Acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is a form of leukemia, or cancer of the white blood cells characterized by excess lymphoblasts. Malignant, immature white blood cells continuously multiply and are overproduced in the bone marrow. ALL causes damage and death by crowding out normal cells in the bone marrow, and by spreading (infiltrating) to other organs. ALL is most common in childhood with a peak incidence at 25 years of age, and another peak in old age. The overall cure rate in children is about 80%, and about 45%-60% of adults have long-term disease-free survival.[1] Acute refers to the relatively short time course of the disease (being fatal in as little as a few weeks if left untreated) to differentiate it from the very different disease of chronic lymphocytic leukemia which has a potential time course of many years. It is interchangeably referred to as Lymphocytic or Lymphoblastic. This refers to the cells that are involved, which if they were normal would be referred to as lymphocytes but are seen in this disease in a relatively immature (also termed 'blast') state.

Diagnosis
Diagnosing ALL begins with a medical history, physical examination, complete blood count, and blood smears. Because the symptoms are so general, many other diseases with similar symptoms must be excluded. Typically, the higher the white blood cell count, the worse the prognosis.[2] Blast cells are seen on blood smear in majority of cases (blast cells are precursors (stem cells) to all immune cell lines). A bone marrow biopsy is conclusive proof of ALL.[3] A lumbar puncture (also known as a spinal tap) will tell if the spinal column and brain has been invaded. Pathological examination, cytogenetics (particularly the presence of Philadelphia chromosome) and immunophenotyping, establish whether the Myeloblastic (neutrophils, eosinophils or basophils) or Lymphoblastic (B lymphocytes or T lymphocytes) cells are the problem. RNA

testing can establish how aggressive the disease is; different mutations have been associated with shorter or longer survival. Immunohistochemical testing may reveal TdT or CALLA antigens on the surface of leukemic cells. TdT is a protein expressed early in the development of pre-T and pre-B cells while CALLA is an antigen found in 80% of ALL cases and also in the "blast crisis" of CML. Medical imaging (such as ultrasound or CT scanning) can find invasion of other organs commonly the lung, liver, spleen, lymph nodes, brain, kidneys and reproductive organs.[4]

Symptoms
Initial symptoms are not specific to ALL, but worsen to the point that medical help is sought. They result from the lack of normal and healthy blood cells because they are crowded out by malignant and immature leukocytes (white blood cells). Therefore, people with ALL experience symptoms from malfunctioning of their erythrocytes (red blood cells), leukocytes, and platelets. Laboratory tests which might show abnormalities include blood count tests, renal function tests, electrolyte tests and liver enzyme tests.[citation needed] The signs and symptoms of ALL are variable but follow from bone marrow replacement and/or organ infiltration.

Generalized weakness and fatigue Anemia Frequent or unexplained fever and infection Weight loss and/or loss of appetite Excessive and unexplained bruising Bone pain, joint pain (caused by the spread of "blast" cells to the surface of the bone or into the joint from the marrow cavity) Breathlessness Enlarged lymph nodes,liver and/or spleen Pitting edema (swelling) in the lower limbs and/or abdomen Petechia, which are tiny red spots or lines in the skin due to low platelet levels

Pathophysiology
In general, cancer is caused by damage to DNA that leads to uncontrolled cellular growth and spread throughout the body, either by increasing chemical signals that cause growth, or interrupting chemical signals that control growth. Damage can be caused through the formation of fusion genes, as well as the dysregulation of a proto-oncogene via juxtaposition of it to the promoter of another gene, e.g. the T-cell receptor gene. This damage may be caused by environmental factors such as chemicals, drugs or radiation. ALL is associated with exposure to radiation and chemicals in animals and humans. The association of radiation and leukemia in humans has been clearly established in studies of victims of the Chernobyl nuclear reactor and atom bombs in Hiroshima and Nagasaki. In

animals, exposure to benzene and other chemicals can cause leukemia. Epidemiological studies have associated leukemia with workplace exposure to chemicals, but these studies are not as conclusive. Some evidence suggests that secondary leukemia can develop in individuals who are treated for other cancers with radiation and chemotherapy as a result of that treatment.[5]

Cytogenetics
Cytogenetic translocations associated with specific molecular genetic abnormalities in ALL Cytogenetic translocation Molecular genetic abnormality % cryptic t(12;21) TEL-AML1 fusion[6] 25.4%[7] t(1;19)(q23;p13) E2A-PBX (PBX1) fusion[8] 4.8%[7] t(9;22)(q34;q11) BCR-ABL fusion(P185)[9] 1.6%[7] t(4;11)(q21;q23) MLL-AF4 fusion[10] 1.6%[7] [11] t(8;14)(q24;q32) IGH-MYC fusion t(11;14)(p13;q11) TCR-RBTN2 fusion [12] 12:21 is the most common translocation and portends a good prognosis. 4:11 is the most common in children under 12 months and portends a poor prognosis.

Prognosis
The survival rate has improved from zero four decades ago, to 20-75 percent currently, largely due to clinical trials on new chemotherapeutic agents and improvements in stem cell transplantation (SCT) technology. Five-year survival rates evaluate older, not current, treatments. New drugs, and matching treatment to the genetic characteristics of the blast cells, may improve those rates. The prognosis for ALL differs between individuals depending on a variety of factors:

Sex: females tend to fare better than males. Ethnicity: Caucasians are more likely to develop acute leukemia than African-Americans, Asians or Hispanics. However, they also tend to have a better prognosis than nonCaucasians. Age at diagnosis: children between 110 years of age are most likely to develop ALL and to be cured of it. Cases in older patients are more likely to result from chromosomal abnormalities (e.g. the Philadelphia chromosome) that make treatment more difficult and prognoses poorer. White blood cell count at diagnosis of less than 50,000/l Cancer spread into the Central nervous system (brain or spinal cord) has worse outcomes. Morphological, immunological, and genetic subtypes Patient's response to initial treatment Genetic disorders such as Down's Syndrome

Cytogenetics, the study of characteristic large changes in the chromosomes of cancer cells, is an important predictor of outcome.[13] Some cytogenetic subtypes have a worse prognosis than others. These include:

A translocation between chromosomes 9 and 22, known as the Philadelphia chromosome, occurs in about 20% of adult and 5% in pediatric cases of ALL. A translocation between chromosomes 4 and 11 occurs in about 4% of cases and is most common in infants under 12 months. Not all translocations of chromosomes carry a poorer prognosis. Some translocations are relatively favorable. For example, Hyperdiploidy (>50 chromosomes) is a good prognostic factor. Genome-wide copy number changes can be assessed by conventional cytogenetics or virtual karyotyping. SNP array virtual karyotyping can detect copy number changes and LOH status, while arrayCGH can detect only copy number changes. Copy neutral LOH (acquired uniparental disomy) has been reported at key loci in ALL, such as CDKN2A gene, which have prognostic significance.[14][15][16] SNP array virtual karyotyping can readily detect copy neutral LOH. Array CGH, FISH, and conventional cytogenetics cannot detect copy neutral LOH. Risk category Poor prognosis Poor prognosis Poor prognosis Poor prognosis Poor prognosis Good prognosis Good prognosis

Cytogenetic change Philadelphia chromosome t(4;11)(q21;q23) t(8;14)(q24.1;q32) Complex karyotype (more than four abnormalities) Low hypodiploidy or near triploidy High hyperdiploidy (specifically, trisomy 4, 10, 17) del(9p)

Correlation of prognosis with bone marrow cytogenetic finding in acute lymphoblastic leukemia Prognosis Cytogenetic findings Favorable Hyperdiploidy > 50 ; t (12;21) Intermediate Hyperdiploidy 47 -50; Normal(diploidy); del (6q); Rearrangements of 8q24 Unfavorable Hypodiploidy-near haploidy; Near tetraploidy; del (17p); t (9;22); t (11q23) Unclassified ALL is considered to have an intermediate prognosis.[17]

Classification
As ALL is not a solid tumour, the TNM notation as used in solid cancers is of little use.

The FAB classification

Subtyping of the various forms of ALL used to be done according to the French-AmericanBritish (FAB) classification,[18] which was used for all acute leukemias (including acute myelogenous leukemia, AML).

ALL-L1: small uniform cells ALL-L2: large varied cells ALL-L3: large varied cells with vacuoles (bubble-like features)

Each subtype is then further classified by determining the surface markers of the abnormal lymphocytes, called immunophenotyping. There are 2 main immunologic types: pre-B cell and pre-T cell. The mature B-cell ALL (L3) is now classified as Burkitt's lymphoma/leukemia. Subtyping helps determine the prognosis and most appropriate treatment in treating ALL.

WHO proposed classification of acute lymphoblastic leukemia

The recent WHO International panel on ALL recommends that the FAB classification be abandoned, since the morphological classification has no clinical or prognostic relevance. It instead advocates the use of the immunophenotypic classification mentioned below. 1- Acute lymphoblastic leukemia/lymphoma Synonyms:Former Fab L1/L2

i. Precursor B acute lymphoblastic leukemia/lymphoma. Cytogenetic subtypes:[19] o t(12;21)(p12,q22) TEL/AML-1 o t(1;19)(q23;p13) PBX/E2A o t(9;22)(q34;q11) ABL/BCR o T(V,11)(V;q23) V/MLL ii. Precursor T acute lymphoblastic leukemia/lymphoma

2- Burkitt's leukemia/lymphoma Synonyms:Former FAB L3 3- Biphenotypic acute leukemia

Variant Features of ALL

1- Acute lymphoblastic leukemia with cytoplasmic granules 2- Aplastic presentation of ALL 3- Acute lymphoblastic leukemia with eosinophilia 4- Relapse of lymphoblastic leukemia 5- Secondary ALL

Immunophenotyping in the diagnosis and classification of ALL

The use of a TdT assay and a panel of monoclonal antibodies (MoAbs) to T cell and B cell associated antigens will identify almost all cases of ALL.

Immunophenotypic categories of acute lymphoblastic leukemia (ALL) Types Precursor B Precursor T B-cell FAB Class Tdt T cell associate antigen B cell associate antigen c Ig s Ig L1,L2 + + -/+ L1,L2 + + L3 - + +

Treatment
The earlier acute lymphocytic leukemia is detected, the more effective the treatment. The aim is to induce a lasting remission, defined as the absence of detectable cancer cells in the body (usually less than 5% blast cells on the bone marrow). Treatment for acute leukemia can include chemotherapy, steroids, radiation therapy, intensive combined treatments (including bone marrow or stem cell transplants), and growth factors.[20]

Chemotherapy
Chemotherapy is the initial treatment of choice. Most ALL patients will receive a combination of different treatments. There are no surgical options, due to the body-wide distribution of the malignant cells. In general, cytotoxic chemotherapy for ALL combines multiple antileukemic drugs in various combinations. Chemotherapy for ALL consists of three phases: remission induction, intensification, and maintenance therapy. Description Agents The aim of remission induction is to rapidly kill most tumor cells and get the patient into remission. This is defined as the presence of less than 5% leukemic blasts in the bone Combination of Prednisolone marrow, normal blood cells and or dexamethasone, absence of tumor cells from blood, vincristine, asparaginase and absence of other signs and Remission induction (better tolerance in pediatric symptoms of the disease. Central patients), and daunorubicin nervous system (CNS) prophylaxis (used in Adult ALL) is used should begin during this phase of to induce remission. treatment and continue during the consolidation/intensification period. The rationale is based on the presence of CNS involvement in 10%-40% of adult patients at diagnosis. Consolidation/Intensification Intensification uses high doses of Typical intensification intravenous multidrug chemotherapy protocols use vincristine, to further reduce tumor burden. Since cyclophosphamide, all cells sometimes penetrate the cytarabine, daunorubicin, Phase

Maintenance therapy

etoposide, thioguanine or mercaptopurine given as CNS, most protocols include delivery blocks in different of chemotherapy into the CNS fluid combinations. For CNS (termed intrathecal chemotherapy). protection, intrathecal Some centers deliver the drug through methotrexate or cytarabine is Ommaya reservoir (a device usually used combined with surgically placed under the scalp and or without cranio-spinal used to deliver drugs to the CNS fluid irradiation (the use of and to extract CNS fluid for various radiation therapy to the head tests). Other centers would perform and spine). Central nervous multiple lumbar punctures as needed system relapse is treated with for testing and treatment delivery. intrathecal administration of hydrocortisone, methotrexate, and cytarabine. For this purpose, daily oral mercaptopurine, once weekly The aim of maintenance therapy is to oral methotrexate, once kill any residual cell that was not monthly 5-day course of killed by remission induction, and intravenous vincristine and intensification regimens. Although oral corticosteroids are such cells are few, they will cause usually used. The length of relapse if not eradicated. maintenance therapy is 3 years for boys, 2 years for girls and adults.[21]

As the chemotherapy regimens can be intensive and protracted (often about 2 years in case of the GMALL UKALL, HyperCVAD or CALGB protocols; for ALL about 3 years, 2 months for males on COG protocols; 2 years, 2 months for females- longer for males as testicles are a potential reservoir), many patients have an intravenous catheter inserted into a large vein (termed a central venous catheter or a Hickman line), or a Portacath, a cone-shaped port with a silicone nose that is surgically planted under the skin, usually near the collar bone, and the most effective product available, due to low infection risks and the long-term viability of a portacath.

Radiation therapy
Radiation therapy (or radiotherapy) is used on painful bony areas, in high disease burdens, or as part of the preparations for a bone marrow transplant (total body irradiation). Radiation in the form of whole brain radiation is also used for central nervous system prophylaxis, to prevent recurrence of leukemia in the brain. Whole brain prophylaxis radiation used to be a common method in treatment of childrens ALL. Recent studies showed that CNS chemotherapy provided results as favorable but with less developmental side effects. As a result, the use of whole brain radiation has been more limited. Most specialists in adult leukemia have abandoned the use of radiation therapy for CNS prophylaxis, instead using intrathecal chemotherapy.

Epidemiology

In the US, the incidence of ALL is roughly 6000 new cases per year (as of 2009),[22] or approximately 1 in 50,000. ALL accounts for approximately 70 percent of all childhood leukemia cases (ages 0 to 19 years), making it the most common type of childhood cancer.[22] It has a peak incident rate of 25 years old, decreasing in incidence with increasing age before increasing again at around 50 years old. ALL is slightly more common in males than females. There is an increased incidence in people with Down Syndrome, Fanconi anemia, Bloom syndrome, Ataxia telangiectasia, X-linked agammaglobulinemia and Severe combined immunodeficiency.

In pregnancy
Leukemia is rarely associated with pregnancy, affecting only about 1 in 10,000 pregnant women. [23] How it is handled depends primarily on the type of leukemia. Acute leukemias normally require prompt, aggressive treatment, despite significant risks of pregnancy loss and birth defects, especially if chemotherapy is given during the developmentally sensitive first trimester.
[23]

It is possible, although extremely rare, for leukemia to spread from mother to the child.[24] This is called vertical transmission.

Additional images

acute lymphoblastic leukemia (ALL), peripheral blood of a child, Pappenheim stain, magnification x100

bone marrow smear (large magnification) from a patient with acute lymphoblastic leukemia

bone marrow smear from a patient with acute lymphoblastic leukemia