Acute lymphoblastic leukemia

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Acute lymphoblastic leukemia
Classification and external resources
Acute leukemia-ALL.jpg
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) or acute lymphoid leukemia is an acute form of leukemia, or cancer of the white blood cells, characterized by the overproduction of cancerous, immature white blood cells—known as lymphoblasts.[1][2] In persons with ALL, lymphoblasts are overproduced in the bone marrow and continuously multiply, causing damage and death by inhibiting the production of normal cells—such as red and white blood cells and platelets—in the bone marrow and by spreading (infiltrating) 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.[2]

The symptoms of ALL are indicative of a reduced production of functional blood cells, because the leukemia wastes the resources of the bone marrow, which are normally used to produce new, functioning blood cells.[1][2] These symptoms can include fever, increased risk of infection (especially bacterial infections like pneumonia, due to neutropenia; symptoms of such an infection include shortness of breath, chest pain, cough, vomiting, changes in bowel or bladder habits), increased tendency to bleed (due to thrombocytopenia) and signs indicative of anemia including pallor, tachycardia (high heart rate), fatigue and headache.[1][2]

About 6,000 cases are reported in the US every year;[3] statistics from other countries are difficult to come by, although it is known to be more common in the United States, Italy and Costa Rica.[2] Cure is a realistic goal and is achieved in over 80% of affected children, although only 20-40% of adults can be cured.[1][2] "Acute" refers to the relatively short time course of the disease to differentiate it from chronic lymphocytic leukemia, which has a potential time course of many years.[4][5]

It was one of the first cancers for which an effective chemotherapeutic treatment was developed as antifolates like aminopterin and methotrexate were developed in the late 1940s by Sidney Farber and Yellapragada Subbarow.[6][7] At this point in time a doctor did not need a patient's or parent's consent to try an experimental treatment on them (as the Nuremberg code had not been signed at the time) and he initially tried folic acid supplementation as a treatment for ALL, which had disastrous consequences — he inadvertently accelerated the deaths of these children.[7]

Signs and symptoms[edit]

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 that might show abnormalities include blood count tests, renal function tests, electrolyte tests, and liver enzyme tests.[2]

The signs and symptoms of ALL are variable but follow from bone marrow replacement and/or organ infiltration.[2]

  • Generalized weakness and fatigue
  • Anemia
  • Dizziness
  • 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
  • Petechiae, which are tiny red spots or lines in the skin due to low platelet levels

Pathophysiology[edit]

Diagram showing the cell ALL starts in

In general, cancer is caused by damage to DNA that leads to uncontrolled cellular growth and spreads throughout the body, either by increasing chemical signals that cause growth or by 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. High level radiation exposure is a known risk factor for developing leukemia, as found by studies of survivors of atom bomb exposure in Hiroshima and Nagasaki.[8][not in citation given] In animals, exposure to benzene and other chemicals can cause leukemia.[citation needed] 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 treated for other cancers with radiation and chemotherapy as a result of that treatment.[9]

Diagnosis[edit]

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.[10] 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.[5] A lumbar puncture (also known as a spinal tap) will tell if the spinal column and brain have been invaded.

Pathological examination, cytogenetics (in particular the presence of Philadelphia chromosome), and immunophenotyping establish whether 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. Immunohistochemicaltesting 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, whereas 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]

Cytogenetics[edit]

Cytogenetic translocations associated with specific molecular genetic abnormalities in ALL

Cytogenetic translocation Molecular genetic abnormality %
cryptic t(12;21) TEL-AML1 fusion[11] 25.4%[12]
t(1;19)(q23;p13) E2A-PBX (PBX1) fusion[13] 4.8%[12]
t(9;22)(q34;q11) BCR-ABL fusion(P185)[14] 1.6%[12]
t(4;11)(q21;q23) MLL-AF4 fusion[15] 1.6%[12]
t(8;14)(q24;q32) IGH-MYC fusion[16]
t(11;14)(p13;q11) TCR-RBTN2 fusion[17]

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.[citation needed]

Classification[edit]

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

FAB[edit]

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.

World Health Organization[edit]

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

Variant features[edit]

  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[edit]

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[edit]

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 in 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[edit]

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. Central nervous system (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. Central nervous system prophylaxis can be achieved via irradiation, cytarabine + methotrexate, or liposomal cytarabine.[21]
Consolidation/Intensification Intensification uses high doses of intravenous multidrug chemotherapy to further reduce tumor burden. Since ALL cells sometimes penetrate the 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.[22]

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[edit]

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, instead using intrathecal chemotherapy.

Biological therapy[edit]

For some subtypes of relapsed ALL, aiming at biological targets such as the proteasome, in combination with chemotherapy, has given promising results in clinical trials.[23] Selection of biological targets on the basis of their combinatorial effects on the leukemic lymphoblasts can lead to clinical trials for improvement in the effects of ALL treatment.[24] In ongoing clinical trials, a CD19-CD3 bi-specific monoclonal murine antibody - Blinatumomab, is showing great promise.

Immunotherapy[edit]

Chimeric antigen receptors (CARs) have been developed as a promising therapy for ALL. This technology uses a single chain variable fragment (scFv) designed to recognize the cell surface marker CD19 as a method of treating ALL. CD19 is a molecule found on all B-cells and can be used as a means of distinguishing the potentially malignant B-cell population in the patient. In this therapy, mice are immunized with the CD19 antigen and produce anti-CD19 antibodies. Hybridomas developed from the mouse spleen cells fused to a myeloma cell line can be developed as a source for the cDNA encoding the CD19 specific antibody.[25] The cDNA is sequenced and the sequence encoding the variable heavy and variable light chains of these antibodies are cloned together using a small peptide linker. This resulting sequence encodes the scFv. This can be cloned into a transgene encoding what will become the endodomain of the CAR. There are varying arrangements of subunits used as the endodomain but they generally consist of the hinge region that attaches to the scFv, a transmembrane region, the intracellular region of a costimulatory molecule such as CD28, and the intracellular domain of CD3-zeta containing ITAM repeats. Other sequences frequently included are: 4-1bb and OX40.[26] The final transgene sequence, containing the scFv and endodomain sequences is then inserted into immune effector cells that are obtained from the patient and expanded in vitro. In previous trials these have been a type of T-cell capable of cytotoxicity.[27] Inserting the DNA into the effector cell can be accomplished by several methods. Most commonly, this is done using a lentivirus which encodes the transgene. Pseudotyped, self-inactivating lentiviruses have been shown to be an effective method for the stable insertion of a desired transgene into the target cell genomic DNA.[28] Other methods include electroporation and transfection but these are limited in their efficacy as transgene expression will diminish over time. The gene-modified effector cells are then transplanted back into the patient. Typically this process is done in conjunction with a conditioning regiment such as cyclophosphamide which has been shown to potentiate the effects of infused T-cells. This effect has been attributed to the creation of an immunologic space niche.[26] The process as a whole results in an effector cell, typically a T-cell, that can recognize a tumor cell antigen in a major histocompatibility complex independent manner and initiate a cytotoxic response

Prognosis[edit]

The 5-year survival rate has improved from zero six decades ago, to 85% currently, largely due to clinical trials on new chemotherapeutic agents and improvements in stem cell transplantation (SCT) technology.[29]

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:[1]

  • Gender: 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 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.[30]

Some cytogenetic subtypes have a worse prognosis than others. These include:[2]

  • 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.[31][32][33] SNP arrayvirtual 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.[34]

Epidemiology[edit]

US[edit]

In the US, the incidence of ALL is roughly 3000-3500 or approximately 1 in 50,000.[1][2] ALL is slightly more common in males than females. In the United States in 2010, incidence in ages birth to 19 was 38.4 per 1,000,000 per year in boys and 30.2 per 1,000,000 per year in girls.[35] Prevalence was 30,171, and observed survival was 90% (based on data from 2003-2009). ALL has a bimodal age distribution, having a high incidence in ages 2–5 and another peak in incidence above 50 years old. There is an increased incidence in people with Down Syndrome, Fanconi anemia, Bloom syndrome, Ataxia telangiectasia, X-linked agammaglobulinemia, and Severe combined immunodeficiency. There is an increased risk in people with a family history of autoimmune diseases, particularly autoimmune thyroid diseases (namely Graves' disease or Hashimoto's thyroiditis).[36]

UK[edit]

ALL accounts for 8% of all leukaemia cases in the UK, and around 650 people were diagnosed with the disease in 2011.[37]

Pregnancy[edit]

Leukemia is rarely associated with pregnancy, affecting only about 1 in 10,000 pregnant women.[38] 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.[38]

It is possible, although extremely rare, for leukemia to spread from mother to the child.[39] This is called vertical transmission.

Additional images[edit]

References[edit]

  1. ^ a b c d e f Weinblatt, ME (10 July 2013). Sakamoto, KM; Windle, ML; Cripe, TP; Arceci, RJ, ed. "Pediatric Acute Myelocytic Leukemia". Medscape Reference. WebMD. Retrieved 17 April 2014. 
  2. ^ a b c d e f g h i j Seiter, K (5 February 2014). Sarkodee-Adoo, C; Talavera, F; Sacher, RA; Besa, EC, ed. "Acute Lymphoblastic Leukemia". Medscape Reference. WebMD. Retrieved 17 April 2014. 
  3. ^ Inaba, H; Greaves, M; Mullighan, CG (June 2013). "Acute lymphoblastic leukaemia." (PDF). Lancet 381 (9881): 1943–55. doi:10.1016/S0140-6736(12)62187-4. PMC 3816716. PMID 23523389. 
  4. ^ a b Rytting, ME, ed. (November 2013). "Acute Leukemia". Merck Manual Professional. Merck Sharp & Dohme Corp. Retrieved 17 April 2014. 
  5. ^ a b Longo, D; Fauci, A; Kasper, D; Hauser, S; Jameson, J; Loscalzo, J (2011). Harrison's Principles of Internal Medicine (18 ed.). New York: McGraw-Hill Professional. ISBN 978-0-07174889-6.  edit
  6. ^ "Evolution of cancer treatments: Chemotherapy". Cancer.org. American Cancer Society. 8 June 2012. 
  7. ^ a b Mukherjee, Siddhartha (2010). The Emperor of all Maladies: a Biography of Cancer (1st Scribner hardcover ed. ed.). New York: Scribner. ISBN 978-1-4391-0795-9. 
  8. ^ "Leukemia--Acute Lymphocytic". American Cancer Society. Retrieved 8 February 2013. 
  9. ^ 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. 
  10. ^ Collier, J.A.B (1991). Oxford Handbook of Clinical Specialties, Third Edition. Oxford. p. 810. ISBN 0-19-262116-5. 
  11. ^ 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. 
  12. ^ a b c d 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. 
  13. ^ 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. PMC 18056. PMID 10500199. 
  14. ^ 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. 
  15. ^ 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. 
  16. ^ 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. 
  17. ^ 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. 
  18. ^ "ACS :: How Is Acute Lymphocytic Leukemia Classified?". 
  19. ^ "Advances in Acute Lymphoblastic Leukemia | Clinical Laboratory Science | Find Articles at BNET.com". Clinical Laboratory Science. 2004. 
  20. ^ Acute lymphoblastic leukemia at Mount Sinai Hospital
  21. ^ Jabbour, E; Thomas, D; Cortes, J; Kantarjian, HM; O'Brien, S (May 15, 2010). "Central nervous system prophylaxis in adults with acute lymphoblastic leukemia: current and emerging therapies.". Cancer 116 (10): 2290–300. doi:10.1002/cncr.25008. PMID 20209620. 
  22. ^ Hoffbrand, Victor; Moss, Paul; Pettit, John (31 October 2006). Essential Haematology. Wiley. ISBN 978-1-4051-3649-5. Retrieved 14 September 2013. 
  23. ^ Messinger YH, Gaynon PS, Sposto R, van der Giessen J, Eckroth E, Malvar J, Bostrom BC; Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) Consortium. (July 2012). "Bortezomib with chemotherapy is highly active in advanced B-precursor acute lymphoblastic leukemia: Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) Study". Blood. 120 (2): 285–90. doi:10.1182/blood-2012-04-418640. PMID 22653976. 
  24. ^ Lambrou GI, Papadimitriou L, Chrousos GP, Vlahopoulos SA. (January 2012). "Glucocorticoid and proteasome inhibitor impact on the leukemic lymphoblast: multiple, diverse signals converging on a few key downstream regulators". Mol Cell Endocrinol. 351 (2): 142–51. doi:10.1016/j.mce.2012.01.003. PMID 22273806. 
  25. ^ Grupp, S.A, et al., Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med, 2013. 368(16): p. 1509-18
  26. ^ a b Barrett, D.M., et al., Chimeric antigen receptor therapy for cancer. Annu Rev Med, 2014. 65: p. 333-47
  27. ^ Alonso-Camino, V., et al., CARbodies: Human Antibodies Against Cell Surface Tumor Antigens Selected From Repertoires Displayed on T Cell Chimeric Antigen Receptors. Mol Ther Nucleic Acids, 2013. 2: p. e93
  28. ^ Zufferey, R., et al., Self-inactivating lentivirus vector for safe and efficient in vivo gene delivery. J Virol, 1998. 72(12): p. 9873-80
  29. ^ Park, KD (March 2014). "How do we prepare ourselves for a new paradigm of medicine to advance the treatment of pediatric acute lymphoblastic leukemia?" (PDF). Blood Research 49 (1): 3–4. doi:10.5045/br.2014.49.1.3. PMC 3974954. PMID 24724058. 
  30. ^ Moorman, AV; Harrison, CJ; Buck, GA; Richards, SM; Secker-Walker, LM; Martineau, M; Vance, GH; Cherry, AM; Higgins, RR; Fielding, AK; Foroni, L; Paietta, E; Tallman, MS; Litzow, MR; Wiernik, PH; Rowe, JM; Goldstone, AH; Dewald, GW; Adult Leukaemia Working Party, Medical Research Council/National Cancer Research, Institute (Apr 15, 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): 3189–3197. doi:10.1182/blood-2006-10-051912. PMID 17170120. 
  31. ^ 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 (Jan 15, 2008). "Molecular allelokaryotyping of pediatric acute lymphoblastic leukemias by high-resolution single nucleotide polymorphism oligonucleotide genomic microarray.". Blood 111 (2): 776–784. doi:10.1182/blood-2007-05-088310. PMC 2200831. PMID 17890455. 
  32. ^ Bungaro, Silvia; Dell'Orto, Marta Campo; Zangrando, Andrea; Basso, Dario; Gorletta, Tatiana; Lo Nigro, Luca; Leszl, Anna; Young, Bryan D.; Basso, Giuseppe; Bicciato, Silvio; Biondi, Andrea; te Kronnie, Gertruy; Cazzaniga, Giovanni (1 January 2009). "Integration of genomic and gene expression data of childhood ALL without known aberrations identifies subgroups with specific genetic hallmarks". Genes, Chromosomes and Cancer 48 (1): 22–38. doi:10.1002/gcc.20616. PMID 18803328. 
  33. ^ 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 (Jan 1, 2009). "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 113 (1): 100–107. doi:10.1182/blood-2008-07-166801. PMID 18838613. 
  34. ^ 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): 125–34. doi:10.1016/S1470-2045(08)70339-5. PMC 2707020. PMID 19138562. 
  35. ^ Ward, E; DeSantis, C; Robbins, A; Kohler, B; Jemal, A (Mar–Apr 2014). "Childhood and adolescent cancer statistics, 2014.". CA: a cancer journal for clinicians 64 (2): 83–103. doi:10.3322/caac.21219. PMID 24488779. 
  36. ^ Florence Perillat-Menegaux, Jacqueline Clavel, Marie-Françoise Auclerc, André Baruchel, Guy Leverger, Brigitte Nelken, Noël Philippe, Danièle Sommelet, Etienne Vilmer, and Denis Hémon (2003). "Family History of Autoimmune Thyroid Disease and Childhood Acute Leukemia". Cancer Epidemiology, Biomarkers & Prevention 12 (1): 60–3. PMID 12540505. Retrieved 11 April 2014. A statistically significant association between a history of autoimmune disease in first- or second-degree relatives and ALL (OR, 1.7; 95% confidence interval (CI), 1.0–2.8) was found. A relationship between thyroid diseases overall and ALL...was observed. This association was more pronounced for potentially autoimmune thyroid diseases (Grave’s disease and/or hyperthyroidism and Hashimoto’s disease and/or hypothyroidism) (OR, 3.5; 95% CI, 1.1–10.7 and OR, 5.6; 95% CI, 1.0–31.1, respectively for ALL and ANLL), whereas it was not statistically significant for the other thyroid diseases...The results suggest that a familial history of autoimmune thyroid disease may be associated with childhood acute leukemia. 
  37. ^ "Acute lymphoblastic leukaemia (ALL) statistics". Cancer Research UK. Retrieved 27 October 2014. 
  38. ^ a b Shapira T, Pereg D, Lishner M (September 2008). "How I treat acute and chronic leukemia in pregnancy". Blood Rev. 22 (5): 247–59. doi:10.1016/j.blre.2008.03.006. PMID 18472198. 
  39. ^ Isoda T, Ford AM, Tomizawa D, et al. (October 2009). "Immunologically silent cancer clone transmission from mother to offspring". Proc. Natl. Acad. Sci. U.S.A. 106 (42): 17882–5. doi:10.1073/pnas.0904658106. PMC 2764945. PMID 19822752. 

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