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Hematopoietic Stem Cells and Their Disorders Terminal Myeloid Element MPN Activating Mutation(s) ffi r$ Neutrophil Chronic myeloid leukemia -----+ BCR.ABL, CSF3R JAK2150-60yot Myelofibrosis crr-R(35-40%) Monocyte MPL(9%I Polycythemia vera JAK2197%) Erythroryte 0 I* Platelet Essentia I th ro m bocythe m i a -----) ff _'*, froi1jfl, Myeloid |* MPL(4%l progenitor ry Eosinophil Hypereosinophilic syndrome -----) FlPl L1 -PDGFRNB Chronic eosinophilic leukemia t Mast cell Systemic mastocytosis tIGURE 1. Myeloproliferativeneoplasms(MPN)arisefromspecificactivatingmutationsthatresultinunregulatedproliferationof its similarities to the other MPNs and its previous MPN classification, systemic mastocytosis is included. CKlf D816V (95%) ->terminal myeloidelements Becauseof

tIGURE 1. Myeloproliferativeneoplasms(MPN)arisefromspecificactivatingmutationsthatresultinunregulatedproliferationof its similarities to the other MPNs and its previous MPN classification, systemic mastocytosis is included. CKlf D816V (95%) ->terminal myeloidelements Becauseof Atthough systemic mastocytosis is no longer an MPN per the chromosome can be detected with routine cy'togenetics, fluo- World Health Organization classification, considering its rescence in situ hybridization, and screening for the BCR-ABI similarities and previous MPN classification, its discussed is transcript through reverse transcriptase polymerase chain included. Although each subtype has unique clinical and pathologic aspects, MPNs as a group share many symptoms, including fever, night sweats, weight loss, and pruritus; spleno- megaly is often present. Patients with MPNs are at increased risk for thrombosis, bleeding, and transformation to more aggressive myeloid malignancies, including acute myeloid leukemia (AML).

Atthough systemic mastocytosis is no longer an MPN per the chromosome can be detected with routine cy'togenetics, fluo- World Health Organization classification, considering its rescence in situ hybridization, and screening for the BCR-ABI similarities and previous MPN classification, its discussed is transcript through reverse transcriptase polymerase chain included. Although each subtype has unique clinical and pathologic aspects, MPNs as a group share many symptoms, including fever, night sweats, weight loss, and pruritus; spleno- megaly is often present. Patients with MPNs are at increased risk for thrombosis, bleeding, and transformation to more aggressive myeloid malignancies, including acute myeloid leukemia (AML). Chronic Myeloid Leukemia Chronic myeloid leukemia (CML) is a clonal process resulting in abnormal production and proliferation of granulocytes, generally with normal differentiation. CML is defined by the presence of the Philadelphia chromosome, a reciprocal trans- location of the ABL gene on chromosome 9, to the BCR gene on chromosome 22. This arrangement results in constitutive tyrosine kinase activity that drives the cellular production and symptoms associated with the disease. Patients may present with aqrmptomatic neutrophil elevation on routine laboratory testing, but many have weight loss, abdominal fi:llness (spleno- megaly), fatigue, or fever. The neutrophilia associated with CML is often accompanied by a left shift, with bands, meta- myelocytes, myelocytes, promyeloqtes, and even myeloblasts (Figure 2). Thromboc5rtosis and a normocytic anemia are com -& rL F I G UR E 2. Chronic myeloid leukemia is characterized by a preponderance of mon. A left shift with basophilia or eosinophilia without a mature granulocytes (upperlert) and less mature myeloid cells such as myelocytes clinical reason for a leukemoid reaction (such as severe (bottom right\ and metamyelocytes (top nght). Basophils (center) are helpful in infection) should raise suspicion for CML. The Philadelphia differentiating the myeloproliferative neoplasms from leukemoid reactions.

Chronic Myeloid Leukemia Chronic myeloid leukemia (CML) is a clonal process resulting in abnormal production and proliferation of granulocytes, generally with normal differentiation. CML is defined by the presence of the Philadelphia chromosome, a reciprocal trans- location of the ABL gene on chromosome 9, to the BCR gene on chromosome 22. This arrangement results in constitutive tyrosine kinase activity that drives the cellular production and symptoms associated with the disease. Patients may present with aqrmptomatic neutrophil elevation on routine laboratory testing, but many have weight loss, abdominal fi:llness (spleno- megaly), fatigue, or fever. The neutrophilia associated with CML is often accompanied by a left shift, with bands, meta- myelocytes, myelocytes, promyeloqtes, and even myeloblasts (Figure 2). Thromboc5rtosis and a normocytic anemia are com -& rL F I G UR E 2. Chronic myeloid leukemia is characterized by a preponderance of mon. A left shift with basophilia or eosinophilia without a mature granulocytes (upperlert) and less mature myeloid cells such as myelocytes clinical reason for a leukemoid reaction (such as severe (bottom right\ and metamyelocytes (top nght). Basophils (center) are helpful in infection) should raise suspicion for CML. The Philadelphia differentiating the myeloproliferative neoplasms from leukemoid reactions. 4

Hematopoietic Stem Cells and Their Disorders reaction. At diagnosis, testing peripheral blood is as accurate may reveal an underlying process contributir.rg to hemoglobin us hone marrow samples. elevation, so smoking history sleep patterns, cardiopulmo CML has three phases: chronic (<tO'7, myeloblasts), accel nary synlptoms, and medications should be reviewed. erated (10')1, 19'1, myeloblasts). and blast (>20?, myeloblasts). Diuretics can cause relative erythrocl.tosis because decreased Most patients present in the chronic phase, which is more plasma volume can be reflected in an increased hematocrit indolent but quite responsive to therapy. The blast phase is level, although the erythrocyte mass remains normal. technically a secondary acute myeloid leukemia (AML). Testosterone supplementation, including occult use, often Treatment is necessary at diagnosis for all patients. 'fyrosine causes erythrocytosis; testosterone cessation or phleboton-ry kinase inhibitors (TKIs) have revolutionized the treatment and may be needed if the hematocrit level exceeds 5,1'7,. Evaluation outcomes olCML. TKIs (imatinib, dasatinib, nilotinib, bosuti of a patient with ar.r elevated hemoglobin level may include nib, ponatinib) target the BCR ABL oncoprotein and prevent pulse oxygenation assessment, including a sleep study, echo downstream signaling. They have resulted in excellent long cardiography, and kidney ultrasonography to rule out sec term control of CML, improved survival, and decreased the ondary causes. An elevated erythrocyte count can be an need fbr HSCT. TKIs are generally well kllerated, but adverse appropriate physiologic response in some situations, which eflects include fluid retention, rash. and QT prolongation: would be worsened by phlebotomy, so management of these drug drug interactions may also occur. They are avoided in patients is complex. pregnancy in tavor of interteron o. TK I resistance or evidence Patients with PV are at increased risk fbr thrombosis, of disease progression despite treatment should ririse suspi including venous and arterial events (stroke, myocardial cion of nonadherence or development ol new mutations. infarction). Splanchnic vein thrombosis occurs uniquely in PV Allogeneic HSCT is considered in the accelerated or blast and portal or hepatic vein thrombosis may be the presenting phase. feature, preceding hematologic manifestations. In a few patients, PV will progress to myelofibrosis or transform to I(EY POI ]II AML. No interventions have been shown to reduce the risk of o All patients with chronic myeloid leukemia require hematologic malignancy transformation. I treatment at diagnosis, and tyrosine kinase inhibitors Treatment is required fbr all patients and consists of treat symptoms and prevent disease progression. phlebotomy to maintain a hematocrit level less than 45'7, and low dose aspirin to reduce thror.nbotic risk. Cytoreductive Polycythemia Vera therapy is considerecl in patients at higher risk, including Polycythemia vera (PV) is a clonal stenl cell disorder. A hall those oldcr than 60 years and those with a history of myocar- nrark of the disease is excess erythrocyte production inde dial infarction, stroke, or venous thrombosis. Hydroxyurea pendent of erythropoietin level. The /AK2 V617F activating and interferon cx are often considered first line cytoreductive mutation is present in 97'1, of patients, and others will harbor agents. The IAKI/2 inhibitor ruxolitinib is used in patients the lAK2 EXONL2 mutation. Patients have an elevated hemo with resistant PV or who cannot tolerate first line agents. globin level (>ro..s g/dL [16s g/L] in men, >16 g/dl [t0o glL] in Patients with venous thromboembolism will generally require women), and thrombocytosis and neutrophilia are comntonly life long rnticoagulill iun. seen. hence the term polgcythemia. Although erythropoietin IEY POIIITS levels are suppressed in most patients, as many as 15'/, of those with PV will have a normal erythropoietin level. Other clinical r The JAK2 mutation is present in almost all patients with features and the presence ot the -IAK2 ntutation usually estab primary polycythemia vera; erythrocytosis without the lish the diagnosis. "IAK2 mutation should prompt evaluation for secondary Some patients may be asymptomatic, with the diagnosis causes.

reaction. At diagnosis, testing peripheral blood is as accurate may reveal an underlying process contributir.rg to hemoglobin us hone marrow samples. elevation, so smoking history sleep patterns, cardiopulmo CML has three phases: chronic (<tO'7, myeloblasts), accel nary synlptoms, and medications should be reviewed. erated (10')1, 19'1, myeloblasts). and blast (>20?, myeloblasts). Diuretics can cause relative erythrocl.tosis because decreased Most patients present in the chronic phase, which is more plasma volume can be reflected in an increased hematocrit indolent but quite responsive to therapy. The blast phase is level, although the erythrocyte mass remains normal. technically a secondary acute myeloid leukemia (AML). Testosterone supplementation, including occult use, often Treatment is necessary at diagnosis for all patients. 'fyrosine causes erythrocytosis; testosterone cessation or phleboton-ry kinase inhibitors (TKIs) have revolutionized the treatment and may be needed if the hematocrit level exceeds 5,1'7,. Evaluation outcomes olCML. TKIs (imatinib, dasatinib, nilotinib, bosuti of a patient with ar.r elevated hemoglobin level may include nib, ponatinib) target the BCR ABL oncoprotein and prevent pulse oxygenation assessment, including a sleep study, echo downstream signaling. They have resulted in excellent long cardiography, and kidney ultrasonography to rule out sec term control of CML, improved survival, and decreased the ondary causes. An elevated erythrocyte count can be an need fbr HSCT. TKIs are generally well kllerated, but adverse appropriate physiologic response in some situations, which eflects include fluid retention, rash. and QT prolongation: would be worsened by phlebotomy, so management of these drug drug interactions may also occur. They are avoided in patients is complex. pregnancy in tavor of interteron o. TK I resistance or evidence Patients with PV are at increased risk fbr thrombosis, of disease progression despite treatment should ririse suspi including venous and arterial events (stroke, myocardial cion of nonadherence or development ol new mutations. infarction). Splanchnic vein thrombosis occurs uniquely in PV Allogeneic HSCT is considered in the accelerated or blast and portal or hepatic vein thrombosis may be the presenting phase. feature, preceding hematologic manifestations. In a few patients, PV will progress to myelofibrosis or transform to I(EY POI ]II AML. No interventions have been shown to reduce the risk of o All patients with chronic myeloid leukemia require hematologic malignancy transformation. I treatment at diagnosis, and tyrosine kinase inhibitors Treatment is required fbr all patients and consists of treat symptoms and prevent disease progression. phlebotomy to maintain a hematocrit level less than 45'7, and low dose aspirin to reduce thror.nbotic risk. Cytoreductive Polycythemia Vera therapy is considerecl in patients at higher risk, including Polycythemia vera (PV) is a clonal stenl cell disorder. A hall those oldcr than 60 years and those with a history of myocar- nrark of the disease is excess erythrocyte production inde dial infarction, stroke, or venous thrombosis. Hydroxyurea pendent of erythropoietin level. The /AK2 V617F activating and interferon cx are often considered first line cytoreductive mutation is present in 97'1, of patients, and others will harbor agents. The IAKI/2 inhibitor ruxolitinib is used in patients the lAK2 EXONL2 mutation. Patients have an elevated hemo with resistant PV or who cannot tolerate first line agents. globin level (>ro..s g/dL [16s g/L] in men, >16 g/dl [t0o glL] in Patients with venous thromboembolism will generally require women), and thrombocytosis and neutrophilia are comntonly life long rnticoagulill iun. seen. hence the term polgcythemia. Although erythropoietin IEY POIIITS levels are suppressed in most patients, as many as 15'/, of those with PV will have a normal erythropoietin level. Other clinical r The JAK2 mutation is present in almost all patients with features and the presence ot the -IAK2 ntutation usually estab primary polycythemia vera; erythrocytosis without the lish the diagnosis. "IAK2 mutation should prompt evaluation for secondary Some patients may be asymptomatic, with the diagnosis causes. suspected by findings on routine comptete blood counts; how . A1l patients with primary polycythemia vera should be ever, many patients have symptoms ol fatigue, headache, or treated with low-dose aspirin and phlebotomy to target itching, particularly alter a warm shower (aquagenic pruri a hematocrit level less than 45'1,. tus). Accompanying splenon.regaly may cause abdominal full . C)'toreductive therapy is considered in patients at higher ness, reflux, or early satiety; some patients may have a ruddy risk, including those older than 60 years and those with complexion and palpable hepatosplenontegaly. a history of myocardial infarction, stroke, or venous Although elevated hemoglobin and hematocrit levels thrombosis. should raise suspicion for PV especially with elevated leuko- cyte and platelet counts, secondary causes of erythrocy'tosis are much more common (Table 3). Secondary causes arise Essential Thrombocythemia through chronic or intermittent hypoxia, with an adaptive An isolated elevateci platelet count may indicate essential increase in erythropoietin and erythrocyte mass, or through thrombocythemia (tiT, a clonal stem cell process with a sus ectopic production of erythropoietin, most commonly fiom a tained increased platelet count). The JAK2 mutation is present renal neoplasm. A careful history and physical examination in approximately half of patients with ET (50'){, 60'2,)' with

suspected by findings on routine comptete blood counts; how . A1l patients with primary polycythemia vera should be ever, many patients have symptoms ol fatigue, headache, or treated with low-dose aspirin and phlebotomy to target itching, particularly alter a warm shower (aquagenic pruri a hematocrit level less than 45'1,. tus). Accompanying splenon.regaly may cause abdominal full . C)'toreductive therapy is considered in patients at higher ness, reflux, or early satiety; some patients may have a ruddy risk, including those older than 60 years and those with complexion and palpable hepatosplenontegaly. a history of myocardial infarction, stroke, or venous Although elevated hemoglobin and hematocrit levels thrombosis. should raise suspicion for PV especially with elevated leuko- cyte and platelet counts, secondary causes of erythrocy'tosis are much more common (Table 3). Secondary causes arise Essential Thrombocythemia through chronic or intermittent hypoxia, with an adaptive An isolated elevateci platelet count may indicate essential increase in erythropoietin and erythrocyte mass, or through thrombocythemia (tiT, a clonal stem cell process with a sus ectopic production of erythropoietin, most commonly fiom a tained increased platelet count). The JAK2 mutation is present renal neoplasm. A careful history and physical examination in approximately half of patients with ET (50'){, 60'2,)' with 5

Hematopoietic Stem Cells and Their Disorders TABLE 3. Causes of ErythrocYtosis Disorders Symptoms and Suggestive Physical Examination Laboratory Studies Medical History Polycythemia vera (primary) Pruritus after a warm shower Splenomegaly Low erythropoietin Erythromelalgiau Plethora Leukocytosis Transient ischemic attack Basophilia Thrombosis Thrombocytosis JAK2 positive

Transient ischemic attack Basophilia Thrombosis Thrombocytosis JAK2 positive Mediated by hypoxemia Thrombosis Plethora Normal leukocyte count (usually) COPD Transient ischemic attack No splenomegaly Normal platelet count Sleep apnea Erythromelalgia u ncommon Findings consistent with underlying hearl or lung No basophilia Congenital heart disease Pruritus uncommon disease JAK2 negative lntrapulmonary shunting Decreased oxygen satu ration High elevation Mediated by ectopic or Thrombosis possible Plethora High erythropoietin levels excessive erythropoietin levels Microscopic hematuria (renal Transient ischemic attack No splenomegaly Renal cell carcinoma uncommon cellcarcinoma) Renal artery stenosis/other Erythromelalgia uncommon Abnormal finding on kidney kidney pathology ultrasonography Pruritus uncommon Hepatocellular carcinoma No basophilia Uterine {ibroids JAK2 negative \ Unusual causes Thrombosis Plethora Hig h erythropoietin levels

Mediated by hypoxemia Thrombosis Plethora Normal leukocyte count (usually) COPD Transient ischemic attack No splenomegaly Normal platelet count Sleep apnea Erythromelalgia u ncommon Findings consistent with underlying hearl or lung No basophilia Congenital heart disease Pruritus uncommon disease JAK2 negative lntrapulmonary shunting Decreased oxygen satu ration High elevation Mediated by ectopic or Thrombosis possible Plethora High erythropoietin levels excessive erythropoietin levels Microscopic hematuria (renal Transient ischemic attack No splenomegaly Renal cell carcinoma uncommon cellcarcinoma) Renal artery stenosis/other Erythromelalgia uncommon Abnormal finding on kidney kidney pathology ultrasonography Pruritus uncommon Hepatocellular carcinoma No basophilia Uterine {ibroids JAK2 negative \ Unusual causes Thrombosis Plethora Hig h erythropoietin levels High-oxygen-affinity Transient ischemic attack No splenomegaly No basophilia hemoglobin Erythromelalgia uncommon Age <30 years No leukocytosis Pruritus uncommon Family history of erythrocytosis JAK2 negative Abnormal hemoglobin electrophoresis Low P50b olntermittently red, hot, painful extremities.

High-oxygen-affinity Transient ischemic attack No splenomegaly No basophilia hemoglobin Erythromelalgia uncommon Age <30 years No leukocytosis Pruritus uncommon Family history of erythrocytosis JAK2 negative Abnormal hemoglobin electrophoresis Low P50b olntermittently red, hot, painful extremities. bP50 is the point on the oxyhemoglobin dissociation curve where the hemoglobin molecule is half saturated wlth oxygen, indicating an increased hemoglobin afinity for oxygen and reduced oxygen delivery to tlssues.

High-oxygen-affinity Transient ischemic attack No splenomegaly No basophilia hemoglobin Erythromelalgia uncommon Age <30 years No leukocytosis Pruritus uncommon Family history of erythrocytosis JAK2 negative Abnormal hemoglobin electrophoresis Low P50b olntermittently red, hot, painful extremities. bP50 is the point on the oxyhemoglobin dissociation curve where the hemoglobin molecule is half saturated wlth oxygen, indicating an increased hemoglobin afinity for oxygen and reduced oxygen delivery to tlssues. other mutations occurring in the calreticulin or MPI recep- common in patients with /AK2 positivity. Extreme thrombo- tors. Up to 10% of patients with ET will have no mutation. cytosis is thought to increase bleeding risk through intrinsic Reactive or secondary causes of thrombocytosis are more platelet dysfunction or development of acquired von common and should be considered before evaluating for an Willebrand disease. Progression to myelofibrosis or AML is less identifiable clonal mutation. Iron deficiency is a common likely than other MPNs, although it is possible. cause of secondarily elevated platelet counts, as well as Treatment depends on the patient and associated risk fac chronic bleeding, splenectomy, infection, or other inflamma- tors. Patients at low risk (age <60 years, !AK2 negative, no tory conditions. Clinical features may overlap with other venous or arterial thrombosis) can be monitored without myeloproliferative neoplasms. A hematology consultation therapy or can be treated with low dose aspirin if vasomotor may be necessary to determine whether findings are most symptoms are present, such as headache or erythromelalgia. consistent with ET. Patients older than 60 years and who are lAK2 positive (with Many patients are asymptomatic, and ET is diagnosed or without venous or arterial thrombosis) are considered high incidentally by finding an elevated platelet count on routine risk, and should be treated with aspirin and cltoreductive laboratory testing. Symptoms include vasomotor manifesta- therapy, usually with hydroxyurea. Interferon c should be tions such as headaches, erythromelalgia, and visual distur considered in younger patients and during pregnancy if bances. Other complications include venous or arterial platelet lowering therapy is needed because hydroxyurea is thrombosis (stroke, transient ischemic attack, myocardial potentially teratogenic. Anagrelide is effective at decreasing infarction) and hemorrhage (more likely with platelet counts platelet counts; however, it is typically reserved for patients exceeding 1 million/pl [1OOO x 10,/L]); these are more who cannot tolerate or do not respond to hydroxyurea. In

other mutations occurring in the calreticulin or MPI recep- common in patients with /AK2 positivity. Extreme thrombo- tors. Up to 10% of patients with ET will have no mutation. cytosis is thought to increase bleeding risk through intrinsic Reactive or secondary causes of thrombocytosis are more platelet dysfunction or development of acquired von common and should be considered before evaluating for an Willebrand disease. Progression to myelofibrosis or AML is less identifiable clonal mutation. Iron deficiency is a common likely than other MPNs, although it is possible. cause of secondarily elevated platelet counts, as well as Treatment depends on the patient and associated risk fac chronic bleeding, splenectomy, infection, or other inflamma- tors. Patients at low risk (age <60 years, !AK2 negative, no tory conditions. Clinical features may overlap with other venous or arterial thrombosis) can be monitored without myeloproliferative neoplasms. A hematology consultation therapy or can be treated with low dose aspirin if vasomotor may be necessary to determine whether findings are most symptoms are present, such as headache or erythromelalgia. consistent with ET. Patients older than 60 years and who are lAK2 positive (with Many patients are asymptomatic, and ET is diagnosed or without venous or arterial thrombosis) are considered high incidentally by finding an elevated platelet count on routine risk, and should be treated with aspirin and cltoreductive laboratory testing. Symptoms include vasomotor manifesta- therapy, usually with hydroxyurea. Interferon c should be tions such as headaches, erythromelalgia, and visual distur considered in younger patients and during pregnancy if bances. Other complications include venous or arterial platelet lowering therapy is needed because hydroxyurea is thrombosis (stroke, transient ischemic attack, myocardial potentially teratogenic. Anagrelide is effective at decreasing infarction) and hemorrhage (more likely with platelet counts platelet counts; however, it is typically reserved for patients exceeding 1 million/pl [1OOO x 10,/L]); these are more who cannot tolerate or do not respond to hydroxyurea. In 5

Hematopoietic Stem Cells and Their Disorders addition to ET treatment, patients with acute venous throm- aspirate bone marrow ("dry tap"). Diagnosis increasingly relies boembolism will generally require lifelong anticoagulation. on evaluation for concomitant mutations because molecular findings help with prognosis. The Dynamic International XEY POITTS Prognostic Scoring System helps determine risk stratification. . The lAK2 mutation is seen in approximately 50% of Low-risk disease has an estimated overall survival rate in patients with essential thrombocythemia. the 15 year range, whereas survival is only approximately . Secondary causes ofthrombocltosis, including iron 16 months with high risk features. deficienry chronic bleeding, infection, other inflamma- Treatment depends on symptoms, risk of disease pro- tory conditions, and after splenectomy, are more cofiuron gression, and survival. The only potentially curative option is than essential thromboclthemia. allogeneic HSCT; however, transplantation carries signiflcant . In patients with essential thrombocl,themia at high risk morbidity and mortality risks, so it is only considered in (age >60 years, history of thrombosis, JAK2 positivity) , those whose disease features indicate poor short*term sur plateletJowering therapy should be considered in vival (constitutional symptoms, more severe cytopenias, addition to aspirin. increased percentage of blasts in the marrow) and who are otherwise healthy enough to undergo transplantation. Other treatments focus on addressing symptoms and controlling Primary Myelofibrosis blood counts. Asymptomatic patients with Iow risk disease Primary myelofibrosis (PMF) is a clonal stem cell disorder can be monitored; however, most patients have some degree with marrow fibrosis and extramedullary hematopoiesis. of symptomatologr and may benefit from supportive medica Proliferation of megakaryocltes, which secrete cytokines, tions. Ruxolitinib is a IAKI/2 inhibitor that has been shown including transforming growth factor B-1, results in fibroblast to significantly improve constitutional symptoms in patients proliferation, deposition of reticulin fibrosis, and impaired with PMF and reduce spleen volume. Fedratinib, another hematopoiesis. A leukoery.throblastic picture is seen on blood approved selective "IAK2 inhibitor, provides similar outcomes. smear (Figure 3). The "IAK2, calreticulin, and MPL mutations Ruxolitinib and fedratinib are effective regardless of lAK2 are common among patients with PMF. mutational status. Many ongoing studies are evaluating Constitutional symptoms include fatigue, fever, night other agents that appear promising. Splenectomy is avoided sweats, generalized pruritus, and weight loss. Splenomegaly is because it is associated with significant morbidigz and mor characteristic and often massive, with associated abdominal tality in this population. fullness, pain, and early satiety. Laboratory results vary con siderably, but an elevated leukocyte count, anemia, and XEY POII{T thrombocy.topenia are common. Diagnosis is made by bone . Allogeneic hematopoietic stem cell transplantation is the marrow biopsy demonstrating extensive fibrosis, which only potentially curative treatment option for patients with excludes miliary tuberculosis or other causes of secondary primary myelofibrosis. fibrosis. This extensive fibrosis often precludes the ability to

addition to ET treatment, patients with acute venous throm- aspirate bone marrow ("dry tap"). Diagnosis increasingly relies boembolism will generally require lifelong anticoagulation. on evaluation for concomitant mutations because molecular findings help with prognosis. The Dynamic International XEY POITTS Prognostic Scoring System helps determine risk stratification. . The lAK2 mutation is seen in approximately 50% of Low-risk disease has an estimated overall survival rate in patients with essential thrombocythemia. the 15 year range, whereas survival is only approximately . Secondary causes ofthrombocltosis, including iron 16 months with high risk features. deficienry chronic bleeding, infection, other inflamma- Treatment depends on symptoms, risk of disease pro- tory conditions, and after splenectomy, are more cofiuron gression, and survival. The only potentially curative option is than essential thromboclthemia. allogeneic HSCT; however, transplantation carries signiflcant . In patients with essential thrombocl,themia at high risk morbidity and mortality risks, so it is only considered in (age >60 years, history of thrombosis, JAK2 positivity) , those whose disease features indicate poor short*term sur plateletJowering therapy should be considered in vival (constitutional symptoms, more severe cytopenias, addition to aspirin. increased percentage of blasts in the marrow) and who are otherwise healthy enough to undergo transplantation. Other treatments focus on addressing symptoms and controlling Primary Myelofibrosis blood counts. Asymptomatic patients with Iow risk disease Primary myelofibrosis (PMF) is a clonal stem cell disorder can be monitored; however, most patients have some degree with marrow fibrosis and extramedullary hematopoiesis. of symptomatologr and may benefit from supportive medica Proliferation of megakaryocltes, which secrete cytokines, tions. Ruxolitinib is a IAKI/2 inhibitor that has been shown including transforming growth factor B-1, results in fibroblast to significantly improve constitutional symptoms in patients proliferation, deposition of reticulin fibrosis, and impaired with PMF and reduce spleen volume. Fedratinib, another hematopoiesis. A leukoery.throblastic picture is seen on blood approved selective "IAK2 inhibitor, provides similar outcomes. smear (Figure 3). The "IAK2, calreticulin, and MPL mutations Ruxolitinib and fedratinib are effective regardless of lAK2 are common among patients with PMF. mutational status. Many ongoing studies are evaluating Constitutional symptoms include fatigue, fever, night other agents that appear promising. Splenectomy is avoided sweats, generalized pruritus, and weight loss. Splenomegaly is because it is associated with significant morbidigz and mor characteristic and often massive, with associated abdominal tality in this population. fullness, pain, and early satiety. Laboratory results vary con siderably, but an elevated leukocyte count, anemia, and XEY POII{T thrombocy.topenia are common. Diagnosis is made by bone . Allogeneic hematopoietic stem cell transplantation is the marrow biopsy demonstrating extensive fibrosis, which only potentially curative treatment option for patients with excludes miliary tuberculosis or other causes of secondary primary myelofibrosis. fibrosis. This extensive fibrosis often precludes the ability to Eosinophilia and Hypereosinophilic Syndrome e Causes of eosinophilia (absolute eosinophil count >500/pL [0.5 x 10'q/L]) canbe recalledbythe mnemonic CHINA (Tablea). Eosinophilia is usually mild, transient, and secondary to ..*r.{*r. ri.1l.}:r. 'iit:i''il W another process. Parasitic infection should be considered in patients who live in or have traveled to endemic areas, includ ing the southeastern United States where strong4oidiasis is encountered.

Eosinophilia and Hypereosinophilic Syndrome e Causes of eosinophilia (absolute eosinophil count >500/pL [0.5 x 10'q/L]) canbe recalledbythe mnemonic CHINA (Tablea). Eosinophilia is usually mild, transient, and secondary to ..*r.{*r. ri.1l.}:r. 'iit:i''il W another process. Parasitic infection should be considered in patients who live in or have traveled to endemic areas, includ ing the southeastern United States where strong4oidiasis is encountered. TABLE 4. Causes of Eosinophilia C Collagenvasculardisease(eosinophilicgranulomatosis with polyangiitis) H Helminthic (parasitic worm) infection (e.g., Strongyloides) I ldiopathichypereosinophilicsyndrome(extensive evaluation unrevealing) FIGURE 3.Aleukoerythroblasticbloodsmearshowsleft*hiftedgranulopoiesis (bands on either side of a large myelocyte above a metamyelocyte N Neoplasia (primary myeloproliferative neoplasms, acute Ibrarkets]) and myeloid leukemia, some solid tumors, lymphomas most n ucleated (bl u e a now) and tea rd rop-sha ped eryth rocytes (green a r row), which common) define a crowded myelophthisic marrow such as is seen in primary myelofibrosis or other secondary processes such as metastatic carcinoma. A mature neutrophil is seen A Allergy, atopy, asthma (also drug induced: carbamazepine, in the bottom right. sulfonamides)

TABLE 4. Causes of Eosinophilia C Collagenvasculardisease(eosinophilicgranulomatosis with polyangiitis) H Helminthic (parasitic worm) infection (e.g., Strongyloides) I ldiopathichypereosinophilicsyndrome(extensive evaluation unrevealing) FIGURE 3.Aleukoerythroblasticbloodsmearshowsleft*hiftedgranulopoiesis (bands on either side of a large myelocyte above a metamyelocyte N Neoplasia (primary myeloproliferative neoplasms, acute Ibrarkets]) and myeloid leukemia, some solid tumors, lymphomas most n ucleated (bl u e a now) and tea rd rop-sha ped eryth rocytes (green a r row), which common) define a crowded myelophthisic marrow such as is seen in primary myelofibrosis or other secondary processes such as metastatic carcinoma. A mature neutrophil is seen A Allergy, atopy, asthma (also drug induced: carbamazepine, in the bottom right. sulfonamides) 7

Hematopoietic Stem Cells and Their Disorders Hypereosinophilic syndrome (HES) is characterized by Symptoms and complications are often related to mast cell medi. organ damage that is directly mediated by eosinophils and is ator release (histamine, Ieukotrienes, prostaglandins) and include associated with a persistently elevated eosinophil count vasodilation, flushing, nausea, vomiting, and diarrhea; patients (>tsoO/pl [1.5 x 10r/L]). Dermatologic, pulmonary and gas- are also at increased risk fbr anaphylaxis. Treatment includes trointestinal complications are among the most commonly antihistamines and antileukotriene drugs to control the symp seen. Although infrequent, eosinophilic myocarditis is a major toms ol mast cell mediator release. Patients should carry cause ol morbidity and mortality. HES can be primary (clear epinephrine in case of anaphylaxis. Qtoreductive therapies are hematologic cause), secondary (infections, solid tumors), or typically only used in patients with more rqgressive forns. idiopathic. Primary HES is a rare, clonal MPN often associated I(EY POIilT with abnormal tyrosine kinase activation mediated by platelet derived growth factor receptor-cx or B (PDGFR o or B). . Systemic mastocytosis involves mast cell proliferation Patients with primary HES with the PDGFR-cI or p muta and infiltration into organ systems. tion respond well to lo',v doses of imatinib. Treatment also includes addressing the underlying cause in secondary HES. Glucocorticoids are effective, but it is imperative to rule out Myelodysplastic Synd romes active Sfrongyloides infection first because glucocorticoids Myelodysplastic syndromes (N4DS) are clonal stem cell disor can cause dissemination. which can be fatal. ders with ineffective hematopoiesis leading to dysplastic, usually hypercellular bone marrow and peripheral blood cyto IEY POITT penias. MDS carries a variable risk of transformation to AML . Hypereosinophilic syndrome is defined by persistent that correlates with prognosis. Most MDS are idiopathic, but eosinophil counts greater than 1500/pL (1.5 x 10e/L) with secondary MDS can result fiom chemotherapy or radiation end-organ damage. (therapy related), chemical exposure (benzene), and other fac tors. Other reversible causes of dysplasia that must be ruled Mastoclrtosis out include vitamin Brr, folate, and copper deflciencies; alco Mastocytosis shares many similar fbahrres with MPNs. lt is char hol consumption; medications; and infections (such as HIV). acterized by excess mast cell prolif'eration and accumulation in Macrocytic anemia is the most common cytoper-ria one or more organ systems. Cutaneous mastocytosis is limited to observed in patients with MDS. The peripheral blood smear skin involvement, whereas systemic mastoc).tosis involves infil shows dysplastic cells (hypogranular neutrophils and plate tration of other organs, which may or may not include the skin. lets), which do not function well and increase the risk of infec Organs involved in systemic mastocltosis include the bone mar tion and bleeding. MDS varies in presentation depending row live( spleen, and gastrointestinal tract. More than 95%, of on the blood cell lineage(s) affected. The World Health patients with systemic mastocltosis have KIT gene mutations. Organization classification of M DS and its features are listed in Most disease is classified as indolent, with normal life expectancy, Table 5. MDS is suspected in patients with otherwise unex although some patients may have more aggressive forms. plained cytopenias, especially with dysplastic findings on

Hypereosinophilic syndrome (HES) is characterized by Symptoms and complications are often related to mast cell medi. organ damage that is directly mediated by eosinophils and is ator release (histamine, Ieukotrienes, prostaglandins) and include associated with a persistently elevated eosinophil count vasodilation, flushing, nausea, vomiting, and diarrhea; patients (>tsoO/pl [1.5 x 10r/L]). Dermatologic, pulmonary and gas- are also at increased risk fbr anaphylaxis. Treatment includes trointestinal complications are among the most commonly antihistamines and antileukotriene drugs to control the symp seen. Although infrequent, eosinophilic myocarditis is a major toms ol mast cell mediator release. Patients should carry cause ol morbidity and mortality. HES can be primary (clear epinephrine in case of anaphylaxis. Qtoreductive therapies are hematologic cause), secondary (infections, solid tumors), or typically only used in patients with more rqgressive forns. idiopathic. Primary HES is a rare, clonal MPN often associated I(EY POIilT with abnormal tyrosine kinase activation mediated by platelet derived growth factor receptor-cx or B (PDGFR o or B). . Systemic mastocytosis involves mast cell proliferation Patients with primary HES with the PDGFR-cI or p muta and infiltration into organ systems. tion respond well to lo',v doses of imatinib. Treatment also includes addressing the underlying cause in secondary HES. Glucocorticoids are effective, but it is imperative to rule out Myelodysplastic Synd romes active Sfrongyloides infection first because glucocorticoids Myelodysplastic syndromes (N4DS) are clonal stem cell disor can cause dissemination. which can be fatal. ders with ineffective hematopoiesis leading to dysplastic, usually hypercellular bone marrow and peripheral blood cyto IEY POITT penias. MDS carries a variable risk of transformation to AML . Hypereosinophilic syndrome is defined by persistent that correlates with prognosis. Most MDS are idiopathic, but eosinophil counts greater than 1500/pL (1.5 x 10e/L) with secondary MDS can result fiom chemotherapy or radiation end-organ damage. (therapy related), chemical exposure (benzene), and other fac tors. Other reversible causes of dysplasia that must be ruled Mastoclrtosis out include vitamin Brr, folate, and copper deflciencies; alco Mastocytosis shares many similar fbahrres with MPNs. lt is char hol consumption; medications; and infections (such as HIV). acterized by excess mast cell prolif'eration and accumulation in Macrocytic anemia is the most common cytoper-ria one or more organ systems. Cutaneous mastocytosis is limited to observed in patients with MDS. The peripheral blood smear skin involvement, whereas systemic mastoc).tosis involves infil shows dysplastic cells (hypogranular neutrophils and plate tration of other organs, which may or may not include the skin. lets), which do not function well and increase the risk of infec Organs involved in systemic mastocltosis include the bone mar tion and bleeding. MDS varies in presentation depending row live( spleen, and gastrointestinal tract. More than 95%, of on the blood cell lineage(s) affected. The World Health patients with systemic mastocltosis have KIT gene mutations. Organization classification of M DS and its features are listed in Most disease is classified as indolent, with normal life expectancy, Table 5. MDS is suspected in patients with otherwise unex although some patients may have more aggressive forms. plained cytopenias, especially with dysplastic findings on TABTE 5. 2016 World Health Organization (WHO) Classification of Myelodysplastic Syndromes ' Subtype Blood Bone Marrow MDS with single Iineage dysplasia Single or bicytopenia Dysplasia >10% of cell line, <5% blasts (MDS-SLD)

TABTE 5. 2016 World Health Organization (WHO) Classification of Myelodysplastic Syndromes ' Subtype Blood Bone Marrow MDS with single Iineage dysplasia Single or bicytopenia Dysplasia >10% of cell line, <5% blasts (MDS-SLD) MDS with ring sideroblasts (MDS-RS) Anemia, no blasts >15% erythroid precursors with RS, or>5% RS with SF3B7 mutation, <5% sideroblasts MDS with multilineage dysplasia Cytopenias; monocytes <1 x 1oe/L Dysplasia 21 0% of cells in >2 lineages, <1 5% RS (MDS.MLD) (<5% RS if SF3Bl present), <5% blasts MDS with excess myeloblasts-1 Cytopenia(s); >2%-4% blasts; monocytes Unilineage or multilineage dysplasia, 5%-9% (MDS-EB 1) <1 x IOell blasts, no Auer rods MDS with excess myeloblasts-2 Cytopenia(s); 57"-1 9"/" blasts; monocytes Unilineage or multilineage dysplasia, (MDS-EB-2) <1 x 10ell 10"/"-197" blasts, +/-Auer rods MDS, unclassifiable (MDS-U) Cytopenia(s), +/- 1% blasts on at least two Unilineage or no dysplasia but MDS occasions cytogenetics, <5% blasts

MDS with excess myeloblasts-2 Cytopenia(s); 57"-1 9"/" blasts; monocytes Unilineage or multilineage dysplasia, (MDS-EB-2) <1 x 10ell 10"/"-197" blasts, +/-Auer rods MDS, unclassifiable (MDS-U) Cytopenia(s), +/- 1% blasts on at least two Unilineage or no dysplasia but MDS occasions cytogenetics, <5% blasts MDS with isolated 5q- Anemia, normal or increased platelets Unilineage erythroid dysplasia, isolated 5q-, <5% blasts +/- one other abnormality except 7q- Refractory cytopenia of childhood Cytopenias, <2% blasts Dysplasia in one to three lineages, (provisional WHO category) <57" blasts MDS = myelodysplastic syndromes; RS = ring sideroblasts. 8

Hematopoietic Stem Cells and Their Disorders 20'X, blasts. Prognosis and treatment is analogous to MDS with poor prognosis. Clonal hematopoiesis of indeterminate potential (CHIP) describes detection of somatic clonal mutations in genes recurrently mutated in hematologic malignancies (e.g', DNMT3A, TET2, ASXLI\ but without a known hematologic malignancy or other clonal disorder. The risk of CHIP prog ressing to MDS is very low, but CHIP carriers are at increased risk of atherosclerosis.

20'X, blasts. Prognosis and treatment is analogous to MDS with poor prognosis. Clonal hematopoiesis of indeterminate potential (CHIP) describes detection of somatic clonal mutations in genes recurrently mutated in hematologic malignancies (e.g', DNMT3A, TET2, ASXLI\ but without a known hematologic malignancy or other clonal disorder. The risk of CHIP prog ressing to MDS is very low, but CHIP carriers are at increased risk of atherosclerosis. TEY POIIIIS o Myelodysplastic syndrome is suspected in patients with cltopenias and with dysplastic findings on peripheral blood smear; bone marrow biopsy is required for diag- nosis and risk stratification. o Allogeneic hematopoietic stem cell transplantation is FIGURE 4. Peripheral blood smearfrom a patientwith myelodysplastic syndrome. A dysplastic neutrophil isseen(white arrow) with hypogranular the only cure for myelodysplastic syndrome, but it is too cytoplasm and a dysplastic nucleus. A nucleated erythrocyte is also seen in this toxic for most older adult patients; however, hypometh- Iield (black arrow). ylating agents decrease transfusion dependence and Figure cou(esy 0l Julia Choi, MD; Baylor 5cofl & White Health. leukemic transformation.

TEY POIIIIS o Myelodysplastic syndrome is suspected in patients with cltopenias and with dysplastic findings on peripheral blood smear; bone marrow biopsy is required for diag- nosis and risk stratification. o Allogeneic hematopoietic stem cell transplantation is FIGURE 4. Peripheral blood smearfrom a patientwith myelodysplastic syndrome. A dysplastic neutrophil isseen(white arrow) with hypogranular the only cure for myelodysplastic syndrome, but it is too cytoplasm and a dysplastic nucleus. A nucleated erythrocyte is also seen in this toxic for most older adult patients; however, hypometh- Iield (black arrow). ylating agents decrease transfusion dependence and Figure cou(esy 0l Julia Choi, MD; Baylor 5cofl & White Health. leukemic transformation. peripheral blood smear (Figure 4). Bone marrow biopsy is required for diagnosis. The prognosis for patients with MDS Acute Leukemias depends on the degree of c),topenias (transfusion depend Acute leukemia is a hematologic malignancy characterized by ence), presence of bone marrow blasts (correlates with the risk infiltration of the bone marrow blood, and other tissues by of AML transformation), and cytogenetics. Patients at low risk uncontrolled prolif'eration and abnormal delayed differenti a may have a median survival of almost 9 years, whereas those tion olclonal myeloid or lymphoid precursor cells, exceeding with greater than l0'7, blasts, severe pancl'topenias (hemo 2o"1, of the bone marrow or blood. In adults, AML is more globin <8 g/dl [80 g/LJ, platelet count <50,000/UL [50 x common than acute lymphoblastic leukemia (ALL). 10e/Ll, absolute neutrophil count <800/pL [o.s x roe/L]), and Managing acute leukemia during pregnancy is challeng- adverse cytogenetics survive less than 1 year. ing because the health of mother and fetus must be consid Asymptomatic low risk MDS can be monitored. ered, as well as long term infant/child well-being. Toxicity in Allogeneic HSCT is the only potentially curative option avail the first trimester can be significant, although chemotherapy able. Transplantation is usually not an option for older patients (anthracycline and cytarabine) is often successfully adminis with MDS because of comorbidities precluding them from tered during the second and third trimesters. being candidates fbr intensive treatment. The primary goals of treatment in MDS are treating Acute Myeloid Leukemia symptomatic cytopenias and reducing the risk of progression AML typically manifests with anemia, thrombocytopenia, or to AML. Symptomatic anemia is treated with transfusions functional neutropenia secondary to bone marrow replace- and erythropoiesis stimulating agents. Patients with MDS ment with abnormal myeloblasts. Petechiae, epistaxis, and who are at high risk have an approximate 25% risk of conver other mucosal hemorrhages occur when the platelet count sion to AML in the first year. Treatment with hypomethylat dips below 20,000/pL (20 x 10'q/L). Symptoms of anemia vary ing agents (azacytidine and decitabine) has been shown to more with the patient's age and comorbidities. Although the decrease transfusion dependence and the risk ofconversion leukocyte count is typically elevated, the absolute neutrophil to AML. Patients with low-risk MDS with the 5q- cytogenetic count tends to be low which confers an increased risk olinfec abnormality could be treated with the immunomodulatory tion. Myeloblasts are usually seen in the peripheral blood drug lenalidomide if they are transfusion dependent. smear but may be absent despite unequivocal bone marrow Lenalidomide is effective in decreasing transfusion needs in infiltration. AML is curable in 35'/n to 40% of adult patients these patients. aged 60 years or younger, but the cure rate decreases to just 5'2, Chronic myelomonocytic Ieukemia has traditionally been to 15'2, in adults older than 60 years, in whom comorbidities considered a subset of MDS but is now classified as a separate (e.g., cardiopulmonary disease) also preclude the use of inten- entity, sharing some features of MDS with those of the MPNs. sive chemotherapy or transplantation. Patients with chronic myelomonocytic leukemia have persis Cytogenetic and molecular classification of AML is tent monocytosis, often with splenomegaly and other cytope increasingly important. Acute promyelocytic leukemia, char- nias; bone marrow shows dysplastic changes and less than acterized by immature leukocytes with distinctive primary

peripheral blood smear (Figure 4). Bone marrow biopsy is required for diagnosis. The prognosis for patients with MDS Acute Leukemias depends on the degree of c),topenias (transfusion depend Acute leukemia is a hematologic malignancy characterized by ence), presence of bone marrow blasts (correlates with the risk infiltration of the bone marrow blood, and other tissues by of AML transformation), and cytogenetics. Patients at low risk uncontrolled prolif'eration and abnormal delayed differenti a may have a median survival of almost 9 years, whereas those tion olclonal myeloid or lymphoid precursor cells, exceeding with greater than l0'7, blasts, severe pancl'topenias (hemo 2o"1, of the bone marrow or blood. In adults, AML is more globin <8 g/dl [80 g/LJ, platelet count <50,000/UL [50 x common than acute lymphoblastic leukemia (ALL). 10e/Ll, absolute neutrophil count <800/pL [o.s x roe/L]), and Managing acute leukemia during pregnancy is challeng- adverse cytogenetics survive less than 1 year. ing because the health of mother and fetus must be consid Asymptomatic low risk MDS can be monitored. ered, as well as long term infant/child well-being. Toxicity in Allogeneic HSCT is the only potentially curative option avail the first trimester can be significant, although chemotherapy able. Transplantation is usually not an option for older patients (anthracycline and cytarabine) is often successfully adminis with MDS because of comorbidities precluding them from tered during the second and third trimesters. being candidates fbr intensive treatment. The primary goals of treatment in MDS are treating Acute Myeloid Leukemia symptomatic cytopenias and reducing the risk of progression AML typically manifests with anemia, thrombocytopenia, or to AML. Symptomatic anemia is treated with transfusions functional neutropenia secondary to bone marrow replace- and erythropoiesis stimulating agents. Patients with MDS ment with abnormal myeloblasts. Petechiae, epistaxis, and who are at high risk have an approximate 25% risk of conver other mucosal hemorrhages occur when the platelet count sion to AML in the first year. Treatment with hypomethylat dips below 20,000/pL (20 x 10'q/L). Symptoms of anemia vary ing agents (azacytidine and decitabine) has been shown to more with the patient's age and comorbidities. Although the decrease transfusion dependence and the risk ofconversion leukocyte count is typically elevated, the absolute neutrophil to AML. Patients with low-risk MDS with the 5q- cytogenetic count tends to be low which confers an increased risk olinfec abnormality could be treated with the immunomodulatory tion. Myeloblasts are usually seen in the peripheral blood drug lenalidomide if they are transfusion dependent. smear but may be absent despite unequivocal bone marrow Lenalidomide is effective in decreasing transfusion needs in infiltration. AML is curable in 35'/n to 40% of adult patients these patients. aged 60 years or younger, but the cure rate decreases to just 5'2, Chronic myelomonocytic Ieukemia has traditionally been to 15'2, in adults older than 60 years, in whom comorbidities considered a subset of MDS but is now classified as a separate (e.g., cardiopulmonary disease) also preclude the use of inten- entity, sharing some features of MDS with those of the MPNs. sive chemotherapy or transplantation. Patients with chronic myelomonocytic leukemia have persis Cytogenetic and molecular classification of AML is tent monocytosis, often with splenomegaly and other cytope increasingly important. Acute promyelocytic leukemia, char- nias; bone marrow shows dysplastic changes and less than acterized by immature leukocytes with distinctive primary 9

Hematopoietic Stem Cells and Their Disorders granules that contribute to coagulopathy (pigure S) and chro- Sweet syndrome, or acute febrile neutrophilic dermatosis, mosomal translocation t(1S;17), was an early prototype for is characterized by fever, neutrophilia, a dense dermal infil- targeted therapy in hematologic malignancies, because many trate on histologz, and characteristic skin lesions (Figure 6). patients achieve cure with all-trcns retinoic acid, which tar- Sweet syndrome may develop in patients with hematologic gets the underlying block in cell differentiation. A growing abnormalities, particularly MDS and MDS evolving into AML. number of molecular markers are used to guide prognosis and therapy. NPMl-mutated AML is found in about half of patients Acute Lymphoblastic Leukemia and is associated with a favorable outcome. In contrast, FlI3- ALL is more common in children and adolescents than in ITD identification (found in approximately one third of adults. Although ALL in children is often curable, survival in patients with cytogenetically normal AML) is associated with adult patients (older than 19 years) remains inferior despite an unfavorable outcome and merits consideration for alloge- the adoption of pediatric ALL regimens. Patients with ALL neic transplantation in first remission. present with malaise, bleeding, infections, bone pain, or a AML treatment consists of induction therapy with an combination of these symptoms, with a small subset (<10%) anthrarycline (such as daunorubicin) and infusional cytara- having symptomatic central nervous system involvement at bine. The goal is to ablate the bone marrow, eliminating the diagnosis. In adults, 75% of ALL is of B-cell lineage; mature blasts, although this transiently destroys the normal hemato- B-cell ALL can manifest as extramedullary disease, including poietic cells as well. Cells are expected to recover after a period gastrointestinal or testicular involvement. A mediastinal mass of aplasia, which extends for 3 to 4 weeks. During this time, with wheezing and stridor or skin involvement can be the pre- the patient is supported by transfusions (erythrocytes and senting features of T-cell ALL. Similar to AML, ALL is classified platelets) and prompt antibiotic treatment of neutropenic by immunophenotype, cytogenetics, and molecular abnor- fever. A complete response is achieved in 60% to 85% of malities. The most important cytogenetic abnormality in adult patients younger than 60 years. Consolidation therapy for ALL is the Philadelphia chromosome, found in 2O"/" to 30o/. of responders consists of additional cycles of conventional che- patients. Historically, Philadelphia chromosome-positive ALL motherapy in patients at low risk and allogeneic HSCT for had a poor prognosis. The use of tyrosine kinase inhibitors, patients at high risk. Midostaurin and gilteritinib are approved such as imatinib and dasatinib, along with more traditional FLI3 inhibitors for first- or second-line therapy. Ivosidenib chemotherapy has dramatically improved remission rates. and enasidenib are isocitrate dehydrogenase (lDH) inhibitors After remission induction, patients with Philadelphia used in patients with IDH1 or IDH2-mutated AML. chromosome-positive ALL often receive additional intensive Treatment for older or frail patients is unsatisfactory; consolidation with allogeneic HSCL symptom management may include blood and platelet trans- Treatment regimens are complex. Regimen backbones fusions along with lower dose, often single-agent chemother- include vincristine, anthracycline, corticosteroids, and apy, such as oral hydroxyurea or low-dose cytarabine. l-asparaginase. Some of these agents have unique toxicities Hypomethylating agents (decitabine and azacitidine) may also such as allergic reactions, hypofibrinogenemia, thrombosis, be combined with targeted therapies (FLI3 inhibitors, IDH and hypertriglyceridemia with r--asparaginase. Induction inhibitors). These patients are expected to survive only therapy is followed by intensification and consolidation. months, and hospice care should be considered. Central nervous system prophylaxis is essential during ALL

granules that contribute to coagulopathy (pigure S) and chro- Sweet syndrome, or acute febrile neutrophilic dermatosis, mosomal translocation t(1S;17), was an early prototype for is characterized by fever, neutrophilia, a dense dermal infil- targeted therapy in hematologic malignancies, because many trate on histologz, and characteristic skin lesions (Figure 6). patients achieve cure with all-trcns retinoic acid, which tar- Sweet syndrome may develop in patients with hematologic gets the underlying block in cell differentiation. A growing abnormalities, particularly MDS and MDS evolving into AML. number of molecular markers are used to guide prognosis and therapy. NPMl-mutated AML is found in about half of patients Acute Lymphoblastic Leukemia and is associated with a favorable outcome. In contrast, FlI3- ALL is more common in children and adolescents than in ITD identification (found in approximately one third of adults. Although ALL in children is often curable, survival in patients with cytogenetically normal AML) is associated with adult patients (older than 19 years) remains inferior despite an unfavorable outcome and merits consideration for alloge- the adoption of pediatric ALL regimens. Patients with ALL neic transplantation in first remission. present with malaise, bleeding, infections, bone pain, or a AML treatment consists of induction therapy with an combination of these symptoms, with a small subset (<10%) anthrarycline (such as daunorubicin) and infusional cytara- having symptomatic central nervous system involvement at bine. The goal is to ablate the bone marrow, eliminating the diagnosis. In adults, 75% of ALL is of B-cell lineage; mature blasts, although this transiently destroys the normal hemato- B-cell ALL can manifest as extramedullary disease, including poietic cells as well. Cells are expected to recover after a period gastrointestinal or testicular involvement. A mediastinal mass of aplasia, which extends for 3 to 4 weeks. During this time, with wheezing and stridor or skin involvement can be the pre- the patient is supported by transfusions (erythrocytes and senting features of T-cell ALL. Similar to AML, ALL is classified platelets) and prompt antibiotic treatment of neutropenic by immunophenotype, cytogenetics, and molecular abnor- fever. A complete response is achieved in 60% to 85% of malities. The most important cytogenetic abnormality in adult patients younger than 60 years. Consolidation therapy for ALL is the Philadelphia chromosome, found in 2O"/" to 30o/. of responders consists of additional cycles of conventional che- patients. Historically, Philadelphia chromosome-positive ALL motherapy in patients at low risk and allogeneic HSCT for had a poor prognosis. The use of tyrosine kinase inhibitors, patients at high risk. Midostaurin and gilteritinib are approved such as imatinib and dasatinib, along with more traditional FLI3 inhibitors for first- or second-line therapy. Ivosidenib chemotherapy has dramatically improved remission rates. and enasidenib are isocitrate dehydrogenase (lDH) inhibitors After remission induction, patients with Philadelphia used in patients with IDH1 or IDH2-mutated AML. chromosome-positive ALL often receive additional intensive Treatment for older or frail patients is unsatisfactory; consolidation with allogeneic HSCL symptom management may include blood and platelet trans- Treatment regimens are complex. Regimen backbones fusions along with lower dose, often single-agent chemother- include vincristine, anthracycline, corticosteroids, and apy, such as oral hydroxyurea or low-dose cytarabine. l-asparaginase. Some of these agents have unique toxicities Hypomethylating agents (decitabine and azacitidine) may also such as allergic reactions, hypofibrinogenemia, thrombosis, be combined with targeted therapies (FLI3 inhibitors, IDH and hypertriglyceridemia with r--asparaginase. Induction inhibitors). These patients are expected to survive only therapy is followed by intensification and consolidation. months, and hospice care should be considered. Central nervous system prophylaxis is essential during ALL F I G U R E 5. Ihis peripheral blood smear shows an immature granulocyte with a I F I G U R E 6 . The tender skin lesions of Sweet syndrome appear as 'luicy" indurated edematous red-purple plaques and nodules, sharply demarcated from the adjacent skin. rod-shaped inclusion body (Auer rod) characteristic of acute myeloid leukemia.

F I G U R E 5. Ihis peripheral blood smear shows an immature granulocyte with a I F I G U R E 6 . The tender skin lesions of Sweet syndrome appear as 'luicy" indurated edematous red-purple plaques and nodules, sharply demarcated from the adjacent skin. rod-shaped inclusion body (Auer rod) characteristic of acute myeloid leukemia. 10

Hematopoietic Stem Cells and Their Disorders therapy, and a maintenance phase of oral mercaptopurine receiving myelosuppressive chemotherapy who are at high (daily) and methotrexate (weekly) can last up to 2 years. risk of febrile neutropenia, such as those receiving intensive Medication adherence can be problematic during the mainte chemotherapy for high-risk breast cancer and those aged nance phase. Immunotherapies with bispecific antibodies or 65 years or older with aggressive lymphoma being treated with chimeric antigen receptor (CAR) T cells are available if the curative chemotherapy. G CSF may also be indicated in disease relapses. patients receiving another course of chemotherapy that has Adult survivors of childhood leukemia face higher risks of already led to neutropenic f'ever. G CSF is not indicated fbr secondary cancer, cardiovascular disease, and the metabolic most patients with neutropenia who are afebrile, as a routine syndrome (high BMI, elevated waist circumference, dyslip adjunct to empiric antibiotics for patients presenting with idemia, elevated fasting glucose, and hypertension) compared febrile neutropenia, or for patients undergoing induction with age matched controls. Primary care physicians encoun chemotherapy for acute leukemia. tering such patients should request a treatment summary fiom the treating facility and encourage patient participation in a local survivorship clinic. Screening for dyslipidemia, dia- Hematopoietic Stem Cell betes, and hypertension is recommended. Echocardiography Transplantation and to screen for left ventricular dysfunction should be performed at intervals of 3 to 5 years, particularly if anthracycline expo- Cellular Therapies sure was high (such as doxorubicin exceeding 300 mg/m2) or Autologous HSCT is performed in select patients who have mul if chest radiation was used. Female survivors have a higher risk tiple myeloma or relapsed aggressive lymphoma. Allogeneic of myocardial dysfunction during pregnancy. High dose glu HSCT is indicated (in addition to high dose antileukemia che cocorticoids, typical of ALL regimens, pose a risk for osteope- motherapy) in patients with high risk AML, ALL, and MDS for nia. The cumulative incidence of secondary cancer after the graft versus leukemia effect. lt is also used to treat patients radiation therapy for childhood ALL reaches 11% at 30 years; with AA and select patients with hemoglobinopathies such as tumors include skin cancer, thyroid and parotid tumors, sar sickle cell anemia. Typically, the allogeneic donor is an HLA comas, and brain tumors. Cranial radiation also increases the matched sibling or unrelated adult donor. The risk of graft risk for stroke and neurocognitive defects. Patients should be versus host disease affecting the skin, gastrointestinal tract, and counseled about lifestyle risk factors, age based screening, liver increases with the degree of donor recipient HLA disparity. and early reporting of persistent symptoms. Better supportive measures and reduced intensity regimens have provided transplant eligibility to older adults. HSCT car XEY POIIIIS ries a significant risk of transplant related mortality, and sur . Acute myeloid leukemia tlpically manifests with anemia, vivors continue to have long term morbidities unrelated to thrombocy.topenia, or functional neutropenia secondary relapse, such as susceptibility to bacterial or viral infections to bone marrow replacement with abnormal myeloblasts; and delayed pulmonary toxicify. Physicians caring for patients petechiae and other signs of mucosal bleeding are com- who have undergone transplantation should evaluate these mon when the platelet count dips below 20,000/pL individuals early for symptoms suggesting infection and follow (20 x 10e/L). recommended immunization schedules that take into account o Treatment of acute myeloid leukemia consists of induc- their prolonged immunosuppressed state (see MKSAP t9 tion therapy with an anthracycline and infusional General Internal Medicine 2). cytarabine, followed by consolidation therapy for Treatment using CAR T cells has become available for responders, consisting of additional cycles of conven certain patients with recurrent ALL. CAR T cells are genetically tional chemotherapy for patients at Iow risk and alloge- modified T lymphocytes (usually collected from the patient) to neic hematopoietic stem cell transplantation for those specilically recognize and attack cells expressing a particular at high risk. tumor antigen (e.g., CD19 in B cell malignancies such as ALL). o Adult survivors of childhood leukemia face higher risks These therapies are highly effective; however, patients with a of secondary cancer, cardiovascular disease, and the high disease burden may develop dangerous cytokine release metabolic slmdrome. syndrome (CRS) or neurotoxicity. Intensitlz of CRS and neuro toxicity symptoms can range from mild (fever or confusion) to severe, with multiorgan failure or seizures requiring manage Hematopoietic G rowth Factors ment in the ICU. Severe CRS requiring ICU admission is often Erythropoiesis stimulating agents (which include erythropoi- characterized by vascular leak, hypotension, pulmonary etin and darbepoetin) are primarily used in patients with edema, cardiac dysfunction, kidney dysfunction, liver failure, anemia and chronic kidney disease. For patients undergoing coagulopathy, multiorgan system failure, and even death. dialysis, the target hemoglobin level should be no greater than Many tumor antigens are under inl,estigation regarding the 10 to 11 g/dl (100 110 g/L) to avoid adverse cardiovascular suitability of this novel cellular therapy approach for hemato outcomes. G-CSF (various formulations) are used in patients logic malignancies and solid tumors.

therapy, and a maintenance phase of oral mercaptopurine receiving myelosuppressive chemotherapy who are at high (daily) and methotrexate (weekly) can last up to 2 years. risk of febrile neutropenia, such as those receiving intensive Medication adherence can be problematic during the mainte chemotherapy for high-risk breast cancer and those aged nance phase. Immunotherapies with bispecific antibodies or 65 years or older with aggressive lymphoma being treated with chimeric antigen receptor (CAR) T cells are available if the curative chemotherapy. G CSF may also be indicated in disease relapses. patients receiving another course of chemotherapy that has Adult survivors of childhood leukemia face higher risks of already led to neutropenic f'ever. G CSF is not indicated fbr secondary cancer, cardiovascular disease, and the metabolic most patients with neutropenia who are afebrile, as a routine syndrome (high BMI, elevated waist circumference, dyslip adjunct to empiric antibiotics for patients presenting with idemia, elevated fasting glucose, and hypertension) compared febrile neutropenia, or for patients undergoing induction with age matched controls. Primary care physicians encoun chemotherapy for acute leukemia. tering such patients should request a treatment summary fiom the treating facility and encourage patient participation in a local survivorship clinic. Screening for dyslipidemia, dia- Hematopoietic Stem Cell betes, and hypertension is recommended. Echocardiography Transplantation and to screen for left ventricular dysfunction should be performed at intervals of 3 to 5 years, particularly if anthracycline expo- Cellular Therapies sure was high (such as doxorubicin exceeding 300 mg/m2) or Autologous HSCT is performed in select patients who have mul if chest radiation was used. Female survivors have a higher risk tiple myeloma or relapsed aggressive lymphoma. Allogeneic of myocardial dysfunction during pregnancy. High dose glu HSCT is indicated (in addition to high dose antileukemia che cocorticoids, typical of ALL regimens, pose a risk for osteope- motherapy) in patients with high risk AML, ALL, and MDS for nia. The cumulative incidence of secondary cancer after the graft versus leukemia effect. lt is also used to treat patients radiation therapy for childhood ALL reaches 11% at 30 years; with AA and select patients with hemoglobinopathies such as tumors include skin cancer, thyroid and parotid tumors, sar sickle cell anemia. Typically, the allogeneic donor is an HLA comas, and brain tumors. Cranial radiation also increases the matched sibling or unrelated adult donor. The risk of graft risk for stroke and neurocognitive defects. Patients should be versus host disease affecting the skin, gastrointestinal tract, and counseled about lifestyle risk factors, age based screening, liver increases with the degree of donor recipient HLA disparity. and early reporting of persistent symptoms. Better supportive measures and reduced intensity regimens have provided transplant eligibility to older adults. HSCT car XEY POIIIIS ries a significant risk of transplant related mortality, and sur . Acute myeloid leukemia tlpically manifests with anemia, vivors continue to have long term morbidities unrelated to thrombocy.topenia, or functional neutropenia secondary relapse, such as susceptibility to bacterial or viral infections to bone marrow replacement with abnormal myeloblasts; and delayed pulmonary toxicify. Physicians caring for patients petechiae and other signs of mucosal bleeding are com- who have undergone transplantation should evaluate these mon when the platelet count dips below 20,000/pL individuals early for symptoms suggesting infection and follow (20 x 10e/L). recommended immunization schedules that take into account o Treatment of acute myeloid leukemia consists of induc- their prolonged immunosuppressed state (see MKSAP t9 tion therapy with an anthracycline and infusional General Internal Medicine 2). cytarabine, followed by consolidation therapy for Treatment using CAR T cells has become available for responders, consisting of additional cycles of conven certain patients with recurrent ALL. CAR T cells are genetically tional chemotherapy for patients at Iow risk and alloge- modified T lymphocytes (usually collected from the patient) to neic hematopoietic stem cell transplantation for those specilically recognize and attack cells expressing a particular at high risk. tumor antigen (e.g., CD19 in B cell malignancies such as ALL). o Adult survivors of childhood leukemia face higher risks These therapies are highly effective; however, patients with a of secondary cancer, cardiovascular disease, and the high disease burden may develop dangerous cytokine release metabolic slmdrome. syndrome (CRS) or neurotoxicity. Intensitlz of CRS and neuro toxicity symptoms can range from mild (fever or confusion) to severe, with multiorgan failure or seizures requiring manage Hematopoietic G rowth Factors ment in the ICU. Severe CRS requiring ICU admission is often Erythropoiesis stimulating agents (which include erythropoi- characterized by vascular leak, hypotension, pulmonary etin and darbepoetin) are primarily used in patients with edema, cardiac dysfunction, kidney dysfunction, liver failure, anemia and chronic kidney disease. For patients undergoing coagulopathy, multiorgan system failure, and even death. dialysis, the target hemoglobin level should be no greater than Many tumor antigens are under inl,estigation regarding the 10 to 11 g/dl (100 110 g/L) to avoid adverse cardiovascular suitability of this novel cellular therapy approach for hemato outcomes. G-CSF (various formulations) are used in patients logic malignancies and solid tumors. 11