Acute Lymphoblastic Leukemia (ALL) 

Updated: Jun 20, 2019
Author: Karen Seiter, MD; Chief Editor: Emmanuel C Besa, MD 

Overview

Practice Essentials

Acute 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 B-cell lymphoblastic leukemia/lymphoma (B-ALL).

Acute lymphoblastic leukemia (ALL): Bone marrow sh Acute lymphoblastic leukemia (ALL): Bone marrow shows proliferation of large and heterogeneous lymphoblasts consistent with pre–B-cell ALL (French-American-British L2 morphology).

See the Childhood Acute Lymphoblastic Leukemia: Diagnosis, Management, and Complications slideshow to help recognize and treat this disease and its associated complications.

Signs and symptoms

Signs and symptoms of ALL include the following:

  • Fever
  • Signs and symptoms of anemia, such as pallor, fatigue, dizziness, palpitations, cardiac flow murmur, and dyspnea with even mild exertion
  • Bleeding 
  • Disseminated intravascular coagulation (DIC) at diagnosis (about 10% of cases)
  • Blood clots
  • Palpable lymphadenopathy
  • Symptoms related to a large mediastinal mass (eg, shortness of breath), particularly with T-cell lymphoblastic leukemia/lymphoma (T-ALL)
  • Bone pain (can be severe and often atypical)
  • Left upper quadrant fullness and early satiety due to splenomegaly (about 10% 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
  • Rashes from skin infiltration with leukemic cells

See Presentation for more detail.

Diagnosis

Laboratory tests and other studies used in the workup for ALL include the following:

  • Complete blood count with differential
  • Coagulation studies, including PT, PTT, fibrinogen and fibrin split products
  • 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, as indicated by symptoms
  • Multiple-gated acquisition scanning or echocardiogram
  • Electrocardiography
  • Lumbar puncture (especially in children)
  • Bone marrow aspiration and biopsy (definitive for confirming leukemia)

Bone marrow studies should include the following:

  • Histology
  • Immunohistochemistry/flow cytometry
  • Cytogenetics
  • Fluorescence in situ hybridization
  • Polymerase chain reaction
  • Next-generation sequencing

See Workup for more detail.

Management

Treatment of ALL is stratified based on patient age (adolescent and young adult versus older) and Philadelphia chromosome status (positive versus negative)

Treatment of newly-diagnosed ALL may include the following:

  • Induction chemotherapy (eg, standard 4- or 5-drug regimen, ALL-2, or hyper-CVAD)
  • Consolidation chemotherapy
  • Maintenance chemotherapy
  • Inclusion of tyrosine kinase inhibitors for Philadelphia chromosome–positive patients
  • Inclusion of rituximab for CD20+ patients
  • Intrathecal chemotherapy for central nervous system (CNS) prophylaxis
  • Stem cell transplantation
  • Supportive care (eg, blood products, antibiotics, growth factors)

Special considerations apply to the treatment of the following:

  • Burkitt leukemia
  • Ph+ ALL
  • ALL in older children and younger adults
  • Relapsed ALL
  • ALL in patients with hyperuricemia or at high risk for tumor lysis syndrome

See Treatment and Medication for more detail.

See also Pediatric Acute Lymphoblastic Leukemia and Acute Myeloid Leukemia (AML).

Pathophysiology

The 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 or abnormalities of chromosome number. The lymphoblasts replace the normal marrow elements, resulting in a decrease in the production of other blood cell lines (red blood cells, platelets, and neutrophils). Consequently, anemia, thrombocytopenia, and neutropenia occur, although typically to a lesser degree than is seen in acute myeloid leukemia. Lymphoblasts can also infiltrate outside the marrow, particularly in the liver, spleen, and lymph nodes, resulting in enlargement of the latter organs.

Etiology

A review of the genetics, cell biology, immunology, and epidemiology of childhood leukemia by Greaves concluded that B-cell precursor acute lymphoblastic leukemia (ALL) has a multifactorial etiology, with a two-step process of genetic mutation and exposure to infection playing a prominent role. The first step occurs in utero, when fusion gene formation or hyperdiploidy generates a covert, pre-leukemic clone. The second step is the postnatal acquisition of secondary genetic changes that drive conversion to overt leukemia. Only 1% of children born with a pre-leukemic clone progress to leukemia.[1, 2]

The second step is triggered by infection. Triggering is more likely to occur in children whose immune response is abnormally regulated because they were not exposed to infections in the first few weeks and months of life. Lack of exposure to these early infections, which prime the immune system, is more likely to occur in societies that are zealous about hygiene; this would help explain why at present, pediatric ALL is seen primarily in industrialized societies.[1, 2]

Less is known about the etiology of ALL in adults, compared with acute myeloid 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.

Analysis of the Surveillance, Epidemiology and End Results (SEER) database showed that the incidence of ALL was higher than expected in patients with a prior history of Hodgkin lymphoma, small cell lung cancer, and ovarian cancer.[3]

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. Some patients receiving lenalidomide as maintenance therapy for multiple myeloma have developed secondary ALL.[4]  In a study of the California Cancer Registry it was noted that 3% of patients had a prior known malignancy and that any prior malignancy predisposed to the development of ALL. The prognosis for these patients with secondary ALL was unfavorable compared with that of patients with de novo ALL.[5]

A genome-wide association study of susceptibility to ALL in adolescents and young adults identified significant susceptibility locus in GATA3: rs3824662 (odds ratio 1.77) and rs3781093 (OR 1.73)[6] . Other studies have shown associations between polymorphisms of arylamine N-acetyltransferases 1 and 2, MMP-8 promoter genotypes, HLA alleles, ARID5B, IKZF1, CEBPE, CDKN2A, PIP4K2A, LHPP and ELK3 and increased risk of ALL[7, 8, 9] .

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.

Epidemiology

Acute lymphoblastic leukemia (ALL) is the most common type of cancer and leukemia in children in the United States. ALL accounts for 74% of pediatric leukemia cases.[10]

In adults, ALL is less common than acute myeloid leukemia (AML). It is estimated that 5930 cases of ALL (adult and pediatric) in the United States will occur in 2019, resulting in 1500 deaths.[11] The estimated 5-year survival is 68.6%. The favorable survival rate is due to the high cure rate of ALL in children. Prognosis declines with increasing age, and the median age at death is 56 years.[10]

Worldwide, the highest incidence of ALL occurs in Italy, the United States, Switzerland, and Costa Rica In Europe overall, B-cell precursor ALL has been increasing by around 1% each year.[2]

Prognosis

Only 20-40% of adults with acute lymphoblastic leukemia (ALL) are cured with current treatment regimens.

Historically, patients with ALL were divided into three prognostic groups: good risk, intermediate risk, and poor risk.

Good-risk criteria included the following:

  • No adverse cytogenetics
  • Age younger than 30 years
  • White blood cell (WBC) count of less than 30,000/μL
  • Complete remission within 4 weeks

Intermediate risk included those whose condition did not meet the criteria for either good risk or poor risk.

Poor-risk criteria included 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/μL
  • Failure to achieve complete remission within 4 weeks

The addition of tyrosine kinase inhibitors to chemotherapy has resulted in improved prognosis of patients with Philadelphia chromosome–positive ALL such that many experts no longer consider these patients poor risk.[12]

Immunophenotype effects on prognosis

Czuczman 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.[13] 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.[13]

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.[14] 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%).[14] However, no significant effect on remission duration or overall survival was observed.

Chromosome number and prognosis

The 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 Number

3-Year Event-Free Survival

Near tetraploidy

46-56%

Normal karyotype

34-44%

Hyperdiploidy >50

32-59%

Hyperdiploidy 47-50

21-53%

Pseudodiploidy

12-25%

Hypodiploidy

11%

 

In a study of 428 patients with Philadelphia chromosome negative ALL treated at MD Anderson Cancer Center, 43% had a diploid karyotype. Other patients had 3 or 4 chromosomal abnormalities (6%), 5 or more chromosome abnormalities (7%), low hypodiploidy/near-triploidy (6%), or tetraploidy (1%). Six percent of patients had an MLL rearrangement and 11% had other recurrent chromosomal abnormalities. The 5 year overall survival rate was 47%. The overall survival of patients with 3 or 4 chromosomal abnormalities was similar to that of diploid patients (51%), whereas the overall survival for patients with 5 or more abnormalities was 28%. Complex karyotype and hypodiploidy/near triploidy retained their prognostic importance independent of treatment minimal residual disease (MRD) status.[15]

Minimal Residual Disease

Case-specific molecular probes or multiparametric flow cytometry can be used to detect 1 leukemic cell in 10,000 mononuclear cells (ie, sensitivity of >104). The presence of such minimal residual disease (MRD) after treatment is a strong predictor for relapse.

A meta-analysis of 39 trials of ALL treatment of children and adults demonstrated that the event-free survival (EFS) hazard ratio for achieving MRD negative status after therapy was 0.23 for pediatric patients and 0.28 for adults.[16]  The hazard ratio for overall survival was 0.28 for both patient populations. The effect was seen across therapies, disease subtypes and methods of detection.

Genomics

Routine use of next-generation sequencing and other molecular methods is identifying recurrent genetic abnormalities with prognostic implications. Patel et al performed genome-wide analysis (GWAS) with single-nucleotide polymorphism (SNP) arrays on 70 patients with B-ALL. The most prevalent deletions occurred in CDKN2A, IKZF1 and PAX5.[17]  Other genes were affected at a lower frequency.

Liu et al performed GWAS on 264 cases of pediatric and young adult T-ALL72. NRAS/FLT3 mutations were associated with immature T-ALL, JAK3/STAT5B mutations were seen in HOXA1 deregulated ALL, PTPN2 mutations were seen in TLX1 deregulated T-ALL, and PIK3R1/PTEN mutations were seen in TAL1 deregulated ALL. Philadelphia chromosome–like ALL (a subtype of ALL with a poor prognosis that is amenable to treatment with tyrosine kinase inhibitors) was identifed by genomic studies.[18]

Further studies correlating genomic and clinical findings are ongoing. These studies will determine the prognostic implication of specific molecular findings and could allow for the development of targeted agents in these diseases.

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 done

For patient education information, see Blood and Lymphatic System Center and Cancer and Tumors Center, as well as Leukemia.

 

Presentation

History

Patients 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/µL, and they are especially severe when it is less than 100/µL. 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 μL).

Patients with a high tumor burden, particularly those with severe hyperuricemia, can present in renal failure.

Physical Examination

Patients 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.

 

DDx

Diagnostic Considerations

Patients with acute lymphoblastic leukemia (ALL) may present with fever without any other evidence of infection. In these patients, all fevers must be assumed to be due to infections until proven otherwise. 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.

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

 

Workup

Approach Considerations

The following studies and procedures are used in the workup for acute lymphoblastic leukemia (ALL):

  • Complete blood count (CBC) with peripheral smear
  • Coagulation studies (prothrombin time [PT], activated partial thromboplastin time [aPTT], fibrinogen)
  • 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, as indicated by symptoms
  • Multiple-gated acquisition (MUGA) scan or echocardiogram
  • Lumbar puncture 

National Comprehensive Cancer Network (NCCN) guidelines note that diagnosis of ALL generally requires the following[19] :

  • Demonstration of ≥20% bone marrow lymphoblasts
  • Morphologic assessment of Wright/Giemsa–stained bone marrow aspirate smears
  • Hematoxylin and eosin (H&E)–stained bone marrow core biopsy and clot sections
  • Comprehensive flow cytometric immunophenotyping
  • Baseline characterization of the leukemic clone, to facilitate subsequent minimal residual disease (MRD) analysis

For 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[19] :

  • Cytogenetics – Karyotyping of G-banded metaphase chromosomes
  • Interphase fluorescence in situ hybridization (FISH, ALL panel to include testing for  BCR-ABL1MLLTEL/AML - ETV6/RUNX1, CEP4 and CEP10)
  • Reverse transcriptase polymerase chain reaction (RT-PCR) for fusion genes (eg,  BCR-ABL1), including determination of transcript size; in  BCR-ABL1–negative cases, testing for other fusions that are associated with Ph-like ALL may be considered
  • Additional assessment (array cGH) may be considered in cases of aneuploidy or failed karyotype

Next-generation sequencing is frequently performed, however the therapeutic and prognostic implicatons of the findings are still evolving in ALL.

See also Acute Lymphoblastic Leukemia Staging.

Routine Laboratory Studies

A 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 ANC is less than 500/µL, and they are especially severe when it is less than 100/µL. See the Absolute Neutrophil Countcalculator.

Coagulation studies and chemistry profiles

Abnormalities 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.

Cultures

Appropriate cultures, in particular blood cultures, should be obtained in patients with fever and in those with other signs of infection even fever is absent.

Radiologic Studies

Chest radiographs 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 Echocardiography

Multiple-gated acquisition (MUGA) scans or echocardiograms 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 Biopsy

Bone 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). Abnormalities of chromosome number are common in ALL.

Histologic Features

The 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); see the image below

  • 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

Acute lymphoblastic leukemia (ALL): Bone marrow sh Acute lymphoblastic leukemia (ALL): Bone marrow shows proliferation of large and heterogeneous lymphoblasts consistent with pre–B-cell ALL (French-American-British L2 morphology).

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.

In 2016 the World Health Organization Classification published a revised classification of ALL.[20]  This classification included 2 new provisional entities for B-ALL. The first, B-lymphoblastic leukemia/lymphoma, BCR-ABL1-like, was originally reported as a subtype of poor-prognosis childhood ALL with a gene expression profile similar to Philadelphia chromosome–positive ALL.[21, 22]  Some cases of this subtype of ALL respond to therapy with tyrosine kinase inhibitors.

The second, B-ALL with intrachromosomal amplification of chromosome 21, is characteristically detected by FISH with a probe for RUNX1 that reveals 5 or more copies of that gene.[23, 24]  This subtype occurs in older children with a low WBC and is associated with a poor prognosis. Currently there is no subdivision of T-ALL, with the exception of two new provisional subtypes. Early T-cell precursor lymphoblastic leukemia is a subtype with only limited early T-cell differentiation with retention of some myeloid and stem cell characteristics.[25, 26]  The prognosis of this subtype is variable from report to report. Natural killer cell lymphoblastic leukemia/lymphoma is another newly decribed subtype.

Current World Health Organization Classification of ALL

B-lymphoblastic leukemia/lymphoma

  • B-lymphoblastic leukemia/lymphoma, NOS
  • B-lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities
  • B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2);  BCR-ABL1
  • B-lymphoblastic leukemia/lymphoma with t(v;11q23.3);  KMT2A rearranged
  • B-lymphoblastic leukemia/lymphoma with t(12;21)(p13.2;q22.1);  ETV6-RUNX1
  • B-lymphoblastic leukemia/lymphoma with hyperdiploidy
  • B-lymphoblastic leukemia/lymphoma with hypodiploidy
  • B-lymphoblastic leukemia/lymphoma with t(5;14)(q31.1;q32.3);  IL3-IGH
  • B-lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3);  TCF3-PBX1
  • Provisional entity: B-lymphoblastic leukemia/lymphoma,  BCR-ABL1-like
  • Provisional entity: B-lymphoblastic leukemia/lymphoma with  iAMP21

T-lymphoblastic leukemia/lymphoma

  • Provisional entity: Early T-cell precursor lymphoblastic leukemia
  • Provisional entity: Natural killer (NK) cell lymphoblastic leukemia/lymphoma

Immunohistochemistry

A 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 performed by flow cytometric demonstration of lymphoid antigens, such as CD3 (T-lineage ALL) or CD19 (B-lineage ALL).

Flow Cytometry and Cytogenetics

Although 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]).

Flow cytometry helps to distinguish B-ALL from T-ALL. A classic phenotype for B-ALL is seen in the diagram below. Flow cytometry can also identify whether patients are eligible for certain therapies, e.g. CD20 (rituximab), and CD22 (inotuzumab). Some patients with ALL have aberrant expression of myeloid markers, such as CD13 or CD33.

Diagnostic workup of a patient with pre–B-cell acute lymphoblastic leukemia. Flow cytometry shows that the cells were positive for CD10, CD19, CD22, CD34, and terminal deoxynucleotidyl transferase.

Pre–B-cell acute lymphoblastic leukemia: Flow cyto Pre–B-cell acute lymphoblastic leukemia: Flow cytometry of bone marrow shows that the cells are 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)

Abnormality

Genes Involved

3-Year Event-Free Survival

t(10;14)(q24;q11)

HOX11/TCRA

75%

6q

Unknown

47%

14q11

TCRA/TCRD

42%

11q23

MLL

18-26%

9p

Unknown

22%

12

TEL

20%

t(1;19)(q23;p13)

PBX1/E2A

20%

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-abl

5-10%*

66%‡

t(4;11)(q21;q23)

AF4-MLL

0-10%

* 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 Cells

TdT

CD19

CD10

CyIg

SIg

Early B-precursor ALL

+

+

-

-

-

Pre–B-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 Cells

TdT

Surface CD3

CD4/CD8

Early T-precursor ALL

+

-

+/+ or -/-

T-cell ALL

+

+

+/- or -/+

Polymerase Chain Reaction or Cytogenetics

Studies for bcr-abl analysis by polymerase chain reaction (PCR) or cytogenetics may help distinguish patients with Philadelphia chromosome–positive 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.

Lumbar Puncture

Lumbar puncture (LP) is used to evaluate CNS involvement. In pediatric patients, LP is typically included in the diagnostic workup. National Comprehensive Cancer Network (NCCN) guidelines advise that timing of LP should be consistent with the chosen treatment regimen, and recommend performing LP concurrently with initial intrathecal therapy.[19]

CNS status is classified as follows, on the basis of cerebrospinal fluid (CSF) findings[19] :

  • CNS-1: No lymphoblasts in CSF, regardless of white blood cell (WBC) count
  • CNS-2: WBC < 5/mcL in CSF with presence of lymphoblasts
  • CNS-3: WBC ≥5/mcL in CSF with presence of lymphoblasts

If the patient has leukemic cells in the peripheral blood and the LP is traumatic and WBC ≥5/mcL in CSF with blasts, CNS status is determined by comparing the WBC/red blood cell (RBC) ratio in the CSF to the WBC/RBC ratio in the blood. If the CSF ratio is at least two-fold greater than the blood ratio, the classification is CNS-3; if not, it is CNS-2. 

 

Treatment

Approach Considerations

Acute 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.

Examples of commonly used regimens include the following:

  • Hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin [Adriamycin], and dexamethasone) [27]
  • CALGB 8811 regimen [28]
  • GRAALL-2005 regimen [29]
  • Linker 4-drug regimen [30]
  • MRC UKALLXII/ECOG2993 regimen [31]
  • ALL-216

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 Chemotherapy

Standard induction therapy typically involves either a four-drug regimen of vincristine, prednisone, an anthracycline, and cyclophosphamide or L-asparaginase or a five-drug regimen of vincristine, prednisone, an 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.

An alternative is the hyper-CVAD regimen, which is based on the success achieved with short-term, dose-intensive chemotherapy regimens in children. It incorporates hyperfractionated cyclophosphamide and intensive doses of cytarabine (Ara-C) and methotrexate in combination with dexamethasone and vincristine.

Maintenance therapy consists of prednisone, vincristine (Oncovin), methotrexate, and mercaptopurine (Purinethol) (ie, POMP protocol). From 1992-2000, 288 patients received hyper-CVAD at MD Anderson Cancer Center; of those, 17% of patients had  Philadelphia chromosome–positive (Ph+) ALL, and 13% had T-cell ALL.[27] 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.[27]

Newer modifications of the hyper-CVAD regimen include the addition of a tyrosine kinase inhibitor in patients whose leukemia is Ph+, and of rituximab in patients whose leukemia is CD20 positive (see below). Both of these approaches have resulted in improvements in disease-free survival.

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.

Patients with CD20+ lymphoblasts benefit from the addition of rituximab. Maury et al randomly assigned adults (18 to 59 years of age) with CD20-positive, Philadelphia chromosome (Ph)–negative  (Ph-) ALL to receive chemotherapy with or without rituximab, with event-free survival as the primary end point[32] . Rituximab was given during all treatment phases, for a total of 16 to 18 infusions. After a median follow-up of 30 months, event-free survival was longer in the rituximab group than in the control group (hazard ratio, 0.66; 95% confidence interval, 0.45 to 0.98; P=0.04), and the estimated 2-year event-free survival rates were 65% and 52%, respectively.

Consolidation Therapy

The 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.[33]

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.[34] 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.[35] 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.[35]

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. Patients who receive hyper-CVAD induction receive alternating cycles of high-dose methotrexate/high-dose Ara-c and hyper-CVAD as consolidation therapy.

Maintenance Therapy

The 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.[36] 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.[37]

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.[38]

Patients who receive hyper-CVAD induction therapy usually receive POMP as maintenance therapy.

The percentage of patients who complete consolidation and maintenance therapy has declined recently as more patients are referred for transplant while they are in first remission. The frequency of transplant has increased with the use of alternative donors (unrelated, cord blood, and haploidentical), which make it unlikely that a patient will not be able to find a donor.

CNS Prophylaxis

In contrast to patients with acute myeloid 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.[39]

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  (hyper-CVAD).[39] All subjects received intrathecal chemotherapy starting in induction. High-risk subjects received 16 intrathecal treatments, and low-risk subjects received four intrathecal treatments.

Treatment of Mature B-Cell ALL

Mature 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.

Short-term intensive therapies show improved results. A report of the hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone)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).[40]

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.[40] 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 plus rituximab resulted in an overall 3-year survival of 80% compared with 50% for historical controls treated without rituximab.[41]

Treatment of Ph Chromosome–Positive ALL

In the past, Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL) was treated with the same regimens as other types of ALL, with poor results. However, tyrosine kinase inhibitors that inhibit the bcr-abl fusion protein of Ph+ ALL allow targeted therapy of this disease.

Imatinib

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.[42] . Longer-term follow-up demonstrated that the 5-year overall survival rate for all patients was 43%.[43]

In the German Multicenter ALL (GMALL) trial—a randomized study of imatinib versus standard induction therapy for patients older than 55 years with Ph+ ALL—the overall complete remission (CR) rate was 96.3% in patients assigned to imatinib and 50% in patients allocated to standard chemotherapy.[44] 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.[44]

The Ph+ arm of the UKALLXII/ECOG2993 study for adult ALL enrolled 266 patients between 1993 and 2003 (pre-imatinib cohort)[45] . In 2003, imatinib was introduced as a single-agent course following induction (N = 86, late imatinib). In 2005, imatinib was added to the second phase of induction (N = 89, early imatinib). The CR rate was 92% in the imatinib cohort vs 82% in the preimatinib cohort (P = .004). At 4 years, the overall survival of all patients in the imatinib cohort was 38% vs 22% in the preimatinib cohort (P = 0.003).

The CALGB 10001 trial studied whether the addition of imatinib to chemotherapy could improve the outcome of autologous transplantation in Ph+ ALL such that the results could be comparable to allogeneic transplantation.[46]  In this study of 58 patients, overall survival (median 6.0 years vs not reached) and disease-free survival (median 3.5 vs 4.1 years) were similar between those who underwent autologous and those who underwent allogeneic stem cell transplantation. The authors concluded that autologous stem cell transplantation represented an alternative to allogeneic stem cell transplantation in patients without sibling donors.

Several other studies have demonstrated improved outcomes with the addition of imatinib to chemotherapy.[47, 48, 49]

Nilotinib

Nilotinib is a tyrosine kinase inhibitor that has a higher binding affinity and selectivity for the ABL kinase than imatinib.[50] 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+ ALL, complete responses were reported in 24% of patients treated with nilotinib.[50]  

Although nilotinib is approved in the relapsed/refractory setting there are few trials of nilotinib in combination with chemotherapy for newly diagnosed Ph+ ALL. Kim et al reported on 90 patients (ages 17 to 71 years) who received induction treatment with vincristine, daunorubicin, prednisolone, and nilotinib. After achieving complete hematologic remission, subjects received either 5 courses of consolidation, followed by 2-year maintenance with nilotinib, or allogeneic stem cell transplantation. The CR rate was 91% and the cumulative MR5 rate was 94%. The 2-year relapse-free survival rate was 72% and the 2-year overall survival rate was 72%.[51]  

Dasatinib

Dasatinib is a potent, orally active inhibitor of the BCR-ABL, c-KIT and the SRC family of kinases.[52] 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.

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.[53] 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.

Ravandi et al reported the long-term follow-up results of hyper-CVAD plus dasatinib for the initial treatment of patients with Ph+ ALL[54] . Patients received dasatinib with 8 cycles of alternating hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone and high-dose cytarabine and methotrexate. Patients in complete remission (CR) continued maintenance dasatinib, vincristine, and prednisone for 2 years, which was followed by dasatinib indefinitely. Patients eligible for allogeneic stem cell transplantation (SCT) received it during their first CR. Seventy-two patients with a median age of 55 years were treated; 96% achieved CR. Sixty-five patients (94%) were negative for minimal residual disease assessed by flow cytometry at a median of 3 weeks (range, 2-37 weeks). Dasatinib-related grade 3 and 4 adverse events included bleeding, pleural/pericardial effusions, and elevated transaminases. The median disease-free survival and overall survival were 31 (range, 0.3-97 months) and 47 months (range, 0.2-97 months), respectively.

Rousellot et al reported a European Working Group on Adult ALL (EWALL) study of dasatinib and low-intensity chemotherapy in elderly patients with Philadelphia chromosome-positive ALL[55] . Patients older than age 55 years treated with dasatinib 140 mg/day (100 mg/day over 70 years) with intrathecal chemotherapy, vincristine, and dexamethasone during induction. Patients in complete remission continued consolidation with dasatinib, sequentially with cytarabine, asparaginase, and methotrexate for 6 months. Maintenance therapy was dasatinib and vincristine/dexamethasone reinductions for 18 months followed by dasatinib until relapse or death. The complete remission rate was 96% and 65% of patients achieved a 3-log reduction in BCR-ABL1 transcript levels during consolidation. At 5 years, overall survival was 36%.

Ponatinib

Ponatinib (Iclusig), a kinase inhibitor, was approved by the US Food and Drug Administration (FDA) in December 2012 for patients with Ph+ ALL, including those with the T315I mutation, who have shown resistance to or intolerance of tyrosine kinase inhibitor therapy. After studies showed that ponatinib poses a high risk for thromboembolic events, its use was restricted to adults with T315I-positive Ph+ ALL, and adults with Ph+ ALL for whom no other tyrosine kinase inhibitor therapy is indicated.[56]

Ph+ ALL is a much more life-threatening disease than chronic myeloid leukemia. Thus, it is possible that the increased potency of ponatinib could justify the toxicity in patients with ALL.  

Sasaki et al studied hyper-CVAD plus ponatinib (47 patients) versus hyper-CVAD plus dasatinib (63 patients) as frontline therapy for patients with Ph+ ALL.[57]  With propensity score matching, the 3-year  event-free survival rates for patients treated with hyper-CVAD plus ponatinib and hyper-CVAD plus dasatinib were 69% and 46%, respectively (P =0.04), and the 3-year OS rates were 83% and 56%, respectively (P =0.03). Patients treated with hyper-CVAD plus ponatinib had significantly higher rates of minimal residual disease negativity by flow cytometry on day 21, complete cytogenetic response at complete response, major molecular response at complete response and at 3 months, and complete molecular response at 3 months.

Treatment of the Younger Adult

Older children and younger adults with acute lymphoblastic leukemia (ALL) can be referred to either adult or pediatric hematologists. In the past, patients were treated with either an adult or pediatric regimen based on the referral pattern. However, several studies suggested that younger adult patients were best treated on pediatric protocols. This has resulted in the use of pediatric-style regimens in younger adult patients.

Stock et al performed a retrospective comparison of presenting features, planned treatment, complete remission (CR) rate, and outcome in 321 adolescents and young adults (AYAs) ages 16 to 20 years with newly diagnosed ALL who were treated in consecutive trials in either the Children's Cancer Group (CCG) or the Cancer and Leukemia Group B (CALGB) from 1988 to 2001. CR rates were identical, 90% for both CALGB and CCG AYAs. CCG AYAs had a 63% event-free survival (EFS) and 67% overall survival at 7 years in contrast to the CALGB AYAs, in which 7-year EFS was only 34% (P < 0.001) and OS was 46% (P < 0.001)[58] .

In a retrospective analysis of patients aged 15-20 years treated on either the FRALLE 93 or LALA 94 trials, the CR rate was 94% for patients receiving the pediatric regimen (FRALLE 93) compared with 83% for those receiving the adult regimen (LALA 94).[59] 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.[59]

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.[60]

Deangelo et al treated adult patients aged 18-50 years with ALL with the DFCI Pediatric ALL Consortium regimen utilizing a 30-week course of pharmacokinetically dose-adjusted E. coli L-asparaginase during consolidation. Between 2002 and 2008, 92 eligible patients aged 18-50 years were enrolled. Seventy-eight patients (85%) achieved a CR after 1 month of intensive induction therapy. With a median follow-up of 4.5 years, the 4-year disease-free survival for the patients achieving a CR was 69% and the 4-year overall survival for all eligible patients was 67%.

Seftel et al. compared 422 HCT recipients aged 18-50 years with Ph-ALL in CR1 reported to the CIBMTR with an age-matched concurrent cohort of 108 Ph- ALL CR1 patients who received a Dana-Farber Consortium pediatric-inspired non-HCT regimen. At 4 years of follow-up, the incidence of relapse after HCT was 24% versus 23% for the non-HCT (chemo) cohort (P=0.97). Treatment-related mortality (TRM) was higher in the HCT cohort (37%) versus chemo (6%), P< 0.0001. DFS in the HCT cohort was 40% versus 71% for chemo, P< 0.0001. Similarly, OS favored chemo (HCT 45%) versus chemo (73%), P< 0.0001.

Alabdulwahab et al compared patients < 50 years treated on the Dana Farber consortium protocol (DFCP) vs. classic Hyper-CVAD for treatment of ALL. The CR rate was 90.7% for DFCP vs. 83.7 for hyper-CVAD (P = 0.7). Three-year leukemia-free survival was 70.9% for DFCP vs. 41.6% for hyper-CVAD (P= 0.1), while 3-year OS was 72.6% for DFCP vs. 48.5% for hyper-CVAD (P= 0.04).

However Rytting et al compared the results inof 106 AYA patients (median age 22 years) who received augmented Berlin-Frankfurt-Münster (BFM) to 102 AYA patients (median age 27 years) who received hyper-CVAD.[61]  The CR rate was 93% with augmented BFM and 98% with hyper-CVAD. The 5-year complete remission durations were 53 and 55%, respectively (P = 0.98). The 5-year overall survival rates were 60 and 60%, respectively. Severe regimen toxicities with augmented BFM included hepatotoxicity in 41%, pancreatitis in 11%, osteonecrosis in 9%, and thrombosis in 19%. Myelosuppression-associated complications were most significant with hyper-CVAD.

Randomized trials are needed to confirm any advantage the pediatric-style regimens may have.

Transplantation

In current practice, most adult patients (except the most elderly and those with significant comorbidities) are offered allogeneic transplantation in first remission. The use of alternative donors (including matched unrelated donors, cord blood, and haploidentical donors) allows for most patients to have an appropriate donor.

However, as nontransplant therapies have improved, controversy has arisen as to whether transplantaiton is always needed. Examples include the addition of tyrosine kinase inhibitors in Philadelphia chromosome–positive (Ph+) ALL, and the addition of rituximab in mature B-cell ALL.

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 bone marrow transplantation (BMT).[62] The remaining subjects received methylprednisolone, Ara-C, mitoxantrone, and etoposide chemotherapy followed by autologous BMT.

For subjects undergoing allogeneic 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.[62]

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%).[63] 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.[64] The other subjects were randomized to receive autologous BMT or chemotherapy. Overall, no difference in was observed in 5-year survival between the groups.[64]

However, when only high-risk patients were considered (ie, Ph+, null ALL; >35 y; white blood cell [WBC] count >30,000/µL; or time to CR >4 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%).[64] 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.

In the GOELAL02 study, patients with any high-risk feature (age >35 y, non–T-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 superior in patients receiving allogeneic transplantation (75%) compared with those receiving autologous transplantation (40%).[62]

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.[65]

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%).[65] 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.[66] 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.[66]

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.

For 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.[67] In patients whose disease was in second CR, URD transplantations resulted in a superior rate of disease-free survival.[67]

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)[68, 69] ; 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 ALL

Patients with relapsed acute lymphoblastic leukemia (ALL) have an extremely poor prognosis. Most patients are referred for investigational therapies. Patients who have not previously undergone transplantation are referred for such therapy, preferably after obtaining a complete response to salvage therapy. Reinduction regimens include standard chemotherapy regimens (similar to the front-line setting), novel chemotherapeutic agents or immunotherapies (blinatumomab, inotuzumab ozogamicin, or tisagenlecleucel). Patients with Ph+ disease generally receive a tyrosine kinase inhibitor either alone or in combination with other therapies. 

The choice of therapy a patient will receive depends on the following:

  • The front-line regimen they received
  • The duration of prior remission
  • Whether the patient relapsed after transplantation
  • The comorbidities that the patient has

Standard chemotherapy regimens that are commonly used in the relapsed setting include hyper-CVAD, other high-dose cytarabine-based regimens, and MOAD (methotrexate, vincristine, asparaginase, and dexamethasone).  

Newer agents that are approved in the salvage setting are listed below. These are used either alone or in combination with other agents.

Clofarabine

In December 2004, the US Food and Drug Administration (FDA) granted accelerated approval for clofarabine, a novel nucleoside analogue, for the treatment of pediatric patients with refractory or relapsed ALL. Two open-label, multicenter, nonrandomized phase II trials established the efficacy and safety profile of clofarabine in that patient population. In one study of 61 patients (median age, 12 years; range, 1-20 years), the response rate to clofarabine was 30% (seven CRs, five CRs without platelet recovery, and six partial remissions), and remissions lasted long enough to allow patients to proceed to hematopoietic stem-cell transplantation (HSCT).[70]

In a second study in 42 patients (median age, 13 years; range, 2-22 years), the response rate was 26% and included one complete response without platelet recovery and 10 partial responses. The median duration of response was 20 weeks.[71]

Nelarabine

In October 2005, the FDA granted accelerated approval for nelarabine for the treatment of T-cell ALL (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) in patients whose disease had not responded to or relapsed following treatment with at least two chemotherapy regimens. Approval was based on two phase II trials, one conducted in pediatric patients and the other in adult patients. In the pediatric trial, of the 39 patients who had relapsed or had been refractory to two or more induction regimens, 5 patients (13%) had a CR and 9 patients (23%) had a CR with incomplete hematologic or bone marrow recovery.[72]

Vincristine liposomal

In August 2012, the 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.[73]

Blinatumomab

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. BiTE antibodies enable CD3-positive T cells to recognize and eliminate CD19-positive ALL blasts. Approval of blinatumomab was based on results of a phase 2, multicenter, single-arm open-label study in which 77 (41.6%) of 185 adult patients achieved complete remission or complete remission with partial hematologic recovery within 2 cycles of treatment with blinatumomab.[74, 75]

A phase III trial in 405 adults with heavily pretreated B-cell precursor ALL found that treatment with blinatumomab (n = 271) resulted in significantly longer overall survival than treatment with chemotherapy (n = 134). Event-free survival estimates at 6 months were 31% with blinatumomab versus 12% with chemotherapy, and median duration of remission was 7.3 vs. 4.6 months, respectively. A total of 24% of the patients in each treatment group underwent allogeneic HSCT.[76]

Inotuzumab

In August 2017, inotuzumab was FDA approved for relapsed or refractory B-cell precursor ALL. Approval was based on findings from the phase III INO-VATE trial, which compared inotuzumab  one of the following three standard regimens: FLAG (fludarabine, cytarabine, and granulocyte colony-stimulating factor) for up to four 28-day cycles, cytarabine plus mitoxantrone for up to four 15-20 day cycles, and mitoxantrone as a single agent.[77]

The risk of progression or death was reduced by 55% with inotuzumab versus standard therapy. Overall, a CR or CR with incomplete hematologic recovery (CR/CRi) was experienced by 80.7% in the inotuzumab arm versus 29.4% with chemotherapy. In those who achieved a CR/CRi, 78.4% were minimal residual disease negative with inotuzumab versus 28.1% for chemotherapy. For patients who were receiving their first salvage therapy, the CR/CRi rate was 87.7% with inotuzumab versus 28.8% with chemotherapy. In the second salvage therapy setting, the CR/CRi rate with inotuzumab was 66.7% versus 30.6% with chemotherapy.[77]

Gene Therapy

Chimeric antigen receptor (CAR) T-cell therapy is a treatment in which the patient's own T-cells are collected from peripheral blood and genetically engineered to express a CAR that targets a specific molecule on the cancer cells. The modified T-cells are then expanded and reinfused into the patient, after lymphodepletion with conditioning chemotherapy.[78]

Studies of treatment with CAR T-cells targeting CD19 have reported high rates of complete and long-lasting remissions in patients with refractory acute lymphoblastic leukemia (ALL). Toxicities, which can be fatal, include cytokine release syndrome (CRS), B-cell aplasia, and cerebral edema.[78]  

In August 2017, the US Food and Drug Administration (FDA) approved the anti-CD19 CAR T-cell therapy agent tisagenlecleucel (Kymriah) for the treatment of patients up to 25 years of age with B-cell precursor ALL that is refractory or in second or later relapse. Because of the risk of adverse effects, the FDA approval includes a risk evaluation and mitigation strategy, which requires special certification for hospitals and clinics that administer the treatment and additional training for their physicians and other staff.[79, 80]

Approval of tisagenlecleucel was based on the results of an open-label, muticenter single-arm trial (Study B2202) that included 88 children and young adults (median age, 12 years) with relapsed or refractory B-cell ALL. Of the treated patients evaluable for efficacy, 52 of 63 responded; of those, 40 patients (63%) had a complete response within the first 3 months after infusion, and 12 (19%) had a complete remission with incomplete blood count recovery. All of those had minimum residual disease–negative status in the bone marrow.[81]

In conjunction with the approval of tisagenlecleucel, the FDA  also expanded the approval of tocilizumab to include the treatment of severe or life-threatening CRS resulting from CAR T-cell therapy in patients 2 years of age or older. In clinical trials, 69% of patients with CRS related to CAR T-cell therapy had complete resolution of CRS within 2 weeks after receiving one or two doses of tocilizumab.[80]

Supportive Care - Blood Products

Patients 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-related graft 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/µL. Patients with pulmonary or gastrointestinal hemorrhage receive platelet transfusions to maintain a value greater than 50,000/µL. Patients with central nervous system CNS hemorrhage are transfused to achieve a platelet count of 100,000/µL.

Fresh frozen plasma is given to patients with a significantly prolonged prothrombin time (PT). Cryoprecipitate is given if the fibrinogen level is less than 100-125 g/dL.

Supportive Care: Therapy and Prophylaxis for Infection

Antibiotics are given to all febrile patients. At a minimum, include a third-generation cephalosporin (or equivalent). 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), voriconazole (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 Factors

The 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/µL (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.[82] No difference was observed in response, remission duration, or survival between the 2 groups.[82]

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.[83] 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.[83]

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.[84]

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.[85] 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.[85]

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.[86]

Hyperuricemia and Tumor Lysis Syndrome

Tumor 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 level with rasburicase alone (4 h) or rasburicase followed by allopurinol (4 h) than with allopurinol alone (27 h).[87]

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.

 

Guidelines

Guidelines Summary

The National Comprehensive Cancer Network (NCCN) provides frequently updated recommendations for the diagnosis and management of acute lymphoblastic leukemia (ALL), along with surveillance milestones or algorithms to monitor response to treatment. The guidelines are further delineated to address differences in the management of adolescent and young adults (AYA), ages 15 to 39 years, from adults 40 years and older. However, the guidelines caution that regardless of chronological age, patients need to be evaluated individually to determine fitness for treatment.[19]

In 2017, the College of American Pathologists and the American Society of Hematology (CAP/ASH) issued guidelines on the initial diagnostic workup of acute leukemia (AL).[88]

In 2016, the European Society for Medical Oncology (ESMO) released updated guidelines for the management of ALL.[89]

Diagnosis and Risk Stratification

CAP/ASH guidelines on the workup of AL include the following recommendations[88] :

  • A complete diagnosis of AL requires knowledge of clinical information combined with morphologic evaluation, immunophenotyping and karyotype analysis, and, often, molecular genetic testing.
  • The treating clinician should provide relevant clinical data, including physical examination and imaging findings, or ensure that those data are readily accessible by the pathologist.
  • The pathologist should review recent or concurrent complete blood cell (CBC) counts and leukocyte differentials and evaluate a peripheral blood (PB) smear.
  • Obtain a fresh bone marrow (BM) aspirate for all patients suspected of AL, a portion of which should be used to make BM aspirate specimens for morphologic evaluation. If performed, the pathologist should evaluate an adequate BM trephine core biopsy, BM trephine touch preparations, and/or marrow clots, in conjunction with the BM aspirates.
  • In addition to morphologic assessment (blood and BM), obtain sufficient samples and perform conventional cytogenetic analysis (ie, karyotype), appropriate molecular-genetic and/or fluorescence in situ hybridization (FISH) testing, and flow cytometry immunophenotyping (FCIp). The flow cytometry panel should be sufficient to distinguish acute myeloid leukemia (including acute promyelocytic leukemia), T-ALL (including early T-cell precursor leukemias), B-cell precursor ALL (BCP-ALL), and AL of ambiguous lineage for all patients diagnosed with AL. Molecular genetic and/or FISH testing does not, however, replace conventional cytogenetic analysis.
  • For patients with suspected or confirmed AL, cytochemical studies to assist in the diagnosis and classification of acute myeloid leukemia (AML) may be requested and evaluated.
  • The treating clinician or pathologist may use cryopreserved cells or nucleic acid, nondecalcified formalin fixed paraffin-embedded (FFPE) tissue, or unstained marrow aspirate or PB specimens obtained and prepared from PB, BM aspirate, or other involved tissues for molecular or genetic studies in which the use of such material has been validated.
  • For patients with ALL receiving intrathecal therapy, a cerebrospinal fluid (CSF) sample should be obtained. The treating clinician or pathologist should ensure that a cell count is performed and that examination/enumeration of blasts on a cytocentrifuge preparation is performed and is reviewed by the pathologist.
  • For patients with suspected or confirmed AL, the pathologist may use flow cytometry in the evaluation of CSF.
  • For patients who present with extramedullary disease without BM or blood involvement, a tissue biopsy should be evaluated and processed for morphologic, immunophenotypic, cytogenetic, and molecular genetic studies, as recommended for the BM.
  • For pediatric patients with suspected or confirmed B-ALL, ensure testing for t(12;21)(p13.2;q22.1); ETV6-RUNX1, t(9;22)(q34.1;q11.2); BCR-ABL1, KMT2A (previously MLL) translocation; iAMP21; and trisomy 4 and 10 is performed.
  • For adult patients with suspected or confirmed B-ALL, ensure testing for t(9;22)(q34.1;q11.2) and BCR-ABL1. In addition, testing for KMT2A (previously MLL) translocations may be performed.

NCCN guidelines note that diagnosis of ALL generally requires the following[19] :

  • Demonstration of ≥20% bone marrow lymphoblasts
  • Morphologic assessment of Wright/Giemsa–stained bone marrow aspirate smears
  • Hematoxylin and eosin (H&E)–stained bone marrow core biopsy and clot sections
  • Comprehensive flow cytometric immunophenotyping

For 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[19] :

  • Cytogenetics – Karyotyping of G-banded metaphase chromosomes
  • Interphase FISH
  • Reverse transcriptase polymerase chain reaction (RT-PCR) for fusion genes (eg,  BCR-ABL)

The NCCN considers tests for hyperdiploidy and hypodiploidy to be optional.

NCCN recommendations for the initial workup include the following:

  • History and physical
  • CBC, platelets, differential
  • Chemistry profile
  • Disseminated intravascular coagulation (DIC) panel
  • Tumor lysis syndrome panel
  • Computed tomography/magnetic resonance imaging (CT/MRI) of head with contrast, if neurologic symptoms
  • Lumbar puncture
  • CT of chest with contrast (for patients with T-ALL), plus baseline positron emission tomography (PET) imaging for patients with a mediastinal mass
  • Testicular exam
  • Infection evaluation: Screen for active infections if febrile or for symptomatic opportunistic infections
  • Consider echocardiogram or cardiac scan, especially in patients with prior cardiac history and prior anthracycline exposure or clinical symptoms suggestive of cardiac dysfunction.
  • Central venous access device of choice
  • Human leukocyte antigen (HLA) typing (except for patients with a major contraindication to hematopoietic cell transplant)

The ESMO recommendations concur with those of NCCN while noting that the initial diagnostic workup should be completed quickly and before any chemotherapy is administered in order to accomplish the following[89] :

  • Confirm diagnosis and shorten time to onset of treatment

  • Distinguish BCP-ALL from T-ALL

  • Distinguish Burkitt leukemia (B-ALL) from BCP-ALL 

  • Distinguish Philadelphia (Ph) chromosome-positive (Ph+) ALL from Ph-negative (Ph−) ALL 

Treatment strategies

As a general rule, the NCCN recommends enrolling patients with ALL in a clinical trial, if possible. Otherwise, NCCN recommendations for first-line treatment are based on risk stratification and age, as follows[19]

  • Philadelphia chromosome–positive (Ph+) ALL (in AYA): Chemotherapy and tyrosine kinase inhibitor (TKI), followed by allogeneic stem cell transplantation (SCT) if an appropriate donor is available; if transplantation is not feasible, continue multiagent chemotherapy and a TKI

  • Ph+ ALL (adults < 65 y): Chemotherapy and tyrosine kinase inhibitor (TKI); consider allogeneic SCT if an appropriate donor is available and the patient has good performance status and no or limited comorbidities; if transplantation is not feasible, continue multiagent chemotherapy and a TKI

  • Ph+ ALL (adults ≥65 y or with substantial comorbidities): TKI and corticosteroids or TKI and chemotherapy (evaluate end-organ reserve, end-organ dysfunction, and performance status)

  • Ph- ALL (AYA): Pediatric-style multiagent chemotherapy

  • Ph- ALL (Adults < 65 y): Multiagent chemotherapy

  • Ph- ALL (Adults ≥ 65 or with substantial comorbidities): Multiagent chemotherapy or corticosteroids (evaluate end-organ reserve, end-organ dysfunction)

NCCN strongly recommends central nervous system (CNS) prophylaxis for all ALL treatment groups.

Stem cell transplantation

In 2012, the American Society for Blood and Marrow Transplantation (ASBMT) updated its treatment recommendations for SCT in adults with ALL, based on new evidence. The updated recommendations include the following[90] :

  • Myeloblative allogeneic SCT is an appropriate treatment for adults younger than 35 years, in all risk groups during the first complete remission

  • Allogeneic SCT is recommended over chemotherapy for all adults with ALL during the second or subsequent complete remission

  • Allogeneic SCT is preferred over autologous SCT, with similar outcomes for related and unrelated allogeneic SCT

  • Imatinib therapy before and/or after SCT for Ph+ ALL results in higher survival rates

The 2016 ESMO guidelines include the following recommendations[89] :

  • Autologous SCT is not recommended outside of clinical trials
  • Allogeneic SCT is recommended after first complete remission in all patients with poor minimal residual disease, but not recommended for standard-risk patients with a sustained molecular response
  • After the second complete remission, allogeneic SCT was found superior to non-transplantation
  • Cord blood transplantation may be considered if no HLA-well-matched donor is found or the patient needs urgent SCT
  • Total body irradiation regimens are recommended for myeloablative SCT; reduced-intencity conditioning regimens should be used only in adults in remission unfit for myeloablative conditioning and elderly fit patients
 

Medication

Medication Summary

Antineoplastic 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
  • Drug therapies for relapsed or refractory ALL include cell-based gene therapy and reinduction regimens
  • 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 chemotherapy

Corticosteroids

Class Summary

Corticosteroids may be used during induction, consolidation, and/or maintenance therapy for acute lymphoblastic leukemia (ALL).

Prednisone (Deltasone, Rayos)

Prednisone is a corticosteroid that has a wide range of activities. In ALL, this agent is used because of its direct antileukemic effects.

Dexamethasone (DexPak, LoCort, ZonaCort)

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.

Antineoplastics

Class Summary

Antineoplastic 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.

Vincristine (Vincasar PFS)

Vincristine is a vinca alkaloid agent that acts by arresting cells in metaphase.

Vincristine 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.

Asparaginase 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.

Pegaspargase (Oncaspar)

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.

Methotrexate (Trexall, Xatmep, Otrexup, Rasuvo)

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.

Mercaptopurine (Purinethol)

Mercaptopurine is antimetabolite of the purine analogue type. Its primary effect is inhibition of DNA synthesis.

Cyclophosphamide

Cyclophosphamide is an alkylating agent of the nitrogen mustard type that acts by inhibiting cell growth and proliferation.

Cytarabine

Cytosine 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.

Daunorubicin (Cerubidine)

Daunorubicin is an anthracycline that inhibits topoisomerase II. This agent also inhibits DNA and RNA synthesis by intercalating between DNA base pairs.

Idarubicin (Idamycin)

Idarubicin is a topoisomerase II inhibitor that inhibits cell proliferation by inhibiting DNA and RNA polymerase.

Mitoxantrone (Novantrone)

Mitoxantrone is also a topoisomerase II inhibitor. This agent inhibits cell proliferation by intercalating DNA and inhibiting topoisomerase II.

Nelarabine (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-cell–selective 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.

Clofarabine (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.

Inotuzumab (Besponsa)

Inotuzumab is a CD22-directed antibody-drug conjugate (ADC) indicated for relapsed or refractory B-cell precursor acute lymphoblastic leukemia. Recognizes human CD22. The small molecule, N-acetyl-gamma-calicheamicin, is a cytotoxic agent which covalently attaches to antibody via a linker. Data suggest anticancer activity of inotuzumab ozogamicin is due to binding of ADC to CD22-expressing tumor cells, followed by internalization of ADC-CD22 complex, and ultimately activating N-acetyl-gamma-calicheamicin 19 dimethylhydrazide, which induces double-strand DNA breaks, subsequently inducing cell cycle arrest and apoptotic cell death.

Tyrosine Kinase Inhibitors

Class Summary

Philadelphia chromosome-positive (Ph+) ALL is treated with tyrosine kinase inhibitors. These agents provide targeted therapy by inhibiting the BCR-ABL fusion protein.

Imatinib (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.

Nilotinib (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.

Dasatinib (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.

Ponatinib (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.

Antineoplastic agents, Anti-CD19/CD3

Class Summary

Bispecific T cell engager antibodies are a type of immunotherapy that assist’s 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.

Blinatumomab (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.

CAR T-Cell Therapies

Class Summary

In chimeric antigen receptor (CAR) T-cell therapy, autologous T-cells are collected from peripheral blood and genetically engineered to express a CAR that targets a specific molecule on cancer cells. The modified T-cells are then expanded and reinfused into the patient, after lymphodepletion with conditioning chemotherapy.

Tisagenlecleucel (Kymriah)

CD19-directed genetically modified autologous T-cell immunotherapy indicated for patients aged 25 years or younger with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse.

Antimicrobials

Class Summary

Prophylactic antimicrobial drugs are given to prevent infection in patients receiving chemotherapy.

Trimethoprim-sulfamethoxazole (Bactrim, Bactrim DS)

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).

Immunomodulators

Class Summary

Immunomodulators (eg, interleukin 6 [IL-6] inhibitors) may be needed for therapies resulting in cytokine release.

Tocilizumab (Actemra)

Interleukin-6 receptor antagonist. Decreases C-reactive protein, rheumatoid factor, erythrocyte sedimentation rate, and amyloid A. It is indicated for treatment of cytokine release syndrome (CRS) resulting from tisagenlecleucel therapy. Clinical signs of CRS correlate with T-cell activation and high levels of cytokines, including interleukin 6 (IL-6).

Colony-Stimulating Factors

Class Summary

Colony-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.

Filgrastim (Neupogen, Granix, Zarxio)

Filgrastim is a granulocyte colony-stimulating factor (G-CSF) that activates and stimulates the production, maturation, migration, and cytotoxicity of neutrophils.

Pegfilgrastim (Neulasta, Neulasta Onpro)

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.

Antifungals

Class Summary

These agents may change the permeability of the fungal cell, resulting in a fungicidal effect.

Nystatin (Bio-Statin)

Nystatin 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.

Clotrimazole

Clotrimazole 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.

Itraconazole (Onmel; Sporanox; Sporanox Pulsepak)

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.

 

Questions & Answers

Overview

What are the signs and symptoms of acute lymphoblastic leukemia (ALL)?

What is acute lymphoblastic leukemia (ALL)?

Which tests and studies are performed in the evaluation of acute lymphoblastic leukemia (ALL)?

How is the treatment of acute lymphoblastic leukemia (ALL) stratified?

What are the treatment options for treatment of newly-diagnosed acute lymphoblastic leukemia (ALL)?

Which factors require consideration in the treatment selection for acute lymphoblastic leukemia (ALL)?

What is the pathophysiology of acute lymphoblastic leukemia (ALL)?

What causes acute lymphoblastic leukemia (ALL)?

What is the role of an antecedent hematologic disorder (AHD) in the etiology of acute lymphoblastic leukemia (ALL)?

What is the role of genetics in the etiology of acute lymphoblastic leukemia (ALL)?

What is the prevalence of acute lymphoblastic leukemia (ALL)?

What is the prognosis of acute lymphoblastic leukemia (ALL)?

How do tumor markers affect the prognosis of acute lymphoblastic leukemia (ALL)?

How do chromosome abnormalities affect the prognosis of acute lymphoblastic leukemia (ALL)?

What does minimal residual disease (MRD) suggest in the prognosis of acute lymphoblastic leukemia (ALL)?

How do genomic findings affect the prognosis of acute lymphoblastic leukemia (ALL)?

What is included in patient education for acute lymphoblastic leukemia (ALL)?

What are activity and dietary modifications for patients with acute lymphoblastic leukemia (ALL)?

Presentation

What is the presentation of acute lymphoblastic leukemia (ALL)?

What is the most common symptom of acute lymphoblastic leukemia (ALL)?

What are the signs and symptoms of acute lymphoblastic leukemia (ALL)?

What are the symptoms of leukemic cell infiltration of the bone marrow in acute lymphoblastic leukemia (ALL)?

How common is splenomegaly present in suspected acute lymphoblastic leukemia (ALL)?

What are the symptoms of leukostasis in acute lymphoblastic leukemia (ALL)?

What does renal failure indicate in acute lymphoblastic leukemia (ALL)?

What are the physical findings characteristic of acute lymphoblastic leukemia (ALL)?

DDX

How is fever assessed in the evaluation for acute lymphoblastic leukemia (ALL)?

What are the differential diagnoses for Acute Lymphoblastic Leukemia (ALL)?

Workup

Which studies and procedures are performed in the workup of acute lymphoblastic leukemia (ALL)?

What are the National Comprehensive Cancer Network (NCCN) criteria for diagnosis of acute lymphoblastic leukemia (ALL)?

What are the NCCN guidelines for risk stratification and treatment planning in acute lymphoblastic leukemia (ALL)?

What is the role of CBC count in the workup of acute lymphoblastic leukemia (ALL)?

What is the role of coagulation studies and chemistry profiles in the workup of acute lymphoblastic leukemia (ALL)?

What is the role of blood cultures in the workup of acute lymphoblastic leukemia (ALL)?

What is the role of radiography in the workup of acute lymphoblastic leukemia (ALL)?

What is the role of cardiac imaging in the management acute lymphoblastic leukemia (ALL)?

How is a diagnosis of acute lymphoblastic leukemia (ALL) confirmed?

What is the French-American-British (FAB) classification of acute lymphoblastic leukemia (ALL)?

What is the WHO classification of acute lymphoblastic leukemia (ALL)?

How is acute lymphoblastic leukemia (ALL) classified by the WHO?

What is the immunochemistry hallmark finding of acute lymphoblastic leukemia (ALL)?

What is the role of flow cytometry in the workup of acute lymphoblastic leukemia (ALL)?

What is the prevalence of cytogenetic abnormalities in acute lymphoblastic leukemia (ALL)?

What are the distinctions of cytogenetic abnormalities in acute lymphoblastic leukemia (ALL)?

What is the role of polymerase chain reaction (PCR) in the workup of acute lymphoblastic leukemia (ALL)?

Treatment

What type of facility should provide treatment for acute lymphoblastic leukemia (ALL)?

What are the components of acute lymphoblastic leukemia (ALL) treatment?

What commonly used regimens for the treatment of acute lymphoblastic leukemia (ALL)?

When is inpatient treatment indicated for the treatment of acute lymphoblastic leukemia (ALL)?

What are the cure rates for acute lymphoblastic leukemia (ALL)?

What is included in standard induction chemotherapy for acute lymphoblastic leukemia (ALL)?

What is the role of the hyper-CVAD regimen in the treatment of acute lymphoblastic leukemia (ALL)?

What is included in maintenance therapy for acute lymphoblastic leukemia (ALL)?

What are the modified hyper-CVAD regimens for the treatment of acute lymphoblastic leukemia (ALL)?

How does the rapidity of achieving complete remission (CR) affect the prognosis of acute lymphoblastic leukemia (ALL)?

What is the role of rituximab in the treatment of acute lymphoblastic leukemia (ALL)?

What is the efficacy of consolidation chemotherapy in the treatment of acute lymphoblastic leukemia (ALL)?

Which consolidation chemotherapy regimens are used in the treatment of acute lymphoblastic leukemia (ALL)?

What is the efficacy of maintenance chemotherapy for acute lymphoblastic leukemia (ALL)?

What are the benefits of intensive maintenance therapy for acute lymphoblastic leukemia (ALL)?

Why has the prevalence of maintenance therapy for acute lymphoblastic leukemia (ALL) declined?

What is the role of CNS prophylaxis in the treatment of acute lymphoblastic leukemia (ALL)?

What is the prognosis of mature B-cell acute lymphoblastic leukemia (ALL)?

What is the efficacy of treatment for mature B-cell acute lymphoblastic leukemia (ALL)?

How is Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL) treated?

What is the role of imatinib in the treatment of Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL)?

What is the efficacy of imatinib for the treatment of Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL)?

What is the role of nilotinib in the treatment of Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL)?

What is the role of dasatinib in the treatment of Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL)?

What is the role of dasatinib in the treatment of Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL)?

What is the role of ponatinib in the treatment of Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL)?

What are the treatment options for older children and younger adults with acute lymphoblastic leukemia (ALL)?

What is the prognosis of with acute lymphoblastic leukemia (ALL) in older children and young adults?

What is the efficacy of specific pediatric regimens in the treatment of older children and young adults with acute lymphoblastic leukemia (ALL)?

What is the efficacy of pediatric regimens for the treatment of adults with acute lymphoblastic leukemia (ALL)?

What is the role of allogeneic transplantation in the treatment of acute lymphoblastic leukemia (ALL)?

What is the efficacy of transplantation for the treatment of acute lymphoblastic leukemia (ALL)?

What are survival rates of acute lymphoblastic leukemia (ALL) following allogeneic bone marrow transplantation (BMT)?

What are survival rates of high-risk acute lymphoblastic leukemia (ALL) following transplantation?

What is the efficacy of allogeneic transplantation for acute lymphoblastic leukemia (ALL) following relapse after chemotherapy?

What is the efficacy of unrelated-donor (URD) transplantation for the treatment of acute lymphoblastic leukemia (ALL)?

What are the survival rates for peripheral-blood stem transplantation for acute lymphoblastic leukemia (ALL)?

What are the treatment options for relapsed acute lymphoblastic leukemia (ALL)?

What is the basis for therapy selection in relapsed acute lymphoblastic leukemia (ALL)?

What standard chemotherapy regimens are used for the treatment of relapsed acute lymphoblastic leukemia (ALL)?

What is the role of clofarabine in the treatment of acute lymphoblastic leukemia (ALL)?

What is the role of nelarabine in the treatment of acute lymphoblastic leukemia (ALL)?

What is the role of vincristine liposomal in the treatment of acute lymphoblastic leukemia (ALL)?

What is the role of blinatumomab (Blincyto) in the treatment of acute lymphoblastic leukemia (ALL)?

What is the role of inotuzumab in the treatment of acute lymphoblastic leukemia (ALL)?

How is gene therapy used to treat acute lymphoblastic leukemia (ALL)?

What is the efficacy of gene therapy for the treatment of acute lymphoblastic leukemia (ALL)?

What is the role of blood products in the treatment of acute lymphoblastic leukemia (ALL)?

What is the role of antibiotics in the treatment of acute lymphoblastic leukemia (ALL)?

What are common prophylactic antibiotic regimens used in the treatment of acute lymphoblastic leukemia (ALL)?

What is the role of granulocyte colony-stimulating factor (G-CSF) in the treatment of acute lymphoblastic leukemia (ALL)?

What is the efficacy of granulocyte colony-stimulating factor (G-CSF) for the treatment of acute lymphoblastic leukemia (ALL)?

What are the benefits of early use of granulocyte colony-stimulating factor (G-CSF) in the treatment of acute lymphoblastic leukemia (ALL)?

What is tumor lysis syndrome in acute lymphoblastic leukemia (ALL)?

How are hyperuricemia and tumor lysis syndrome treated in acute lymphoblastic leukemia (ALL)?

What is included in long-term monitoring of acute lymphoblastic leukemia (ALL)?

Guidelines

Which organizations have issued guidelines for the diagnosis and management of acute lymphoblastic leukemia (ALL)?

What are the College of American Pathologists and the American Society of Hematology (CAP/ASH diagnostic guidelines for acute lymphoblastic leukemia (ALL)?

What are the National Comprehensive Cancer Network (NCCN) diagnostic guidelines for acute lymphoblastic leukemia (ALL)?

What are the National Comprehensive Cancer Network (NCCN) recommendations for the initial workup for acute lymphoblastic leukemia (ALL)?

What are the European Society for Medical Oncology (ESMO) recommendations for the workup for acute lymphoblastic leukemia (ALL)?

What are the NCCN recommendations for first-line treatment of acute lymphoblastic leukemia (ALL)?

What are the American Society for Blood and Marrow Transplantation (ASBMT) guidelines for stem cell transplantation (SCT) in acute lymphoblastic leukemia (ALL)?

Medications

Which medications are used in the treatment of acute lymphoblastic leukemia (ALL)?

Which medications in the drug class Antifungals are used in the treatment of Acute Lymphoblastic Leukemia (ALL)?

Which medications in the drug class Colony-Stimulating Factors are used in the treatment of Acute Lymphoblastic Leukemia (ALL)?

Which medications in the drug class Immunomodulators are used in the treatment of Acute Lymphoblastic Leukemia (ALL)?

Which medications in the drug class Antimicrobials are used in the treatment of Acute Lymphoblastic Leukemia (ALL)?

Which medications in the drug class CAR T-Cell Therapies are used in the treatment of Acute Lymphoblastic Leukemia (ALL)?

Which medications in the drug class Antineoplastic agents, Anti-CD19/CD3 are used in the treatment of Acute Lymphoblastic Leukemia (ALL)?

Which medications in the drug class Tyrosine Kinase Inhibitors are used in the treatment of Acute Lymphoblastic Leukemia (ALL)?

Which medications in the drug class Antineoplastics are used in the treatment of Acute Lymphoblastic Leukemia (ALL)?

Which medications in the drug class Corticosteroids are used in the treatment of Acute Lymphoblastic Leukemia (ALL)?