Hematopoietic stem cells nest in the bone marrow and have the capacity to differentiate and self-renew. Hematopoietic stem cells are multipotent and can differentiate into progenitor cells; in turn, these produce leukocytes, erythrocytes, and platelets. This differentiation and proliferation to mature blood cells happens in an orderly manner called hematopoiesis. Hematopoiesis is tightly regulated by multiple factors, including the bone marrow microenvironment and hematopoietic growth factors. This includes erythropoietin, which stimulates erythrocytes; thrombopoietin, which stimulates platelet production; and granulocyte colony-stimulating factor and macrophage colony-stimulating factor, which stimulate granulocyte, monocyte, basophil, and eosinophil production. Disorders of hematopoiesis can occur at the hematopoietic stem cell or progenitor level and can lead to underproduction or overproduction of blood cells.
Bone marrow failure syndromes are characterized by the failure of hematopoiesis to keep up with physiologic demands for blood cell production, leading to peripheral cytopenias. Although rare inherited causes exist, acquired disorders are much more common and can occur secondary to intrinsic bone marrow disorders, such as myelodysplastic syndrome, or extrinsic disorders resulting from toxins or autoimmunity, as in aplastic anemia.
Myeloproliferative neoplasms are clonal myeloid neoplasms with deregulation and excess proliferation of subsets of hematopoietic stem cells. The diagnosis can be made through identification of clonal genetic abnormalities, such as BCR-ABL translocation and JAK2 (JAK2 V617F) mutation on peripheral blood testing.
Acute leukemias, either myeloid or lymphoid in origin, are aggressive clonal neoplasms in which cells also lose the capability to differentiate into mature cells. These disorders usually require emergent evaluation and treatment.
Aplastic anemia (AA) is an acquired hematopoietic stem cell disorder characterized by severely decreased bone marrow cellularity and pancytopenia. Although the condition is classified as an anemia, patients usually present with a combination of anemia, neutropenia, and thrombocytopenia. Bone marrow cellularity decreases with age while the fat content of the marrow increases. These changes are amplified in AA, which is categorized as severe or very severe based on the degree of bone marrow cellularity and the severity of cytopenias.
AA is caused by a decrease in stem cells as a result of autoimmunity, toxins, and infections. Medications, such as antithyroid medications (methimazole and propylthiouracil), β-lactam antibiotics, sulfonamides, NSAIDs, anticonvulsants, and gold, have also been associated with development of AA. Discontinuing the offending medication usually improves the AA, but it can take many weeks for cell counts to recover.
Most AA is felt to be related to autoimmunity against stem cells. In patients older than 50 years and in younger patients without a suitable stem cell donor, AA is treated by immunosuppression with antithymocyte globulin, cyclosporine, and prednisone. Patients younger than 50 years with a suitable donor are usually treated with allogeneic hematopoietic stem cell transplantation. With advances in immunosuppression, bone marrow transplantation, and supportive care, the overall survival of young patients with a good risk profile has reached greater than 80%. Asymptomatic patients with mild to moderate AA can be closely monitored without immediate treatment.
Patients with AA can develop a clone of paroxysmal nocturnal hemoglobinuria cells, which lack complement-stabilizing CD55 and CD59 proteins. However, identifying the paroxysmal nocturnal hemoglobinuria clone does not routinely change treatment of AA, although it does help explain pathophysiology. AA can be differentiated from a hypoplastic variant of myelodysplastic syndrome (MDS) with decreased bone marrow cellularity by finding dysplastic cells and cytogenetic abnormalities typical for MDS. Hypoplastic MDS is also commonly treated with immunosuppressive treatment.
Pure red cell aplasia (PRCA) is characterized by normocytic or macrocytic anemia with decreased reticulocytes and absent or decreased erythrocyte precursors in the bone marrow. Leukocyte and platelet counts are normal. Several conditions have been implicated in the pathogenesis of PRCA, some of which are listed in Table 1.
Parvovirus B19 is cytotoxic to the erythrocyte precursors in the bone marrow. Parvovirus infection is usually transient, lasting 2 to 3 weeks in immunocompetent patients, and does not usually cause clinically significant anemia in healthy patients. However, patients with chronic hemolysis (such as sickle cell anemia) who depend on increased erythrocyte production can have significant anemia with a decreased reticulocyte count. Immunocompromised patients can have sustained viremia leading to prolonged anemia requiring intravenous immune globulin treatment to hasten viral clearance.
A few patients with PRCA have an underlying occult thymoma and can improve with thymectomy. Large granular lymphocyte leukemia is a T-cell lymphoproliferative disorder that can be associated with PRCA. Flow cytometry of the peripheral blood can help identify this disorder.
A bone marrow biopsy specimen showing decreased erythrocyte precursors is required to diagnose PRCA. Idiopathic PRCA is commonly immunologically mediated and treated with immunosuppressive medications, such as prednisone, cyclosporine, and cyclophosphamide.
Isolated neutropenia is a common finding in internal medicine practice. Most patients with neutropenia have a mild form (1000-1500/µL [1-1.5 × 109/L]), but some have moderate (500-1000/µL [0.5-1 × 109/L]) or severe (500/µL [0.5 × 109/L]) neutropenia. Clinically significant infections do not usually occur unless neutrophil counts are less than 500/µL (0.5 × 109/L). Isolated neutropenia can be secondary to congenital or acquired conditions (Table 2).
Benign ethnic neutropenia is a congenital neutropenia seen in Black patients and those of Mediterranean descent. These patients have good neutrophil reserve and are not prone to infections. In a healthy Black patient with mild neutropenia found on routine testing, no further evaluation is needed.
Cyclical neutropenia is another rare congenital condition in which neutrophil counts decrease every 2 to 5 weeks. The neutrophil count can get low enough that patients develop recurrent infections every 2 to 5 weeks.
Instead of causing leukocytosis, infections can cause neutropenia; this can happen after viral, bacterial, or rickettsial infections. Neutropenia resolves with improvement of the underlying infection. Several drugs have been implicated in causing neutropenia, including chemotherapy, NSAIDs, carbamazepine, phenytoin, propylthiouracil, cephalosporins, trimethoprim-sulfamethoxazole, and psychotropics. Drug-induced neutropenia can be dose dependent or idiosyncratic. In mild, dose-dependent neutropenia, the offending drug may be continued if clinically indicated.
Isolated neutropenia can occur with various autoimmune disorders, such as systemic lupus erythematosus. The neutropenia is usually mild, is rarely clinically significant, and improves with treatment of the underlying autoimmune disorder with immunosuppression. The triad of neutropenia, splenomegaly, and rheumatoid arthritis is called Felty syndrome; the neutropenia can be severe, and patients can have significant infections. Treatment of the underlying rheumatoid arthritis can alleviate the neutropenia, but granulocyte colony-stimulating factor is needed in some patients. Large granular lymphocyte leukemia can also be associated with clinical features of Felty syndrome.
The myelodysplastic syndromes (MDSs) are clonal stem cell disorders with ineffective hematopoiesis leading to dysplastic, hypercellular bone marrow and peripheral blood cytopenias. MDS carries a varied risk of transformation to acute myeloid leukemia (AML) that correlates with prognosis. Most MDS is idiopathic, but secondary MDS can result from chemotherapy, radiation, chemical exposure (benzene), and other factors. Other reversible causes of dysplasia that must be ruled out include vitamin B12, folate, and copper deficiency; alcohol consumption; medications; and infections (such as HIV).
Macrocytic anemia is the most common cytopenia observed in MDS. The peripheral blood smear shows dysplastic cells (such as hypogranular neutrophils and platelets). These blood cells do not function well and increase the risk of infection and bleeding. MDS can have a varied presentation with numerous cell lines involved. The World Health Organization classification of MDS and its features are listed in Table 3. MDS is suspected in patients with otherwise unexplained cytopenias, especially with dysplastic findings on peripheral blood smear (Figure 1). Bone marrow biopsy is required for diagnosis. The prognosis for patients with MDS depends on bone marrow blasts, degree of cytopenias, and cytogenetics. Patients with few blasts in the bone marrow, reasonable peripheral blood cell counts, and a favorable cytogenetic profile have a median survival of almost 9 years, whereas those with greater than 10% blasts, severe pancytopenia (hemoglobin <8 g/dL [80 g/L], platelet count <50,000/µL [50 × 109/L], absolute neutrophil count <800/µL [0.8 × 109/L]), and adverse cytogenetic mutations survive less than 1 year.
Older adult patients who are asymptomatic and have mild cytopenias and features of MDS can be monitored without detailed evaluation. Allogeneic hematopoietic stem cell transplantation is the only potentially curative option available. Transplantation is not an option for most patients with MDS because most are older and are usually not candidates for intensive treatment.
The two main goals of treatment of MDS are treatment of symptomatic cytopenias and reducing the risk of progression to AML. Symptomatic anemia is treated with transfusions and erythropoiesis-stimulating agents. Patients with MDS who are at high risk have approximately a 25% risk of conversion to AML in the first year. Treatment of these patients with hypomethylating agents, such as azacytidine and decitabine, has been shown to decrease transfusion dependence and the risk of conversion to AML. A group of patients with low-risk MDS with the −5q cytogenetic abnormality could be treated with the immunomodulatory drug lenalidomide if they are transfusion dependent. Lenalidomide has been approved for this indication and is effective in decreasing transfusion requirements.
Chronic myelomonocytic leukemia has traditionally been considered a subset of MDS but is now classified as a separate entity, sharing some features of MDS with those of myeloproliferative neoplasms. Patients with chronic myelomonocytic leukemia have persistent monocytosis, often with other cytopenias; bone marrow shows dysplastic changes and less than 20% blasts. Prognosis and treatment is analogous to MDS with poor prognosis.
Myeloproliferative neoplasms (MPNs) are clonal stem cell disorders characterized by proliferation of the components of the myeloid, erythroid, or megakaryocyte lineage. They are named based on the dominant cell line affected; for example, erythrocytes are increased in polycythemia, and platelets are increased in essential thrombocythemia. Overlap is considerable among these disorders, and multiple cell lines are usually elevated. A disease-defining genetic chromosomal translocation is seen in chronic myeloid leukemia (CML). Another commonly found mutation involving JAK2 V617 is associated with polycythemia vera, essential thrombocythemia, myelofibrosis, and other myeloid disorders. Based on the type of MPN, patients are at varied risk of hepatosplenomegaly, thrombosis, and conversion to myelofibrosis or acute myeloid leukemia (AML).
CML is a clonal hematopoietic stem cell disorder characterized by translocation of the long arm of chromosomes 9 and 22 [t(9;22), Philadelphia chromosome] leading to a BCR-ABL fusion gene. This gene codes for an abnormal activated tyrosine kinase that promotes dysregulated cell proliferation. At diagnosis, patients with CML can be asymptomatic, with elevated neutrophil counts found on routine laboratory studies, or they can have symptoms such as fatigue, weight loss, abdominal fullness (splenomegaly), and bleeding. CML must be distinguished from a leukemoid reaction, characterized by significant elevation of the neutrophil count with left shift, increased band forms, and, at times, metamyelocytes, seen in acutely ill patients and those with infections such as Clostridium difficile. The clinical setting usually allows leukemoid reaction to be distinguished from CML, but in difficult presentations, chromosomal evaluation can help make the diagnosis.
CML has three phases of progression: the chronic phase, the accelerated phase, and blast crisis. The chronic phase is an indolent phase and responds well to therapy. Most patients with CML present in the chronic phase. Accelerated and blast crisis phases denote more aggressive disease that is less responsive to treatment. Blast crisis is considered to be secondary AML.
In CML, peripheral blood neutrophilia along with immature myeloid forms, such as myelocytes and metamyelocytes, are seen (Figure 2). In the chronic phase, fewer than 10% of blasts are present in circulation. Peripheral eosinophilia, basophilia, and thrombocytosis can also be seen. CML can be diagnosed by identifying the Philadelphia chromosome (either the fusion gene, t(9:22), or gene transcript, BCR-ABL) in a peripheral blood sample using fluorescence in situ hybridization or reverse transcriptase polymerase chain reaction, respectively.
Therapy is required at diagnosis in all patients to treat symptoms and to prevent progression to blast phase and subsequent AML. Tyrosine kinase inhibitors (TKIs) are highly effective and are the treatment of choice for patients with chronic phase CML. Three TKIs, imatinib, dasatinib, and nilotinib, are FDA approved for the initial treatment of CML. TKIs bind to the BCR-ABL oncoprotein and prevent downstream signaling. Development of these TKIs has revolutionized the treatment of CML, with improved survival, and has significantly decreased the need for stem cell transplantation. Although TKIs are relatively well tolerated, they have unique adverse effects, such as fluid retention and QTc prolongation, requiring close monitoring. They also have significant drug-drug interactions that necessitate caution when starting new medications. TKIs are contraindicated during pregnancy, so either close monitoring of patients off treatment or a switch to interferon is indicated. In patients receiving TKI therapy in whom CML progresses, medication adherence or novel mutation development should be considered. Novel TKIs (bosutinib and ponatinib) are available for refractory CML. For patients with accelerated or blast phase CML, allogeneic hematopoietic stem cell transplantation is considered.
Polycythemia vera (PV) is a clonal myeloid stem cell neoplasm characterized by excess erythrocyte mass. This increase in erythrocyte mass is independent of erythropoietin level. Thrombocytosis and neutrophilia are commonly seen, justifying the term polycythemia, in addition to the increased erythrocyte mass. Activating mutation of the JAK2 (JAK2 V617F) gene is observed in 97% of patients with PV. Most patients with PV are identified by an elevated hemoglobin level (>16.5 g/dL [165 g/L] in men or >16 g/dL [160 g/L] in women) on routine blood testing. Some patients present with symptoms such as fatigue, headache, erythromelalgia (redness and paresthesias of the extremities), pruritus, uncontrolled hypertension, and thrombosis.
Secondary erythrocytosis is much more common than PV. Refer to Table 4 for common causes of secondary erythrocytosis and its clinical features. In most cases of secondary erythrocytosis, the increase in erythrocyte mass depends on the erythropoietin level. Relative polycythemia is seen in patients who have a relative decrease in plasma volume from dehydration with a normal erythrocyte mass leading to elevated hemoglobin levels.
Evaluation of a patient with PV starts with a careful history and physical examination, looking for secondary causes of polycythemia. Smoking history, occupational exposures, and use of medications should be explored. Polycythemia is a common adverse effect of testosterone supplementation, and evaluating the hematocrit level at initiation, 3 to 6 months after testosterone initiation, and annually thereafter is recommended by Endocrine Society guidelines. Guidelines also recommend interrupting the testosterone supplementation if the hematocrit value is greater than 54%. Splenomegaly is a common finding in PV. Patients with PV often have elevated leukocyte and platelet counts along with erythrocytosis. All patients suspected of having PV should undergo a complete blood count, serum erythropoietin level evaluation, and JAK2 mutation testing. To evaluate for hypoxia, pulse oximetry should be performed. Sleep apnea can be associated with secondary polycythemia but might not be apparent, so careful assessment for signs and symptoms of sleep apnea is important; in patients at high risk, a sleep study may be necessary to evaluate for sleep apnea. Underlying causes of secondary erythrocytosis should be managed; phlebotomy decisions are more complex in these patients because the elevated hemoglobin level may be an appropriate physiologic response.
Finding a low serum erythropoietin level and JAK2 positivity in a patient with an elevated hemoglobin level is usually diagnostic of PV.
Thrombosis is a major complication in patients with untreated PV. Whole blood viscosity is increased, with increased risk of arterial thrombosis (stroke and myocardial infarction) and venous thrombosis. JAK2 mutation has also been implicated in thrombotic risk. Other hematologic complications in PV include progression to post-PV myelofibrosis and transformation to AML. Prognosis after transformation is poor.
Treatment of PV is required at diagnosis. Phlebotomy with a goal hematocrit level of less than 45% has been shown to decrease the risk of thrombosis and is applied to all patients with PV. Phlebotomy keeps the hematocrit level under control by causing iron deficiency, so iron supplementation should not be given. Low-dose aspirin is considered in all patients with PV to decrease the risk of thrombosis. Hydroxyurea is used in patients with a high risk of thrombosis, such as those older than 60 years and those with a history of thrombosis. The JAK1/2 inhibitor ruxolitinib is approved for treatment of patients who are intolerant of hydroxyurea or for refractory PV.
Essential thrombocythemia (ET) is suspected in patients with sustained elevation of platelet counts greater than 450,000/µL (450 × 109/L). Diagnosis of ET requires ruling out other MPNs such as CML, PV, primary myelofibrosis, and myelodysplastic syndromes. JAK2 mutation is present in about 50% of patients with ET. Other clonal mutations in ET have been identified involving the calreticulin and MPL genes. In patients without these clonal mutations, diagnosis of ET requires ruling out reactive thrombocytosis. Iron deficiency anemia is a common cause for reactive thrombocytosis. Other common causes of secondary thrombocytosis are infection, inflammation, and splenectomy.
Most patients with ET are asymptomatic and present with an elevated platelet count found on routine laboratory testing. Patients can present with vasomotor symptoms such as headache, visual disturbances, dysesthesia of the palms and soles, syncope, and livedo reticularis. Other complications of ET include thrombosis and hemorrhage. Thrombosis can be venous or arterial, manifesting as a cerebrovascular accident, transient ischemic attack, digital ischemia, vision loss, or myocardial infarction. Hemorrhage in ET is commonly seen in patients with a platelet count greater than 1.5 million/µL (1500 × 109/L) or use of high-dose aspirin. Extreme thrombocytosis is thought to increase bleeding risk by causing acquired von Willebrand disease.
Patients with ET might not require immediate platelet-lowering therapy at diagnosis. The most important factors in defining high risk for thrombosis and the need for preventive therapy are age older than 60 years or history of thrombosis. Patients with platelet counts greater than 1,000,000/µL (1000 × 109/L) are at risk for bleeding and should also be treated with hydroxyurea to lower the platelet count. Other therapies for patients who do not respond to hydroxyurea or who experience significant adverse effects include anagrelide and interferon-α. Low-dose aspirin is considered in all patients at high risk and in patients at low risk who have vasomotor symptoms. Primary care providers should be alert to the value of identifying asymptomatic thrombocytosis that may be discovered incidentally as part of a complete blood count, of ruling out a secondary cause of thrombocytosis, and, in patients with ET who are older than 60 years, of starting hydroxyurea to prevent complications. ET is less likely than other MPNs to progress to AML or myelofibrosis.
Primary myelofibrosis (PMF) carries the worst prognosis of the MPNs. It is a clonal myeloid stem cell disorder with characteristic marrow fibrosis and extramedullary hematopoiesis. This increased fibrosis is thought to be related to proliferation of clonal megakaryocytes, which secrete excess fibroblast growth factor. Hematopoietic progenitors are increased in the circulation, providing a leukoerythroblastic picture seen on peripheral blood smear (Figure 3). A leukoerythroblastic smear can also be seen in other myelophthisic disorders, such as bone involvement with carcinoma. As in ET, JAK2 mutation test results are positive in about 50% of patients with PMF.
Most patients with PMF have significant symptoms at presentation. Cytokine-related hypercatabolic symptoms, such as fatigue, weight loss, fever, and chills, are prominent. Massive splenomegaly is common from extramedullary hematopoiesis and portal hypertension, and it is often accompanied by abdominal discomfort and early satiety. Extramedullary hematopoiesis in the gastrointestinal tract, varices from portal hypertension, and thrombocytopenia can lead to gastrointestinal bleeding. Although patients with PMF present with significant symptoms, some patients can present with more indolent disease.
Diagnosis of PMF requires bone marrow biopsy to document fibrosis in the marrow and to exclude other causes. Biopsy is usually a dry tap with no aspirate because the bone marrow is fibrotic. The Dynamic International Prognostic Scoring System has been developed using various clinical and pathological variables to stratify patients into risk categories. Patients in each risk group have significantly different prognoses; for example, patients in the low-risk group have a median survival of 185 months compared with 16 months in the high-risk group. Treatment of PMF depends on symptoms, risk of disease progression, and survival. The only treatment with potential for cure is allogeneic hematopoietic stem cell transplantation. This type of transplantation is considered in patients who have an HLA-matched donor and who are healthy enough to survive the procedure and have poor prognostic features, including older age, constitutional symptoms, more severe anemia and thrombocytopenia, and increased numbers of blasts in the marrow.
Ruxolitinib has been shown to help improve hypercatabolic symptoms and splenomegaly, with activity independent of JAK2 mutational status. It does not alter progression to AML. Ruxolitinib is reserved for treatment in patients with debilitating symptoms who are not candidates for hematopoietic stem cell transplantation. Hydroxyurea may be used for patients with low-risk PMF. Splenectomy is only performed in patients with debilitating symptoms related to massive spleen size because it can result in significant morbidity and mortality in PMF.
Mild eosinophilia with an eosinophil count of 500 to 1500/µL (0.5-1.5 × 109/L) is not commonly associated with end-organ damage. The causes for eosinophilia, recalled with the mnemonic CHINA (Table 5), can be varied. A common cause of eosinophilia, helminth infection should be considered in all patients. Strongyloidiasis can cause eosinophilia and is endemic in the southeastern United States. Eosinophilia may be the only manifestation of this disease, and affected patients can develop disseminated disease if glucocorticoids are mistakenly given to treat hypereosinophilic syndrome (HES).
HES is characterized by sustained eosinophil counts greater than 1500/µL (1.5 × 109/L) and associated end-organ damage attributed to eosinophilia, typically affecting the skin, lungs, heart, gastrointestinal tract, and brain, regardless of causes attributable to eosinophilia. The hypereosinophilic syndrome may be seen in patients with secondary eosinophilia or in those with a primary MPN.
Primary (neoplastic) hypereosinophilic syndrome is an MPN with eosinophilia commonly associated with activation of tyrosine kinase platelet-derived growth factor receptor α or β. Other neoplasms, such as MPNs, AML, lymphomas, and solid tumors, can also manifest with eosinophilia. Treatment of underlying conditions can alleviate eosinophilia. Glucocorticoids are used for treatment of idiopathic HES. In patients with platelet-derived growth factor receptor mutation, imatinib has been shown to be effective.
Acute leukemia is a hematologic malignancy characterized by infiltration of the bone marrow, blood, and other tissues by uncontrolled proliferation and abnormal delayed differentiation of clonal myeloid or lymphoid precursor cells, exceeding 20% of the bone marrow or blood. In adults, acute myeloid leukemia (AML) is more common than acute lymphoblastic leukemia (ALL).
AML typically manifests with anemia, thrombocytopenia, or functional neutropenia secondary to bone marrow replacement with abnormal myeloblasts. Petechiae, epistaxis, and other mucosal hemorrhages occur when the platelet count dips below 20,000/µL (20 × 109/L). Symptoms of anemia vary more with patient's age and comorbidities. Although the leukocyte count is typically elevated, the absolute neutrophil count tends to be low, which confers an increased risk of infection. Myeloblasts are usually seen in the peripheral blood smear but may be absent despite unequivocal bone marrow infiltration. AML is curable in 35% to 40% of adult patients 60 years of age or younger, but the cure rate decreases to just 5% to 15% in adults older than 60 years, when comorbidities, such as cardiopulmonary disease, also preclude the use of intensive chemotherapy.
Cytogenetic and molecular classification of AML has gained increasing importance in recent years. Acute promyelocytic leukemia, characterized by poorly differentiated leukocytes with distinctive primary granules that contribute to coagulopathy (Figure 4) and chromosomal translocation t(15;17), was an earlier prototype for targeted therapy in hematologic malignancies because many patients achieved, and continue to achieve, cure with all-trans retinoic acid, which targets the underlying defect in cell differentiation. A growing number of molecular markers are used to guide therapy. NPM1-mutated AML is found in about half of patients and appears overtly normal cytogenetically; it is associated with a favorable outcome. In contrast, FLT3-ITD identification (found in approximately one third of patients with cytogenetically normal AML) is associated with an unfavorable outcome and merits consideration for allogeneic transplantation in first remission.
The treatment of AML consists of induction therapy with an anthracycline (such as daunorubicin) and infusional cytarabine. The goal is to ablate the bone marrow, eliminating the blasts, although this transiently destroys the normal hematopoietic cells as well. Cells are expected to recover after a period of aplasia, which extends for 3 to 4 weeks, during which time the patient is supported by transfusions (erythrocytes and platelets) and prompt antibiotic treatment of neutropenic fever. A complete response is achieved in 60% to 85% of patients younger than 60 years. Consolidation therapy for responders consists of additional cycles of conventional chemotherapy in patients at low risk and allogeneic hematopoietic stem cell transplantation for patients at high risk. Treatment for older or frail patients is unsatisfactory; symptom management may include blood and platelet transfusions along with lower dose, often single-agent chemotherapy, such as oral hydroxyurea, low-dose cytarabine, and the hypomethylating agents decitabine and azacitidine. These patients are expected to survive only months. Hospice care should also be considered.
ALL is more common in children and adolescents than in adults. Although ALL in children is often curable, survival in adult patients (older than 19 years) remains inferior despite the adoption of pediatric ALL regimens. Patients with ALL present with malaise, bleeding, infections, bone pain, or a combination of these symptoms, with a small subset (<10%) having symptomatic central nervous system involvement at diagnosis. In adults, 75% of ALL is of B-cell lineage; mature B-cell ALL can present as extramedullary disease, including gastrointestinal or testicular involvement. A mediastinal mass with wheezing and stridor or skin involvement can be the presenting features of T-cell ALL. Similar to AML, ALL is classified by immunophenotype, cytogenetics, and molecular abnormalities. The most important cytogenetic abnormality in adult ALL is the Philadelphia chromosome, found in 20% to 30% of patients. Historically, Philadelphia chromosome–positive ALL had a poor prognosis. In the modern era, the use of tyrosine kinase inhibitors, such as imatinib and dasatinib, along with more traditional chemotherapy has dramatically improved remission rates. After remission induction, patients with Philadelphia chromosome–positive ALL should receive additional intensive consolidation, such as autologous or allogeneic hematopoietic stem cell transplantation.
Treatment regimens are complex. Regimen backbones include vincristine, anthracycline, corticosteroids, and L-asparaginase. Some of these agents have unique toxicities such as allergic reactions, hypofibrinogenemia and hypertriglyceridemia with L-asparaginase. Induction therapy is followed by intensification and consolidation. Unlike in AML, central nervous system prophylaxis is essential during ALL therapy, and a maintenance phase of oral mercaptopurine (daily) and methotrexate (weekly) can extend up to 2 years. Medication adherence can be problematic during the maintenance phase.
Adult survivors of childhood leukemia face higher risks of secondary cancer, cardiovascular disease, and the metabolic syndrome (high BMI, truncal obesity, dyslipidemia, insulin resistance, and hypertension) compared with age-matched controls. Primary care physicians encountering such patients should request a treatment summary from the treating facility and encourage patient participation in a local survivor clinic. Screening for lipid profile, diabetes, and hypertension is recommended. Echocardiography to screen for left ventricular dysfunction should be performed at intervals of 3 to 5 years, particularly if anthracycline exposure was high (such as doxorubicin exceeding 300 mg/m2) or if chest radiation was used. Female survivors have a higher risk of myocardial dysfunction during pregnancy. High-dose glucocorticoids, typical of ALL regimens, pose a risk for osteopenia. The cumulative incidence of secondary cancer after radiation therapy for childhood ALL reaches 11% at 30 years; tumors include skin cancer, thyroid and parotid tumors, sarcomas, and brain tumors. Cranial radiation also increases the risk for stroke and neurocognitive defects. Patients should be counseled about lifestyle risk factors, age-based screening, and early reporting of persistent symptoms.
Erythropoiesis-stimulating agents (which include erythropoietin and darbepoetin) are primarily used in patients with anemia and chronic kidney disease; for patients receiving dialysis, the target hemoglobin level should be no greater than 12 g/dL (120 g/L) to avoid adverse cardiovascular outcomes. Granulocyte colony-stimulating factors (with various formulations) are used to prevent febrile neutropenia in patients receiving myelosuppressive chemotherapy who are at high risk of febrile neutropenia, such as those receiving intensive chemotherapy for high-risk breast cancer and those aged 65 or older with diffuse aggressive lymphoma being treated with curative chemotherapy. Granulocyte colony-stimulating factor is not indicated for most patients with neutropenia who are afebrile, as a routine adjunct to empiric antibiotics for patients presenting with febrile neutropenia, or for patients undergoing induction chemotherapy for acute leukemia.
Autologous hematopoietic stem cell transplantation is performed in select patients who have multiple myeloma or relapsed aggressive lymphoma. Allogeneic transplantation is indicated in patients at high risk with acute leukemia and for the graft-versus-leukemia effect. Allogeneic transplantation is also used to treat patients with aplastic anemia and select patients with hemoglobinopathies such as sickle cell anemia. The allogeneic donor is typically an HLA-matched sibling or unrelated adult donor; the risk of graft-versus-host disease, which includes skin, gastrointestinal, and liver manifestations, increases with the degree of donor-recipient HLA disparity. Better supportive measures and reduced-intensity regimens have provided transplant eligibility to older adults. Although hematopoietic stem cell transplantation carries a significant risk of transplant-related mortality, survivors continue to have long-term morbidities unrelated to relapse, such as susceptibility to bacterial or viral infections and delayed pulmonary toxicity. Internists caring for patients who have undergone transplantation should evaluate patients early for symptoms suggesting infection and follow recommended immunization schedules that take into account the prolonged immunosuppressed state of these patients (see MKSAP 18 General Internal Medicine).