter, palpable splenomegaly, elevated lactate dehydrogenase, and leukoerythroblastosis on the peripheral blood smear.

The clinical presentation of primary myelofibrosis reflects the progressive failure of normal bone marrow function and the compensatory shift of blood cell production to extramedullary sites. Anemia is the most common presenting symptom, resulting from impaired marrow production and often reaching severity requiring transfusion support. Massive splenomegaly is a hallmark of the disease, caused by extramedullary hematopoiesis as the spleen assumes blood-producing functions normally performed by the marrow, and may be so pronounced that the spleen fills the abdomen causing early satiety, abdominal pain, and mechanical discomfort. Constitutional symptoms including fatigue, drenching night sweats, unintentional weight loss, and low-grade fever are common and can profoundly impair quality of life. Bone pain may result from marrow infarcts and expansion of the marrow cavity by fibrotic tissue. Portal hypertension with hepatomegaly and ascites can develop from hepatic extramedullary hematopoiesis and increased portal blood flow from the massively enlarged spleen.

The laboratory findings in primary myelofibrosis are distinctive and often suggest the diagnosis before bone marrow examination. Anemia is a near-universal finding that is frequently severe and progressive. The peripheral blood smear reveals leukoerythroblastosis, characterized by the presence of nucleated red blood cells and immature white blood cells including myelocytes and metamyelocytes that have been released prematurely from the disrupted marrow architecture. Tear-drop cells, also known as dacrocytes, are characteristic findings that result from red blood cells being distorted as they squeeze through the fibrotic marrow sinusoids and the congested splenic microcirculation. Bone marrow aspiration characteristically yields a "dry tap," meaning that no marrow material can be aspirated due to the dense fibrosis occupying the marrow space, making biopsy rather than aspirate essential for diagnosis. Bone marrow biopsy demonstrates fibrosis on reticulin and trichrome stains, with the degree of fibrosis graded from 0 to 3 to assess disease severity.

<image>Panel A: Bone marrow biopsy with reticulin and trichrome stains demonstrating dense fibrosis replacing normal hematopoietic elements. Panel B: Peripheral blood smear showing characteristic tear-drop cells (dacrocytes) and leukoerythroblastic picture with nucleated red cells. Panel C: CT scan demonstrating massive splenomegaly from extramedullary hematopoiesis causing early satiety and abdominal discomfort. Panel D: Dry tap from bone marrow aspiration due to fibrosis with requirement for biopsy for diagnosis.</image>

VII. PMF - Treatment and Prognosis

Prognostic scoring in primary myelofibrosis uses the Dynamic International Prognostic Scoring System-Plus (DIPSS-Plus), which assigns points for multiple clinical and laboratory features to stratify patients into risk categories with distinct survival expectations. The scoring assigns 1 point each for age greater than 65, constitutional symptoms, white blood cell count greater than 25,000, circulating blasts of 1 percent or more, platelet count less than 100,000, red blood cell transfusion dependence, and unfavorable karyotype, while hemoglobin less than 10 g/dL receives 2 points due to its particularly strong prognostic impact. Low-risk disease with 0 points carries a median survival exceeding 15 years, intermediate-1 risk with 1 point carries a median survival of 6.5 years, intermediate-2 risk with 2 to 3 points carries a median survival of 2.9 years, and high-risk disease with 4 or more points carries a median survival of only 1.3 years. This wide range of outcomes underscores the heterogeneous nature of primary myelofibrosis and the importance of individualized treatment decisions based on accurate risk assessment.

Treatment of primary myelofibrosis is guided by risk category and symptom burden, with approaches ranging from observation to allogeneic transplantation. Asymptomatic low-risk patients may be observed without therapy, as early treatment has not been shown to alter disease course in this favorable group. Symptomatic patients benefit from JAK inhibitor therapy, with ruxolitinib or fedratinib providing meaningful reductions in splenomegaly, constitutional symptoms, and overall symptom burden. Anemia management may include androgens such as danazol, erythropoietin-stimulating agents for patients with relatively preserved endogenous EPO levels, red blood cell transfusions for more severe anemia, and lenalidomide for selected patients. Symptomatic splenomegaly is primarily addressed with JAK inhibitors, though splenectomy or splenic radiation may be considered for refractory cases.

The JAK inhibitor class has transformed the management of myelofibrosis, though it is essential to understand both their benefits and limitations. Ruxolitinib was the first JAK inhibitor approved for myelofibrosis and demonstrates significant efficacy in reducing spleen volume and improving disease-related symptoms such as night sweats, pruritus, and bone pain. Fedratinib is an alternative JAK inhibitor that is particularly useful for patients who have failed or are intolerant of ruxolitinib therapy. Pacritinib has been developed specifically for patients with severe thrombocytopenia, where the use of other JAK inhibitors may be limited by their myelosuppressive effects. Critically, JAK inhibitors do not cure myelofibrosis and the underlying disease continues to progress, but they provide meaningful improvements in quality of life, reduction in spleen size, and potentially a modest survival benefit.

Allogeneic hematopoietic stem cell transplantation remains the only curative treatment option for primary myelofibrosis and is generally considered for patients with intermediate-2 or high-risk disease who are of appropriate age and fitness. Eligibility depends on patient age, comorbidity burden, and availability of a suitable donor, with reduced-intensity conditioning protocols expanding transplant access to somewhat older patients. Timing of transplant referral is important, with earlier consideration in the disease course for eligible intermediate-2 and high-risk patients, as outcomes deteriorate with advancing disease and increasing comorbidities. However, transplant-related morbidity and mortality remain substantial, with treatment-related death rates ranging from 20 to 40 percent depending on conditioning intensity and patient factors, necessitating careful weighing of the curative potential against the procedural risks.

<image>Panel A: DIPSS-Plus scoring system with points for age, constitutional symptoms, hemoglobin, WBC, blasts, platelets, transfusion dependence, and karyotype. Panel B: Risk category-specific median survival from greater than 15 years for low risk to 1.3 years for high risk. Panel C: JAK inhibitor effects showing splenomegaly reduction, constitutional symptom improvement, and quality of life benefit without disease cure. Panel D: Transplant decision algorithm considering intermediate-2 or high-risk disease, age, comorbidities, and donor availability.</image>

VIII. Myelodysplastic Syndromes Overview

Myelodysplastic syndromes are a heterogeneous group of clonal stem cell disorders characterized by dysplastic morphology and ineffective hematopoiesis resulting in peripheral blood cytopenias. The fundamental distinguishing feature of MDS is ineffective hematopoiesis, meaning that despite a typically hypercellular bone marrow with active cell production, the dysplastic cells undergo premature apoptosis and fail to reach the peripheral blood as functional mature cells. This stands in direct contrast to myeloproliferative neoplasms, where hematopoiesis is effective and the marrow produces excessive numbers of mature cells. Approximately 30 percent of MDS cases transform to acute myeloid leukemia over time, establishing MDS as a pre-leukemic condition with variable but clinically significant malignant potential.

The pathophysiology of myelodysplastic syndromes involves a sequence of events beginning with stem cell mutations that lead to clonal expansion of hematopoietic progenitors with impaired differentiation capacity. The clonal population demonstrates dysplasia, defined as abnormal morphologic maturation affecting one or more myeloid lineages. Increased apoptosis of these dysplastic precursors within the bone marrow is the mechanism responsible for the paradox of cytopenias despite hypercellularity, as the marrow is actively producing cells that die before they can be released into circulation. The result is a clinical picture dominated by the consequences of peripheral blood cytopenias, including anemia, neutropenia, and thrombocytopenia, in a patient whose bone marrow biopsy shows increased rather than decreased cellularity.

The risk factors for developing myelodysplastic syndromes span both acquired and inherited categories. The majority of cases are de novo, arising without an identifiable cause and increasing in incidence with advancing age, with a median age at diagnosis of approximately 70 years. Therapy-related MDS develops following exposure to cytotoxic chemotherapy, particularly alkylating agents, or radiation therapy, typically appearing 5 to 7 years after exposure and carrying a worse prognosis than de novo disease. Environmental toxic exposures, most notably benzene, are well-established risk factors for MDS development. Congenital conditions predisposing to MDS include Fanconi anemia and inherited familial MDS syndromes with germline mutations in genes such as DDX41, RUNX1, and GATA2.

The clinical features of myelodysplastic syndromes are driven by the specific cytopenias present and their severity. Anemia is the most common finding, presenting with fatigue, dyspnea, and reduced exercise tolerance, and is the primary reason most patients come to medical attention. Neutropenia increases susceptibility to bacterial and fungal infections, which may be recurrent or severe. Thrombocytopenia predisposes to bleeding manifestations including easy bruising, petechiae, and mucosal hemorrhage. The clinical presentation may closely resemble aplastic anemia, but the presence of morphologic dysplasia in the marrow and characteristic cytogenetic abnormalities distinguishes MDS from aplastic anemia and guides the distinct therapeutic approach required for each condition.

<image>Panel A: Ineffective hematopoiesis concept showing hypercellular marrow with increased apoptosis resulting in peripheral cytopenias. Panel B: Dysplastic morphology examples including ringed sideroblasts in erythroid lineage, hypogranular neutrophils with pseudo-Pelger-Huet nuclei, and micromegakaryocytes. Panel C: Risk factors including prior chemotherapy and radiation for therapy-related MDS, benzene exposure, and inherited syndromes. Panel D: Comparison with MPN showing cytopenias in MDS versus proliferation in MPN despite both being clonal stem cell disorders.</image>

IX. MDS - Diagnosis and Classification

The diagnosis of myelodysplastic syndromes requires the integration of clinical, morphologic, and genetic findings to establish the presence of a clonal disorder causing cytopenias through dysplastic hematopoiesis. The essential diagnostic criteria include the presence of one or more cytopenias, morphologic dysplasia affecting at least 10 percent of cells in one or more myeloid lineages, a blast percentage below 20 percent (since 20 percent or greater defines acute myeloid leukemia), and characteristic cytogenetic abnormalities when present. Critically, the diagnosis requires exclusion of other causes of cytopenias and dysplasia, including nutritional deficiencies such as vitamin B12 and folate, viral infections, toxic exposures, autoimmune conditions, and congenital disorders, as these can mimic MDS morphologically but require entirely different management.

Morphologic dysplasia is assessed across the three myeloid lineages, with each demonstrating characteristic abnormal features. Erythroid dysplasia manifests as ringed sideroblasts visible on Prussian blue staining where iron granules encircle more than one-third of the nucleus, along with nuclear irregularity including budding and multinucleation, and megaloblastoid changes reflecting impaired DNA synthesis. Granulocytic dysplasia presents as hypogranulation or hypergranulation of neutrophils and the characteristic pseudo-Pelger-Huet anomaly, where neutrophils display bilobed rather than the normal multilobed nuclei. Megakaryocytic dysplasia is recognized by micromegakaryocytes that are abnormally small, and hypolobated nuclei in megakaryocytes that should normally demonstrate multilobation, sometimes presenting as mononuclear megakaryocytes.

The WHO 2022 classification of myelodysplastic syndromes categorizes disease based on blast percentage, lineage dysplasia, and specific cytogenetic and molecular features. MDS with low blasts contains fewer than 5 percent blasts and encompasses both single-lineage and multilineage dysplasia variants. MDS with ring sideroblasts also has fewer than 5 percent blasts but demonstrates 15 percent or more ringed sideroblasts and is frequently associated with SF3B1 mutation, which carries a relatively favorable prognosis. MDS with increased blasts is subdivided into MDS-IB1 with 5 to 9 percent blasts and MDS-IB2 with 10 to 19 percent blasts, the latter carrying significantly higher risk of AML transformation. MDS with isolated del(5q) is a distinct entity with fewer than 5 percent blasts and a favorable prognosis, notable for its responsiveness to lenalidomide therapy.

Cytogenetic analysis provides essential prognostic information in MDS and contributes to risk stratification through established categorization of chromosomal abnormalities. The good-risk cytogenetic category includes normal karyotype, isolated deletion of the long arm of chromosome 5 (del(5q)), deletion of the long arm of chromosome 20 (del(20q)), and isolated loss of the Y chromosome, all associated with more favorable outcomes. The intermediate-risk category encompasses other single or double chromosomal abnormalities not classified as good or poor risk. The poor-risk cytogenetic category includes complex karyotype with three or more chromosomal abnormalities and any abnormality involving chromosome 7, including monosomy 7 and del(7q), which are associated with the worst outcomes and highest rates of AML transformation. These cytogenetic categories are integral to the prognostic scoring systems used to guide treatment decisions.

<image>Panel A: Dysplastic morphology across lineages with nuclear irregularity and megaloblastoid changes in erythroid, hypogranulation in granulocytic, and hypolobation in megakaryocytic. Panel B: Prussian blue stain demonstrating ringed sideroblasts with iron granules surrounding greater than one-third of nucleus associated with SF3B1 mutation. Panel C: Cytogenetic risk categories showing good prognosis with del(5q), del(20q), and normal karyotype versus poor with complex and chromosome 7 abnormalities. Panel D: WHO 2022 classification categories based on blast percentage, ring sideroblasts, and specific cytogenetic findings.</image>

X. MDS - Treatment

The Revised International Prognostic Scoring System (IPSS-R) is the primary tool for risk stratification in MDS, incorporating five clinical and laboratory variables to predict survival and guide treatment decisions. The scoring system evaluates cytogenetic category across five risk groups, bone marrow blast percentage, hemoglobin level, platelet count, and absolute neutrophil count, each contributing points that are summed to determine overall risk. The resulting risk categories range from very low risk with a median survival of 8.8 years, through low risk at 5.3 years, intermediate risk at 3 years, and high risk at 1.6 years, to very high risk with a median survival of only 0.8 years. This wide spectrum of outcomes highlights the remarkable heterogeneity of MDS and the critical importance of accurate risk assessment in guiding the intensity of therapeutic intervention.

Treatment of MDS is fundamentally divided by risk category, with lower-risk disease managed primarily through supportive and targeted approaches while higher-risk disease requires more aggressive intervention. Lower-risk MDS is managed with supportive care including red blood cell and platelet transfusions as needed, erythropoiesis-stimulating agents (ESAs) for patients with low endogenous erythropoietin levels, and lenalidomide for patients with del(5q) where it can produce durable transfusion independence and cytogenetic responses. Higher-risk MDS requires treatment aimed at altering the natural history of disease, with hypomethylating agents as the standard of care and allogeneic transplantation for eligible patients seeking cure.

The specific treatment options available for MDS each serve defined roles within the risk-adapted framework. Supportive care with transfusions, erythropoietin, granulocyte colony-stimulating factor (G-CSF), and iron chelation for transfusion-dependent patients forms the foundation of lower-risk management. Lenalidomide is particularly effective in del(5q) MDS, reducing transfusion requirements and achieving cytogenetic remission in a majority of these patients. Azacitidine, a hypomethylating agent (HMA), is the standard treatment for higher-risk MDS and has been demonstrated to prolong survival compared with conventional care regimens. Decitabine is an alternative hypomethylating agent with similar mechanism and comparable efficacy to azacitidine. Allogeneic hematopoietic stem cell transplantation remains the only curative option and is considered for higher-risk patients and selected fit patients with lower-risk disease who have failed other therapies. Luspatercept, an erythroid maturation agent, is approved for lower-risk MDS with ring sideroblasts who have failed ESA therapy, offering another option to reduce transfusion burden.

Prognosis in MDS is primarily determined by the IPSS-R risk category, but several additional factors modify outcomes. TP53 mutation confers very poor prognosis regardless of other features, with poor response to standard therapies and rapid progression to AML. Transformation to acute myeloid leukemia is a common and often fatal event in higher-risk MDS, occurring in a substantial proportion of patients and generally conferring worse outcomes than de novo AML due to the adverse genetic features characteristic of secondary leukemia. Response to hypomethylating agent therapy is an important prognostic factor, as patients who fail to respond to azacitidine or decitabine have limited subsequent treatment options and poor outcomes, underscoring the importance of timely transplant referral for eligible patients.

<image>Panel A: IPSS-R scoring system incorporating cytogenetics, blast percentage, hemoglobin, platelets, and ANC with risk category determination. Panel B: Treatment algorithm for lower-risk MDS with supportive care, erythropoiesis-stimulating agents, and lenalidomide for del(5q) versus higher-risk with hypomethylating agents and transplant. Panel C: Azacitidine mechanism as hypomethylating agent incorporating into DNA and inhibiting DNA methyltransferase to restore gene expression. Panel D: Survival impact of therapies including median survival by IPSS-R risk category and importance of allogeneic transplant as only curative option.</image>

Summary

• MPNs: Clonal stem cell disorders with effective hematopoiesis and increased mature cells
• JAK2 V617F: Present in PV (95%), ET (55%), PMF (55%)
• Polycythemia vera: Elevated Hct, low EPO; phlebotomy to Hct <45%; aspirin + cytoreduction
• Essential thrombocythemia: Platelets >450K; CALR best prognosis; treat based on thrombosis risk
• Primary myelofibrosis: Bone marrow fibrosis, splenomegaly, tear-drop cells; JAK inhibitors
• MDS: Cytopenias + dysplasia; ineffective hematopoiesis; AML transformation risk
• MDS treatment: Lower-risk (supportive, lenalidomide for del5q); higher-risk (HMA, transplant)
• Transformation: Both MPN and MDS can transform to AML

Key Terms

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