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InternalMed_Harrison. Like aplastic anemia, PRCA results cytopathic effect of B19 parvovirus infection of the erythroid progenitor cell. B. Uninuclear mega-from diverse mechanisms. Antibodies karyocyte and microblastic erythroid precursors typical of the 5q–myelodysplasia syndrome. to RBC precursors are frequently pres-C. Ringed sideroblast showing perinuclear iron granules. D. Tumor cells present on a touch preparaent in the blood, but T cell inhibition tion made from the marrow biopsy of a patient with metastatic carcinoma. is indicated, but anemia does not necessarily improve with surgery. The diagnosis of parvovirus infection requires detection of viral DNA sequences in the blood (IgG and IgM antibodies are commonly absent). The presence of erythroid colonies has been considered predictive of response to immunosuppressive therapy in idiopathic PRCA.


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InternalMed_Harrison. Red cell aplasia is compatible with long-term survival with supportive care alone: a combination of erythrocyte transfusions and iron chelation. For persistent B19 parvovirus infection, almost all patients respond to intravenous immunoglobulin therapy (e.g., 0.4 g/kg daily for 5 days), although relapse and retreatment may be expected, especially in patients with AIDS. The majority of patients with idiopathic PRCA respond favorably to immunosuppression. Most first receive a course of glucocorticoids. Also effective are cyclosporine, ATG, azathioprine, and cyclophosphamide.


InternalMed_Harrison

InternalMed_Harrison. The myelodysplastic syndromes (MDS) are a heterogeneous group of hematologic disorders broadly characterized by both (1) cytopenias due to bone marrow failure and (2) a high risk of development of acute myeloid leukemia (AML). Anemia, often with thrombocytopenia and 669 neutropenia, occurs with dysmorphic (abnormal appearing) and usually cellular bone marrow, which is evidence of ineffective blood cell production. In patients with “low-risk” MDS, marrow failure dominates the clinical course. In other patients, myeloblasts are present at diagnosis, chromosomes are abnormal, and the “high risk” is due to leukemic progression. MDS may be fatal due to the complications of pancytopenia or the incurability of leukemia, but a large proportion of patients will die of concurrent disease, the comorbidities typical in an elderly population. A clinically useful nosology of these often confusing entities was first developed by the French-American-British Cooperative Group in 1983. Five entities


InternalMed_Harrison

InternalMed_Harrison. typical in an elderly population. A clinically useful nosology of these often confusing entities was first developed by the French-American-British Cooperative Group in 1983. Five entities were defined: refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-t), and chronic myelomonocytic leukemia (CMML). The World Health Organization (WHO) classification (2002) recognized that the distinction between RAEB-t and AML is arbitrary and grouped them together as acute leukemia and that CMML behaves as a myeloproliferative disease; the WHO classification also separated refractory anemias with dysmorphic change restricted to erythroid lineage from those with multilineage changes. In a 2008 revision, specific categories for unilineage dysplasias were added (Table 130-5).


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InternalMed_Harrison. Refractory cytopenias with unilineage dysplasia (RCUD): Refractory anemia (RA) 10–20% Anemia Unilineage erythroid dysplasia (in ≥10% of cells) <1% of blasts <5% blasts Refractory neutropenia (RN) <1% Neutropenia Unilineage granulocytic dysplasia <1% blasts <5% blasts Refractory thrombocytopenia (RT) <1% Thrombocytopenia Unilineage megakaryocytic dysplasia <1% blasts <5% blasts Refractory anemia with ringed 3–11% Anemia Unilineage erythroid dysplasia ≥15% of erythroid sideroblasts (RARS) precursors are ringed sideroblasts Refractory cytopenias with 30% Cytopenia(s) Multilineage dysplasia ± ringed sideroblasts multilineage dysplasia (RCMD) Refractory anemia with excess blasts, 40% Cytopenia(s) Unilineage or multilineage dysplasia Refractory anemia with excess blasts, MDS associated with isolated del(5q) Uncommon Anemia Isolated 5q31 chromosome deletion Childhood MDS, including refractory <1% Pancytopenia <5% marrow blasts for RCC cytopenia of childhood (provisional) (RCC)


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InternalMed_Harrison. Childhood MDS, including refractory <1% Pancytopenia <5% marrow blasts for RCC cytopenia of childhood (provisional) (RCC) MDS, unclassifiable (MDS-U) ? Cytopenia Does not fit other categories


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InternalMed_Harrison. MDS, unclassifiable (MDS-U) ? Cytopenia Does not fit other categories If no dysplasia, MDS-associated karyotype Note: If peripheral blood blasts are 2–4%, the diagnosis is RAEB-1 even if marrow blasts are <5%. If Auer rods are present, the WHO considers the diagnosis RAEB-2 if the blast proportion is <20% (even if <10%), or acute myeloid leukemia (AML) if at least 20% blasts. For all subtypes, peripheral blood monocytes are <1 × 109/L. Bicytopenia may be observed in RCUD subtypes, but pancytopenia with unilineage marrow dysplasia should be classified as MDS-U. Therapy-related MDS (t-MDS), whether due to alkylating agents or topoisomerase II inhibitors (t-MDS/t-AML) is now included in the WHO classification of myeloid neoplasms. The listing in this table excludes MDS/myeloproliferative neoplasm overlap categories, such as chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, and the provisional entity RARS with thrombocytosis.


InternalMed_Harrison

InternalMed_Harrison. Abbreviation: MDS, myelodysplastic syndrome. 670 The diagnosis of MDS may be a challenge, because sometimes subtle clinical and pathologic features must be distinguished and precise diagnostic categorization requires a hematopathologist knowledgeable in the latest classification scheme. Nonetheless, it is important that the internist and primary care physician be sufficiently familiar with MDS to expedite referral to a hematologist, both because many new therapies are now available to improve hematopoietic function and the judicious use of supportive care can improve the patient’s quality of life.


InternalMed_Harrison

InternalMed_Harrison. Idiopathic MDS is a disease of the elderly; the mean age at onset is older than 70 years. There is a slight male preponderance. MDS is a relatively common form of bone marrow failure, with reported incidence rates of 35 to >100 per million persons in the general population and 120 to >500 per million in the older adult. MDS is rare in children, but monocytic leukemia can be seen. Secondary or therapy-related MDS is not age related. Rates of MDS have increased over time, due to better recognition of the syndrome by physicians and an aging population.


InternalMed_Harrison

InternalMed_Harrison. MDS is associated with environmental exposures such as radiation and benzene; other risk factors have been reported inconsistently. Secondary MDS occurs as a late toxicity of cancer treatment, usually a combination of radiation and the radiomimetic alkylating agents such as busulfan, nitrosourea, or procarbazine (with a latent period of 5–7 years) or the DNA topoisomerase inhibitors (2-year latency). Acquired aplastic anemia, Fanconi anemia, and other constitutional marrow failure diseases can evolve into MDS. However, the typical MDS patient does not have a suggestive environmental exposure history or a preceding hematologic disease. MDS is a disease of aging, suggesting random cumulative intrinsic and environmental damage to marrow cells.


InternalMed_Harrison

InternalMed_Harrison. MDS is a clonal hematopoietic stem cell disorder characterized by disordered cell proliferation and impaired differentiation, resulting in cytopenias and risk of progression to leukemia. Both chromosomal and genetic instability have been implicated, and both are likely aging-related. Cytogenetic abnormalities are found in approximately one-half of patients, and some of the same specific lesions are also seen in frank leukemia; aneuploidy (chromosome loss or gain) is more frequent than translocations. More sensitive assays, such as comparative genomic hybridization and single nucleotide polymorphism arrays, reveal chromosomal abnormalities in a large proportion of patients with normal conventional cytogenetics. Accelerated telomere attrition may destabilize the genome in marrow failure and predispose to acquisition of chromosomal lesions. Cytogenetic abnormalities are not random (loss of all or part of 5, 7, and 20, trisomy of 8) and may be related to etiology (11q23 following


InternalMed_Harrison

InternalMed_Harrison. and predispose to acquisition of chromosomal lesions. Cytogenetic abnormalities are not random (loss of all or part of 5, 7, and 20, trisomy of 8) and may be related to etiology (11q23 following topoisomerase II inhibitors). The type and number of cytogenetic abnormalities strongly correlate with the probability of leukemic transformation and survival.


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InternalMed_Harrison. Genomics has illuminated the role of point mutations in the pathophysiology of MDS. Recurrent somatic mutations, acquired in the abnormal marrow cells and absent in the germline, have been identified in almost 100 genes. Many of the same genes are also mutated in AML without MDS, whereas others are distinctive in subtypes of MDS. A prominent example of the latter is the discovery of mutations in genes of the RNA splicing machinery, especially SF3B1, which strongly associate with sideroblastic anemia. Some mutations correlate with prognosis: spliceosome defects with favorable outcome, and mutations in EZH2, TP53, RUNX1, and ASXL1 with poor outcome. Mutations and cytogenetic abnormalities are not independent: TP53 mutations associate with complex cytogenetic abnormalities and TET2 mutations with normal cytogenetics. Correlation and exclusion in the pattern of mutations indicate a functional genomic architecture. Analysis of deep sequencing results in patients whose MDS evolved to AML


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InternalMed_Harrison. with normal cytogenetics. Correlation and exclusion in the pattern of mutations indicate a functional genomic architecture. Analysis of deep sequencing results in patients whose MDS evolved to AML has shown evidence of clonal succession, with founder clones acquiring further mutations that allow clonal dominance. Furthermore, the prevalence of abnormal cells by morphology underestimates bone marrow involvement by MDS clones, as cells normal in appearance are apparently derived from the abnormal clones. Both presenting and evolving hematologic manifestations result from the accumulation of multiple genetic lesions: loss of tumor-suppressor genes, activating oncogene mutations, epigenetic pathways that affect mRNA processing and methylation status, or other harmful alterations. Pathophysiology has been linked to mutations and chromosome abnormalities in some specific MDS syndromes. The 5q– deletion leads to heterozygous loss of a ribosomal protein gene that is also mutant in


InternalMed_Harrison

InternalMed_Harrison. has been linked to mutations and chromosome abnormalities in some specific MDS syndromes. The 5q– deletion leads to heterozygous loss of a ribosomal protein gene that is also mutant in Diamond-Blackfan anemia, and both are characterized by deficient erythropoiesis. An immune pathophysiology may underlie trisomy 8 MDS, in which patients often experience improved blood counts after immunosuppressive therapy; there is T cell activity directed to hematopoietic progenitors, which the cytogenetically aberrant clone resists. However, in general for MDS, the role of the immune system and its cells and cytokines; the role of the hematopoietic stem cell niche, the microenvironment, and cell-cell interactions; the fate of normal cells in the Darwinian competitive environment of the dysplastic marrow; and how mutant cells produce marrow failure in MDS are not well understood.


InternalMed_Harrison

InternalMed_Harrison. Anemia dominates the early course. Most symptomatic patients complain of the gradual onset of fatigue and weakness, dyspnea, and pallor, but at least one-half the patients are asymptomatic, and their MDS is discovered only incidentally on routine blood counts. Previous chemotherapy or radiation exposure is an important historic fact. Fever and weight loss should point to a myeloproliferative rather than myelodysplastic process. MDS in childhood is rare and, when diagnosed, increases the likelihood of an underlying genetic disease. Children with Down syndrome are susceptible to MDS, and a family history may indicate a hereditary form of sideroblastic anemia, Fanconi anemia, or a telomeropathy. Inherited GATA2 mutations, as in the MonoMAC syndrome (with increased susceptibility to viral, mycobacteria, and fungal infections, as well as deficient numbers of monocytes, natural killer cells, and B lymphocytes), also cause MDS in young patients.


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InternalMed_Harrison. The physical examination is remarkable for signs of anemia; approximately 20% of patients have splenomegaly. Some unusual skin lesions, including Sweet syndrome (febrile neutrophilic dermatosis), occur with MDS. Accompanying autoimmune syndromes are not infrequent. In the younger patient, stereotypical anomalies point to a constitutional syndrome (short stature, abnormal thumbs in Fanconi anemia; early graying in the telomeropathies; cutaneous warts in GATA2 deficiency).


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InternalMed_Harrison. LABORATORY STUDIES Blood Anemia is present in most cases, either alone or as part of bi-or pancytopenia; isolated neutropenia or thrombocytopenia is more unusual. Macrocytosis is common, and the smear may be dimorphic with a distinctive population of large red blood cells. Platelets are also large and lack granules. In functional studies, they may show marked abnormalities, and patients may have bleeding symptoms despite seemingly adequate numbers. Neutrophils are hypogranulated; have hyposegmented, ringed, or abnormally segmented nuclei; contain Döhle bodies; and may be functionally deficient. Circulating myeloblasts usually correlate with marrow blast numbers, and their quantity is important for classification and prognosis. The total white blood cell count (WBC) is usually normal or low, except in chronic myelomonocytic leukemia. As in aplastic anemia, MDS can be associated with a clonal population of PNH cells. Genetic testing is commercially available for constitutional


InternalMed_Harrison

InternalMed_Harrison. or low, except in chronic myelomonocytic leukemia. As in aplastic anemia, MDS can be associated with a clonal population of PNH cells. Genetic testing is commercially available for constitutional syndromes.


InternalMed_Harrison

InternalMed_Harrison. Bone Marrow The bone marrow is usually normal or hypercellular, but in about 20% of cases, it is sufficiently hypocellular to be confused with aplasia. No single characteristic feature of marrow morphology distinguishes MDS, but the following are commonly observed: dyserythropoietic changes (especially nuclear abnormalities) and ringed sideroblasts in the erythroid lineage; hypogranulation and hyposegmentation in granulocytic precursors, with an increase in myeloblasts; and megakaryocytes showing reduced numbers of or disorganized aGood, normal, –Y, del(5q), del (20q); poor, complex (≥3 abnormalities) or chromosome 7 abnormalities; intermediate, all other abnormalities. bCytopenias defined as hemoglobin <100 g/L, platelet count <100,000/μL, and absolute neutrophil count <1500/μL.


InternalMed_Harrison

InternalMed_Harrison. nuclei. Megaloblastic nuclei associated with defective hemoglobinization in the erythroid lineage are common. Prognosis strongly correlates with the proportion of marrow blasts. Cytogenetic analysis and fluorescent in situ hybridization can identify chromosomal abnormalities. Deficiencies of vitamin B12 or folate should be excluded by appropriate blood tests; vitamin B6 deficiency can be assessed by a therapeutic trial of pyridoxine if the bone marrow shows ringed sideroblasts. Marrow dysplasia can be observed in acute viral infections, drug reactions, or chemical toxicity but should be transient. More difficult are the distinctions between hypocellular MDS and aplasia or between refractory anemia with excess blasts and early acute leukemia. The WHO considers the presence of 20% blasts in the marrow as the criterion that separates AML from MDS. In young patients, underlying, predisposing genetic diseases should be considered (see above).


InternalMed_Harrison

InternalMed_Harrison. The median survival varies greatly from years for patients with 5q– or sideroblastic anemia to a few months in refractory anemia with excess blasts or severe pancytopenia associated with monosomy 7; an International Prognostic Scoring System (IPSS; Table 130-6) assists in making predictions. Even “low-risk” MDS has significant morbidity and mortality. Most patients die as a result of complications of pancytopenia and not due to leukemic transformation; perhaps one-third will succumb to other diseases unrelated to their MDS. Precipitous worsening of pancytopenia, acquisition of new chromosomal abnormalities on serial cytogenetic determination, increase in the number of blasts, and marrow fibrosis are all poor prognostic indicators. The outlook in therapy-related MDS, regardless of type, is extremely poor, and most patients will progress within a few months to refractory AML.


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InternalMed_Harrison. Historically, the therapy of MDS has been unsatisfactory, but new drugs recently have been approved for this disease. Several regimens appear to not only improve blood counts but to delay onset of leukemia and to improve survival. The choice of therapy for an individual patient, administration of treatment, and management of toxicities are complicated and require hematologic expertise.


InternalMed_Harrison

InternalMed_Harrison. Only hematopoietic stem cell transplantation offers cure of MDS. The current survival rate in selected patient cohorts is ~50% at 3 years and is improving. Results using unrelated matched donors are now similar to those obtained using siblings, and patients in their 50s and 60s have been successfully transplanted. Nevertheless, treatment-related mortality and morbidity increase with recipient age. Complicating the decision to undertake transplant is that the high-risk patient, for whom the procedure is most obviously indicated, has a high probability of a poor outcome from transplant-related mortality or disease relapse, whereas the low-risk patient, who is more likely to tolerate transplant, also may do well for years 671 with less aggressive therapies.


InternalMed_Harrison

InternalMed_Harrison. MDS has been regarded as particularly refractory to cytotoxic chemotherapy regimens, and as in AML in the older adult, drug toxicity is frequent and often fatal, and remissions if achieved are brief. Low doses of cytotoxic drugs have been administered for their “differentiation” potential, and from this experience, drug therapies have emerged based on pyrimidine analogues. These new drugs are classified as epigenetic modulators, believed to act through a demethylating mechanism to alter gene regulation and allow differentiation to mature blood cells from the abnormal MDS stem cell (although global methylation status has not correlated with clinical efficacy). Azacitidine and decitabine are two epigenetic modifiers frequently used in bone marrow failure clinics. Azacitidine improves blood counts and survival in MDS, compared to best supportive care. Azacitidine is usually administered subcutaneously, daily for 7 days, at 4-week intervals, for at least four cycles before assessing for


InternalMed_Harrison

InternalMed_Harrison. counts and survival in MDS, compared to best supportive care. Azacitidine is usually administered subcutaneously, daily for 7 days, at 4-week intervals, for at least four cycles before assessing for response. Overall, generally improved blood counts with a decrease in transfusion requirements occurred in ~50% of patients in published trials. Response is dependent on continued drug administration, and most patients eventually will no longer respond and experience recurrent cytopenias or progression to AML. Decitabine is closely related to azacitidine and more potent; 30–50% of patients show responses in blood counts, with a duration of response of almost a year. Decitabine is usually administered by continuous intravenous infusion in regimens of varying doses and durations of 3 to 10 days in repeating cycles. The major toxicity of azacitidine and decitabine is myelosuppression, leading to worsened blood counts. Other symptoms associated with cancer chemotherapy frequently occur.


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InternalMed_Harrison. days in repeating cycles. The major toxicity of azacitidine and decitabine is myelosuppression, leading to worsened blood counts. Other symptoms associated with cancer chemotherapy frequently occur. Demethylating agents are frequently used in the high-risk patient who is not a candidate for stem cell transplant. In the lower risk patient, they are also effective, but alternative therapies should be considered.


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InternalMed_Harrison. Lenalidomide, a thalidomide derivative with a more favorable toxicity profile, is particularly effective in reversing anemia in MDS patients with 5q– syndrome; not only do a high proportion of these patients become transfusion independent with normal or near-normal hemoglobin levels, but their cytogenetics also become normal. The drug has many biologic activities, and it is unclear which is critical for clinical efficacy. Lenalidomide is administered orally. Most patients will improve within 3 months of initiating therapy. Toxicities include myelosuppression (worsening thrombocytopenia and neutropenia, necessitating blood count monitoring) and an increased risk of deep vein thrombosis and pulmonary embolism.


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InternalMed_Harrison. Immunosuppression, as used in aplastic anemia, also may produce sustained independence from transfusion and improve survival. ATG, cyclosporine, and the anti-CD52 monoclonal antibody alemtuzumab are especially effective in younger MDS patients (<60 years old) with more favorable IPSS scores and who bear the histocompatibility antigen HLA-DR15. HGFs can improve blood counts but, as in most other marrow failure states, have been most beneficial to patients with the least severe pancytopenia. EPO alone or in combination with G-CSF can improve hemoglobin levels, but mainly in those with low serum EPO levels who have no or only a modest need for transfusions. Survival does not appear to be improved by G-CSF treatment alone but may be enhanced by erythropoietin and amelioration of anemia. G-CSF treatment alone failed to improve survival in a controlled trial.


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InternalMed_Harrison. The same principles of supportive care described for aplastic anemia apply to MDS. Despite improvements in drug therapy, many patients will be anemic for years. RBC transfusion support should be accompanied by iron chelation to prevent secondary hemochromatosis.


InternalMed_Harrison

InternalMed_Harrison. Fibrosis of the bone marrow (see Fig. 129-2), usually accompanied by a characteristic blood smear picture called leukoerythroblastosis, can occur as a primary hematologic disease, called myelofibrosis or myeloid metaplasia (Chap. 131), and as a secondary process, called 672 myelophthisis. Myelophthisis, or secondary myelofibrosis, is reactive. Fibrosis can be a response to invading tumor cells, usually an epithelial cancer of breast, lung, or prostate origin or neuroblastoma. Marrow fibrosis may occur with infection of mycobacteria (both Mycobacterium tuberculosis and Mycobacterium avium), fungi, or HIV and in sarcoidosis. Intracellular lipid deposition in Gaucher’s disease and obliteration of the marrow space related to absence of osteoclast remodeling in congenital osteopetrosis also can produce fibrosis. Secondary myelofibrosis is a late consequence of radiation therapy or treatment with radiomimetic drugs. Usually the infectious or malignant underlying processes are obvious.


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InternalMed_Harrison. can produce fibrosis. Secondary myelofibrosis is a late consequence of radiation therapy or treatment with radiomimetic drugs. Usually the infectious or malignant underlying processes are obvious. Marrow fibrosis can also be a feature of a variety of hematologic syndromes, especially chronic myeloid leukemia, multiple myeloma, lymphomas, myeloma, and hairy cell leukemia. The pathophysiology has three distinct features: proliferation of fibroblasts in the marrow space (myelofibrosis); the extension of hematopoiesis into the long bones and into extramedullary sites, usually the spleen, liver, and lymph nodes (myeloid metaplasia); and ineffective erythropoiesis. The etiology of the fibrosis is unknown but most likely involves dysregulated production of growth factors: platelet-derived growth factor and transforming growth factor β have been implicated. Abnormal regulation of other hematopoietins would lead to localization of blood-producing cells in nonhematopoietic tissues and


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InternalMed_Harrison. growth factor and transforming growth factor β have been implicated. Abnormal regulation of other hematopoietins would lead to localization of blood-producing cells in nonhematopoietic tissues and uncoupling of the usually balanced processes of stem cell proliferation and differentiation. Myelofibrosis is remarkable for pancytopenia despite very large numbers of circulating hematopoietic progenitor cells. Anemia is dominant in secondary myelofibrosis, usually normocytic and normochromic. The diagnosis is suggested by the characteristic leukoerythroblastic smear (see Fig. 129-1). Erythrocyte morphology is highly abnormal, with circulating nucleated RBCs, teardrops, and shape distortions. WBC numbers are often elevated, sometimes mimicking a leukemoid reaction, with circulating myelocytes, promyelocytes, and myeloblasts. Platelets may be abundant and are often of giant size. Inability to aspirate the bone marrow, the characteristic “dry tap,” can allow a presumptive diagnosis in the


InternalMed_Harrison

InternalMed_Harrison. promyelocytes, and myeloblasts. Platelets may be abundant and are often of giant size. Inability to aspirate the bone marrow, the characteristic “dry tap,” can allow a presumptive diagnosis in the appropriate setting before the biopsy is decalcified. The course of secondary myelofibrosis is determined by its etiology, usually a metastatic tumor or an advanced hematologic malignancy. Treatable causes must be excluded, especially tuberculosis and fungus. Transfusion support can relieve symptoms.


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InternalMed_Harrison. Polycythemia Vera and Other Myeloproliferative Neoplasms Jerry L. Spivak The World Health Organization (WHO) classification of the chronic myeloproliferative neoplasms (MPNs) includes eight disorders, some of which are rare or poorly characterized (Table 131-1) but all of 131 which share an origin in a multipotent hematopoietic progenitor cell; overproduction of one or more of the formed elements of the blood without significant dysplasia; and a predilection to extramedullary hematopoiesis, myelofibrosis, and transformation at varying rates to acute leukemia. Within this broad classification, however, significant phenotypic heterogeneity exists. Some diseases such as chronic myelogenous leukemia (CML), chronic neutrophilic leukemia (CNL), and chronic eosinophilic leukemia (CEL) express primarily a myeloid phenotype, whereas in other diseases, such as polycythemia vera (PV), primary myelofibrosis (PMF), and essential thrombocytosis (ET), erythroid or megakaryocytic hyperplasia


InternalMed_Harrison

InternalMed_Harrison. primarily a myeloid phenotype, whereas in other diseases, such as polycythemia vera (PV), primary myelofibrosis (PMF), and essential thrombocytosis (ET), erythroid or megakaryocytic hyperplasia predominates. The latter three disorders, in contrast to the former three, also appear capable of transforming into each other.


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InternalMed_Harrison. Chronic myeloid leukemia, bcr-abl–positive Chronic eosinophilic leukemia, not otherwise specified Myeloproliferative neoplasms, unclassifiable


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InternalMed_Harrison. Such phenotypic heterogeneity has a genetic basis; CML is the consequence of the balanced translocation between chromosomes 9 and 22 [t(9;22)(q34;11)]; CNL has been associated with a t(15;19) translocation; and CEL occurs with a deletion or balanced translocations involving the PDGFRα gene. By contrast, to a greater or lesser extent, PV, PMF, and ET are characterized by a mutation, V617F, that causes constitutive activation of JAK2, a tyrosine kinase essential for the function of the erythropoietin and thrombopoietin receptors but not the granulocyte colony-stimulating factor receptor. This important distinction is also reflected in the natural histories of CML, CNL, and CEL, which are usually measured in years, and their high rate of leukemic transformation. By contrast, the natural history of PV, PMF, and ET is usually measured in decades, and transformation to acute leukemia is uncommon in PV and ET in the absence of exposure to mutagenic drugs. This chapter, therefore, will focus


InternalMed_Harrison

InternalMed_Harrison. of PV, PMF, and ET is usually measured in decades, and transformation to acute leukemia is uncommon in PV and ET in the absence of exposure to mutagenic drugs. This chapter, therefore, will focus only on PV, PMF, and ET, because their clinical and genetic overlap is substantial even though their clinical courses are distinctly different.


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InternalMed_Harrison. The other chronic myeloproliferative neoplasms will be discussed in Chaps. 133 and 135e. PV is a clonal disorder involving a multipotent hematopoietic progenitor cell in which phenotypically normal red cells, granulocytes, and platelets accumulate in the absence of a recognizable physiologic stimulus. The most common of the chronic MPNs, PV occurs in 2.5 per 100,000 persons, sparing no adult age group and increasing with age to rates over 10/100,000. Familial transmission is infrequent, and women predominate among sporadic cases.


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InternalMed_Harrison. The etiology of PV is unknown. Although nonrandom chromo some abnormalities such as deletion 20q and trisomy 8 and 9 have been documented in up to 30% of untreated PV patients, unlike CML, no consistent cytogenetic abnormality has been associated with the disorder. However, a mutation in the autoinhibitory pseudokinase domain of the tyrosine kinase JAK2—that replaces valine with phenylalanine (V617F), causing constitutive kinase activation—appears to have a central role in the pathogenesis of PV.


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InternalMed_Harrison. JAK2 is a member of an evolutionarily well-conserved, nonreceptor tyrosine kinase family and serves as the cognate tyrosine kinase for the erythropoietin and thrombopoietin receptors. It also functions as an obligate chaperone for these receptors in the Golgi apparatus and is responsible for their cell-surface expression. The conformational change induced in the erythropoietin and thrombopoietin receptors following binding to their respective cognate ligands, erythropoietin or thrombopoietin, leads to JAK2 autophosphorylation, receptor phosphorylation, and phosphorylation of proteins involved in cell proliferation, differentiation, and resistance to apoptosis. Transgenic animals lacking JAK2 die as embryos from severe anemia. Constitutive activation of JAK2, on the other hand, explains the erythropoietin hypersensitivity, erythropoietin-independent erythroid colony formation, rapid terminal differentiation, increase in Bcl-XL expression, and apoptosis resistance in the absence of


InternalMed_Harrison

InternalMed_Harrison. the erythropoietin hypersensitivity, erythropoietin-independent erythroid colony formation, rapid terminal differentiation, increase in Bcl-XL expression, and apoptosis resistance in the absence of erythropoietin that characterize the in vitro behavior of PV erythroid progenitor cells.


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InternalMed_Harrison. Importantly, the JAK2 gene is located on the short arm of chromo some 9, and loss of heterozygosity on chromosome 9p due to mitotic recombination is the most common cytogenetic abnormality in PV. The segment of 9p involved contains the JAK2 locus, and loss of heterozygosity in this region leads to homozygosity for JAK2 V617F. More than 95% of PV patients express this mutation, as do approximately 50% of PMF and ET patients. Homozygosity for the mutation occurs in approximately 30% of PV patients and 60% of PMF patients but is rare in ET. Over time, a portion of PV JAK2 V617F heterozygotes become homozygotes due to mitotic recombination, but usually not after 10 years of the disease. Most PV patients who do not express JAK2 V617F express a mutation in exon 12 of the kinase and are not clinically different from those who do, nor do JAK2 V617F heterozygotes differ clinically from homozygotes. Interestingly, the predisposition to acquire mutations in JAK2 appears to be associated with a


InternalMed_Harrison

InternalMed_Harrison. different from those who do, nor do JAK2 V617F heterozygotes differ clinically from homozygotes. Interestingly, the predisposition to acquire mutations in JAK2 appears to be associated with a specific JAK2 gene haplotype, GGCC. JAK2 V617F is the basis for many of the phenotypic and biochemical characteristics of PV such as elevation of the leukocyte alkaline phosphatase (LAP) score; however, it cannot solely account for the entire PV phenotype and is probably not the initiating lesion in the three MPNs. First, PV patients with the same phenotype and documented clonal disease lack any mutation of JAK2. Second, ET and PMF patients have the same mutation but different clinical phenotypes. Third, familial PV can occur without the mutation, even when other members of the same family express it. Fourth, not all the cells of the malignant clone express JAK2 V617F. Fifth, JAK2 V617F has been observed in patients with long-standing idiopathic erythrocytosis. Sixth, in some patients, JAK2 V617F


InternalMed_Harrison

InternalMed_Harrison. Fourth, not all the cells of the malignant clone express JAK2 V617F. Fifth, JAK2 V617F has been observed in patients with long-standing idiopathic erythrocytosis. Sixth, in some patients, JAK2 V617F appears to be acquired after another mutation. Finally, in some JAK2 V617F–positive PV or ET patients, acute leukemia can occur in a JAK2 V617F–negative progenitor cell. However, although JAK2 V617F alone may not be sufficient to cause PV, it appears essential for the transformation of ET to PV, although not for its transformation to PMF.


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InternalMed_Harrison. Although isolated thrombocytosis, leukocytosis, or splenomegaly may be the initial presenting manifestation of PV, most often the disorder is first recognized by the incidental discovery of a high hemoglobin or hematocrit. With the exception of aquagenic pruritus, no symptoms distinguish PV from other causes of erythrocytosis.


InternalMed_Harrison

InternalMed_Harrison. Uncontrolled erythrocytosis causes hyperviscosity, leading to neurologic symptoms such as vertigo, tinnitus, headache, visual disturbances, and transient ischemic attacks (TIAs). Systolic hypertension is also a feature of the red cell mass elevation. In some patients, venous or arterial thrombosis may be the presenting manifestation of PV. Any vessel can be affected; but cerebral, cardiac, or mesenteric vessels are most commonly involved. Intraabdominal venous thrombosis is particularly common in young women and may be catastrophic if a sudden and complete obstruction of the hepatic vein occurs. Indeed, PV should be suspected in any patient who develops hepatic vein thrombosis. Digital ischemia, easy bruising, epistaxis, acid-peptic disease, or gastrointestinal hemorrhage may occur due to vascular stasis or thrombocytosis. Erythema, burning, and pain in the extremities, a symptom complex known as erythromelalgia, are other complications of the thrombocytosis of PV due to increased


InternalMed_Harrison

InternalMed_Harrison. to vascular stasis or thrombocytosis. Erythema, burning, and pain in the extremities, a symptom complex known as erythromelalgia, are other complications of the thrombocytosis of PV due to increased platelet stickiness. Given the large turnover of hematopoietic cells, hyperuricemia with secondary gout, uric acid stones, and symptoms due to hypermetabolism can also complicate the disorder.


InternalMed_Harrison

InternalMed_Harrison. When PV presents with erythrocytosis in combination with leukocytosis, thrombocytosis, or splenomegaly or a combination of these, the diagnosis is apparent. However, when patients present with an elevated hemoglobin or hematocrit alone, the diagnostic evaluation is more complex because of the many diagnostic possibilities (Table 131-2). Furthermore, unless the hemoglobin level is ≥20 g/dL (hematocrit ≥60%), it is not possible to distinguish true erythrocytosis from disorders causing plasma volume contraction. This is because uniquely in PV, in contrast to other causes of true erythrocytosis, there is expansion of the plasma volume, which can mask the elevated red Hemoconcentration secondary to dehydration, diuretics, ethanol abuse, androgens, or tobacco abuse Adrenal tumors Right to left cardiac or vascular glomerulonephritis Erythropoietin receptor mutation Postrenal transplantation VHL mutations (Chuvash polycythemia) Renal cysts 2,3-BPG mutationBartter’s syndrome


InternalMed_Harrison

InternalMed_Harrison. Abbreviations: 2,3-BPG, 2,3-bisphosphoglycerate; VHL, von Hippel-Lindau. cell mass; thus, red cell mass and plasma volume determinations are necessary to establish the presence of an absolute erythrocytosis and to distinguish this from relative erythrocytosis due to a reduction in plasma volume alone (also known as stress or spurious erythrocytosis or Gaisböck’s syndrome). Figure 77-18 illustrates a diagnostic algorithm for the evaluation of suspected erythrocytosis. Assay for JAK2 mutations in the presence of a normal arterial oxygen saturation provides an alternative diagnostic approach to erythrocytosis when red cell mass and plasma volume determinations are not available; a normal serum erythropoietin level does not exclude the presence of PV, but an elevated erythropoietin level is more consistent with a secondary cause for the erythrocytosis.


InternalMed_Harrison

InternalMed_Harrison. Other laboratory studies that may aid in diagnosis include the red cell count, mean corpuscular volume, and red cell distribution width (RDW), particularly when the hematocrit or hemoglobin levels are less than 60% or 20 g/dL, respectively. Only three situations cause microcytic erythrocytosis: β thalassemia trait, hypoxic erythrocytosis, and PV. With β thalassemia trait, the RDW is normal, whereas with hypoxic erythrocytosis and PV, the RDW may be elevated due to associated iron deficiency. Today, however, the assay for JAK2 V617F has superseded other tests for establishing the diagnosis of PV. Of course, in patients with associated acid-peptic disease, occult gastrointestinal bleeding may lead to a presentation with hypochromic, microcytic anemia, masking the presence of PV.


InternalMed_Harrison

InternalMed_Harrison. A bone marrow aspirate and biopsy provide no specific diagnostic information because these may be normal or indistinguishable from ET or PMF. Similarly, no specific cytogenetic abnormality is associated with the disease, and the absence of a cytogenetic marker does not exclude the diagnosis.


InternalMed_Harrison

InternalMed_Harrison. Many of the clinical complications of PV relate directly to the increase in blood viscosity associated with red cell mass elevation and indirectly to the increased turnover of red cells, leukocytes, and platelets with the attendant increase in uric acid and cytokine production. The latter appears to be responsible for constitutional symptoms. Peptic ulcer disease can also be due to Helicobacter pylori infection, the incidence of which is increased in PV, while the pruritus associated with this disorder may be a consequence of mast cell activation by JAK2 V617F. A sudden increase in spleen size can be associated with painful splenic infarction. Myelofibrosis appears to be part of the natural history of the disease but is a reactive, reversible process that does not itself 674 impede hematopoiesis and by itself has no prognostic significance. In approximately 15% of patients, however, myelofibrosis is accompanied by significant extramedullary hematopoiesis, hepatosplenomegaly, and


InternalMed_Harrison

InternalMed_Harrison. and by itself has no prognostic significance. In approximately 15% of patients, however, myelofibrosis is accompanied by significant extramedullary hematopoiesis, hepatosplenomegaly, and transfusion-dependent anemia, which are manifestations of stem cell failure. The organomegaly can cause significant mechanical discomfort, portal hypertension, and progressive cachexia. Although the incidence of acute nonlymphocytic leukemia is increased in PV, the incidence of acute leukemia in patients not exposed to chemotherapy or radiation therapy is low. Interestingly, chemotherapy, including hydroxyurea, has been associated with acute leukemia in JAK2 V617F– negative stem cells in some PV patients. Erythromelalgia is a curious syndrome of unknown etiology associated with thrombocytosis, primarily involving the lower extremities and usually manifested by erythema, warmth, and pain of the affected appendage and occasionally digital infarction. It occurs with a variable frequency and is usually


InternalMed_Harrison

InternalMed_Harrison. involving the lower extremities and usually manifested by erythema, warmth, and pain of the affected appendage and occasionally digital infarction. It occurs with a variable frequency and is usually responsive to salicylates. Some of the central nervous system symptoms observed in patients with PV, such as ocular migraine, appear to represent a variant of erythromelalgia. Left uncontrolled, erythrocytosis can lead to thrombosis involving vital organs such as the liver, heart, brain, or lungs. Patients with massive splenomegaly are particularly prone to thrombotic events because the associated increase in plasma volume masks the true extent of the red cell mass elevation measured by the hematocrit or hemoglobin level. A “normal” hematocrit or hemoglobin level in a PV patient with massive splenomegaly should be considered indicative of an elevated red cell mass until proven otherwise.


InternalMed_Harrison

InternalMed_Harrison. PV is generally an indolent disorder, the clinical course of which is measured in decades, and its management should reflect its tempo. Thrombosis due to erythrocytosis is the most significant complication and often the presenting manifestation, and maintenance of the hemoglobin level at ≤140 g/L (14 g/dL; hematocrit <45%) in men and ≤120 g/L (12 g/dL; hematocrit <42%) in women is mandatory to avoid thrombotic complications. Phlebotomy serves initially to reduce hyperviscosity by bringing the red cell mass into the normal range while further expanding the plasma volume. Periodic phlebotomies thereafter serve to maintain the red cell mass within the normal range and to induce a state of iron deficiency that prevents an accelerated reexpansion of the red cell mass. In most PV patients, once an iron-deficient state is achieved, phlebotomy is usually only required at 3-month intervals. Neither phlebotomy nor iron deficiency increases the platelet count relative to the effect of the


InternalMed_Harrison

InternalMed_Harrison. once an iron-deficient state is achieved, phlebotomy is usually only required at 3-month intervals. Neither phlebotomy nor iron deficiency increases the platelet count relative to the effect of the disease itself, and thrombocytosis is not correlated with thrombosis in PV, in contrast to the strong correlation between erythrocytosis and thrombosis in this disease. The use of salicylates as a tonic against thrombosis in PV patients is not only potentially harmful if the red cell mass is not controlled by phlebotomy, but is also an unproven remedy. Anticoagulants are only indicated when a thrombosis has occurred and can be difficult to monitor if the red cell mass is substantially elevated owing to the artifactual imbalance between the test tube anticoagulant and plasma that occurs when blood from these patients is assayed for prothrombin or partial thromboplastin activity. Asymptomatic hyperuricemia (<10 mg/dL) requires no therapy, but allopurinol should be administered to avoid


InternalMed_Harrison

InternalMed_Harrison. blood from these patients is assayed for prothrombin or partial thromboplastin activity. Asymptomatic hyperuricemia (<10 mg/dL) requires no therapy, but allopurinol should be administered to avoid further elevation of the uric acid when chemotherapy is used to reduce splenomegaly or leukocytosis or to treat pruritus. Generalized pruritus intractable to antihistamines or antidepressants such as doxepin can be a major problem in PV; interferon α (IFN-α), psoralens with ultraviolet light in the A range (PUVA) therapy, and hydroxyurea are other methods of palliation. Asymptomatic thrombocytosis requires no therapy unless the platelet count is sufficiently high to cause bleeding due an acquired form of von Willebrand’s disease in which there is adsorption and proteolysis of high-molecular-weight von Willebrand factor (VWF) multimers by the expanded platelet mass. Symptomatic splenomegaly can be treated with pegylated IFN-α. Pegylated IFN-α can also produce complete hematologic and


InternalMed_Harrison

InternalMed_Harrison. von Willebrand factor (VWF) multimers by the expanded platelet mass. Symptomatic splenomegaly can be treated with pegylated IFN-α. Pegylated IFN-α can also produce complete hematologic and molecular remissions in PV, and its role in this disorder is currently under investigation. Anagrelide, a phosphodiesterase inhibitor, can reduce the platelet count and, if tolerated, is preferable to hydroxyurea because it lacks marrow toxicity and is protective against venous thrombosis. A reduction in platelet number may be necessary for the treatment of erythromelalgia or ocular migraine if salicylates are not effective or if the platelet count is sufficiently high to increase the risk of hemorrhage but only to the degree that symptoms are alleviated. Alkylating agents and radioactive sodium phosphate (32P) are leukemogenic in PV, and their use should be avoided. If a cytotoxic agent must be used, hydroxyurea is preferred, but this drug does not prevent either thrombosis or myelofibrosis in PV,


InternalMed_Harrison

InternalMed_Harrison. (32P) are leukemogenic in PV, and their use should be avoided. If a cytotoxic agent must be used, hydroxyurea is preferred, but this drug does not prevent either thrombosis or myelofibrosis in PV, is itself leukemogenic, and should be used for as short a time as possible. Previously, PV patients with massive splenomegaly unresponsive to reduction by chemotherapy or interferon required splenectomy. However, with the introduction of the nonspecific JAK2 inhibitor ruxolitinib, it has been possible in the majority of patients with PV complicated by myelofibrosis and myeloid metaplasia to reduce spleen size while at the same time alleviating constitutional symptoms to due to cytokine release. This drug is currently undergoing clinical trials in PV patients intolerant of hydroxyurea. In some patients with end-stage disease, pulmonary hypertension may develop due to fibrosis or extramedullary hematopoiesis. A role for allogeneic bone marrow transplantation in PV has not been defined.


InternalMed_Harrison

InternalMed_Harrison. Most patients with PV can live long lives without functional impairment when their red cell mass is effectively managed with phlebotomy alone. Chemotherapy is never indicated to control the red cell mass unless venous access is inadequate.


InternalMed_Harrison

InternalMed_Harrison. Chronic PMF (other designations include idiopathic myelofibrosis, agnogenic myeloid metaplasia, or myelofibrosis with myeloid metaplasia) is a clonal disorder of a multipotent hematopoietic progenitor cell of unknown etiology characterized by marrow fibrosis, extramedullary hematopoiesis, and splenomegaly. PMF is the least common chronic MPN, and establishing this diagnosis in the absence of a specific clonal marker is difficult because myelofibrosis and splenomegaly are also features of both PV and CML. Furthermore, myelofibrosis and splenomegaly also occur in a variety of benign and malignant disorders (Table 131-3), many of which are amenable to specific therapies not effective in PMF. In contrast to the other chronic MPNs and so-called acute or malignant myelofibrosis, which can occur at any age, PMF primarily afflicts men in their sixth decade or later.


InternalMed_Harrison

InternalMed_Harrison. The etiology of PMF is unknown. Nonrandom chromosome abnormalities such as 9p, 20q−, 13q−, trisomy 8 or 9, or partial trisomy 1q are common, but no cytogenetic abnormality specific to the disease has been identified. JAK2 V617F is present in approximately 50% of PMF patients, and mutations in the thrombopoietin receptor Mpl occur in about 5%. Most of the rest have mutations in the


InternalMed_Harrison

InternalMed_Harrison. Acute leukemia (lymphocytic, HIV infection myelogenous, megakaryocytic) calreticulin gene (CALR) that alter the carboxy-terminal portion of the gene product. The degree of myelofibrosis and the extent of extramedullary hematopoiesis are also not related. Fibrosis in this disorder is associated with overproduction of transforming growth factor β and tissue inhibitors of metalloproteinases, whereas osteosclerosis is associated with overproduction of osteoprotegerin, an osteoclast inhibitor. Marrow angiogenesis occurs due to increased production of vascular endothelial growth factor. Importantly, fibroblasts in PMF are polyclonal and not part of the neoplastic clone.


InternalMed_Harrison

InternalMed_Harrison. No signs or symptoms are specific for PMF. Many patients are asymptomatic at presentation, and the disease is usually detected by the discovery of splenic enlargement and/or abnormal blood counts during a routine examination. However, in contrast to its companion MPN, night sweats, fatigue, and weight loss are common presenting complaints. A blood smear will show the characteristic features of extramedullary hematopoiesis: teardrop-shaped red cells, nucleated red cells, myelocytes, and promyelocytes; myeloblasts may also be present (Fig. 131-1). Anemia, usually mild initially, is the rule, whereas the leukocyte and platelet counts are either normal or increased, but either can be depressed. Mild hepatomegaly may accompany the splenomegaly but is unusual in the absence of splenic enlargement; isolated lymphadenopathy should suggest another diagnosis. Both serum lactate dehydrogenase and alkaline phosphatase levels can be elevated. The LAP score can be low, normal, or high. Marrow is


InternalMed_Harrison

InternalMed_Harrison. isolated lymphadenopathy should suggest another diagnosis. Both serum lactate dehydrogenase and alkaline phosphatase levels can be elevated. The LAP score can be low, normal, or high. Marrow is usually inaspirable due to the myelofibrosis (Fig. 131-2), and bone x-rays may reveal osteosclerosis. Exuberant extramedullary hematopoiesis can cause ascites; portal, pulmonary, or intracranial hypertension; intestinal or ureteral obstruction; pericardial tamponade; spinal cord compression; or skin nodules. Splenic enlargement can be sufficiently rapid to cause splenic infarction with fever and pleuritic chest pain. Hyperuricemia and secondary gout may ensue.


InternalMed_Harrison

InternalMed_Harrison. While the clinical picture described above is characteristic of PMF, all of the clinical features described can also be observed in PV or CML. Massive splenomegaly commonly masks erythrocytosis in PV, and reports of intraabdominal thrombosis in PMF most likely represent instances of unrecognized PV. In some patients with PMF, erythrocytosis has developed during the course of the disease. Furthermore, because many other disorders have features that overlap with PMF but respond to distinctly different therapies, the diagnosis of PMF is one of exclusion, which requires that the disorders listed in Table 131-3 be ruled out. FIGURE 131-1 Teardrop-shaped red blood cells indicative of mem-brane damage from passage through the spleen, a nucleated red blood cell, and immature myeloid cells indicative of extramedullary hematopoiesis are noted. This peripheral blood smear is related to any cause of extramedullary hematopoiesis.


InternalMed_Harrison

InternalMed_Harrison. FIGURE 131-2 This marrow section shows the marrow cavity replaced by fibrous tissue composed of reticulin fibers and collagen. When this fibrosis is due to a primary hematologic process, it is called myelofibrosis. When the fibrosis is secondary to a tumor or a granulomatous process, it is called myelophthisis.


InternalMed_Harrison

InternalMed_Harrison. The presence of teardrop-shaped red cells, nucleated red cells, myelocytes, and promyelocytes establishes the presence of extramedullary hematopoiesis, while the presence of leukocytosis, thrombocytosis with large and bizarre platelets, and circulating myelocytes suggests the presence of an MPN as opposed to a secondary form of myelofibrosis (Table 131-3). Marrow is usually inaspirable due to increased marrow reticulin, but marrow biopsy will reveal a hypercellular marrow with trilineage hyperplasia and, in particular, increased numbers of megakaryocytes in clusters and with large, dysplastic nuclei. However, there are no characteristic bone marrow morphologic abnormalities that distinguish PMF from the other chronic MPNs. Splenomegaly due to extramedullary hematopoiesis may be sufficiently massive to cause portal hypertension and variceal formation. In some patients, exuberant extramedullary hematopoiesis can dominate the clinical picture. An intriguing feature of PMF is the


InternalMed_Harrison

InternalMed_Harrison. massive to cause portal hypertension and variceal formation. In some patients, exuberant extramedullary hematopoiesis can dominate the clinical picture. An intriguing feature of PMF is the occurrence of autoimmune abnormalities such as immune complexes, antinuclear antibodies, rheumatoid factor, or a positive Coombs’ test. Whether these represent a host reaction to the disorder or are involved in its pathogenesis is unknown. Cytogenetic analysis of blood is useful both to exclude CML and for prognostic purposes, because complex karyotype abnormalities portend a poor prognosis in PMF. For unknown reasons, the number of circulating CD34+ cells is markedly increased in PMF (>15,000/μL) compared to the other chronic MPNs, unless they too develop myeloid metaplasia.


InternalMed_Harrison

InternalMed_Harrison. Importantly, approximately 50% of PMF patients, like patients with its companion myeloproliferative disorders PV and ET, express the JAK2 V617F mutation, often as homozygotes. Such patients are usually older and have higher hematocrits than the patients who are JAK2 V617F–negative, whereas PMF patients expressing an MPL mutation tend to be more anemic and have lower leukocyte counts. Somatic mutations in exon 9 of the calreticulin gene (CALR) have been found in a majority of patients with PMF and ET who lack mutations in either JAK2 or MPL, and their clinical course appears to be more indolent than patients expressing either a JAK2 or an MPL mutation.


InternalMed_Harrison

InternalMed_Harrison. Survival in PMF varies according to specific risk factors at diagnosis (Tables 131-4 and 131-5) but is shorter in most patients than in PV or ET patients. The natural history of PMF is one of increasing marrow failure with transfusion-dependent anemia and increasing organomegaly due to extramedullary hematopoiesis. As with CML, PMF can evolve from a chronic phase to an accelerated phase with constitutional symptoms and increasing marrow failure. About 10% of patients spontaneously transform to an aggressive form of acute leukemia for which therapy is usually ineffective. Additional important prognostic


InternalMed_Harrison

InternalMed_Harrison. Note: The Dynamic International Prognostic Scoring System (DIPSS) was developed to determine if the International Prognostic Scoring System (IPSS) risk factors identified as important for survival at the time of primary myelofibrosis (PMF) diagnosis could also be used for risk stratification following their acquisition during the course of the disease. One point is assigned to each risk factor for IPSS scoring. For DIPSS, the same is true, but age >65 years, anemia, blood blasts, and constitutional symptoms are assigned 2 points each. The DIPSS Plus scoring system represents recognition that the addition of unfavorable karyotype, thrombocytopenia, and transfusion dependence improved the DIPSS risk stratification system for which additional points are assigned (Table 131-5). More recent studies suggest that mutational analysis of the ASXL1, EZH2, SRSF2, and IDH1/2 genes further improves risk stratification for survival and leukemic transformation (Leukemia 27:1861, 2013).


InternalMed_Harrison

InternalMed_Harrison. factors for disease acceleration during the course of PMF include the presence of complex cytogenetic abnormalities, thrombocytopenia, and transfusion-dependent anemia. Most recently, mutations in the ASXL1, EZH2, SRSF2, and IDH1/2 genes have been identified as risk factors for early death or transformation to acute leukemia and may prove to be more useful for PMF risk assessment than any clinical scoring system.


InternalMed_Harrison

InternalMed_Harrison. No specific therapy exists for PMF. The causes for anemia are multifarious and include ineffective erythropoiesis uncompensated by splenic extramedullary hematopoiesis, hemodilution due to splenomegaly, splenic sequestration, blood loss secondary to thrombocytopenia or portal hypertension, folic acid deficiency, systemic inflammation, and autoimmune hemolysis. Neither recombinant erythropoietin nor androgens such as danazol have proven to be consistently effective as therapy for anemia. Erythropoietin may worsen splenomegaly and will be ineffective if the serum erythropoietin level is >125 mU/L. Given the inflammatory milieu that characterizes PMF, corticosteroids can ameliorate anemia as well as constitutional symptoms such as fever, chills, night sweats, anorexia, and weight loss, and low-dose thalidomide together with prednisone has proved effective as well. Thrombocytopenia can be due to impaired marrow function, splenic sequestration, or autoimmune destruction


InternalMed_Harrison

InternalMed_Harrison. Number of Risk Factors aThe corresponding survival curves for each risk category can be found in the references cited in the footnotes of Table 131-4. Abbreviations: DIPSS, Dynamic International Prognostic Scoring System; IPSS, International Prognostic Scoring System.


InternalMed_Harrison

InternalMed_Harrison. and may also respond to low-dose thalidomide together with prednisone. Splenomegaly is by far the most distressing and intractable problem for PMF patients, causing abdominal pain, portal hypertension, easy satiety, and cachexia, whereas surgical removal of a massive spleen is associated with significant postoperative complications including mesenteric venous thrombosis, hemorrhage, rebound leukocytosis and thrombocytosis, and hepatic extramedullary hematopoiesis with no amelioration of either anemia or thrombocytopenia when present. For unexplained reasons, splenectomy also increases the risk of blastic transformation. Splenic irradiation is, at best, temporarily palliative and associated with a significant risk of neutropenia, infection, and subsequent operative hemorrhage if splenectomy is attempted. Allopurinol can control significant hyperuricemia, and bone pain can be alleviated by local irradiation. The role of IFN-α is still undefined; its side effects are more pronounced in


InternalMed_Harrison

InternalMed_Harrison. is attempted. Allopurinol can control significant hyperuricemia, and bone pain can be alleviated by local irradiation. The role of IFN-α is still undefined; its side effects are more pronounced in the older individuals, and it may exacerbate the bone marrow failure. The JAK2 inhibitor, ruxolitinib, has proved effective in reducing splenomegaly and alleviating constitutional symptoms in a majority of advanced PMF patients while also prolonging survival, although it does not significantly influence the JAK2 V617F allele burden. Although anemia and thrombocytopenia are its major side effects, these are dose-dependent, and with time, anemia stabilizes and thrombocytopenia may improve. Allogeneic bone marrow transplantation is the only curative treatment for PMF and should be considered in younger patients; nonmyeloablative conditioning regimens may permit hematopoietic cell transplantation to be extended to older individuals, but this approach is currently under investigation.


InternalMed_Harrison

InternalMed_Harrison. Essential thrombocytosis (other designations include essential thrombocythemia, idiopathic thrombocytosis, primary thrombocytosis, and hemorrhagic thrombocythemia) is a clonal disorder of unknown etiology involving a multipotent hematopoietic progenitor cell manifested clinically by overproduction of platelets without a definable cause. ET is an uncommon disorder, with an incidence of 1–2/100,000 and a distinct female predominance. No clonal marker is available to consistently distinguish ET from the more common nonclonal, reactive forms of thrombocytosis (Table 131-6), making its diagnosis difficult. Once considered a disease of the elderly and responsible for significant morbidity due to hemorrhage or thrombosis, with the widespread use of electronic cell counters, it is now clear that ET can occur at any age in adults and often without symptoms or disturbances of hemostasis. There is an unexplained female predominance in contrast to PMF or the reactive forms of thrombocytosis where


InternalMed_Harrison

InternalMed_Harrison. can occur at any age in adults and often without symptoms or disturbances of hemostasis. There is an unexplained female predominance in contrast to PMF or the reactive forms of thrombocytosis where no sex difference exists. Because no specific clonal marker is available, clinical criteria have been proposed to distinguish ET from the other chronic MPNs, which may also present with thrombocytosis but have differing prognoses and therapies (Table 131-6). These criteria do not establish clonality; therefore, they are truly useful only in identifying disorders such as CML, PV, or myelodysplasia, which can masquerade as ET, as opposed to actually establishing the presence of ET. Furthermore, as with “idiopathic” erythrocytosis, nonclonal benign forms of thrombocytosis


InternalMed_Harrison

InternalMed_Harrison. Tissue inflammation: collagen vascular Hemorrhage disease, inflammatory bowel disease Myeloproliferative disorders: polycythe-Rebound: Correction of vitamin mia vera, primary myelofibrosis, essential B12 or folate deficiency, postthrombocytosis, chronic myelogenous ethanol abuse leukemia Myelodysplastic disorders: 5q–syndrome, Hemolysis idiopathic refractory sideroblastic anemia Postsplenectomy or hyposplenism Familial: Thrombopoietin overproduction, MPL mutations exist (such as hereditary overproduction of thrombopoietin) that are not widely recognized because we currently lack adequate diagnostic tools. Approximately 50% of ET patients carry the JAK2 V617F mutation, but its absence does not exclude the disorder.


InternalMed_Harrison

InternalMed_Harrison. Megakaryocytopoiesis and platelet production depend on thrombopoietin and its receptor Mpl. As in the case of early erythroid and myeloid progenitor cells, early megakaryocytic progenitors require the presence of interleukin 3 (IL-3) and stem cell factor for optimal proliferation in addition to thrombopoietin. Their subsequent development is also enhanced by the chemokine stromal cell-derived factor 1 (SDF-1). However, megakaryocyte maturation requires thrombopoietin.


InternalMed_Harrison

InternalMed_Harrison. Megakaryocytes are unique among hematopoietic progenitor cells because reduplication of their genome is endomitotic rather than mitotic. In the absence of thrombopoietin, endomitotic megakaryocytic reduplication and, by extension, the cytoplasmic development necessary for platelet production are impaired. Like erythropoietin, thrombopoietin is produced in both the liver and the kidneys, and an inverse correlation exists between the platelet count and plasma thrombopoietic activity. Unlike erythropoietin, thrombopoietin is only constitutively produced, and the plasma thrombopoietin level is controlled by the size of its progenitor cell pool. Also, in contrast to erythropoietin, but like its myeloid counterparts, granulocyte and granulocyte-macrophage colony-stimulating factors, thrombopoietin not only enhances the proliferation of its target cells but also enhances the reactivity of their end-stage product, the platelet. In addition to its role in thrombopoiesis, thrombopoietin also


InternalMed_Harrison

InternalMed_Harrison. not only enhances the proliferation of its target cells but also enhances the reactivity of their end-stage product, the platelet. In addition to its role in thrombopoiesis, thrombopoietin also enhances the survival of multipotent hematopoietic stem cells and their bone marrow residence.


InternalMed_Harrison

InternalMed_Harrison. The clonal nature of ET was established by analysis of glucose-6-phosphate dehydrogenase isoenzyme expression in patients hemizygous for this gene, by analysis of X-linked DNA polymorphisms in informative female patients, and by the expression in patients of nonrandom, though variable, cytogenetic abnormalities. Although thrombocytosis is its principal manifestation, like the other chronic MPNs, a multipotent hematopoietic progenitor cell is involved in ET. Furthermore, a number of families have been described in which ET was inherited, in one instance as an autosomal dominant trait. In addition to ET, PMF and PV have also been observed in some kindreds. Like PMF, most patients who do not have JAK2 mutations have CALR mutations.


InternalMed_Harrison

InternalMed_Harrison. Clinically, ET is most often identified incidentally when a platelet count is obtained during the course of a routine medical evaluation. Occasionally, review of previous blood counts will reveal that an elevated platelet count was present but overlooked for many years. No symptoms or signs are specific for ET, but these patients can have hemorrhagic and thrombotic tendencies expressed as easy bruising for the former and microvascular occlusive events for the latter such as erythromelalgia, ocular migraine, or a TIA. Physical examination is generally unremarkable except occasionally for mild splenomegaly. Splenomegaly is indicative of another MPN, in particular PV, PMF, or CML.


InternalMed_Harrison

InternalMed_Harrison. Anemia is unusual, but a mild neutrophilic leukocytosis is not. The blood smear is most remarkable for the number of platelets present, some of which may be very large. The large mass of circulating platelets may prevent the accurate measurement of serum potassium due to release of platelet potassium upon blood clotting. This type of hyperkalemia is a laboratory artifact and not associated with electrocardiographic abnormalities. Similarly, arterial oxygen measurements can be inaccurate unless thrombocythemic blood is collected on ice. The prothrombin and partial thromboplastin times are normal, whereas abnormalities of platelet function such as a prolonged bleeding time and impaired platelet aggregation can be present. However, despite much study, no platelet function abnormality is characteristic of ET, and no platelet function test predicts the risk of clinically significant bleeding or thrombosis.


InternalMed_Harrison

InternalMed_Harrison. The elevated platelet count may hinder marrow aspiration, but 677 marrow biopsy usually reveals megakaryocyte hypertrophy and hyperplasia, as well as an overall increase in marrow cellularity. If marrow reticulin is increased, another diagnosis should be considered. The absence of stainable iron demands an explanation because iron deficiency alone can cause thrombocytosis, and absent marrow iron in the presence of marrow hypercellularity is a feature of PV. Nonrandom cytogenetic abnormalities occur in ET but are uncommon, and no specific or consistent abnormality is notable, even those involving chromosomes 3 and 1, where the genes for thrombopoietin and its receptor Mpl, respectively, are located.


InternalMed_Harrison

InternalMed_Harrison. Thrombocytosis is encountered in a broad variety of clinical disorders (Table 131-6), in many of which production of cytokines is increased. The absolute level of the platelet count is not a useful diagnostic aid for distinguishing between benign and clonal causes of thrombocytosis. About 50% of ET patients express the JAK2 V617F mutation.


InternalMed_Harrison

InternalMed_Harrison. When JAK2 V617F is absent, cytogenetic evaluation is mandatory to determine if the thrombocytosis is due to CML or a myelodysplastic disorder such as the 5q− syndrome. Because the bcr-abl translocation can be present in the absence of the Ph chromosome, and because bcr-abl reverse transcriptase polymerase chain reaction is associated with false-positive results, fluorescence in situ hybridization (FISH) analysis for bcr-abl is the preferred assay in patients with thrombocytosis in whom a cytogenetic study for the Ph chromosome is negative. CALR mutations are present in most patients who do not have JAK2 mutations, but diagnostic tools to detect these mutations are not yet widespread. Anemia and ringed sideroblasts are not features of ET, but they are features of idiopathic refractory sideroblastic anemia, and in some of these patients, the thrombocytosis occurs in association with JAK2 V617F expression. Splenomegaly should suggest the presence of another MPN, and in this setting, a


InternalMed_Harrison

InternalMed_Harrison. anemia, and in some of these patients, the thrombocytosis occurs in association with JAK2 V617F expression. Splenomegaly should suggest the presence of another MPN, and in this setting, a red cell mass determination should be performed because splenomegaly can mask the presence of erythrocytosis. Importantly, what appears to be ET can evolve into PV or PMF after a period of many years, revealing the true nature of the underlying MPN. There is sufficient overlap of the JAK2 V617F neutrophil allele burden between ET and PV that this cannot be used as a distinguishing diagnostic feature; only a red cell mass and plasma volume determination can distinguish PV from ET, and importantly in this regard, 64% of JAK2 V617F–positive ET patients actually were found to have PV when red cell mass and plasma volume determinations were performed.


InternalMed_Harrison

InternalMed_Harrison. Perhaps no other condition in clinical medicine has caused otherwise astute physicians to intervene inappropriately more often than thrombocytosis, particularly if the platelet count is >1 × 106/μL. It is commonly believed that a high platelet count causes intravascular stasis and thrombosis; however, no controlled clinical study has ever established this association, and in patients younger than age 60 years, the incidence of thrombosis was not greater in patients with thrombocytosis than in age-matched controls, and tobacco use appears to be the most important risk factor for thrombosis in ET patients.


InternalMed_Harrison

InternalMed_Harrison. To the contrary, very high platelet counts are associated primarily with hemorrhage due to acquired von Willebrand’s disease. This is not meant to imply that an elevated platelet count cannot cause symptoms in an ET patient, but rather that the focus should be on the patient, not the platelet count. For example, some of the most dramatic neurologic problems in ET are migraine-related and respond only to lowering of the platelet count, whereas other symptoms such as erythromelalgia respond simply to platelet cyclooxygenase-1 inhibitors such as aspirin or ibuprofen, without a reduction in platelet number. Still others may represent an interaction between an atherosclerotic vascular system and a high platelet count, and others may have no relationship to the platelet count whatsoever. Recognition that PV can present with thrombocytosis alone as well as the discovery of previously unrecognized causes of hypercoagulability (Chap. 142) make the older literature on the complications of


InternalMed_Harrison

InternalMed_Harrison. that PV can present with thrombocytosis alone as well as the discovery of previously unrecognized causes of hypercoagulability (Chap. 142) make the older literature on the complications of thrombocytosis unreliable.


InternalMed_Harrison

InternalMed_Harrison. 678 ET can also evolve into PMF, but whether this is a feature of ET or represents PMF presenting initially with isolated thrombocytosis is unknown.


InternalMed_Harrison

InternalMed_Harrison. Survival of patients with ET is not different than for the general population. An elevated platelet count in an asymptomatic patient without cardiovascular risk factors requires no therapy. Indeed, before any therapy is initiated in a patient with thrombocytosis, the cause of symptoms must be clearly identified as due to the elevated platelet count. When the platelet count rises above 1 × 106/μL, a substantial quantity of high-molecular-weight von Willebrand multimers are removed from the circulation and destroyed by the enlarged platelet mass, resulting in an acquired form of von Willebrand’s disease. This can be identified by a reduction in ristocetin cofactor activity. In this situation, aspirin could promote hemorrhage. Bleeding in this situation usually responds to ε-aminocaproic acid, which can be given prophylactically before and after elective surgery. Plateletpheresis is at best a temporary and inefficient remedy that is rarely required. Importantly, ET patients treated with


InternalMed_Harrison

InternalMed_Harrison. which can be given prophylactically before and after elective surgery. Plateletpheresis is at best a temporary and inefficient remedy that is rarely required. Importantly, ET patients treated with 32P or alkylating agents are at risk of developing acute leukemia without any proof of benefit; combining either therapy with hydroxyurea increases this risk. If platelet reduction is deemed necessary on the basis of symptoms refractory to salicylates alone, pegylated IFN-α, the quinazoline derivative, anagrelide, or hydroxyurea can be used to reduce the platelet count, but none of these is uniformly effective or without significant side effects. Hydroxyurea and aspirin are more effective than anagrelide and aspirin for prevention of TIAs but not more effective for the prevention of other types of arterial thrombosis and are actually less effective for venous thrombosis. The effectiveness of hydroxyurea in preventing TIAs is because it is an NO donor. Normalizing the platelet count also does


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InternalMed_Harrison. arterial thrombosis and are actually less effective for venous thrombosis. The effectiveness of hydroxyurea in preventing TIAs is because it is an NO donor. Normalizing the platelet count also does not prevent either arterial or venous thrombosis. The risk of gastrointestinal bleeding is also higher when aspirin is combined with anagrelide.


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InternalMed_Harrison. As more clinical experience is acquired, ET appears more benign than previously thought. Evolution to acute leukemia is more likely to be a consequence of therapy than of the disease itself. In managing patients with thrombocytosis, the physician’s first obligation is to do no harm.


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InternalMed_Harrison. Acute Myeloid Leukemia Guido Marcucci, Clara D. Bloomfield INCIDENCE Acute myeloid leukemia (AML) is a neoplastic disease characterized by infiltration of the blood, bone marrow, and other tissues by prolifera-tive, clonal undifferentiated cells of the hematopoietic system. These 132 leukemias comprise a spectrum of malignancies that, untreated, range from rapidly fatal to slowly growing. In 2013, the estimated number of new AML cases in the United States was 14,590. The incidence of AML is ~3.5 per 100,000 people per year, and the age-adjusted incidence is higher in men than in women (4.5 vs 3.1). AML incidence increases with age; it is 1.7 in individuals age <65 years and 15.9 in those age >65 years. The median age at diagnosis is 67 years.


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InternalMed_Harrison. Heredity Certain syndromes with somatic cell chromosome aneuploidy, such as trisomy 21 noted in Down syndrome, are associated with an increased incidence of AML. Inherited diseases with defective DNA repair, e.g., Fanconi anemia, Bloom syndrome, and ataxiatelangiectasia, are also associated with AML. Congenital neutropenia (Kostmann syndrome) is a disease with mutations in the genes encoding the granulocyte colony-stimulating factor (G-CSF) receptor and, often, neutrophil elastase that may evolve into AML. Germline mutations of CCAAT/enhancer-binding protein α (CEBPA), runt-related transcription factor 1 (RUNX1), and tumor protein p53 (TP53) have also been associated with a higher predisposition to AML in some series.


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InternalMed_Harrison. Radiation High-dose radiation, like that experienced by survivors of the atomic bombs in Japan or nuclear reactor accidents, increases the risk of myeloid leukemias that peaks 5–7 years after exposure. Therapeutic radiation alone seems to add little risk of AML but can increase the risk in people also exposed to alkylating agents. Chemical and Other Exposures Exposure to benzene, a solvent used in the chemical, plastic, rubber, and pharmaceutical industries, is associated with an increased incidence of AML. Smoking and exposure to petroleum products, paint, embalming fluids, ethylene oxide, herbicides, and pesticides have also been associated with an increased risk of AML.


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InternalMed_Harrison. Drugs Anticancer drugs are the leading cause of therapy-associated AML. Alkylating agent–associated leukemias occur on average 4–6 years after exposure, and affected individuals have aberrations in chromosomes 5 and 7. Topoisomerase II inhibitor–associated leukemias occur 1–3 years after exposure, and affected individuals often have aberrations involving chromosome 11q23. Newer agents for treatment of other hematopoietic malignancies and solid tumors are also under scrutiny for increased risk of AML. Chloramphenicol, phenylbutazone, and, less commonly, chloroquine and methoxypsoralen can result in bone marrow failure that may evolve into AML.


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InternalMed_Harrison. The current categorization of AML uses the World Health Organization (WHO) classification (Table 132-1), which includes different biologically distinct groups based on clinical features and cytogenetic and molecular abnormalities in addition to morphology. In contrast to the previously used French-American-British (FAB) schema, the WHO classification places limited reliance on cytochemistry. A major difference between the WHO and the FAB systems is the blast cutoff for a diagnosis of AML as opposed to myelodysplastic syndrome (MDS); it is 20% in the WHO classification and 30% in the FAB. However, within the WHO classification, specific chromosomal rearrangements, i.e., t(8;21)(q22;q22), inv(16)(p13.1q22), t(16;16)(p13.1;q22), and t(15;17) (q22;q12), define AML even with <20% blasts.


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InternalMed_Harrison. Immunophenotype and Relevance to the WHO Classification The immunophenotype of human leukemia cells can be studied by multiparameter flow cytometry after the cells are labeled with monoclonal antibodies to cell-surface antigens. This can be important for separating AML from acute lymphoblastic leukemia (ALL) and identifying some subtypes of AML. For example, AML with minimal differentiation that is characterized by immature morphology and no lineage-specific cytochemical reactions may be diagnosed by flow-cytometric demonstration of the myeloid-specific antigens cluster designation (CD) 13 and/ or 117. Similarly, acute megakaryoblastic leukemia can often be diagnosed only by expression of the platelet-specific antigens CD41 and/ or CD61. Although flow cytometry is useful, widely used, and in some cases essential for the diagnosis of AML, it is supportive only in establishing the different subtypes of AML through the WHO classification.


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InternalMed_Harrison. Clinical Features and Relevance to the WHO Classification The WHO ETIOLOGY classification also considers clinical features in subdividing AML. For Heredity, radiation, chemical and other occupational exposures, and example, it identifies therapy-related AML as a separate entity that drugs have been implicated in the development of AML. No direct develops following prior therapy (e.g., alkylating agents, topoisomevidence suggests a viral etiology. erase II inhibitors, ionizing radiation). It also identifies AML with AML with recurrent genetic abnormalities


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InternalMed_Harrison. AML with recurrent genetic abnormalities AML with t(8;21)(q22;q22); RUNX1-RUNX1T1b AML with inv(16)(pl3.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11b Acute promyelocytic leukemia with t(15;17)(q22;q12); PML-RARAb AML with t(9;11)(p22;q23); MLLT3-MLL AML with t(6;9)(p23;q34); DEK-NUP214 AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1 AML (megakaryoblastic) with t(1;22)(p13;q13); RBM15-MKL1 Provisional entity: AML with mutated NPM1 Provisional entity: AML with mutated CEBPA AML with myelodysplasia-related changes Therapy-related myeloid neoplasms AML, not otherwise specified AML with minimal differentiation AML with maturation Acute panmyelosis with myelofibrosis Myeloid sarcoma Myeloid proliferations related to Down syndrome


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InternalMed_Harrison. AML with minimal differentiation AML with maturation Acute panmyelosis with myelofibrosis Myeloid sarcoma Myeloid proliferations related to Down syndrome Transient abnormal myelopoiesis Myeloid leukemia associated with Down syndrome aFrom SH Swerdlow et al (eds): World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, IARC Press, 2008. bDiagnosis is AML regardless of blast count. myelodysplasia-related changes based in part on medical history of an antecedent MDS or myelodysplastic/myeloproliferative neoplasm. The clinical features likely contribute to the prognosis of AML and have therefore been included in the classification. Genetic Findings and Relevance to the WHO Classification The


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InternalMed_Harrison. WHO classification uses clinical, morphologic, and cytogenetic and/or molecular criteria to identify subtypes of AML and forces the clinician to take the appropriate steps to correctly identify the entity and thus tailor treatment(s) accordingly. The WHO classification is indeed the first AML classification that incorporates genetic (chromosomal and molecular) information. In this classification, subtypes of AML are recognized based on the presence or absence of specific recurrent genetic abnormalities. For example, the diagnosis of acute promyelocytic leukemia (APL) is based on the presence of either the t(15;17)(q22;q12) cytogenetic rearrangement or the PML-RARA fusion product of the translocation. A similar approach is taken with regard to core binding factor (CBF) AML that is now designated based on the presence of t(8;21)(q22;q22), inv(16)(p13.1q22), or t(16;16) (p13.1;q22) or the respective fusion products RUNX1-RUNX1T1 and CBFB-MYH11.


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InternalMed_Harrison. The WHO classification incorporates cytogenetics in the AML classification by recognizing a category of AML with recurrent genetic abnormalities and a category of AML with myelodysplasia-related changes (Table 132-1). The latter category is diagnosed not only by morphologic changes, but also in part by selected myelodysplasiarelated cytogenetic abnormalities (e.g., complex karyotypes and unbalanced and balanced changes involving, among others, chromosomes 5, 7, and 11). Only one cytogenetic abnormality has been invariably associated with specific morphologic features: t(15;17)(q22;q12) with APL. Other chromosomal abnormalities have been associated primarily with one morphologic/immunophenotypic group, including inv(16) (p13.1q22) with AML with abnormal bone marrow eosinophils; t(8;21) 679 (q22;q22) with slender Auer rods, expression of CD19, and increased normal eosinophils; and t(9;11)(p22;q23), and other translocations involving 11q23, with monocytic features. Recurring chromosomal


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InternalMed_Harrison. (q22;q22) with slender Auer rods, expression of CD19, and increased normal eosinophils; and t(9;11)(p22;q23), and other translocations involving 11q23, with monocytic features. Recurring chromosomal abnormalities in AML may also be associated with specific clinical characteristics. More commonly associated with younger age are t(8;21) and t(15;17), and with older age, del(5q) and del(7q). Myeloid sarcomas (see below) are associated with t(8;21), and disseminated intravascular coagulation (DIC) is associated with t(15;17).


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InternalMed_Harrison. The WHO classification also incorporates molecular abnormalities by recognizing fusion genes that are products of recurrent cytogenetic aberrations or have been found mutated and may be involved in leukemogenesis. For instance, t(15;17) results in the fusion gene PML-RARA that encodes a chimeric protein, promyelocytic leukemia (Pml)–retinoic acid receptor α (Rarα), which is formed by the fusion of the retinoic acid receptor α (RARA) gene from chromosome 17 and the promyelocytic leukemia (PML) gene from chromosome 15. The RARA gene encodes a member of the nuclear hormone receptor family of transcription factors. After binding retinoic acid, RARA can promote expression of a variety of genes. The 15;17 translocation juxtaposes PML with RARA in a head-to-tail configuration that is under the transcriptional control of PML. Three different breakpoints in the PML gene lead to various fusion protein isoforms. The Pml-Rarα fusion protein tends to suppress gene transcription and blocks


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InternalMed_Harrison. the transcriptional control of PML. Three different breakpoints in the PML gene lead to various fusion protein isoforms. The Pml-Rarα fusion protein tends to suppress gene transcription and blocks differentiation of the cells. Pharmacologic doses of the Rarα ligand, all-trans-retinoic acid (tretinoin), relieve the block and promote hematopoietic cell differentiation (see below). Similar examples of molecular subtypes of the disease included in the category of AML with recurrent genetic abnormalities are those characterized by the leukemogenic fusion genes RUNX1-RUNX1T1, CBFB-MYH11, MLLT3-MLL, and DEK-NUP214, resulting, respectively, from t(8;21), inv(16) or t(16;16), t(9;11), and t(6;9)(p23;q34).


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InternalMed_Harrison. Two new provisional entities defined by the presence of gene mutations, rather than microscopic chromosomal abnormalities, have been added to the category of AML with recurrent genetic abnormalities: AML with mutated nucleophosmin (nucleolar phosphoprotein B23, numatrin) (NPM1) and AML with mutated CEBPA. AML with fmsrelated tyrosine kinase 3 (FLT3) mutations is not considered a distinct entity, although determining the presence of such mutations is recommended by WHO in patients with cytogenetically normal AML (CN-AML) because the relatively frequent FLT3-internal tandem duplication (ITD) carries a negative prognostic significance and therefore is clinically relevant. FLT3 encodes a tyrosine kinase receptor important in the development of myeloid and lymphoid lineages. Activating mutations of FLT3 are present in ~30% of adult AML patients due to ITDs in the juxtamembrane domain or point mutations of the activating loop of the kinase (called tyrosine kinase domain mutations). Aberrant


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InternalMed_Harrison. of FLT3 are present in ~30% of adult AML patients due to ITDs in the juxtamembrane domain or point mutations of the activating loop of the kinase (called tyrosine kinase domain mutations). Aberrant activation of the FLT3-encoded protein provides increased proliferation and antiapoptotic signals to the myeloid progenitor cell. FLT3-ITD, the more common of the FLT3 mutations, occurs preferentially in patients with CN-AML. The importance of identifying FLT3-ITD at diagnosis relates to the fact that not only is it a useful prognosticator but it also may predict response to specific treatment such as the tyrosine kinase inhibitors that are in clinical investigation.


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InternalMed_Harrison. Several factors have been demonstrated to predict outcome of AML patients treated with chemotherapy, and they can be used for risk stratification and treatment guidance.


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InternalMed_Harrison. Chromosome findings at diagnosis are currently the most important independent prognostic factors. Several studies have categorized patients as having favorable, intermediate, or poor cytogenetic risk based on the presence of structural and/or numerical aberrations. Patients with t(15;17) have a very good prognosis (~85% cured), and those with t(8;21) and inv(16) have a good prognosis (~55% cured), whereas those with no cytogenetic abnormality have an intermediate outcome risk (~40% cured). Patients with a complex karyotype, t(6;9), inv(3), or –7 have a very poor prognosis. Another cytogenetic subgroup, the monosomal karyotype, has been suggested to adversely 680 impact the outcome of AML patients other than those with t(15;17), t(8;21), or inv(16) or t(16;16). The monosomal karyotype subgroup is defined by the presence of at least two autosomal monosomies (loss of chromosomes other than Y or X) or a single autosomal monosomy with additional structural abnormalities. For patients


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InternalMed_Harrison. subgroup is defined by the presence of at least two autosomal monosomies (loss of chromosomes other than Y or X) or a single autosomal monosomy with additional structural abnormalities. For patients lacking prognostic cytogenetic abnormalities, such as those with CN-AML, outcome prediction uses mutated or aberrantly expressed genes. NPM1 mutations without concurrent presence of FLT3-ITD, and CEBPA mutations, especially if concurrently present in two different alleles, have been shown to predict favorable outcome, whereas FLT3-ITD predicts poor outcome. Given the proven prognostic importance of NPM1 and CEBPA mutations and FLT3-ITD, molecular assessment of these genes at diagnosis has been incorporated in AML management guidelines by the National Comprehensive Cancer Network (NCCN) and the European LeukemiaNet (ELN). The same markers have also been incorporated in the definitions of the genetic groups of the ELN standardized reporting system, which are based on both cytogenetic and


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InternalMed_Harrison. the European LeukemiaNet (ELN). The same markers have also been incorporated in the definitions of the genetic groups of the ELN standardized reporting system, which are based on both cytogenetic and molecular abnormalities and used for comparing clinical features and treatment response among subsets of patients reported in different studies (Table 132-2). More recently, the prognostic impact of the genetic groups recognized by the ELN reporting system has been demonstrated. Thus, these genetic groups may also be used for risk stratification and treatment guidance. In addition to NPM1 and CEBPA mutations and FLT3-ITD, other molecular aberrations (Table 132-3) may in the future be routinely used for prognostication in AML and incorporated in the WHO classification and the ELN reporting system. Among these prognostic mutated genes are those encoding receptor tyrosine kinases (e.g., v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog [KIT]), transcription factors (i.e., RUNX1


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InternalMed_Harrison. Among these prognostic mutated genes are those encoding receptor tyrosine kinases (e.g., v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog [KIT]), transcription factors (i.e., RUNX1 and Wilms tumor 1 [WT1]), and epigenetic modifiers (i.e., additional sex combs like transcriptional regulator 1 [ASXL1], DNA (cytosine-5-)-methyltransferase 3 alpha [DNMT3A], isocitrate dehydrogenase 1 (NADP+), soluble [IDH1] and isocitrate dehydrogenase 2 (NADP+), mitochondrial [IDH2], lysine (K)-specific methyltransferase 2A [KMT2A, also known as MLL], and tet methylcytosine dioxygenase 2 [TET2]). Although KIT mutations are almost exclusively present in CBF AML and impact adversely the outcome, the remaining markers have been reported primarily in CN-AML. These gene mutations have been shown to be associated with outcome in multivariable analyses independently from other prognostic factors. However, for some of them, the prognostic impact (e.g., TET2 mutations) or the type (adverse vs


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InternalMed_Harrison. to be associated with outcome in multivariable analyses independently from other prognostic factors. However, for some of them, the prognostic impact (e.g., TET2 mutations) or the type (adverse vs favorable) of prognostic impact (e.g., IDH1, IDH2) has been found in the majority, but not in all, of the reported studies. An independent prognostic impact remains to be determined for mutated genes that are either associated primarily with unfavorable


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InternalMed_Harrison. Favorable t(8;21)(q22;q22); RUNX1-RUNX1T1 inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11 Mutated NPM1 without FLT3-ITD (normal karyotype) Mutated CEBPA (normal karyotype) Intermediate-II t(9;11)(p22;q23); MLLT3-MLL Cytogenetic abnormalities not classified as favorable or adverse Adverse inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1 t(6;9)(p23;q34); DEK-NUP214 t(v;11)(v;q23); MLL rearranged –5 or del(5q); –7; abn(17p); complex karyotype (≥3 abnormalities) aH Döhner et al: Blood 115:453, 2010. Abbreviation: ITD, internal tandem duplication. Genes Included in the WHO Classification and ELN Reporting System Abbreviations: AML, acute myeloid leukemia; ELN, European LeukemiaNet; ITD, internal tandem duplication; PTD, partial tandem duplication; TKD, tyrosine kinase domain; WHO, World Health Organization.


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InternalMed_Harrison. cytogenetic aberrations (e.g., TP53) or are found with a relatively lower frequency in AML patients like those encoding epigenetic modifiers (e.g., enhancer of zeste 2 polycomb repressive complex 2 subunit [EZH2]), phosphatases (e.g., protein tyrosine phosphatase, non-receptor type 11 (PTPN11]), putative transcription factors (e.g., PHD finger protein 6 [PHF6]), splicing factors (e.g., U2 small nuclear RNA auxiliary factor 1 [U2AF1]), and proteins involved in chromosome segregation and genome stability (e.g., structural maintenance of chromosomes 1A [SMC1A] or structural maintenance of chromosomes 3 [SMC3]). Finally, other mutated genes are recognized as predictors of treatment response to distinct therapies rather than prognosticators; for example, neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS) and Kirsten rat sarcoma viral oncogene homolog (KRAS) predict a better response to high-dose cytarabine in CBF AML.


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InternalMed_Harrison. In addition to gene mutations, deregulation of the expression levels of coding genes and of short noncoding RNAs (microRNAs) have been reported to provide prognostic information (Table 132-3). Overexpression of genes such as brain and acute leukemia, cytoplasmic (BAALC), v-ets avian erythroblastosis virus E26 oncogene homologue (avian) (ERG), meningioma (disrupted in balanced translocation) 1 (MN1), and MDS1 and EVI1 complex locus (MECOM, also known as EVI1) have been found to be predictive for poor outcome, especially in CN-AML. Similarly, deregulated expression levels of microRNAs, naturally occurring noncoding RNAs that have been shown to regulate the expression of proteins involved in hematopoietic differentiation and survival pathways by degradation or translation inhibition of target coding RNAs, have been associated with prognosis in AML. Overexpression of miR-155 and miR-3151 has been found to affect outcome adversely in CN-AML, whereas overexpression of miR-181a predicts a


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InternalMed_Harrison. coding RNAs, have been associated with prognosis in AML. Overexpression of miR-155 and miR-3151 has been found to affect outcome adversely in CN-AML, whereas overexpression of miR-181a predicts a favorable outcome both in CN-AML and cytogenetically abnormal AML.


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InternalMed_Harrison. Because prognostic molecular markers in AML are not mutually exclusive and often occur concurrently (>80% patients have at least two or more prognostic gene mutations), the likelihood that distinct marker combinations may be more informative than single markers is being recognized. Epigenetic changes (e.g., DNA methylation) and microRNAs are often involved in deregulation of genes involved in hematopoiesis, contribute to leukemogenesis, and are often associated with the previously discussed prognostic gene mutations. These changes not only have been shown to provide biologic insights into leukemogenic mechanisms, but also independent prognostic information. Indeed, it is anticipated that with the enormous progress made in DNA and RNA sequencing technology, additional genetic and epigenetic aberrations will soon be discovered and will contribute to classification and reporting systems and outcome risk determination in AML patients.