Practice EssentialsAcute lymphoblastic leukemia (ALL) is a malignant (clonal) disease of the bone marrow in which early lymphoid precursors proliferate and replace the normal hematopoietic cells of the marrow. ALL is the most common type of cancer and leukemia in children in the United States. The image below shows preB-cell ALL.Diagnostic workup of a patient with preB-cell acute lymphoblastic leukemia. Bone marrow aspiration revealed French-American-British L2 morphology. Essential update: FDA approves first of new class of drugs for relapsed or refractory B-cellderived ALLThe FDA has approved blinatumomab (Blincyto) for the treatment of patients with Philadelphia chromosomenegative precursor B-cell ALL that has relapsed or is refractory to other treatment. Blinatumomab is the first of a novel class of drugs known as bispecific T-cell engagers; it is designed to promote cancer cell lysis by simultaneously binding with CD3 on cytotoxic T-cells and with CD19, which is expressed on the surface of B-cellderived ALL (and also non-Hodgkin lymphomas).[1, 2] Approval was based on a study of 185 adult patients in which 32% experienced complete remission for approximately 6.7 months after at least 4 weeks of infusion treatment. Labeling includes a boxed warning on a risk of low blood pressure and difficulty breathing as a result of cytokine-release syndrome when treatment is initiated. Cases of encephalopathy and other central nervous system adverse events were also observed in the pre-approval study. A postmarketing study will be conducted to verify that blinatumomab improves survival.[1, 2] Signs and symptomsSigns and symptoms of ALL include the following: Fever Decreased neutrophil count Signs and symptoms of anemia, such as pallor, fatigue, dizziness, palpitations, cardiac flow murmur, and dyspnea with even mild exertion Bleeding (eg, from thrombocytopenia due to marrow replacement) Disseminated intravascular coagulation (DIC) at diagnosis (about 10% of cases) Palpable lymphadenopathy Symptoms related to a large mediastinal mass (eg, shortness of breath), particularly with T-cell ALL Bone pain (severe and often atypical) Left upper quadrant fullness and early satiety due to splenomegaly (about 10-20% of cases) Symptoms of leukostasis (eg, respiratory distress, altered mental status) Renal failure in patients with a high tumor burden Infections, including pneumonia Petechiae (particularly on lower extremities) and ecchymoses Signs relating to organ infiltration with leukemic cells and lymphadenopathy Rashes from skin infiltration with leukemic cellsSee Clinical Presentation for more detail.DiagnosisLaboratory tests and other studies used in the workup for ALL include the following: Complete blood count with differential Coagulation studies Peripheral blood smear Chemistry profile, including lactic dehydrogenase, uric acid, liver function studies, and BUN/creatinine Appropriate cultures (in particular, blood cultures) in patients with fever or other signs of infection Chest x-ray Computed tomography Multiple-gated acquisition scanning Electrocardiography Bone marrow aspiration and biopsy (definitive for confirming leukemia) Immunohistochemistry Flow cytometry Cytogenetics Polymerase chain reaction Gene expression profilingSee Workup for more detail.ManagementTreatment of ALL may include the following: Induction chemotherapy (eg, standard 4- or 5-drug regimen, ALL-2, or hyper-CVAD) Consolidation chemotherapy Maintenance chemotherapy Intrathecal chemotherapy for central nervous system (CNS) prophylaxis Supportive care (eg, blood products, antibiotics, growth factors)Special considerations apply to the treatment of the following: Mature B-cell ALL Ph+ ALL ALL in older children and younger adults Relapsed ALL ALL in patients with hyperuricemia or at high risk for tumor lysis syndromeSee Treatment and Medication for more detail.BackgroundAcute lymphoblastic leukemia (ALL) is a malignant (clonal) disease of the bone marrow in which early lymphoid precursors proliferate and replace the normal hematopoietic cells of the marrow. ALL may be distinguished from other malignant lymphoid disorders by the immunophenotype of the cells, which is similar to B- or T-precursor cells. Immunochemistry, cytochemistry, and cytogenetic markers may also aid in categorizing the malignant lymphoid clone. The image below shows preB-cell ALL.Diagnostic workup of a patient with preB-cell acute lymphoblastic leukemia. Bone marrow aspiration revealed French-American-British L2 morphology. See also Pediatric Acute Lymphoblastic Leukemia and Acute Myelogenous Leukemia.PathophysiologyThe malignant cells of acute lymphoblastic leukemia (ALL) are lymphoid precursor cells (ie, lymphoblasts) that are arrested in an early stage of development. This arrest is caused by an abnormal expression of genes, often as a result of chromosomal translocations. The lymphoblasts replace the normal marrow elements, resulting in a marked decrease in the production of normal blood cells. Consequently, anemia, thrombocytopenia, and neutropenia occur to varying degrees. The lymphoblasts also proliferate in organs other than the marrow, particularly the liver, spleen, and lymph nodes.Etiology Less is known about the etiology of acute lymphoblastic leukemia (ALL) in adults compared with acute myelogenous leukemia (AML). Most adults with ALL have no identifiable risk factors. Although most leukemias occurring after exposure to radiation are AML rather than ALL, an increased prevalence of ALL was noted in survivors of the Hiroshima atomic bomb but not in those who survived the Nagasaki atomic bomb. Rare patients have an antecedent hematologic disorder (AHD) such as myelodysplastic syndrome (MDS) that evolves to ALL. However, most patients with MDS that evolves to acute leukemia develop AML rather than ALL.Increasingly, cases of ALL with abnormalities of chromosome band 11q23 following treatment with topoisomerase II inhibitors for another malignancy have been described. However, most patients who develop secondary acute leukemia after chemotherapy for another cancer develop AML rather than ALL. EpidemiologyAcute lymphoblastic leukemia (ALL) is the most common type of cancer and leukemia in children in the United States. ALL accounts for 26% of all cancers in children up to 14 years of age, and for 75% of pediatric leukemia cases.[3] In adults, this disease is less common than acute myelogenous leukemia (AML). Approximately 1000 new cases of ALL occur in adults each year. However, due to the fact that there are more adults than children, the number of cases seen in adults is comparable to that seen in children. ALL is slightly more common in males than in females. Worldwide, the highest incidence of ALL occurs in Italy, the United States, Switzerland, and Costa Rica.Prognosis Only 20-40% of adults with acute lymphoblastic leukemia (ALL) are cured with current treatment regimens.Patients with ALL are divided into three prognostic groups: good risk, intermediate risk, and poor risk.Good risk criteria include the following: No adverse cytogenetics Age younger than 30 years White blood cell (WBC) count of less than 30,000/L Complete remission within 4 weeksIntermediate risk includes those whose condition does not meet the criteria for either good risk or poor risk.Poor risk criteria include the following: Adverse cytogenetics Translocations t(9;22), t(4;11) Age older than 60 years Precursor B-cell WBCs with WBC count greater than 100,000/L Failure to achieve complete remission within 4 weeksPatients with precursor B-cell ALL have an extremely poor prognosis. Essentially, following standard chemotherapy or autologous transplantation, long-term survival is not achieved. Several reports have indicated that some patients with precursor B-cell ALL and t(4;11) may have prolonged survival following allogeneic transplantation; therefore, this is the treatment of choice. Immunophenotype effects on prognosisCzuczman et al studied 259 patients treated with several Cancer and Leukemia Group B (CALGB) protocols for newly diagnosed ALL and found no significant difference in response rates, remission duration, or survival for patients expressing myeloid antigens versus those not expressing myeloid antigens.[4] B-lineage phenotype was expressed in 79% of patients; one third of these coexpressed myeloid antigens. Seventeen percent of patients demonstrated T-lineage ALL; one quarter of these coexpressed myeloid antigens.[4] T-lineage ALL was associated with younger age, male sex, presence of a mediastinal mass, higher WBC count and hemoglobin level, longer survival, and longer disease-free survival. The number of T markers expressed also had prognostic significance. Patients expressing six or more markers had longer disease-free and overall survival compared with patients expressing three or fewer markers. In a report by Preti et al, 64 of 162 patients with newly diagnosed ALL coexpressed myeloid markers.[5] Patients coexpressing myeloid markers were significantly older, had a higher prevalence of CD34 expression, and had a lower prevalence of common ALL antigen expression than patients without myeloid expression. A trend toward a decreased remission rate was observed for patients coexpressing myeloid markers (64%) relative to those who did not coexpress such markers (78%).[5] However, no significant effect on remission duration or overall survival was observed. Chromosome number and prognosisThe effect of chromosome number on prognosis is displayed in Table 1, below.Table 1. Effect of Chromosome Number on Prognosis (Open Table in a new window)Chromosome Number3-Year Event-Free Survival

Near tetraploidy46-56%

Normal karyotype34-44%

Hyperdiploidy >5032-59%

Hyperdiploidy 47-5021-53%

Pseudodiploidy12-25%

Hypodiploidy11%

Complications and prognosisA study by Ness et al found neuromuscular impairments were prevalent in survivors of childhood ALL and these impairments interfered with physical performance.[6] Increased cumulative doses of intrathecal methotrexate and/or vincristine were associated with long-term neuromuscular impairments, and these have implications on future function with age.The most common complication is failure of the leukemia to respond to chemotherapy. These patients do poorly, because they usually do not respond to other chemotherapy regimens.Death in those with ALL may occur as a result of uncontrolled infection or hemorrhage. This may occur even after the use of appropriate blood product and antibiotic support. Patient Education Patients with acute lymphoblastic leukemia (ALL) should be instructed to immediately seek medical attention if they are febrile or have signs of bleeding. Furthermore, while receiving chemotherapy, patients with leukemia should avoid exposure to crowds and people with contagious illnesses, especially children with viral infections. Although activity may occur as tolerated, patients with ALL may not participate in strenuous activities such as lifting or exercise. In addition, a neutropenic diet is recommended in these individuals, as follows: No fresh fruits or vegetables may be eaten All foods must be cooked Meats are to be cooked until well doneFor patient education information, see Blood and Lymphatic System Center and Cancer and Tumors Center, as well as Leukemia.HistoryPatients with acute lymphoblastic leukemia (ALL) present with either symptoms relating to direct infiltration of the marrow or other organs by leukemic cells, or symptoms relating to the decreased production of normal marrow elements. Fever is one of the most common symptoms of ALL, and patients with ALL often have fever without any other evidence of infection. However, in these patients, one must assume that all fevers are from infections until proved otherwise, because a failure to treat infections promptly and aggressively can be fatal. Infections are still the most common cause of death in patients undergoing treatment for ALL. Patients with ALL often have decreased neutrophil counts, regardless of whether their total white blood cell (WBC) count is low, normal, or elevated. As a result, these individuals are at an increased risk of infection. The prevalence and severity of infections are inversely correlated with the absolute neutrophil count (ANC), which is defined as the number of mature neutrophils plus bands per unit of volume. Infections are common when the absolute neutrophil count is less than 500/L, and they are especially severe when it is less than 100/L. See the Absolute Neutrophil Count calculator. Symptoms of anemia are common and include fatigue, dizziness, palpitations, and dyspnea upon even mild exertion. Other patients present with signs of bleeding. Bleeding can be the result of thrombocytopenia due to marrow replacement. Additionally, approximately 10% of patients with ALL have disseminated intravascular coagulation (DIC) at the time of diagnosis. These patients may present with hemorrhagic or thrombotic complications. Some patients present with palpable lymphadenopathy. Others, particularly those with T-cell ALL, present with symptoms related to a large mediastinal mass, such as shortness of breath. Infiltration of the marrow by massive numbers of leukemic cells frequently manifests as bone pain. This pain can be severe and is often atypical in distribution. About 10-20% of ALL patients may present with left upper quadrant fullness and early satiety due to splenomegaly.Although patients may present with symptoms of leukostasis (eg, respiratory distress, altered mental status) because of the presence of large numbers of lymphoblasts in the peripheral circulation, leukostasis is much less common in people with ALL than those with acute myelogenous leukemia (AML), and it occurs only in patients with the highest WBC counts (ie, several hundred thousand per L). Patients with a high tumor burden, particularly those with severe hyperuricemia, can present in renal failure.Physical ExaminationPatients with acute lymphoblastic leukemia (ALL) commonly have physical signs of anemia, including pallor and a cardiac flow murmur. Fever and other signs of infection, including lung findings of pneumonia, can also occur. Fever should be interpreted as evidence of infection, even in the absence of other signs. Patients with thrombocytopenia usually demonstrate petechiae, particularly on the lower extremities. A large number of ecchymoses is usually an indicator of a coexistent coagulation disorder such as disseminated intravascular coagulation (DIC). Signs relating to organ infiltration with leukemic cells and, to a lesser degree, lymphadenopathy may be present.Occasionally, patients have rashes that result from infiltration of the skin with leukemic cells.Other conditions that should be considered in the evaluation of suspected acute ALL include acute biphenotypic leukemia and natural killer (NK)-cell leukemia. Differential Diagnoses Acute Myelogenous Leukemia Lymphoma, B-Cell Lymphoma, High-Grade Malignant Immunoblastic Lymphoma, Mantle Cell Lymphoma, Non-HodgkinApproach ConsiderationsThe following studies and procedures are used in the workup for acute lymphoblastic leukemia (ALL): Complete blood count (CBC) with peripheral smear Coagulation studies Chemistry profile, including liver and renal function studies Bone marrow aspiration and biopsy Definitive diagnostic tests Cultures, in particular blood cultures Chest radiography Chest computed tomography (CT) scan Multiple-gated acquisition (MUGA) scan or electrocardiogram (ECG)National Comprehensive Cancer Network (NCCN) guidelines note that diagnosis of ALL generally requires the following[7] : Demonstration of 20% bone marrow lymphoblasts Morphologic assessment of Wright/Giemsastained bone marrow aspirate smears Hematoxylin and eosin (H&E)stained bone marrow core biopsy and clot sections Comprehensive flow cytometric immunophenotypingFor optimal risk stratification and treatment planning in patients with ALL, the NCCN advises that bone marrow or peripheral blood lymphoblasts must be tested for specific recurrent genetic abnormalities, as follows[7] : Cytogenetics Karyotyping of G-banded metaphase chromosomes Interphase fluorescence in situ hybridization (FISH) Reverse transcriptase polymerase chain reaction (RT-PCR) for fusion genes (eg, BCR-ABL)In addition, flow cytometric DNA index/ploidy testing can be done to assess for hyperdiploidy and hypodiploidy.See also Acute Lymphoblastic Leukemia Staging.Routine Laboratory StudiesA complete blood cell (CBC) count with differential demonstrates anemia and thrombocytopenia to varying degrees in individuals with acute lymphoblastic leukemia (ALL). Patients with ALL can have a high, normal, or low white blood cell (WBC) count, but they usually exhibit neutropenia. The prevalence and severity of infections are inversely correlated with the absolute neutrophil count (ANC); infections are common when the absolute neutrophil count is less than 500/L, and they are especially severe when it is less than 100/L. See the Absolute Neutrophil Count calculator. Coagulation studies and chemistry profilesAbnormalities in the prothrombin time (PT) / activated partial thromboplastin time (aPTT) / fibrinogen / fibrin degradation products may suggest concomitant disseminated intravascular coagulation (DIC), which results in an elevated PT, decreased fibrinogen levels, and the presence of fibrin split products. A review of the peripheral blood smear confirms the findings of the CBC count. Circulating blasts are usually seen. Schistocytes are sometimes seen if DIC is present. A chemistry profile is recommended. Most patients with ALL have an elevated lactic dehydrogenase level (LDH), and they frequently have an elevated uric acid level. In addition, liver function tests and blood urea nitrogen (BUN)/creatinine determinations are necessary before the initiation of therapy. CulturesAppropriate cultures, in particular blood cultures, should be obtained in patients with fever or with other signs of infection without fever. Radiologic StudiesChest x-ray films may reveal signs of pneumonia and/or a prominent mediastinal mass in some cases of T-cell acute lymphoblastic leukemia (ALL). Computed tomography (CT) scans can further define the degree of lymphadenopathy in some patients, including those with mediastinal masses. MUGA Scanning and ElectrocardiographyMultiple-gated acquisition (MUGA) scans or electrocardiograms (ECGs) are needed when the diagnosis of acute lymphoblastic leukemia (ALL) is confirmed, because many chemotherapeutic agents used in the treatment of acute leukemia are cardiotoxic. An ECG is recommended before the initiation of treatment.Bone Marrow Aspiration and BiopsyBone marrow aspiration and biopsy are the definitive diagnostic tests to confirm the diagnosis of leukemia. Immunophenotyping helps to elucidate the subtype. Aspiration slides should be stained for morphology with either Wright or Giemsa stain. The diagnosis of acute lymphoblastic leukemia (ALL) is made when at least 30% lymphoblasts (French-American-British [FAB] classification) or 20% lymphoblasts (World Health Organization [WHO] classification) are present in the bone marrow and/or peripheral blood. In addition, slides should be stained with myeloperoxidase (MPO) (or Sudan black) and terminal deoxynucleotidyl transferase (TdT), unless another method is used, such as flow cytometry. Bone marrow samples should also be sent for flow cytometry and cytogenetics. Approximately 15% of patients with ALL have a t(9;22) translocation (ie, Philadelphia [Ph] chromosome), but other chromosomal abnormalities may also occur, such as t(4;11), t(2;8), and t(8;14). Histologic FeaturesThe older, traditional classification of acute lymphoblastic leukemia (ALL) is the French-American-British (FAB) classification. This has now been replaced by the newer World Health Organization (WHO) classification but the FAB system is listed for historical purposes, as follows: L1 Small cells with homogeneous chromatin, regular nuclear shape, small or absent nucleolus, and scanty cytoplasm; subtype represents 25-30% of adult cases L2 Large and heterogeneous cells, heterogeneous chromatin, irregular nuclear shape, and nucleolus often large; subtype represents 70% of cases (most common) L3 Large and homogeneous cells with multiple nucleoli, moderate deep blue cytoplasm, and cytoplasmic vacuolization that often overlies the nucleus (most prominent feature); subtype represents 1-2% of adult cases The WHO classifies the L1 and L2 subtypes of ALL as either precursor B lymphoblastic leukemia/lymphoblastic lymphoma (see the following image) or precursor T lymphoblastic leukemia/lymphoblastic lymphoma depending on the cell of origin. The L3 subtype of ALL is included in the group of mature B-cell neoplasms, as the subtype Burkitt lymphoma/leukemia. Diagnostic workup of a patient with preB-cell acute lymphoblastic leukemia. Bone marrow aspiration revealed French-American-British L2 morphology. ImmunohistochemistryA negative myeloperoxidase (MPO) stain and a positive and terminal deoxynucleotidyl transferase (TdT) is the hallmark of the diagnosis of most cases of acute lymphoblastic leukemia (ALL). However, positive confirmation of lymphoid (and not myeloid) lineage should be sought by flow cytometric demonstration of lymphoid antigens, such as CD3 (T-lineage ALL) or CD19 (B-lineage ALL), in order to avoid confusion with some types of myeloid leukemia (eg, M0), which also stain negative with myeloperoxidase. Flow Cytometry and CytogeneticsAlthough more than 95% of cases of the L1 or L2 subtype of acute lymphoblastic leukemia (ALL) are positive for Terminal deoxynucleotidyl transferase (TdT), TdT is not specific for ALL; TdT is absent in L3 (mature B-cell) ALL. However, TdT helps to distinguish ALL from malignancies of more mature lymphocytes (ie, non-Hodgkin lymphoma [NHL]). In cases of acute leukemia that are myeloperoxidase (MPO) negative and TdT positive, the distinction between acute myelogenous leukemia (AML) and ALL is made on the basis of flow cytometry results. Patients with AML demonstrate myeloid markers such as CD33, whereas patients with ALL demonstrate lymphoid markers. Further confusion arises because some patients with ALL have aberrant expression of myeloid markers, such as CD13. However, if the cells are TdT positive, MPO negative, CD33 negative, and demonstrate lymphoid markers, the leukemia is considered ALL. See an example of a flow cytometry study below. Diagnostic workup of a patient with preB-cell acute lymphoblastic leukemia. Flow cytometry shows that the cells were positive for CD10, CD19, CD22, CD34, and terminal deoxynucleotidyl transferase. Cytogenetic abnormalities occur in approximately 70% of cases of ALL in adults (see Table 2, below). These abnormalities include balanced translocations as occur in cases of AML. However, abnormalities of chromosome number (hypodiploidy, hyperdiploidy) are more common in ALL than in AML. Table 2. Common Cytogenetic Abnormalities in ALL (Open Table in a new window)AbnormalityGenes Involved3-Year Event-Free Survival

t(10;14)(q24;q11)HOX11/TCRA75%

6qUnknown47%

14q11TCRA/TCRD42%

11q23MLL18-26%

9pUnknown22%

12TEL20%

t(1;19)(q23;p13)PBX1/E2A20%

t(8;14)(q24;q32)

t(2;8)(p12;q24)

t(8;22)(q24;q11)

c-myc/IGH

IGK/c-myc

c-myc/IGL

17%*

80%

t(9;22)(q34;q11)bcr-abl5-10%*

66%

t(4;11)(q21;q23)AF4-MLL0-10%

* Traditional regimens.

Hyper-CVAD (cyclophosphamide, vincristine, doxorubicin [Adriamycin], dexamethasone) with rituxan.

Hyper-CVAD with imatinib.

Eighty-five percent of cases of ALL are derived from B cells. The primary distinction is among the following (see also Table 3, below): Early (pro-B) ALL, which is TDT positive, CD10 (CALLA) negative, surface immunoglobulin (Ig) negative Precursor B ALL, which is TDT positive, CD10 (CALLA) positive, surface Ig negative Mature B cell (Burkitt) ALL, which is TdT negative, surface Ig positive. Fifteen percent of these cases are derived from T cells. Table 3. Immunophenotyping of ALL Cells ALL of B-Cell Lineage (85% of cases of adult ALL) (Open Table in a new window)ALL CellsTdTCD19CD10CyIgSIg

Early B-precursor ALL++---

PreB-cell ALL ++++-

B-cell ALL-++/-+/-+

ALL = acute lymphoblastic leukemia; Cylg = Cytoplasmic immunoglobulin; SIg =Surface immunoglobulin; TdT = terminal deoxynucleotidyl transferase.

These cases are subclassified into different stages corresponding to the phases of normal thymocyte development. The early subtype is surface CD3 negative, cytoplasmic CD3 positive, and either double negative (CD4-, CD8-) or double positive (CD4+, CD8+). The latter subtype is surface CD3 positive, CD1a negative, and positive for either CD4 or CD8, but not both. See Table 4, below. Table 4. Immunophenotyping of ALL Cells ALL of T-Cell Lineage (15% of cases of adult ALL) (Open Table in a new window)ALL CellsTdTSurface CD3CD4/CD8

Early T-precursor ALL+-+/+ or -/-

T-cell ALL+++/- or -/+

Polymerase Chain Reaction or CytogenicsStudies for bcr-abl analysis by polymerase chain reaction (PCR) or cytogenetics may help distinguish patients with Philadelphia chromosomepositive acute lymphoblastic leukemia (Ph+ ALL) from those with the lymphoid blastic phase of chronic myelogenous leukemia (CML). Most patients with Ph+ ALL have the p190 type of bcr-abl, whereas patients with lymphoid blastic CML have the p210 type of bcr-abl. Gene Expression ProfilingNewer studies are analyzing ALL subtypes by gene expression profiling. In children with ALL, Bogni et al distinguished three groups of patients.[8] Interestingly, one of these groups had a significantly increased risk of developing treatment-related acute myelogenous leukemia (AML) following chemotherapy for their ALL. Approach ConsiderationsAcute lymphoblastic leukemia (ALL) is best treated by physicians who have significant experience in the treatment of patients with acute leukemia. In addition, these patients should receive treatment in a setting where appropriate supportive care measures (high-level blood banking and leukapheresis) are available. Patients admitted to hospitals that lack appropriate blood product support facilities, leukapheresis capabilities, or physicians and nurses familiar with the treatment of patients with leukemia should be transferred to an appropriate (generally, tertiary care) hospital. Traditionally, the four components of ALL treatment are induction, consolidation, maintenance, and central nervous system (CNS) prophylaxis; these are briefly reviewed in the following sections. Other aspects of treatment are also discussed. See also Acute Lymphoblastic Leukemia Treatment Protocols.Patients with ALL require hospital admission for induction chemotherapy, and they require readmission for consolidation chemotherapy or for the treatment of toxic effects of chemotherapy. Surgical intervention may be required for the placement of a central venous catheter, such as a triple lumen, Broviac, or Hickman catheter. Only 20-30% of adults with ALL are cured with standard chemotherapy regimens. Consequently, all patients must be evaluated for entry into well-designed clinical trials. If a clinical trial is not available, the patient can be treated with standard therapy. Induction ChemotherapyStandard induction therapy typically involves either a four-drug regimen of vincristine, prednisone, anthracycline, and cyclophosphamide or L -asparaginase or a five-drug regimen of vincristine, prednisone, anthracycline, cyclophosphamide, and L -asparaginase given over the course of 4-6 weeks. Using this approach, complete remissions (CRs) are obtained in 65-85% of patients.The rapidity with which a patient's disease enters CR correlates with treatment outcome. Several studies have shown that patients whose disease is in CR within 4 weeks of therapy have longer disease-free survival and overall survival than those whose disease enters remission after 4 weeks of treatment. In a large French study, patients with greater than 5% blasts in their bone marrow on day 15 had a lower response rate (34% vs 91%), worse disease-free survival, and worse overall survival than patients with low blast counts on day 15.[9] Consolidation TherapyThe use of consolidation chemotherapy in acute lymphoblastic leukemia (ALL) is supported by several studies. Fiere et al compared consolidation therapy with daunorubicin and cytosine arabinoside (Ara-C) versus no consolidation therapy in adults with ALL, demonstrating a 38% 3-year, leukemia-free survival rate for subjects receiving consolidation and maintenance therapy compared with 0% for those receiving maintenance therapy without consolidation.[10] In a study reported by Hoelzer et al, subjects whose disease was in remission after induction received consolidation therapy consisting of dexamethasone, vincristine, and doxorubicin, followed by cyclophosphamide, Ara-C, and 6-thioguanine beginning at week 20.[11] Subjects also received maintenance therapy with 6-mercaptopurine and methotrexate during weeks 10-20 and 28-130. The median remission of 20 months was among the longest reported at the time. In the United Kingdom Acute Lymphoblastic Leukemia XA study, subjects were randomized to receive early intensification with Ara-C, etoposide, thioguanine, daunorubicin, vincristine, and prednisone at 5 weeks; late intensification with the same regimen at 20 weeks; both; or neither.[12] The disease-free survival rates at 5 years were 34%, 25%, 37%, and 28%, respectively. These data suggest a benefit to early, rather than late, intensification.[12] A study by the Cancer and Leukemia Group B (CALGB) did not show a benefit to consolidation therapy. Subjects whose disease was in complete remission were randomized to receive maintenance therapy or intensification with 2 courses of Ara-C and daunorubicin followed by maintenance. Remission duration and overall survival were not affected by the randomization. Because most studies have showed a benefit to consolidation therapy, regimens using a standard 4- to 5-drug induction usually include consolidation therapy with Ara-C in combination with an anthracycline or epipodophyllotoxin. Maintenance TherapyThe effectiveness of maintenance chemotherapy in adults with acute lymphoblastic leukemia (ALL) has not been studied in a controlled clinical trial. However, several phase II studies without maintenance therapy have shown inferior results compared with historical controls. A Cancer and Leukemia Group B (CALGB) study of daunorubicin or mitoxantrone, vincristine, prednisone, and methotrexate induction followed by four intensifications and no maintenance was closed early because the median remission duration was shorter than in previous studies.[13] A Dutch study using intensive postremission chemotherapy, three courses of high-dose Ara-C in combination with amsacrine (course 1), mitoxantrone (course 2), and etoposide (course 3), without maintenance, also yielded inferior results.[14] Although maintenance appears necessary, using a more intensive versus less intensive regimen does not appear to be beneficial. Intensification of maintenance therapy from a 12-month course of a four-drug regimen compared with a 14-month course of a seven-drug regimen did not show a difference in disease-free survival between the two groups.[15] CNS ProphylaxisIn contrast to patients with acute myelogenous leukemia (AML), patients with acute lymphoblastic leukemia (ALL) frequently have meningeal leukemia at the time of relapse. A minority of patients have meningeal disease at the time of initial diagnosis. As a result, central nervous system (CNS) prophylaxis with intrathecal chemotherapy is essential. Cortes et al analyzed the prevalence of CNS leukemia in four consecutive clinical trials at the MD Anderson Cancer Center and found that that high-dose systemic chemotherapy reduces CNS relapse. However, early intrathecal chemotherapy is necessary to achieve the lowest risk of CNS relapse.[16] CNS relapse rates were 31% for group 1 (standard chemotherapy, no CNS prophylaxis), 18% for group 2 (high-dose systemic chemotherapy, no CNS prophylaxis), 17% for group 3 (high-dose systemic chemotherapy, intrathecal chemotherapy for high-risk subjects after achieving remission), and 3% for group 4 hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD).[16] All subjects received intrathecal chemotherapy starting in induction. High-risk subjects received 16 intrathecal treatments, and low-risk subjects received four intrathecal treatments. Newer Induction ApproachesStandard induction regimens are modeled after pediatric programs and were originally developed when supportive care was significantly inferior to what is available today. Few antibiotics were available, and transfusion capabilities were minimal. Consequently, milder regimens were designed in an attempt to minimize early deaths during induction. With the addition of third-generation cephalosporins and sophisticated blood-banking techniques, the ability to support patients through a pancytopenic phase has increased dramatically. As a result, more intensive induction approaches are used by many physicians. Two notable examples are the Memorial Acute Lymphoblastic Leukemia2 (ALL-2) protocol and the hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) protocol. ALL-2 protocolThe ALL-2 protocol uses an intensive, high-dose, mitoxantrone-based, acute myelogenous leukemia (AML)-style induction regimen. In a phase I study of high-dose mitoxantrone combined with high-dose cytosine arabinoside (Ara-C), Arlin et al reported that all eight patients newly diagnosed with ALL and eight of 10 patients with ALL who relapsed achieved complete remission (CR).[17] Weiss et al reported treatment of 37 subjects with newly diagnosed ALL with this induction regimen followed by a first consolidation with vincristine, prednisone, L -asparaginase, and methotrexate; a second consolidation with Ara-C and etoposide; and then 2 years of maintenance therapy.[18] Of these subjects, 84% achieved CR. The median remission duration was 17 months, and median survival was 20 months.[18] In a randomized phase III trial comparing the ALL-2 regimen with the L-20 regimen (vincristine, prednisone, cyclophosphamide and doxorubicin), the CR rate was 83% for patients receiving ALL-2 compared with 70% for patients receiving L-20.[19] Overall survival at 4 years was superior for patients receiving ALL-2 (40%) versus those receiving L-20 (22%). Hyper-CVAD regimenThe hyper-CVAD regimen is based on the success achieved with short-term, dose-intensive chemotherapy regimens in children. It incorporates hyperfractionated cyclophosphamide and intensive doses of Ara-C and methotrexate in combination with dexamethasone and vincristine. Maintenance therapy with prednisone, vincristine (Oncovin), methotrexate, and mercaptopurine (Purinethol) (ie, POMP protocol) is given to patients with nonmature B-cell ALL. From 1992-2000, 288 patients received hyper-CVAD at MD Anderson Cancer Center, which 17% of patients had the Philadelphia (Ph) chromosome, and 13% had T-cell ALL.[20] Overall, 92% of patients obtained a CR. The 5-year survival and percentage of patients in CR at 5 years were both 38%. Patients with Ph+ ALL had a 92% CR rate but only a 12% 5-year survival. Patients with T-cell ALL had a 75% CR rate and a 48% 5-year survival. Patients with Burkitt ALL had a 93% CR rate and a 67% 5-year survival.[20] Newer modifications of the hyper-CVAD regimen include the addition of imatinib to patients whose leukemia is Philadelphia chromosome positive, and rituxan to patients whose leukemia is CD20 positive. Both of these approaches have resulted in improvements in disease-free survival (see below). Treatment of Mature B-Cell ALLMature B-cell acute lymphoblastic leukemia (ALL) is a special type, representing only 5% of adult patients with ALL. The hallmark of mature B-cell ALL is the presence of surface immunoglobulin on the lymphoblasts. Using conventional regimens, only 30-40% of patients enter complete remission (CR) and few patients survive long term. Newer short-term intensive therapies show improved results. A report of the hyper-CVAD regimen showed that disease in 93% of subjects entered CR, median survival was 16 months, and disease in 67% of subjects alive at 5 years. In a report by Hoelzer et al, with the use of regimens containing intensive cyclophosphamide and intermediate methotrexate or ifosfamide and high-dose methotrexate, CR rates were 63% (cyclophosphamide + intermediate methotrexate) and 74% (ifosfamide + high-dose methotrexate).[21] Disease-free survival rates increased to 50% in the first group and 71% in the second group, and overall survival increased to 50% compared with 0% for historical controls.[21] Although previously these patients were referred for transplantation in first remission, many physicians now defer transplantation for the time of relapse because of these improved results. Burkitt ALL cells are CD20 positive. This allows for the addition of targeted therapy with rituximab. Many studies are have demonstrated improved efficacy, including prolonged survival, when rituximab is added to chemotherapy in these patients. The combination of hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) plus rituxan resulted in an overall 3-year survival of 80% compared with 50% for historical controls treated without rituxan.[22] Treatment of Ph ChromosomePositive ALLIn the past, Philadelphia chromosomepositive (Ph+) acute lymphoblastic leukemia (ALL) was treated with the same regimens as other types of ALL, with poor results. However, the tyrosine kinase inhibitor imatinib inhibits the bcr-abl fusion protein of Ph+ ALL and thus allows targeted therapy of this disease. As a single agent, imatinib has limited activity. In an early study of patients with Ph+ ALL or chronic myelogenous leukemia (CML) in lymphoid blast crisis, only 4 of 20 patients had a complete response, and all patients progressed in less than 6 months.[23] ImatinibThe German Multicenter ALL (GMALL) trial conducted a randomized study of imatinib versus standard induction therapy for patients with Ph-positive ALL older than 55 years and reported the overall complete remission (CR) rate was 96.3% in patients randomly assigned to imatinib and 50% in patients allocated to standard chemotherapy.[24] Severe adverse events were significantly more frequent during standard induction chemotherapy (90% vs 39%). The estimated overall survival of all patients was 42% at 24 months, with no significant difference between the 2 cohorts.[24] The addition of imatinib to chemotherapy has resulted in significantly improved outcomes. The addition of imatinib to hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) resulted in a 3-year disease-free survival rate of 66% and overall survival of 55% compared with a 14% 3-year disease-free survival rate and 15% overall survival for patients treated with hyper-CVAD without imatinib.[25] Similar results have been reported when imatinib is added to other chemotherapy regimens. Newer tyrosine kinase inhibitors have been developed for patients with chronic myelogenous leukemia (CML) that has become resistant to imatinib. These agents are also being studied in Ph-positive ALL. Nilotinib and dasatinibNilotinib is a tyrosine kinase inhibitor that has a higher binding affinity and selectivity for the ABL kinase than imatinib.[26] Nilotinib has 20 to 50 times the inhibitory activity against imatinib-sensitive CML cell lines relative to imatinib. In a phase II study in patients with relapsed/refractory Ph-positive ALL, complete responses were reported in 10 (24%) patients treated with nilotinib.[26] Dasatinib is a potent, orally active inhibitor of the BCR-ABL, c-KIT and the SRC family of kinases.[27] Dasatinib is a more potent inhibitor of BCR-ABL and c-KIT than imatinib mesylate, and it is effective in patients with CML that is resistant to or intolerant of imatinib. The Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) presented the interim results of a prospective study of dasatinib in patients with newly diagnosed Ph-positive ALL. Prednisone was started 7 days before the first dasatinib administration and continued until day 31. Dasatinib was administered for a total of 84 days. At the time of the report, all 23 patients treated showed a complete hematologic response by day 22. Although nilotinib and dasatinib are clearly active in Ph-positive ALL, it is likely that, similar to the results seen with imatinib, these responses will likely not be durable. Therefore each of these agents is currently being studied in combination with standard chemotherapy regimens.That said, these new tyrosine kinase inhibitors are not without their drawbacks and adverse events. Dasatinib has been associated with pleural effusions and pulmonary arterial hypertension,[28] while nilotinib has been linked to biochemical changes in liver function and QT-interval prolongation. Development of resistance may also occur with these agents.In the GIMEMA LAL1205 protocol, patients who had newly diagnosed Ph+ ALL received only dasatinib (for 84 d), steroids (for the first 32 d), and intrathecal chemotherapy as induction therapy.[29] Fifty-three patients were able to be evaluated (median age, 53.6 y). All patients achieved a complete hematologic remission; 49 patients (92.5%) achieved this at day 22. Postinduction management was decided by the investigator and included no further treatment (2 patients), tyrosine kinase inhibitor alone (19 patients), tyrosine kinase inhibitor plus chemotherapy and/or autografting (14 patients), and allografting (18 patients). At 20 months, the overall survival was 69.2% and disease-free survival was 51.1%. Twenty-three patients relapsed after completing induction. PonatinibPonatinib (Iclusig), a kinase inhibitor, was approved by the US Food and Drug Administration (FDA) in December 2012 for patients with Ph+ ALL that is resistant or intolerant to prior tyrosine kinase inhibitor therapy, including those with the T315I mutation. Because ponatinib has a high risk for thromboembolic events, its use is restricted to patients for whom no other tyrosine kinase inhibitor therapy is indicated.In the phase II PACE trial, 54% of chronic-phase chronic myeloid leukemia (CML) patients, including 70% of patients with the T315I mutation, achieved a major cytogenetic response. In patients with advanced disease, 52% of those with accelerated-phase CML, 31% of those with blast-phase CML, and 41% of those with Ph+ ALL achieved a major hematologic response to ponatinib.[30] These results confirm the phase I cinical trial results.[31] In October 2013, at the FDAs request, ponatinib was temporarily removed from the market because of safety concerns. The FDA cited an increased risk for life-threatening blood clots and severe narrowing of blood vessels. Ponatinib was returned to the US market within 2 months, but with new safety measures to address the risk for serious cardiovascular and thrombotic events.The revised indications for patients with ALL are now limited to two groups: adults with T315I-positive Ph+ ALL; and adults with Ph+ ALL for whom no other tyrosine kinase inhibitor therapy is indicated.[32] The revised labeling also states that the optimal dose of ponatinib has not been determined. The recommended starting dose remains at 45 mg PO once daily with or without food, but additional information has been included regarding dose decreases and discontinuations. The boxed warning has been revised to include the risk for heart failure, including fatalities, and the incidence of vascular occlusion (at least 27%). Treatment of the Younger AdultOlder children and younger adults with acute lymphoblastic leukemia (ALL) can be referred to either adult or pediatric hematologists. Usually, the patient will receive either an adult or pediatric regimen based on this referral pattern. However, several studies have suggested that younger patients are best treated on pediatric protocols. For example, in a retrospective analysis of patients aged 15-20 years treated on either the FRALLE 93 or LALA 94 trials, the complete remission (CR) rate was 94% for patients receiving the pediatric regimen compared with 83% for those receiving the adult.[33] The 5-year survival was 67% in the pediatric-regimen group and 41% in the adult-regimen group. Patients treated on the pediatric regimen were younger (15.9 y) than those treated on the adult regimen (17.9 y); however, prognostic factors were otherwise matched.[33] Similarly, the Childrens Cancer Group (CCG) and CALGB performed an analysis on patients aged 16-21 years treated on their studies and, again, event-free and overall survival were improved for patients treated on the CCG protocols.[34] In a study by the Programme for the Study of Therapeutics for Haematological Malignancies (PETHEMA), adolescents and young adults were treated with a pediatric regimen (ALL-96), demonstrating a response to therapy that was similar to previously reported, although a slight increase in hematologic toxicity was observed in the adult patients.[35] The majority of children with ALL are cured with frontline chemotherapy regimens. Many investigators are trying to translate these results into the adult population. Areas being studied include increased intensity of standard agents including asparaginase, risk-adapted chemotherapy, and evaluation of minimal disease. TransplantationMost authorities agree that allogeneic transplantation should be offered to young patients with high-risk features whose acute lymphoblastic leukemia (ALL) is in first remission. Young patients without adverse features should receive induction, consolidation, and maintenance therapy. In these patients, transplantation is reserved for relapse. Older patients whose disease is in complete remission (CR) may be considered for such investigational approaches as allogeneic transplantation with nonmyeloablative chemotherapy (ie, mini-transplants). Previously, patients with mature B-cell ALL would have been referred for transplantation when their disease was in first CR; however, with improving results from more intensive chemotherapy regimens, many clinicians are reserving transplantation for patients who have experienced relapse. Hematopoietic stem cell transplantation (HSCT) seems to be a valuable option for a subgroup of infants with mixed-lineage ALL carrying poor prognostic factors that include age younger than 6 months and either poor response to steroids at day 8 or leukocyte levels of 300 g/L or higher.[36] Relatively few studies have compared transplantation with chemotherapy in adults with ALL. In a study by the Groupe Ouest-Est des Leucemies Airgues et Maladies du Sang (GOELAMS), subjects younger than 45 years who had a sibling donor and whose disease was in remission were assigned to allogeneic transplantation.[37] The remaining subjects received methylprednisolone, Ara-C, mitoxantrone, and etoposide chemotherapy followed by autologous bone marrow transplantation (BMT). For subjects undergoing allogeneic bone marrow transplantation (BMT), the rate of freedom from relapse was 70% at 4 years. However, because of transplant-related complications, the event-free survival rate was only 33%. No toxic deaths occurred in the subjects who underwent autologous BMT. However, the event-free survival rate was only 17% at 4 years because of a high rate of relapse.[37] In a prospective, nonrandomized trial, the Bordeaux, Grenoble, Marseille, Toulouse group found that the 3-year probability of disease-free survival was significantly higher with allogeneic BMT (68%) than with autologous BMT (26%).[38] No benefit was observed with the addition of recombinant interleukin 2 (IL-2) after autologous BMT. In the French Group on Therapy for Adult Acute Lymphoblastic Leukemia study, subjects aged 15-40 years whose disease was in CR and who had a human leukocyte antigen (HLA)-compatible sibling donor underwent allogeneic BMT.[9] The other subjects were randomized to receive autologous BMT or chemotherapy. Overall, no difference in was observed in 5-year survival between the groups.[9] However, when only high-risk patients were considered (ie, Philadelphia chromosomepositive (Ph+), null ALL; >35 y; white blood cell [WBC] count >30,000/L; or time to CR > wk), allogeneic BMT proved superior to autologous BMT or chemotherapy with respect to overall survival rates (44% vs 20%) and disease-free survival rates (39% vs 14%).[9] Other phase 2 studies have confirmed a benefit for high-risk patients who undergo allogeneic BMT, with as many as 50% achieving long-term remissions. Stem cell transplantationIn the GOELAL02 study, patients with any high-risk feature (age >35 y, nonT-ALL, WBC >30,000, adverse cytogenetics: t[9;22], t[4;11], or t[1;19], or no CR after induction) received either allogeneic or autologous stem cell transplantation. For patients younger than 50 years, the 6-year overall survival rate was improved for patients receiving allogeneic transplantation (75%) compared with those receiving autologous transplantation (40%).[37] The United Kingdom Medical Research Council Acute Lymphoblastic Leukemia joint trial with the Eastern Cooperative Oncology Group (MRC UKALL XII/ECOG E2993) demonstrated that matched related allogeneic transplantations for ALL in first complete CR provide the most potent antileukemic therapy and considerable survival benefit for standard-risk patients. A donor versus no-donor analysis showed that Ph-negative patients with a donor had a 5-year improved overall survival, 53% versus 45% (P = 0.01), and that the relapse rate was significantly lower.[39] The survival difference was significant in standard-risk patients but not in high-risk patients with a high nonrelapse mortality rate in the high-risk donor group. Patients randomized to chemotherapy had a higher 5-year overall survival (46%) than those randomized to autologous transplantation (37%).[39] However, the transplantation-related mortality for high-risk older patients was unacceptably high and abrogated the reduction in relapse risk. Allogeneic transplantation can also be effective therapy for patients who have experienced relapse after chemotherapy. Martino et al treated 37 consecutive patients with primary refractory or relapsed ALL with intensive salvage chemotherapy.[40] Of the 19 patients assigned to autologous BMT, 10 did not reach transplantation, mostly because of early relapse; 9 received transplants. Of these, 1 died early and 8 experienced relapse 2-30 months after transplantation. Of the 10 patients who received allogeneic BMT, 4 died early and 6 were alive and free from disease 9.7-92.6 months after the transplantation.[40] These results are similar to those in patients in earlier stages, indicating that transplant-related complications are increased in the allogeneic setting. However, a significant number of patients can be cured. Yet, although autologous transplantation is relatively safe, it is associated with a high relapse rate, making this modality of little use in patients with ALL. Unrelated donor transplantationFor patients without a sibling donor, an alternative is an unrelated donor (URD) transplant. Weisdorf et al found that autologous BMT was associated with a lower transplant-related mortality rate, but URD transplantations had a lower risk of relapse.[41] In patients whose disease was in second CR, URD transplantations resulted in a superior rate of disease-free survival.[41] Although peripheral blood has come to be preferred to bone marrow as the source for stem cells from unrelated donors (about 75% of transplants), a randomized phase III trial found that peripheral-blood stem cells did not yield improved survival as compared with bone-marrow cells and were significantly associated with chronic graft-vs-host disease (GVHD)[42, 43] ; the authors suggested that peripheral-blood stem cells might be appropriate for patients at higher risk for graft failure and bone-marrow cells for all others.Treatment of Relapsed ALLPatients with relapsed acute lymphoblastic leukemia (ALL) have an extremely poor prognosis. Most patients are referred for investigational therapies. Young patients who have not previously undergone transplantation are referred for such therapy. Reinduction regimens include the hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone) protocol and high-dose cytosine arabinoside (Ara-C)based regimens. As noted earlier, the hyper-CVAD regimen is based on hyperfractionated cyclophosphamide and intermediate doses of Ara-C and methotrexate. In a study at the MD Anderson Cancer Center of 66 patients with relapsed ALL, the complete remission (CR) rate was 44% and median survival was 42 weeks. Arlin et al reported that 8 of 10 patients with relapsed ALL achieved CR with high-dose Ara-C and high-dose mitoxantrone.[17] A similar regimen using a single high dose of idarubicin in combination with Ara-C (the Memorial ALL-3 protocol) resulted in CR rates of 58-78% in patients who experienced relapse. The Italian ALL R-87 study suggested that a small number of patients who experience relapse will survive long-term after allogeneic bone marrow transplantation (BMT)[44] ; however, autologous BMT is less useful because it is associated with a high rate of relapse. Sixty-one subjects with ALL in first relapse received induction chemotherapy with intermediate-dose Ara-C, idarubicin, and prednisone. Subjects whose disease was in remission were to receive consolidation chemotherapy and then BMT. Of these subjects, 56% achieved CR; however, only nine of the responders underwent BMT.[44] The remaining subjects did not undergo transplantations because of either early relapse or excessive toxicity. Of the four subjects who underwent allogeneic BMT, three were alive and achieved remission at 22, 43, and 63 months, whereas only one of the five subjects who underwent autologous BMT was alive.[44] In August 2012, the US Food and Drug Administration (FDA) approved vincristine liposomal (Marqibo) for the treatment of Philadelphia chromosome negative (Ph-) ALL in adults. It is indicated for patients in second or greater relapse or whose disease has progressed following two or more anti-leukemia therapies. This product is a sphingomyelin/cholesterol liposome-encapsulated formulation of vincristine. In a trial of 65 patients that received at least one dose of vincristine liposomal, 15.4% of the patients had CR lasting a median of 28 days.[45] In December 2012, the FDA approved the kinase inhibitor ponatinib for Ph+ ALL that is resistant or intolerant to prior tyrosine kinase inhibitor therapy. For more information, see Treatment of Ph ChromosomePositive ALL.Blinatumomab (Blincyto), a bispecific T-cell engager (BiTE) antibody, was approved by the FDA in December 2014 for Ph- relapsed or refractory B-cell precursor ALL. Its approval was based on results of a Phase 2, multicenter, single-arm open-label study. Eligible patients were >18 years of age with Ph- relapsed or refractory B-cell precursor ALL. Of the 185 patients evaluated in the trial, 41.6% (77/185; 95% CI: 34.4-49.1) achieved complete remission or complete remission with partial hematologic recovery (Cr/CRh) within 2 cycles of treatment with blinatumomab, which was the primary endpoint of the study. The majority of responses (81% [62/77]) occurred within the first cycle of treatment. Among patients who achieved CR/CRh, 39% (30/77) went on to HSCT, and 75.3% (58/77 95% CI: 64.2-84.4) achieved minimal residual disease (MRD) response, a measure of eradication of residual disease at the molecular level.[46, 47] Novel and Experimental Drug TherapiesA number of new drugs are in development for the treatment of acute lymphoblastic leukemia (ALL).Clofarabine is a novel nucleoside analogue that is approved for the treatment of pediatric patients with refractory or relapsed ALL.[48] This agent inhibits DNA synthesis at both DNA polymerase I and at RNA reductase. Overall response rates average 25%. 506U78 (nelarabine [Arranon]) is a novel purine nucleoside that is a prodrug of guanine arabinoside (ara-G).[49] This agent was approved as an orphan drug by the US Federal Drug Administration (FDA) in October 2005. Complete responses have been reported in 31% of patients and in 54% of patients with T-cell ALL. The dose-limiting toxicity of this drug is neurotoxicity.[49] Supportive Care - Blood ProductsPatients with acute lymphoblastic leukemia (ALL) have a deficiency in the ability to produce normal blood cells, and they need replacement therapy. This deficiency is temporarily worsened by the addition of chemotherapy. All blood products must be irradiated to prevent transfusion-relatedgraft versus host disease, which is almost invariably fatal. Packed red blood cells are given to patients with a hemoglobin level of less than 7-8 g/dL or at a higher level if the patient has significant cardiovascular or respiratory compromise. Platelets are transfused if the count is less than 10,000-20,000/L. Patients with pulmonary or gastrointestinal hemorrhage receive platelet transfusions to maintain a value greater than 50,000/L. Patients with central nervous system CNS hemorrhage are transfused to achieve a platelet count of 100,000/L. Fresh frozen plasma is given to patients with a significantly prolonged prothrombin time (PT). Cryoprecipitate is given if the fibrinogen level is less than 100 g/dL. Supportive Care - Therapy and Prophylaxis for InfectionAntibiotics are given to all febrile patients. At a minimum, include a third-generation cephalosporin (or equivalent), usually with an aminoglycoside. In addition to this minimum, other antibiotic agents are added to treat specific documented or possible infections. Patients with persistent fever after 3-5 days of antibacterial antibiotics should have an antifungal antibiotic (liposomal or lipid complex amphotericin, new generation azole or echinocandin) added to their regimen. Patients with sinopulmonary complaints would receive anti-Aspergillus treatment. Particular care is warranted for patients receiving steroids as part of their treatment, because the signs and symptoms of infection may be subtle or even absent. The use of prophylactic antibiotics in neutropenic patients who are not febrile is controversial. However, most clinicians prescribe them for patients undergoing induction therapy. A commonly used regimen includes the following: Ciprofloxacin (oral [PO] 500 mg twice daily [bid]) Fluconazole (200 mg PO daily), itraconazole (200 mg PO bid), or posaconazole (200 mg PO three times daily [tid]) Acyclovir (200 mg PO 5 times/d) or valacyclovir (500 mg PO daily)Once patients taking these antibiotics become febrile, they are switched to intravenous antibiotics.Supportive Care - Growth FactorsThe use of granulocyte colony-stimulating factor (G-CSF) during induction chemotherapy for acute lymphoblastic leukemia (ALL) is supported by several studies. In a randomized phase 3 trial conducted by Ottoman, 76 subjects received either G-CSF or no growth factor with the induction chemotherapy (ie, cyclophosphamide, cytosine arabinoside (Ara-C), 6-mercaptopurine, intrathecal methotrexate, and cranial irradiation). The median duration of neutropenia was 8 days in subjects receiving G-CSF versus 12 days in subjects receiving no growth factor, and the prevalence of nonviral infections was decreased by 50% in subjects receiving G-CSF. No difference in disease-free survival was observed between the 2 groups. In a randomized phase III study reported by Geissler et al, subjects who received G-CSF beginning on day 2 of induction chemotherapy (ie, with daunorubicin, vincristine, L -asparaginase, and prednisone) had a marked decrease in the proportion of days with neutropenia of less than 1000/L (29% for G-CSF vs 84% for controls), a reduction in the prevalence of febrile neutropenia (12% vs 42% in controls), and a decrease in the prevalence of documented infections (40% vs 77%) relative to those who received chemotherapy without G-CSF.[50] No difference was observed in response, remission duration, or survival between the 2 groups.[50] In the Cancer and Leukemia Group B (CALGB) 9111 study, subjects who received G-CSF beginning on day 4 of induction chemotherapy had significantly shorter durations of neutropenia and significantly fewer days of hospitalization compared with those in the group that received placebo.[51] In this study, subjects receiving G-CSF also had higher complete remission (CR) rates, because fewer deaths occurred during remission induction. Again, no significant effect on disease-free survival or overall survival was observed.[51] The importance of the early use of G-CSF FOR ALL was demonstrated by the study of Bassan et al, in which subjects who received induction chemotherapy with idarubicin, vincristine, L -asparaginase, and prednisone and G-CSF on day 4 recovered significantly faster from neutropenia, had fewer infectious complications, and required less antibiotic than subjects beginning G-CSF on day 15.[52] Outside of the setting of a clinical trial, few data support the use of granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with ALL. The GOELAMS investigators randomly assigned 67 subjects to receive GM-CSF or placebo during induction chemotherapy with idarubicin, methylprednisolone, and high-dose Ara-C and observed no difference in the CR rate, the duration of neutropenia, or days with fever for the two groups.[53] In addition, mucositis of higher than grade 3 was reduced in subjects receiving GM-CSF (two of 35 patients vs six of 29 patients, respectively.[53] In a Groupe d'Etude et de Traitement de la Leucemie Aigue Lymphoblastique de l'Adulte (GET-LALA) study, in patients who received G-CSF, GM-CSF, or no growth factor during induction therapy, the median time for neutrophil recovery was 17 days for G-CSF, 18 days for GM-CSF, and 21 days for no growth factors.[54] Hyperuricemia and Tumor Lysis SyndromeTumor lysis syndrome is a potentially life-threatening complication that may be seen in patients receiving chemotherapy for acute leukemias and high-grade non-Hodgkin lymphomas. This syndrome is characterized by elevated blood levels of uric acid, phosphate, and potassium; decreased levels of calcium; and acute renal failure. As mentioned earlier, patients with a high tumor burden, particularly those with severe hyperuricemia, can present in renal failure. Allopurinol at 300 mg 1-3 times per day is recommended during induction therapy until blasts are cleared and hyperuricemia resolves. High-risk patients (those with very high lactate dehydrogenase [LDH] or leukemic infiltration of the kidneys) can benefit from rasburicase. In a study by Cortes et al, adults with hyperuricemia or those at high risk for tumor lysis syndrome not only had an improved plasma uric acid response rate with rasburicase alone (0.20 mg/kg/d intravenously [IV], days 1-5) (87%) or in combination with allopurinol (IV rasburicase 0.20 mg/kg/d, days 1-3, followed by oral [PO] allopurinol 300 mg/d, days 3-5) (78%) than with allopurinol alone (300 mg/d PO, days 1-5) (66%), but they also had more rapid control of their plasma uric acid with rasburicase alone (4 h) or with allopurinol (4 h) than with allopurinol alone (27 h).[55] Long-Term Monitoring Patients with acute lymphoblastic leukemia (ALL) are monitored on an outpatient basis for disease status and the effects of chemotherapy. Maintenance therapy for these patients is also administered in an outpatient setting. In addition, all patients should be on trimethoprim-sulfamethoxazole (TMP-SMZ) to prevent Pneumocystis jiroveci pneumonia, and patients may benefit from receiving oral nystatin or clotrimazole troches to reduce the risk of candidiasis. Patients with a high risk of relapse may also need additional antifungal therapy, such as itraconazole. Medication SummaryAntineoplastic agents are used for induction, consolidation, and maintenance therapy and central nervous system (CNS) prophylaxis in patients with acute lymphoblastic leukemia (ALL). Those medications cause severe bone marrow depression, and only physicians specifically trained in their use should administer them. In addition, access to appropriate supportive care is required.Other drug classes used in treatment of ALL include the following: Corticosteroids may be used during induction, consolidation, and/or maintenance therapy Tyrosine kinase inhibitors are used in treatment of Philadelphia chromosome positive (Ph+) ALL Colony-stimulating factors are used to treat or prevent neutropenia and to mobilize autologous peripheral blood progenitor cells for bone marrow transplantation (BMT) and in management of chronic neutropenia Prophylactic antibiotics and antifungal drugs are given to prevent infection in patients receiving chemotherapyCorticosteroidsClass SummaryCorticosteroids may be used during induction, consolidation, and/or maintenance therapy for acute lymphoblastic leukemia (ALL).View full drug informationPrednisonePrednisone is a corticosteroid that has a wide range of activities. In ALL, this agent is used because of its direct antileukemic effects. View full drug informationDexamethasone (Baycadron, Maxidex, Ozurdex)Dexamethasone is another corticosteroid that acts as an important chemotherapeutic agent in the treatment of ALL. Like prednisone, this agent is used in induction and reinduction therapy and is also given as intermittent pulses during continuation therapy. AntineoplasticsClass SummaryAntineoplastic agents are used for induction, consolidation, maintenance, and central nervous system (CNS) prophylaxis. Cancer chemotherapy is based on an understanding of tumor cell growth and how drugs affect this growth. After cells divide, they enter a period of growth (ie, phase G1), followed by DNA synthesis (ie, phase S). The next phase is a premitotic phase (ie, G2), then, finally, a mitotic cell division (ie, phase M). Cell-division rates vary for different tumors. Most common cancers grow slowly compared with normal tissues, and the rate may be decreased in large tumors. This difference allows normal cells to recover from chemotherapy more quickly than malignant ones and is the rationale behind current cyclic dosage schedules. Antineoplastic agents interfere with cell reproduction. Some agents act at specific phases of the cell cycle, whereas others (ie, alkylating agents, anthracyclines, cisplatin) are not phase specific. Cellular apoptosis (ie, programmed cell death) is another potential mechanism of many antineoplastic agents. View full drug informationVincristine (Vincasar PFS)Vincristine is a vinca alkaloid agent that acts by arresting cells in metaphase.View full drug informationVincristine liposomal (Marqibo)A sphingomyelin/cholesterol liposome-encapsulated formulation of vincristine. Indicated for treatment of Ph-negative ALL for patients in second or greater relapse or whose disease has progressed following 2 or more antileukemia therapies. View full drug informationAsparaginase Erwinia chrysanthemi (Erwinaze)Catalyzes deamidation of asparagine to aspartic acid and ammonia, thereby reducing circulating levels of asparagine. Lack of asparagine synthetase activity results in cytotoxicity specific for leukemic cells that depend on an exogenous source of the amino acid asparagine. Indicated as part of a multiagent chemotherapeutic regimen as a substitute for asparaginase (Elspar), which was discontinued by the manufacturer in August 2012. View full drug informationPegaspargase (Oncaspar, PEG L Asparaginase)Modified version of L-asparaginase. Selective killing of leukemic cells it thought to be due to depletion of plasma asparagine, the amino acid required for protein synthesis. It is indicated as a component of a multi-agent chemotherapeutic regimen for the first line treatment of ALL. It is also indicated for use in patients with hypersensitivity to native forms of L-asparaginase. View full drug informationMethotrexate (Trexall)Methotrexate is an antimetabolite of the folic acid analogue type. This agent inhibits dihydrofolate reductase, resulting in inhibition of DNA synthesis, repair, and cellular replication. View full drug informationMercaptopurine (Purinethol)Mercaptopurine is antimetabolite of the purine analogue type. Its primary effect is inhibition of DNA synthesis.View full drug informationCyclophosphamideCyclophosphamide is an alkylating agent of the nitrogen mustard type that acts by inhibiting cell growth and proliferation.View full drug informationCytarabineCytosine arabinoside is an antimetabolite that induces activity as a result of activation to cytarabine triphosphate and includes inhibition of DNA polymerase and incorporation into DNA and RNA. View full drug informationDaunorubicin (Cerubidine)Daunorubicin is an anthracycline that inhibits topoisomerase II. This agent also inhibits DNA and RNA synthesis by intercalating between DNA base pairs. View full drug informationIdarubicin (Idamycin)Idarubicin is a topoisomerase II inhibitor that inhibits cell proliferation by inhibiting DNA and RNA polymerase.View full drug informationMitoxantrone (Novantrone)Mitoxantrone is also a topoisomerase II inhibitor. This agent inhibits cell proliferation by intercalating DNA and inhibiting topoisomerase II. View full drug informationDasatinib (Sprycel)Dasatinib is a multiple tyrosine kinase inhibitor that inhibits the growth of cell lines overexpressing BCR-ABL. This agent is indicated for Philadelphia chromosomepositive acute lymphoblastic leukemia (Ph+ ALL) in individuals with resistance to or who were intolerant of previous therapy. View full drug informationNelarabine (Arranon)Nelarabine is a prodrug of the deoxyguanosine analogue 9-beta-D-arabinofuranosylguanine (ara-G) that is converted to the active 5'-triphosphate, ara-GTP, a T-cellselective nucleoside analogue. Leukemic blast cells accumulate ara-GTP, which allows for incorporation into DNA, leading to inhibition of DNA synthesis and cell death.This agent is approved by the US Food and Drug Administration (FDA) as an orphan drug to treat persons with T-cell ALL whose disease has not responded to or which has relapsed with at least 2 chemotherapy regimens.View full drug informationClofarabine (Clolar)Clofarabine is a purine nucleoside antimetabolite that inhibits DNA synthesis and is indicated for relapsed or refractory acute lymphoblastic leukemia in pediatric patients. Pools of cellular deoxynucleotide triphosphate are decreased by inhibiting ribonucleotide reductase and terminating DNA chain elongation and repair. This agent also disrupts mitochondrial membrane integrity. It is indicated for the treatment of patients aged 1-21 years who have relapsed or refractory acute ALL. For adults older than 21 years, base dosing on surface area as in pediatrics. Clofarabine is not indicated for adults older than 21 years. Tyrosine Kinase InhibitorsClass SummaryPhiladelphia chromosome-positive (Ph+) ALL is treated with tyrosine kinase inhibitors. These agents provide targeted therapy by inhibiting the BCR-ABL fusion protein. View full drug informationImatinib (Gleevec)Imatinib is indicated for relapsed or refractory Ph+ ALL. It is also indicated for newly diagnosed PH+ CML in chronic phase and for Ph+ CML in blast crisis, accelerated phase, or chronic phase after failure of interferon-alpha therapy. View full drug informationNilotinib (Tasigna)Nilotinib is indicated for newly diagnosed Ph+ CML in chronic phase and for the treatment of Ph+ CML (chronic phase, accelerated phase) in patients resistant or intolerant to prior therapy including imatinib. View full drug informationDasatinib (Sprycel)Dasatinib is indicated for Ph+ ALL with resistance or intolerance to prior therapy. It is also indicated for newly diagnosed Ph+ CML in chronic phase, CML (chronic, accelerated, or plast phase Ph+) with resistance or intolerance to prior therapy including imatinib. View full drug informationPonatinib (Iclusig)Ponatinib is a kinase inhibitor indicated for patients with CML or Ph+ ALL that is resistant or intolerant to prior tyrosine kinase inhibitor therapy, including those with the T315I mutation. Because ponatinib has a high risk for thromboembolic events, its use is restricted for patients whom no other TKI therapy is indicated. Bispecific T-Cell Engager (BiTE) AntibodiesClass SummaryBispecific T cell engager antibodies are a type of immunotherapy that assists the body's immune system to detect and target malignant cells. The modified antibodies are designed to engage 2 different targets simultaneously, thereby juxtaposing T cells to cancer cells, thereby helping place the T cells within reach of the targeted cell, with the intent of allowing T cells to inject toxins and trigger apoptosis. View full drug informationBlinatumomab (Blincyto)Bispecific CD19-directed CD3 T-cell engager that binds to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T cells. It activates endogenous T-cells by connecting CD3 in the T-cell receptor (TCR) complex with CD19 on benign and malignant B cells. It is indicated for treatment of Ph- relapsed or refractory B-cell precursor ALL. Colony-Stimulating FactorsClass SummaryColony-stimulating factors (CSF) act as hematopoietic growth factors that stimulate the development of granulocytes. These agents are used to treat or prevent neutropenia when patients receive myelosuppressive cancer chemotherapy and to reduce the period of neutropenia that is associated with bone marrow transplantation (BMT). Colony-stimulating factors are also used to mobilize autologous peripheral blood progenitor cells for BMT and in management of chronic neutropenia.View full drug informationFilgrastim (Neupogen)Filgrastim is a granulocyte colony-stimulating factor (G-CSF) that activates and stimulates the production, maturation, migration, and cytotoxicity of neutrophils. View full drug informationPegfilgrastim (Neulasta)Pegfilgrastim is a long-acting filgrastim created by the covalent conjugate of recombinant G-CSF (ie, filgrastim) and monomethoxypolyethylene glycol. As with filgrastim, this agent acts on hematopoietic cells by binding to specific cell surface receptors, thereby activating and stimulating production, maturation, migration, and cytotoxicity of neutrophils. AntimicrobialsClass SummaryProphylactic antimicrobial drugs are given to prevent infection in patients receiving chemotherapy.View full drug informationTrimethoprim-sulfamethoxazole (Septra, Bactrim)Trimethoprim-sulfamethoxazole (TMP-SMZ) inhibits bacterial growth by inhibiting the synthesis of dihydrofolic acid. All immunocompromised patients should be treated with TMP-SMZ to prevent Pneumocystis carinii pneumonia (PCP). AntifungalsClass SummaryThese agents may change the permeability of the fungal cell, resulting in a fungicidal effect.View full drug informationNystatinNystatin is used to prevent fungal infections in mucositis. This agent is a fungicidal and fungistatic antibiotic from Streptomyces noursei that is effective against various yeasts and yeastlike fungi. Nystatin acts by changing the permeability of the fungal cell membrane after binding to cell membrane sterols, causing cellular contents to leak.Treatment with this agent should continue until 48 hours after the symptoms disappear. Nystatin is not substantially absorbed from the gastrointestinal tract.View full drug informationClotrimazoleClotrimazole may be used instead of nystatin to prevent fungal infections. It is a broad-spectrum antifungal agent that inhibits yeast growth by altering cell membrane permeability, causing death of fungal cells. View full drug informationItraconazole (Sporanox)Itraconazole has fungistatic activity and is used to prevent fungal infections in high-risk patients. This drug is a synthetic triazole antifungal agent that slows fungal cell growth by inhibiting CYP-dependent synthesis of ergosterol, a vital component of fungal cell membranes. The bioavailability of this drug is greater in the oral solution compared with the capsule formulation.