Acute lymphoblastic leukemia
| Acute lymphoblastic leukemia (ALL) | |
|---|---|
| Classification and external resources | |
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| ICD-10 | C91.0 |
| ICD-9 | 204.0 |
| ICD-O: | M9835/3 |
| DiseasesDB | 195 |
| eMedicine | med/3146 ped/2587 |
| MeSH | D054198 |
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 (metastasizing) to other organs. ALL is most common in childhood with a peak incidence at 2-5 years of age, and another peak in old age. The overall cure rate in children is less than 30%, and about 35%-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.
Contents |
Symptoms
Initial symptoms are not specific to ALL, but worsen to the point that medical help is sought. 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 infections
- Weight loss and/or loss of appetite
- Excessive and unexplained bruising
- Bone pain, joint pains (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
- Petechiae, which are tiny red spots or lines in the skin due to low platelet levels
The signs and symptoms of ALL 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.
Diagnosis
Diagnosing ALL begins with a medical history and 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 90% of cases. 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 "blast" cells began from the B lymphocytes or T lymphocytes. DNA 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]
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 promotor 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] |
| t(8;14)(q24;q32) | IGH-MYC fusion[11] | |
| 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 and Hispanics and tend to have a better prognosis than non-Caucasians.
- Age at diagnosis: children between 1–10 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/µl
- 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.
| Cytogenetic change | Risk category |
|---|---|
| Philadelphia chromosome | Poor prognosis |
| t(4;11)(q21;q23) | Poor prognosis |
| t(8;14)(q24.1;q32) | Poor prognosis |
| Complex karyotype (more than four abnormalities) | Poor prognosis |
| Low hypodiploidy or near triploidy | Poor prognosis |
| High hyperdiploidy (specifically, trisomy 4, 10, 17) | Good prognosis |
| del(9p) | Good prognosis |
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-American-British (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]
- t(12;21)(p12,q22) TEL/AML-1
- t(1;19)(q23;p13) PBX/E2A
- t(9;22)(q34;q11) ABL/BCR
- 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 | FAB Class | Tdt | T cell associate antigen | B cell associate antigen | c Ig | s Ig |
|---|---|---|---|---|---|---|
| Precursor B | L1,L2 | + | - | + | -/+ | - |
| Precursor T | L1,L2 | + | + | - | - | - |
| B-cell | 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.
| Phase | Description | Agents |
|---|---|---|
| Remission induction | 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 marrow, normal blood cells and absence of tumor cells from blood, and absence of other signs and symptoms of the disease. CNS prophylaxis should begin during this phase of 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. | Combination of Prednisolone or dexamethasone, vincristine, asparaginase (better tolerance in pediatric patients), and daunorubicin (used in Adult ALL) is used to induce remission. |
| Consolidation/Intensification | Intensification uses high doses of intravenous multidrug chemotherapy to further reduce tumor burden. Since ALL cells sometimes penetrate the Central Nervous System (CNS), most protocols include delivery of chemotherapy into the CNS fluid (termed intrathecal chemotherapy). Some centers deliver the drug through Ommaya reservoir (a device surgically placed under the scalp and used to deliver drugs to the CNS fluid and to extract CNS fluid for various tests). Other centers would perform multiple lumbar punctures as needed for testing and treatment delivery. | Typical intensification protocols use vincristine, cyclophosphamide, cytarabine, daunorubicin, etoposide, thioguanine or mercaptopurine given as blocks in different combinations. For CNS protection, intrathecal methotrexate or cytarabine is usually used combined with or without cranio-spinal irradiation (the use of radiation therapy to the head and spine). Central nervous system relapse is treated with intrathecal administration of hydrocortisone, methotrexate, and cytarabine. |
| Maintenance therapy | The aim of maintenance therapy is to kill any residual cell that was not killed by remission induction, and intensification regimens. Although such cells are few, they will cause relapse if not eradicated. | For this purpose, daily oral mercaptopurine, once weekly oral methotrexate, once monthly 5-day course of intravenous vincristine and oral corticosteroids are usually used. The length of 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 children’s 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.
Epidemiology
The number of annual ALL cases in the US is roughly 4000, 3000 of which afflict children. ALL accounts for approximately 80 percent of all childhood leukemia cases, making it the most common type of childhood cancer. It has a peak incident rate of 2–5 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.
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 |
See also
- Maarten van der Weijden, diagnosed with ALL in 2001, winner of the 10 km open water marathon race at the 2008 Summer Olympics in Beijing
- Virtual Karyotype
References
- ↑ Harrison's Principles of Internal Medicine, 16th Edition, Chapter 97. Malignancies of Lymphoid Cells. Clinical Features, Treatment, and Prognosis of Specific Lymphoid Malignancies.
- ↑ Collier, J.A.B (1991). Oxford Handbook of Clinical Specialties, Third Edition. Oxford. pp. 810. ISBN 0-19-262116-5.
- ↑ Harrison's Principles of Internal Medicine, 16th EditioN, Chapter 97. Malignancies of Lymphoid Cells. Clinical Features, Treatment, and Prognosis of Specific Lymphoid Malignancies.
- ↑ Merck Manual
- ↑ Smith, Malcolm A.; et al. (Feb 1999). "Secondary Leukemia or Myelodysplastic Syndrome After Treatment With Epipodophyllotoxins" (PDF). Journal of Clinical Oncology (American Society for Clinical Oncology) 17 (2): 569–77. PMID 10080601. http://jco.ascopubs.org/cgi/reprint/17/2/569.
- ↑ Stams WA, den Boer ML, Beverloo HB, et al. (April 2005). "Expression levels of TEL, AML1, and the fusion products TEL-AML1 and AML1-TEL versus drug sensitivity and clinical outcome in t(12;21)-positive pediatric acute lymphoblastic leukemia". Clin. Cancer Res. 11 (8): 2974–80. doi:10.1158/1078-0432.CCR-04-1829. PMID 15837750. http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=15837750.
- ↑ 7.0 7.1 7.2 7.3 Pakakasama S, Kajanachumpol S, Kanjanapongkul S, et al. (August 2008). "Simple multiplex RT-PCR for identifying common fusion transcripts in childhood acute leukemia". Int J Lab Hematol 30 (4): 286–91. doi:10.1111/j.1751-553X.2007.00954.x. PMID 18665825. http://www3.interscience.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=1751-5521&date=2008&volume=30&issue=4&spage=286.
- ↑ McWhirter JR, Neuteboom ST, Wancewicz EV, Monia BP, Downing JR, Murre C (September 1999). "Oncogenic homeodomain transcription factor E2A-Pbx1 activates a novel WNT gene in pre-B acute lymphoblastoid leukemia". Proc. Natl. Acad. Sci. U.S.A. 96 (20): 11464–9. doi:10.1073/pnas.96.20.11464. PMID 10500199. PMC 18056. http://www.pnas.org/cgi/pmidlookup?view=long&pmid=10500199.
- ↑ Rudolph C, Hegazy AN, von Neuhoff N, et al. (August 2005). "Cytogenetic characterization of a BCR-ABL transduced mouse cell line". Cancer Genet. Cytogenet. 161 (1): 51–6. doi:10.1016/j.cancergencyto.2004.12.021. PMID 16080957. http://linkinghub.elsevier.com/retrieve/pii/S0165-4608(05)00019-1.
- ↑ Caslini C, Serna A, Rossi V, Introna M, Biondi A (June 2004). "Modulation of cell cycle by graded expression of MLL-AF4 fusion oncoprotein". Leukemia 18 (6): 1064–71. doi:10.1038/sj.leu.2403321. PMID 14990976.
- ↑ Martín-Subero JI, Odero MD, Hernandez R, et al. (August 2005). "Amplification of IGH/MYC fusion in clinically aggressive IGH/BCL2-positive germinal center B-cell lymphomas". Genes Chromosomes Cancer 43 (4): 414–23. doi:10.1002/gcc.20187. PMID 15852472.
- ↑ Zalcberg IQ, Silva ML, Abdelhay E, et al. (October 1995). "Translocation 11;14 in three children with acute lymphoblastic leukemia of T-cell origin". Cancer Genet. Cytogenet. 84 (1): 32–8. doi:10.1016/0165-4608(95)00062-3. PMID 7497440. http://linkinghub.elsevier.com/retrieve/pii/0165460895000623.
- ↑ Moorman A, Harrison C, Buck G, Richards S, Secker-Walker L, Martineau M, Vance G, Cherry A, Higgins R, Fielding A, Foroni L, Paietta E, Tallman M, Litzow M, Wiernik P, Rowe J, Goldstone A, Dewald G (2007). "Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial". Blood 109 (8): 3189–97. doi:10.1182/blood-2006-10-051912. PMID 17170120.
- ↑ Kawamata N, Ogawa S, Zimmermann M, Kato M, Sanada M, Hemminki K, Yamatomo G, Nannya Y, Koehler R, Flohr T, Miller CW, Harbott J, Ludwig WD, Stanulla M, Schrappe M, Bartram CR, Koeffler HP. Molecular allelokaryotyping of pediatric acute lymphoblastic leukemias by high-resolution single nucleotide polymorphism oligonucleotide genomic microarray. Blood. 2008 Jan 15;111(2):776-84.
- ↑ Bungaro S, Dell'Orto MC, Zangrando A, Basso D, Gorletta T, Lo Nigro L, Leszl A, Young BD, Basso G, Bicciato S, Biondi A, te Kronnie G, Cazzaniga G. Integration of genomic and gene expression data of childhood ALL without known aberrations identifies subgroups with specific genetic hallmarks. Genes Chromosomes Cancer. 2009 Jan;48(1):22-38.
- ↑ Sulong S, Moorman AV, Irving JA, Strefford JC, Konn ZJ, Case MC, Minto L, Barber KE, Parker H, Wright SL, Stewart AR, Bailey S, Bown NP, Hall AG, Harrison CJ. A comprehensive analysis of the CDKN2A gene in childhood acute lymphoblastic leukemia reveals genomic deletion, copy number neutral loss of heterozygosity, and association with specific cytogenetic subgroups. Blood. 2009 Jan 1;113(1):100-7.
- ↑ Den Boer ML, van Slegtenhorst M, De Menezes RX, et al. (January 2009). "A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study". Lancet Oncol. 10 (2): 125. doi:10.1016/S1470-2045(08)70339-5. PMID 19138562. PMC 2707020. http://linkinghub.elsevier.com/retrieve/pii/S1470-2045(08)70339-5.
- ↑ "ACS :: How Is Acute Lymphocytic Leukemia Classified?". http://www.cancer.org/docroot/CRI/content/CRI_2_4_3X_How_Is_Acute_Lymphocytic_Leukemia_Classified.asp?rnav=cri.
- ↑ "Advances in Acute Lymphoblastic Leukemia". http://findarticles.com/p/articles/mi_qa3890/is_200410/ai_n9429273/pg_2.
- ↑ Acute lymphoblastic leukemia at Mount Sinai Hospital
- ↑ Hoffbrand AV, Moss PAH, and Pettit JE, "Essential Haematology", Blackwell, 5th ed., 2006.
External links
- Acute Lymphocytic Leukemia at American Cancer Society
- Information about ALL from the Leukemia & Lymphoma Society
- Information about ALL from Cancer Research UK
- Directory of children's cancer-related resources from Children's Cancer Web
- Information about ALL from the Centre for Cancer and Blood Disorders at Sydney Children’s Hospital
- Information about ALL from European LeukemiaNet
- Information on childhood ALL from ACOR's Ped-Onc Resource Center, including disease details (MRD, phenotypes, molecular characterization), a layman's list of current and past clinical trials, a collection of articles on the possible causes of ALL, a bibliography of journal articles, and links to sources of support for parents of children with ALL.
- Association of Cancer Online Resource (ACOR) Leukemia Links - provides links to information on leukemia, including ALL, primarily in adults.
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