View source for Acute lymphoblastic leukemia

{{Short description|Blood cancer characterized by overproduction of lymphoblasts}}
{{Use dmy dates|date=December 2022}}
{{Use American English|date=November 2017}}
{{cs1 config |name-list-style=vanc |display-authors=6}}
{{Infobox medical condition (new)
| name = Acute lymphoblastic leukemia
| synonyms = Acute lymphocytic leukemia, acute lymphoid leukemia
| image = Morphological types of acute lymphoblastic leukemia.jpg
| caption = Left to right: L1, L2, L3 morphological types of acute lymphoblastic leukemias
| field = [[Hematology]], [[oncology]]
| symptoms = Feeling tired, pale color, fever, easy bleeding or bruising, bone pain, [[lymphadenopathy|enlarged lymph nodes]]<ref name=NCI2017Pt/>
| complications = [[Infection]], [[tumor lysis syndrome]]<ref name=NEJM2015/><ref name=Fer2018/>
| onset = 2–5 years old<ref name=Inaba2013/>
| duration =
| types = [[Precursor B-cell lymphoblastic leukemia|B-cell ALL]], [[T-lymphoblastic leukemia/lymphoma|T-cell ALL]]<ref name=NEJM2015/>
| causes = Usually unknown<ref name=MDAnd2016/>
| risks = [[Identical twin]] with ALL, [[Down syndrome]], [[Fanconi anemia]], [[ataxia telangiectasia]], [[Klinefelter syndrome]], [[high birth weight]], significant [[radiation]] exposure<ref name=Vora2017 /><ref name=MDAnd2016/><ref name=NCI2017Pt/>
| diagnosis = [[Blood tests]] and [[bone marrow examination]]<ref name=Fer2018/>
| differential = [[Infectious mononucleosis]], [[acute myeloid leukemia]], [[lymphoblastic lymphoma]], [[aplastic anemia]]<ref name=Fer2018/>
| prevention =
| treatment = [[Chemotherapy]], [[stem cell transplantation]], [[radiation therapy]], [[targeted therapy]]<ref name=BCDtargetedTherapy/><ref name=NCI2017Pt/>
| medication =
| prognosis = '''Children''': 90% [[five-year survival rate]]<ref name=NEJM2015/><br />'''Adults''': 35% five-year survival<ref name="Paul 1645–1666"/>
| frequency = 1 in 1,750 children<ref name=Inaba2013/><ref name=Boer2017/>
| deaths = 111,000 (2015)<ref name=GBD2015De/>
}}
<!-- Definition and symptoms -->

'''Acute lymphoblastic leukemia''' ('''ALL''') is a [[cancer]] of the [[Lymphocyte|lymphoid line]] of [[blood cell]]s characterized by the development of large numbers of [[lymphoblast|immature lymphocytes]].<ref name=NCI2017Pt>{{cite web|title=Childhood Acute Lymphoblastic Leukemia Treatment|url=https://www.cancer.gov/types/leukemia/hp/child-all-treatment-pdq |website=National Cancer Institute|access-date=20 December 2017|date=8 December 2017}}</ref> Symptoms may include feeling tired, pale skin color, [[fever]], easy bleeding or bruising, [[lymphadenopathy|enlarged lymph nodes]], or bone pain.<ref name=NCI2017Pt/> As an [[acute leukemia]], ALL progresses rapidly and is typically fatal within weeks or months if left untreated.<ref>{{cite book |last1=Marino |first1=Bradley S. |last2=Fine |first2=Katie S. |title=Blueprints Pediatrics|date=2013|publisher=Lippincott Williams & Wilkins |isbn=978-1-4511-1604-5 |page=205 |url=https://books.google.com/books?id=OsmaeXtE7sQC&pg=PA205 }}</ref>

<!-- Cause and mechanism -->
In most cases, the cause is unknown.<ref name=NEJM2015/> Genetic risk factors may include [[Down syndrome]], [[Li–Fraumeni syndrome]], or [[neurofibromatosis type 1]].<ref name=NCI2017Pt/> Environmental risk factors may include significant [[radiation exposure]] or prior [[chemotherapy]].<ref name=NCI2017Pt/> Evidence regarding [[electromagnetic field]]s or [[pesticide]]s is unclear.<ref name=Inaba2013/><ref name=Vora2017>{{cite book|title=Childhood acute lymphoblastic leukemia|publisher=Springer International Publishing|editor1-last=Vora |editor1-first=Ajay |year=2017|isbn=978-3-319-39707-8|location=Cham, Switzerland|pages=1–44, 61–86|oclc=984342596}}</ref> Some hypothesize that an abnormal immune response to a common [[infection]] may be a trigger.<ref name=Inaba2013/> The underlying mechanism involves multiple [[genetic mutations]] that results in rapid [[cell division]].<ref name=NEJM2015/> The excessive immature lymphocytes in the [[bone marrow]] interfere with the production of new [[red blood cell]]s, [[white blood cell]]s, and [[platelet]]s.<ref name=NCI2017Pt/> Diagnosis is typically based on [[blood tests]] and [[bone marrow examination]].<ref name=Fer2018>{{cite book|last1=Ferri|first1=Fred F.|title=Ferri's Clinical Advisor 2018 E-Book: 5 Books in 1|date=2017|publisher=Elsevier Health Sciences|isbn=978-0-323-52957-0|page=743|url=https://books.google.com/books?id=wGclDwAAQBAJ&pg=PA743}}</ref>

<!-- Treatment-->
Acute lymphoblastic leukemia is typically treated initially with [[chemotherapy]] aimed at bringing about [[remission (medicine)|remission]].<ref name=NEJM2015/> This is then followed by further chemotherapy typically over a number of years.<ref name=NEJM2015/> Treatment usually also includes [[intrathecal chemotherapy]] since systemic chemotherapy can have limited penetration into the central nervous system and the central nervous system is a common site for relapse of acute lymphoblastic leukemia.<ref>{{cite journal|last1=Pui|first1=Ching-Hon|last2=Evans|first2=William E.|date=12 January 2006|title=Treatment of Acute Lymphoblastic Leukemia|journal=New England Journal of Medicine|volume=354|issue=2|pages=166–178|doi=10.1056/NEJMra052603|issn=0028-4793|pmid=16407512}}</ref><ref>{{cite journal|last=Larson|first=Richard A.|date=2 January 2018|title=Managing CNS disease in adults with acute lymphoblastic leukemia|journal=Leukemia & Lymphoma|volume=59|issue=1|pages=3–13|doi=10.1080/10428194.2017.1326597|issn=1042-8194|pmid=28535095|s2cid=24564241}}</ref>

Treatment can also include [[radiation therapy]] if spread to the [[brain]] has occurred.<ref name="NEJM2015" /> [[Hematopoietic stem cell transplantation|Stem cell transplantation]] may be used if the disease recurs following standard treatment.<ref name="NEJM2015" /> Additional treatments such as [[Chimeric antigen receptor T cell]] [[immunotherapy]] are being used and further studied.<ref name="NEJM2015" />

<!-- Epidemiology and history -->
Acute lymphoblastic leukemia affected about 876,000 people globally in 2015 and resulted in about 111,000 deaths.<ref name=GBD2015Pre>{{cite journal | title = Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015 | journal = Lancet | volume = 388 | issue = 10053 | pages = 1545–1602 | date = October 2016 | pmid = 27733282 | pmc = 5055577 | doi = 10.1016/S0140-6736(16)31678-6 | last1 = Vos | first1 = Theo | last2 = Allen | first2 = Christine | last3 = Arora | first3 = Megha | last4 = Barber | first4 = Ryan M. | last5 = Bhutta | first5 = Zulfiqar A. | last6 = Brown | first6 = Alexandria | last7 = Carter | first7 = Austin | last8 = Casey | first8 = Daniel C. | last9 = Charlson | first9 = Fiona J. | last10 = Chen | first10 = Alan Z. | last11 = Coggeshall | first11 = Megan | last12 = Cornaby | first12 = Leslie | last13 = Dandona | first13 = Lalit | last14 = Dicker | first14 = Daniel J. | last15 = Dilegge | first15 = Tina | last16 = Erskine | first16 = Holly E. | last17 = Ferrari | first17 = Alize J. | last18 = Fitzmaurice | first18 = Christina | last19 = Fleming | first19 = Tom | last20 = Forouzanfar | first20 = Mohammad H. | last21 = Fullman | first21 = Nancy | last22 = Gething | first22 = Peter W. | last23 = Goldberg | first23 = Ellen M. | last24 = Graetz | first24 = Nicholas | last25 = Haagsma | first25 = Juanita A. | last26 = Hay | first26 = Simon I. | last27 = Johnson | first27 = Catherine O. | last28 = Kassebaum | first28 = Nicholas J. | last29 = Kawashima | first29 = Toana | last30 = Kemmer | first30 = Laura }}</ref><ref name=GBD2015De>{{cite journal | title = Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015 | journal = Lancet | volume = 388 | issue = 10053 | pages = 1459–1544 | date = October 2016 | pmid = 27733281 | pmc = 5388903 | doi = 10.1016/s0140-6736(16)31012-1 | last1 = Wang | first1 = Haidong | last2 = Naghavi | first2 = Mohsen | last3 = Allen | first3 = Christine | last4 = Barber | first4 = Ryan M. | last5 = Bhutta | first5 = Zulfiqar A. | last6 = Carter | first6 = Austin | last7 = Casey | first7 = Daniel C. | last8 = Charlson | first8 = Fiona J. | last9 = Chen | first9 = Alan Zian | last10 = Coates | first10 = Matthew M. | last11 = Coggeshall | first11 = Megan | last12 = Dandona | first12 = Lalit | last13 = Dicker | first13 = Daniel J. | last14 = Erskine | first14 = Holly E. | last15 = Ferrari | first15 = Alize J. | last16 = Fitzmaurice | first16 = Christina | last17 = Foreman | first17 = Kyle | last18 = Forouzanfar | first18 = Mohammad H. | last19 = Fraser | first19 = Maya S. | last20 = Fullman | first20 = Nancy | last21 = Gething | first21 = Peter W. | last22 = Goldberg | first22 = Ellen M. | last23 = Graetz | first23 = Nicholas | last24 = Haagsma | first24 = Juanita A. | last25 = Hay | first25 = Simon I. | last26 = Huynh | first26 = Chantal | last27 = Johnson | first27 = Catherine O. | last28 = Kassebaum | first28 = Nicholas J. | last29 = Kinfu | first29 = Yohannes | last30 = Kulikoff | first30 = Xie Rachel }}</ref> It occurs most commonly in children, particularly those between the ages of two and five.<ref name=SEER2017>{{cite web|title=Acute Lymphocytic Leukemia – Cancer Stat Facts|url=https://seer.cancer.gov/statfacts/html/alyl.html|website=SEER|access-date=20 December 2017}}</ref><ref name=Inaba2013>{{cite journal | vauthors = Inaba H, Greaves M, Mullighan CG | title = Acute lymphoblastic leukaemia | journal = Lancet | volume = 381 | issue = 9881 | pages = 1943–55 | date = June 2013 | pmid = 23523389 | pmc = 3816716 | doi = 10.1016/S0140-6736(12)62187-4 | bibcode = 2013Lanc..381.1943I }}</ref> In the United States it is the most common cause of cancer and death from cancer among children.<ref name=NEJM2015>{{cite journal | vauthors = Hunger SP, Mullighan CG | title = Acute Lymphoblastic Leukemia in Children | language = EN | journal = The New England Journal of Medicine | volume = 373 | issue = 16 | pages = 1541–52 | date = October 2015 | pmid = 26465987 | doi = 10.1056/nejmra1400972 | s2cid = 609394 | url = https://repositorio.unal.edu.co/handle/unal/79516 }}</ref> Acute lymphoblastic leukemia is notable for being the first [[disseminated cancer]] to be cured.<ref name=NelsonTbPeds19e>{{cite book|title=Nelson Textbook of Pediatrics| vauthors = Tubergen DG, Bleyer A, Ritchey AK |date=2011 |publisher=Elsevier/Saunders|isbn=978-1-4377-0755-7| veditors = Kliegman RM, Stanton BM, Geme J, Schor NF, Behrman RE |edition=19th|location=Philadelphia, PA|pages=1732–1737|chapter=Acute Lymphoblastic Leukemia|oclc=706780860}}</ref> Survival for children increased from under 10% in the 1960s to 90% in 2015.<ref name=NEJM2015/> Survival rates remain lower for babies (50%)<ref>{{cite journal | vauthors = Brown P | title = Treatment of infant leukemias: challenge and promise | journal = Hematology. American Society of Hematology. Education Program | volume = 2013 | issue = 1 | pages = 596–600 | date = 6 December 2013 | pmid = 24319237 | pmc = 4729208 | doi = 10.1182/asheducation-2013.1.596 }}</ref> and adults (35%).<ref name="Paul 1645–1666">{{cite journal | vauthors = Paul S, Kantarjian H, Jabbour EJ | title = Adult Acute Lymphoblastic Leukemia | journal = Mayo Clinic Proceedings | volume = 91 | issue = 11 | pages = 1645–1666 | date = November 2016 | pmid = 27814839 | doi = 10.1016/j.mayocp.2016.09.010 | doi-access = free }}</ref>
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== Signs and symptoms ==
Initial [[symptoms]] can be nonspecific, particularly in children. Over 50% of children with leukemia had one or more of five features: a [[liver]] one can feel (64%), a [[spleen]] one can feel (61%), pale complexion (54%), fever (53%), and bruising (52%).<ref name=Clarke2016>{{cite journal | vauthors = Clarke RT, Van den Bruel A, Bankhead C, Mitchell CD, Phillips B, Thompson MJ | title = Clinical presentation of childhood leukaemia: a systematic review and meta-analysis | journal = Archives of Disease in Childhood | volume = 101 | issue = 10 | pages = 894–901 | date = October 2016 | pmid = 27647842 | doi = 10.1136/archdischild-2016-311251 | doi-access = free }}</ref> Additionally, recurrent infections, feeling tired, arm or leg pain, and [[lymphadenopathy|enlarged lymph nodes]] can be prominent features. The [[B symptoms]], such as fever, night sweats, and weight loss, are often present as well.<ref>{{cite web |url= https://www.lecturio.com/concepts/acute-lymphoblastic-leukemia/ | title= Acute Lymphoblastic Leukemia | website= The Lecturio Medical Concept Library |access-date= 27 June 2021}}</ref>

Central nervous system (CNS) symptoms such as cranial neuropathies due to meningeal infiltration are identified in less than 10% of adults and less than 5% of children, particularly mature B-cell ALL (Burkitt leukemia) at presentation.<ref>{{cite journal | vauthors = Cortes J | title = Central nervous system involvement in adult acute lymphocytic leukemia | journal = Hematology/Oncology Clinics of North America | volume = 15 | issue = 1 | pages = 145–62 | date = February 2001 | pmid = 11253605 | doi = 10.1016/s0889-8588(05)70203-3 }}</ref>

The signs and symptoms of acute lymphoblastic leukemia are variable and include:<ref name=Seiter2014>{{EMedicine|article|207631|Acute Lymphoblastic Leukemia}}</ref>
* Generalized weakness and feeling tired
* Anemia
* Dizziness
* Headache, vomiting, lethargy, neck stiffness,<ref>{{cite journal | vauthors = Bleyer WA | title = Central nervous system leukemia | journal = Pediatric Clinics of North America | volume = 35 | issue = 4 | pages = 789–814 | date = August 1988 | pmid = 3047654 | doi = 10.1016/s0031-3955(16)36510-5 }}</ref> or cranial nerve palsies<ref>{{cite journal | vauthors = Ingram LC, Fairclough DL, Furman WL, Sandlund JT, Kun LE, Rivera GK, Pui CH | title = Cranial nerve palsy in childhood acute lymphoblastic leukemia and non-Hodgkin's lymphoma | journal = Cancer | volume = 67 | issue = 9 | pages = 2262–8 | date = May 1991 | pmid = 2013032 | doi = 10.1002/1097-0142(19910501)67:9<2262::aid-cncr2820670909>3.0.co;2-u | doi-access = free }}</ref> (CNS involvement)
* 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
* Testicular enlargement
* Mediastinal mass

== Cause ==

[[File:Diagram showing the cell that ALL starts in CRUK 295.svg|thumb|right|In acute lymphoblastic leukemia, lymphoid cell development stops at the lymphoblast (arrow), which are also overproduced.]]

The cancerous cell in ALL is the lymphoblast. Normal lymphoblasts develop into mature, infection-fighting B-cells or T-cells, also called [[lymphocyte]]s. Signals in the body control the number of lymphocytes so neither too few nor too many are made. In ALL, the normal development of some lymphocytes and the control over the number of lymphoid cells become defective.<ref name="Inaba2013" /><ref>{{cite journal | vauthors = Terwilliger T, Abdul-Hay M | title = Acute lymphoblastic leukemia: a comprehensive review and 2017 update | journal = Blood Cancer Journal | volume = 7 | issue = 6 | pages = e577 | date = June 2017 | pmid = 28665419 | pmc = 5520400 | doi = 10.1038/bcj.2017.53 }}</ref>

ALL emerges when a single lymphoblast gains many [[mutation]]s to [[gene]]s that affect [[blood cell]] development and proliferation. In childhood ALL, this process begins at conception with the inheritance of some of these genes. These genes, in turn, increase the risk that more mutations will occur in developing lymphoid cells. Certain genetic syndromes, like [[Down syndrome|Down Syndrome]], have the same effect. Environmental risk factors are also needed to help create enough genetic mutations to cause disease. Evidence for the role of the environment is seen in childhood ALL among twins, where only 10–15% of both [[Identical twins|genetically identical twins]] get ALL. Since they have the same genes, different environmental exposures explain why one twin gets ALL and the other does not.<ref name="Inaba2013" />

Infant ALL is a rare variant that occurs in babies less than one-year-old. ''[[KMT2A]]'' (formerly ''MLL'') gene rearrangements are most common and happen in the embryo or fetus before birth.<ref name="Inaba2013" /> These rearrangements result in increased expression of blood cell development genes by promoting gene transcription and through [[Epigenetics|epigenetic]] changes.<ref>{{cite journal | vauthors = Meyer C, Hofmann J, Burmeister T, Gröger D, Park TS, Emerenciano M, Pombo de Oliveira M, Renneville A, Villarese P, Macintyre E, Cavé H, Clappier E, Mass-Malo K, Zuna J, Trka J, De Braekeleer E, De Braekeleer M, Oh SH, Tsaur G, Fechina L, van der Velden VH, van Dongen JJ, Delabesse E, Binato R, Silva ML, Kustanovich A, Aleinikova O, Harris MH, Lund-Aho T, Juvonen V, Heidenreich O, Vormoor J, Choi WW, Jarosova M, Kolenova A, Bueno C, Menendez P, Wehner S, Eckert C, Talmant P, Tondeur S, Lippert E, Launay E, Henry C, Ballerini P, Lapillone H, Callanan MB, Cayuela JM, Herbaux C, Cazzaniga G, Kakadiya PM, Bohlander S, Ahlmann M, Choi JR, Gameiro P, Lee DS, Krauter J, Cornillet-Lefebvre P, Te Kronnie G, Schäfer BW, Kubetzko S, Alonso CN, zur Stadt U, Sutton R, Venn NC, Izraeli S, Trakhtenbrot L, Madsen HO, Archer P, Hancock J, Cerveira N, Teixeira MR, Lo Nigro L, Möricke A, Stanulla M, Schrappe M, Sedék L, Szczepański T, Zwaan CM, Coenen EA, van den Heuvel-Eibrink MM, Strehl S, Dworzak M, Panzer-Grümayer R, Dingermann T, Klingebiel T, Marschalek R | title = The MLL recombinome of acute leukemias in 2013 | journal = Leukemia | volume = 27 | issue = 11 | pages = 2165–76 | date = November 2013 | pmid = 23628958 | pmc = 3826032 | doi = 10.1038/leu.2013.135 }}</ref><ref>{{cite journal | vauthors = Benedikt A, Baltruschat S, Scholz B, Bursen A, Arrey TN, Meyer B, Varagnolo L, Müller AM, Karas M, Dingermann T, Marschalek R | title = The leukemogenic AF4-MLL fusion protein causes P-TEFb kinase activation and altered epigenetic signatures | journal = Leukemia | volume = 25 | issue = 1 | pages = 135–44 | date = January 2011 | pmid = 21030982 | doi = 10.1038/leu.2010.249 | s2cid = 6045674 | doi-access =  }}</ref> In contrast to childhood ALL, environmental factors are not thought to play a significant role. Aside from the ''KMT2A'' rearrangement, only one extra mutation is typically found.<ref name="Inaba2013" /> Environmental exposures are not needed to help create more mutations.

=== Risk factors ===

==== Genetics ====

Common inherited risk factors include mutations in ''[[ARID5B]]'', ''[[CDKN2A]]/[[CDKN2B|2B]]'', ''[[CEBPE]]'', ''[[IKZF1]]'', ''[[GATA3]]'', ''[[PIP4K2A]]'' and, more rarely, ''[[TP53]]''. These genes play important roles in cellular development, proliferation, and differentiation.<ref name="Vora2017"/><ref name="Inaba2013" /><ref name="NEJM2015" /> Individually, most of these mutations are low risk for ALL. A significant risk of disease occurs when a person inherits several of these mutations together.<ref name="Inaba2013" />

The uneven distribution of genetic risk factors may help explain differences in disease rates among ethnic groups. For instance, the ''ARID5B'' mutation is less common in ethnic African populations.<ref name="Inaba2013" />

Several genetic syndromes also carry an increased risk of ALL. These include: [[Down syndrome]], [[Fanconi anemia]], [[Bloom syndrome]], [[X-linked agammaglobulinemia]], [[severe combined immunodeficiency]], [[Shwachman–Diamond syndrome]], [[Kostmann syndrome]], [[neurofibromatosis type 1]], [[ataxia-telangiectasia]], [[paroxysmal nocturnal hemoglobinuria]], and [[Li–Fraumeni syndrome]].<ref name="NelsonTbPeds19e" /> Fewer than 5% of cases are associated with a known genetic syndrome.<ref name="Paul 1645–1666"/>

Rare mutations in ''ETV6'' and ''[[PAX5]]'' are associated with a familial form of ALL with [[Autosome|autosomal]] [[Dominance (genetics)|dominant]] patterns of [[Heredity|inheritance]].<ref name="NEJM2015" />

==== Environmental ====

The environmental exposures that contribute to the emergence of ALL are contentious and a subject of ongoing debate.<ref name="Vora2017" /><ref name="Inaba2013" />

High levels of radiation exposure from nuclear fallout is a known risk factor for developing leukemia.<ref>{{cite journal | vauthors = Preston DL, Kusumi S, Tomonaga M, Izumi S, Ron E, Kuramoto A, Kamada N, Dohy H, Matsuo T, Matsuo T | title = Cancer incidence in atomic bomb survivors. Part III. Leukemia, lymphoma and multiple myeloma, 1950–1987 | journal = Radiation Research | volume = 137 | issue = 2 Suppl | pages = S68–97 | date = February 1994 | pmid = 8127953 | doi = 10.2307/3578893 | bibcode = 1994RadR..137S..68P | jstor = 3578893 }}</ref> Evidence whether lesser radiation, as from [[Radiography|x-ray imaging]] during pregnancy, increases the risk of disease remains inconclusive.<ref name="Vora2017" /> Studies that have identified an association between x-ray imaging during pregnancy and ALL found only a slightly increased risk.<ref name="Inaba2013" /> Exposure to strong electromagnetic radiation from power lines has also been associated with a slightly increased ALL risk. This result is questioned as no causal mechanism linking electromagnetic radiation with cancer is known.<ref name="Vora2017" /><ref name="Inaba2013" />

High birth weight (greater than 4000&nbsp;g or 8.8&nbsp;lbs) is also associated with a small increased risk. The mechanism connecting high birth weight to ALL is also not known.<ref name="Vora2017" />

Evidence suggests that [[Neoplasm#Types|secondary leukemia]] can develop in individuals treated with certain types of chemotherapy, such as [[epipodophyllotoxin]]s and [[cyclophosphamide]].<ref name="Vora2017" /><ref name=smith>{{cite journal | vauthors = Smith MA, Rubinstein L, Anderson JR, Arthur D, Catalano PJ, Freidlin B, Heyn R, Khayat A, Krailo M, Land VJ, Miser J, Shuster J, Vena D | title = Secondary leukemia or myelodysplastic syndrome after treatment with epipodophyllotoxins | journal = Journal of Clinical Oncology | volume = 17 | issue = 2 | pages = 569–77 | date = February 1999 | pmid = 10080601 | doi = 10.1200/JCO.1999.17.2.569 }}</ref>

==== Infections ====
There is some evidence that a common infection, such as [[influenza]], may indirectly promote the emergence of ALL.<ref name="Vora2017" /><ref name="Inaba2013" /> The delayed-infection hypothesis states that ALL results from an abnormal immune response to infection in a person with genetic risk factors. Delayed development of the immune system due to limited disease exposure may result in excessive production of lymphocytes and increased mutation rate during an illness.  Several studies have identified lower ALL rates among children with greater exposure to illness early in life. Very young children who attend daycare have lower rates of ALL. Evidence from many other studies looking at disease exposure and ALL is inconclusive.<ref name="Vora2017" /> Some researchers have linked the [[hygiene hypothesis]].<ref>{{cite journal | vauthors = Greaves M | title = A causal mechanism for childhood acute lymphoblastic leukaemia | journal = Nature Reviews. Cancer | volume = 18 | issue = 8 | pages = 471–484 | date = August 2018 | pmid = 29784935 | pmc = 6986894 | doi = 10.1038/s41568-018-0015-6 }}</ref>

== Mechanism ==

Several characteristic genetic changes lead to the creation of a leukemic lymphoblast. These changes include [[chromosomal translocation]]s, [[Chromosomal rearrangement|intrachromosomal rearrangements]], changes in the number of chromosomes in leukemic cells, and additional mutations in individual genes.<ref name="NEJM2015" /> Chromosomal translocations involve moving a large region of DNA from one chromosome to another. This move can result in placing a [[Oncogene|gene]] from one chromosome that promotes [[cell division]] to a more actively [[Transcription (biology)|transcribed]] area on another chromosome. The result is a cell that divides more often. An example of this includes the translocation of ''[[Myc|C-MYC]]'', a gene that encodes a [[transcription factor]] that leads to increased cell division, next to the [[Immunoglobulin heavy chain|immunoglobulin heavy]]- or [[Immunoglobulin light chain|light-chain]] gene [[Enhancer (genetics)|enhancers]], leading to increased ''C-MYC'' expression and increased cell division.<ref name="NEJM2015" /> Other large changes in chromosomal structure can result in the placement of two genes directly next to each other. The result is the combination of two usually separate proteins into a new [[fusion protein]]. This protein can have a new function that promotes the development of cancer. Examples of this include the ''[[ETV6]]''–''[[RUNX1]]'' fusion gene that combines two factors that promote blood cell development and the [[BCR (gene)|''BCR'']]-[[ABL (gene)|''ABL1'']] fusion gene of the [[Philadelphia chromosome]]. ''BCR''–''ABL1'' encodes an always-activated [[tyrosine kinase]] that causes frequent cell division. These mutations produce a cell that divides more often, even in the absence of [[growth factor]]s.<ref name="Inaba2013" /><ref name="NEJM2015" />

Other genetic changes in B-cell ALL include changes to the number of chromosomes within the leukemic cells. Gaining at least five additional chromosomes, called high hyperdiploidy, occurs more commonly. Less often, chromosomes are lost, called [[Hypodiploid acute lymphoblastic leukemia|hypodiploidy]], which is associated with a poorer prognosis. Additional common genetic changes in B-cell ALL involve non-inherited mutations to ''PAX5'' and ''IKZF1''.<ref name="NEJM2015" /> In T-cell ALL, ''[[LYL1]]'', ''[[TAL1]]'', ''[[TLX1]]'', and ''[[TLX3]]'' rearrangements can occur.<ref name="Inaba2013" />

Acute lymphoblastic leukemia results when enough of these genetic changes are present in a single lymphoblast. In childhood ALL, for example, one fusion gene translocation is often found along with six to eight other ALL-related genetic changes.<ref name="Inaba2013" /> The initial leukemic lymphoblast copies itself into an excessive number of new lymphoblasts, none of which can develop into functioning lymphocytes. These lymphoblasts build up in the bone marrow and may spread to other sites in the body, such as [[lymph node]]s, the [[mediastinum]], the [[spleen]], the [[testicle]]s, and the [[brain]], leading to the common symptoms of the disease.<ref name="NEJM2015" />

== Diagnosis ==

[[medical diagnosis|Diagnosing]] ALL begins with a thorough medical history, [[physical examination]], [[Full blood count|complete blood count]], and blood smears. While many symptoms of ALL can be found in common illnesses, persistent or unexplained symptoms raise suspicion of cancer. Because many features on the medical history and examination are not specific to ALL, further testing is often needed. A large number of white blood cells and lymphoblasts in the circulating blood can be suspicious for ALL because they indicate a rapid production of lymphoid cells in the marrow. The higher these numbers typically point to a worse prognosis.<ref>{{cite book |last = Collier |first = J.A.B |title = Oxford Handbook of Clinical Specialties, Third Edition |publisher = Oxford |year = 1991 |page = 810 |isbn = 978-0-19-262116-0 }}</ref> While white blood cell counts at initial presentation can vary significantly, circulating lymphoblast cells are seen on peripheral [[Blood film|blood smears]] in the majority of cases.<ref name=MDAnd2016>{{cite book|chapter-url=https://accessmedicine.mhmedical.com/content.aspx?bookid=1772&sectionid=121896350 |title=The MD Anderson Manual of Medical Oncology | vauthors = Baljevic M, Jabbour E, O'Brien S, Kantarjian HM |date=2016|publisher=McGraw-Hill Education| veditors = Kantarjian HM, Wolff RA |edition=3|location=New York|chapter=Acute Lymphoblastic Leukemia|access-date=22 November 2017 }}</ref>

A [[bone marrow biopsy]] provides conclusive proof of ALL, typically with >20% of all cells being leukemic lymphoblasts.<ref name="Harrison">{{cite book |title = Harrison's Principles of Internal Medicine |publisher = McGraw-Hill Professional |year = 2011 |isbn = 978-0-07-174889-6 |edition = 18 |location = New York |chapter = Chapter 110: Malignancies of Lymphoid Cells |last1 = Longo |first1 = D }}</ref> A [[lumbar puncture]] (also known as a spinal tap) can determine whether the [[central nervous system|spinal column and brain]] have been invaded. Brain and spinal column involvement can be diagnosed either through confirmation of leukemic cells in the lumbar puncture or through clinical signs of CNS leukemia as described above. Laboratory tests that might show abnormalities include blood count, kidney function, electrolyte, and liver enzyme tests.<ref name=Seiter2014/>

[[Histopathology|Pathological]] examination, [[cytogenetics]] (in particular the presence of [[Philadelphia chromosome]]), and [[immunophenotyping]] establish whether the leukemic cells are [[myeloblast]]ic (neutrophils, eosinophils, or basophils) or lymphoblastic ([[B lymphocyte]]s or [[T lymphocyte]]s). [[Genetic testing|Cytogenetic testing]] on the marrow samples can help classify disease and predict how aggressive the disease course will be. Different mutations have been associated with shorter or longer survival. [[Immunohistochemistry|Immunohistochemical]] testing may reveal [[Terminal deoxynucleotidyl transferase|TdT]] or [[Neprilysin|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 [[Neprilysin|CALLA]] is an antigen found in 80% of ALL cases and also in the "blast crisis" of [[Chronic myelogenous leukemia|CML]].

[[Medical imaging]] (such as [[medical ultrasonography|ultrasound]] or [[CT scan]]ning) can find invasion of other [[Organ (anatomy)|organs]], commonly the [[lung]]s, [[liver]], [[spleen]], [[Lymph node|lymph nodes]], [[brain]], [[Kidney|kidneys]], and [[Sex organ|reproductive organs]].<ref name="MM">{{cite web |url = http://www.merckmanuals.com/professional/hematology_and_oncology/leukemias/acute_leukemia.html |title = Acute Leukemia |date = November 2013 |publisher = Merck Sharp & Dohme Corp. |work = Merck Manual Professional |access-date = 17 April 2014 |editor = Rytting, ME |url-status = live |archive-url = https://web.archive.org/web/20140715103150/http://www.merckmanuals.com/professional/hematology_and_oncology/leukemias/acute_leukemia.html |archive-date = 15 July 2014 }}</ref>

<gallery>
File:ALL - Peripherial Blood - Diagnosis - 01.jpg|Acute lymphoblastic leukemia (ALL), peripheral blood of a child, Pappenheim stain, magnification x100
File:ALL-KM-2.jpg|Bone marrow smear (large magnification) from a person with ALL
File:ALL-KM-3.jpg|Bone marrow smear from a person with ALL
</gallery>

=== Immunophenotyping <!-- might be beyond the scope of Wikipedia - would appreciate any advice --> ===

In addition to cell morphology and cytogenetics, [[immunophenotyping]], a laboratory technique used to identify proteins that are expressed on their cell surface, is a key component in the diagnosis of ALL. The preferred method of immunophenotyping is through [[flow cytometry]]. In the malignant lymphoblasts of ALL, expression of [[terminal deoxynucleotidyl transferase]] (TdT) on the cell surface can help differentiate malignant lymphocyte cells from [[reactive lymphocyte]]s, white blood cells that are reacting normally to an infection in the body. On the other hand, [[myeloperoxidase]] (MPO), a marker for the [[Myeloid leukemia|myeloid]] lineage, is typically not expressed. Because precursor B cells and precursor T cells look the same, immunophenotyping can help differentiate the subtype of ALL and the level of maturity of the malignant white blood cells. The subtypes of ALL as determined by immunophenotype and according to the stages of maturation.<ref name=MDAnd2016 />
{| class="wikitable"
|-
!B cell lineage
!T cell lineage
|-
|pre-pre-B ALL (pro-B-ALL)
|precursor T- ALL
|-
|common ALL
|mature T-cell ALL
|-
|pre-B ALL
|
|-
|mature B-cell ALL (Burkitt leukemia – FAB L3)
|
|}
An extensive panel of monoclonal antibodies to cell surface markers, particularly CD or cluster of differentiation markers, are used to classify cells by lineage. Below are immunological markers associated with B cell and T cell ALL.<ref name=":0" />
{| class="wikitable"
|-
!Immunological markers
!B cell Lineage
!T cell Lineage
|-
|colspan="3" style="text-align:center;" | ''B cell lineage''
|-
|CD19, CD22, CD79a
| +
| −
|-
|CD10
| − or + (common ALL)
|
|-
|cytoplasmic Ig
| − or + (pre-B ALL)
|
|-
|surface Ig
| − or + (mature B-cell ALL)
|
|-
|TdT
| +
| +
|-
|colspan="3" style="text-align:center;" | ''T cell lineage''
|-
|CD2, CD3, CD4, CD5, CD7, CD8
| −
| +
|-
|TdT
| +
| +
|}

=== Cytogenetics<!-- Thinking about taking this paragraph out. Potentially beyond the scope of Wikipedia. Alternatively can try to combine it with the WHO table --> ===

Cytogenetic analysis has shown different proportions and frequencies of genetic abnormalities in cases of ALL from different age groups. This information is particularly valuable for classification and can in part explain the different prognoses of these groups. In regards to genetic analysis, cases can be stratified according to [[ploidy]], a number of sets of chromosomes in the cell, and specific genetic abnormalities, such as [[Chromosomal translocation|translocations]]. Hyperdiploid cells are defined as cells with more than 50 chromosomes, while hypodiploid are defined as cells with less than 44 chromosomes. Hyperdiploid cases tend to carry a good prognosis while hypodiploid cases do not.<ref name=":0" /> For example, the most common specific abnormality in childhood B-ALL is the t(12;21) ''[[ETV6]]''–''RUNX1'' translocation, in which the ''[[RUNX1]]'' gene, encoding a protein involved in transcriptional control of [[Haematopoiesis|hemopoiesis]], has been translocated and repressed by the ''ETV6''–''RUNX1'' fusion protein.<ref>{{cite journal | vauthors = Bhojwani D, Pei D, Sandlund JT, Jeha S, Ribeiro RC, Rubnitz JE, Raimondi SC, Shurtleff S, Onciu M, Cheng C, Coustan-Smith E, Bowman WP, Howard SC, Metzger ML, Inaba H, Leung W, Evans WE, Campana D, Relling MV, Pui CH | title = ETV6-RUNX1-positive childhood acute lymphoblastic leukemia: improved outcome with contemporary therapy | journal = Leukemia | volume = 26 | issue = 2 | pages = 265–70 | date = February 2012 | pmid = 21869842 | pmc = 3345278 | doi = 10.1038/leu.2011.227 }}</ref>

Below is a table with the frequencies of some cytogenetic [[translocations]] and molecular genetic abnormalities in ALL.
{| class="wikitable"
|-
!Cytogenetic translocation
!Molecular genetic abnormality
!%
|-
|cryptic t(12;21)
| [[ETV6|TEL]]–[[RUNX1|AML1]] fusion<ref name="pmid15837750">{{cite journal | vauthors = Stams WA, den Boer ML, Beverloo HB, Meijerink JP, van Wering ER, Janka-Schaub GE, Pieters R | title = 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 | journal = Clinical Cancer Research | volume = 11 | issue = 8 | pages = 2974–80 | date = April 2005 | pmid = 15837750 | doi = 10.1158/1078-0432.CCR-04-1829 | doi-access = free }}</ref>
| 25.4%<ref name="pmid18665825">{{cite journal | vauthors = Pakakasama S, Kajanachumpol S, Kanjanapongkul S, Sirachainan N, Meekaewkunchorn A, Ningsanond V, Hongeng S | title = Simple multiplex RT-PCR for identifying common fusion transcripts in childhood acute leukemia | journal = International Journal of Laboratory Hematology | volume = 30 | issue = 4 | pages = 286–91 | date = August 2008 | pmid = 18665825 | doi = 10.1111/j.1751-553X.2007.00954.x | doi-access = free }}</ref>
|-
|t(1;19)(q23;p13)
|[[TCF3|E2A]]–[[Pre-B-cell leukemia homeobox|PBX]] ([[PBX1]]) fusion<ref name="pmid10500199">{{cite journal | vauthors = McWhirter JR, Neuteboom ST, Wancewicz EV, Monia BP, Downing JR, Murre C | title = Oncogenic homeodomain transcription factor E2A-Pbx1 activates a novel WNT gene in pre-B acute lymphoblastoid leukemia | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 20 | pages = 11464–9 | date = September 1999 | pmid = 10500199 | pmc = 18056 | doi = 10.1073/pnas.96.20.11464 | bibcode = 1999PNAS...9611464M | doi-access = free }}</ref>
| 4.8%<ref name="pmid18665825" />
|-
|t(9;22)(q34;q11)
|[[BCR-ABL]] fusion(P185)<ref name="pmid16080957">{{cite journal | vauthors = Rudolph C, Hegazy AN, von Neuhoff N, Steinemann D, Schröck E, Stripecke R, Klein C, Schlegelberger B | title = Cytogenetic characterization of a BCR-ABL transduced mouse cell line | journal = Cancer Genetics and Cytogenetics | volume = 161 | issue = 1 | pages = 51–6 | date = August 2005 | pmid = 16080957 | doi = 10.1016/j.cancergencyto.2004.12.021 }}</ref>
| 1.6%<ref name="pmid18665825" />
|-
|t(4;11)(q21;q23)
|[[MLL (gene)|MLL]]–[[AF4/FMR2 family member 1|AF4]] fusion<ref name="pmid14990976">{{cite journal | vauthors = Caslini C, Serna A, Rossi V, Introna M, Biondi A | title = Modulation of cell cycle by graded expression of MLL-AF4 fusion oncoprotein | journal = Leukemia | volume = 18 | issue = 6 | pages = 1064–71 | date = June 2004 | pmid = 14990976 | doi = 10.1038/sj.leu.2403321 | s2cid = 19189264 | doi-access =  }}</ref>
| 1.6%<ref name="pmid18665825" />
|-
|t(8;14)(q24;q32)
|[[Immunoglobulin heavy chain|IGH]]–[[MYC]] fusion<ref name="pmid15852472">{{cite journal | vauthors = Martín-Subero JI, Odero MD, Hernandez R, Cigudosa JC, Agirre X, Saez B, Sanz-García E, Ardanaz MT, Novo FJ, Gascoyne RD, Calasanz MJ, Siebert R | title = Amplification of IGH/MYC fusion in clinically aggressive IGH/BCL2-positive germinal center B-cell lymphomas | journal = Genes, Chromosomes & Cancer | volume = 43 | issue = 4 | pages = 414–23 | date = August 2005 | pmid = 15852472 | doi = 10.1002/gcc.20187 | s2cid = 2025900 | hdl = 10171/19527 | hdl-access = free }}</ref>
|
|-
|t(11;14)(p13;q11)
|[[T-cell receptor|TCR]]–[[RBTN2]] fusion<ref name="pmid7497440">{{cite journal | vauthors = Zalcberg IQ, Silva ML, Abdelhay E, Tabak DG, Ornellas MH, Simões FV, Pucheri W, Ribeiro R, Seuánez HN | title = Translocation 11;14 in three children with acute lymphoblastic leukemia of T-cell origin | journal = Cancer Genetics and Cytogenetics | volume = 84 | issue = 1 | pages = 32–8 | date = October 1995 | pmid = 7497440 | doi = 10.1016/0165-4608(95)00062-3 }}</ref>
|
|}

=== Classification ===

'''French-American-British'''

Historically, before 2008, ALL was classified morphologically using the [[French–American–British classification|French-American-British]] (FAB) system that heavily relied on morphological assessment. The FAB system takes into account information on size, [[cytoplasm]], [[Nucleolus|nucleoli]], [[basophilia]] (color of cytoplasm), and [[Vacuole|vacuolation]] (bubble-like properties).<ref>{{cite journal | vauthors = Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C | title = Proposals for the classification of the acute leukaemias. French-American-British (FAB) co-operative group | journal = British Journal of Haematology | volume = 33 | issue = 4 | pages = 451–8 | date = August 1976 | pmid = 188440 | doi = 10.1111/j.1365-2141.1976.tb03563.x | s2cid = 9985915 }}</ref><ref name="urlACS :: How Is Acute Lymphocytic Leukemia Classified?">{{cite web|url=http://www.cancer.org/docroot/CRI/content/CRI_2_4_3X_How_Is_Acute_Lymphocytic_Leukemia_Classified.asp?rnav=cri|title=ACS :: How Is Acute Lymphocytic Leukemia Classified?|archive-url=https://web.archive.org/web/20080323074708/http://www.cancer.org/docroot/CRI/content/CRI_2_4_3X_How_Is_Acute_Lymphocytic_Leukemia_Classified.asp?rnav=cri|archive-date=23 March 2008}}</ref>
{| class="wikitable"
|-
!FAB Subtype
!Cell Type
!Characteristics
!Comments
|-
|ALL - L1
|T cell or pre-B cell
|Small and homogeneous (uniform) cells
|
|-
|ALL - L2
|T cell or pre-B cell
|Large and heterogeneous  (varied) cells
|
|-
|ALL - L3
|B cell
|Large and varied cells with vacuoles
|Mature B-cell ALL also named Burkitt leukemia. Typically, poor prognosis with standard therapy
|}
While some clinicians still use the FAB scheme to describe tumor cell appearance, much of this classification has been abandoned because of its limited impact on treatment choice and prognostic value.<ref name="DeAngelo2013" />{{rp|491}}

'''World Health Organization'''

In 2008, the [[World Health Organization]] (WHO) classification of ALL was developed in an attempt to create a classification system that was more clinically relevant and could produce meaningful prognostic and treatment decisions. This system recognized differences in genetic, [[Immunophenotyping|immunophenotype]], molecular, and morphological features found through [[cytogenetics|cytogenetic]] and [[molecular diagnostics]] tests.<ref name="Nathan_2014_8" />{{rp|1531–1535}}<ref name=":0">{{cite book|title=Hoffbrand's Essential Haematology | vauthors = Hoffbrand AV, Moss PA |isbn=978-1-118-40863-6|edition=Seventh|location=Chichester, West Sussex|oclc=910009732|date = 6 October 2015}}{{page needed|date=April 2020}}</ref> This subtyping helps determine the prognosis and the most appropriate treatment for each specific case of ALL.

The WHO subtypes related to ALL are:<ref>{{cite journal | vauthors = Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, Bloomfield CD, Cazzola M, Vardiman JW | title = The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia | journal = Blood | volume = 127 | issue = 20 | pages = 2391–405 | date = May 2016 | pmid = 27069254 | doi = 10.1182/blood-2016-03-643544 | s2cid = 18338178 | doi-access = free }}</ref>
* B-lymphoblastic leukemia/lymphoma
** Not otherwise specified (NOS)
** with recurrent genetic abnormalities
** with t(9;22)(q34.1;q11.2);''BCR-ABL1''
** with t(v;11q23.3);''KMT2A''&nbsp;rearranged
** with t(12;21)(p13.2;q22.1);&nbsp;''ETV6-RUNX1''
** with t(5;14)(q31.1;q32.3)&nbsp;''IL3-IGH''
** with t(1;19)(q23;p13.3);''TCF3-PBX1''
** with hyperdiploidy
** with hypodiploidy
* T-lymphoblastic leukemia/lymphoma
* Acute leukemias of ambiguous lineage
** Acute undifferentiated leukemia
** [[Mixed phenotype acute leukemia]] (MPAL) with t(9;22)(q34.1;q11.2);&nbsp;''BCR–ABL1''
** MPAL with t(v;11q23.3);&nbsp;''KMT2A''&nbsp;rearranged
** MPAL, B/myeloid, NOS
** MPAL, T/myeloid, NOS

== Treatment ==

[[File:Pediatric patients receiving chemotherapy.jpg|thumb|Two girls with ALL demonstrating [[intravenous therapy|intravenous access]] for [[chemotherapy]]]]

The aim of treatment is to induce a lasting [[remission (medicine)|remission]], defined as the absence of detectable cancer cells in the body (usually less than 5% blast cells in the bone marrow) or the absence of [[minimal residual disease]].

Over the past several decades, there have been strides to increase the efficacy of treatment regimens, resulting in increased survival rates. Possible treatments for acute leukemia include [[chemotherapy]], [[steroid]]s, [[radiation therapy]], intensive combined treatments (including [[bone marrow transplant|bone marrow]] or [[stem cell]] transplants), targeted therapy, and/or growth factors.<ref name="BCDtargetedTherapy">{{cite journal | vauthors = Cordo V, Meijerink J | title = T-cell Acute Lymphoblastic Leukemia: A Roadmap to Targeted Therapies | journal = Blood Cancer Discovery | volume = 2 | pages = 19–31 |date=January 2021 | issue = 1 |doi = 10.1158/2643-3230.BCD-20-0093 | pmid = 34661151 |pmc=8447273 | doi-access = free }}</ref><ref>{{cite web|url=http://www.mountsinai.org/patient-care/health-library/diseases-and-conditions/acute-lymphoblastic-leukemia|title=Acute lymphoblastic leukemia (ALL) Information – Mount Sinai – New York|website=Mount Sinai Health System|archive-url=https://web.archive.org/web/20160803150421/https://www.mountsinai.org/patient-care/health-library/diseases-and-conditions/acute-lymphoblastic-leukemia|archive-date=3 August 2016|url-status=live|access-date=18 November 2017}}</ref>

=== Chemotherapy ===

[[Chemotherapy]] is the initial treatment of choice, and most people with ALL receive a combination of medications. There are no surgical options because of the body-wide distribution of the [[malignant cells]]. In general, cytotoxic chemotherapy for ALL combines multiple antileukemic drugs tailored to each person. Chemotherapy for ALL consists of three phases: remission induction, intensification, and maintenance therapy.
{| class="wikitable"
|-
! Phase
! Description<ref name="HoffbrandMoss2006">{{cite book|url=https://books.google.com/books?id=IFFL_1YNy_oC|title=Essential Haematology |last1=Hoffbrand |first1=Victor |last2=Moss |first2=Paul |last3=Pettit |first3=John |date=31 October 2006|publisher=Wiley|isbn=978-1-4051-3649-5|pages=192–196|access-date=14 September 2013|archive-url=https://web.archive.org/web/20150321090633/http://books.google.com/books?id=IFFL_1YNy_oC|archive-date=21 March 2015|url-status=live}}</ref><ref name=":2" />
! Agents<ref name="HoffbrandMoss2006" /><ref name=":2" />
|-
| '''Remission induction'''
|Aim to:
* Rapidly kill most tumor cells
* Reduce leukemic blasts in the bone marrow to <5% and eliminate tumor cells from blood
* Induce the absence of other signs and symptoms of the disease.

Must monitor closely for [[tumor lysis syndrome]] after initiating therapy

Monitoring the initial response to treatment is important as failure to show clearance of blood or bone marrow blasts within the first two weeks of therapy has been associated with a higher risk of relapse
* May need to intensify treatment if remission is not induced

Start CNS prophylaxis and administer [[intrathecal chemotherapy]] via [[Ommaya reservoir]] or multiple lumbar punctures
| Combination of:
* steroids – [[prednisolone]] or [[dexamethasone]]
* [[vincristine]]
* [[asparaginase]] (better tolerance in people in pediatric care)
* [[daunorubicin]] (used in Adult ALL)

[[Central nervous system prophylaxis]] can be achieved via:<ref name="pmid20209620">{{cite journal | vauthors = Jabbour E, Thomas D, Cortes J, Kantarjian HM, O'Brien S | title = Central nervous system prophylaxis in adults with acute lymphoblastic leukemia: current and emerging therapies | journal = Cancer | volume = 116 | issue = 10 | pages = 2290–300 | date = May 2010 | pmid = 20209620 | doi = 10.1002/cncr.25008 | s2cid = 13634096 }}</ref>
* cranio-spinal irradiation
* [[cytarabine]] + [[methotrexate]]
* or liposomal cytarabine

In [[Philadelphia chromosome]]-positive ALL, the intensity of initial induction treatment may be less than has been traditionally given.<ref name="pmid26069331">{{cite journal | vauthors = Yanada M | title = Time to tune the treatment of Ph+ ALL | journal = Blood | volume = 125 | issue = 24 | pages = 3674–5 | date = June 2015 | pmid = 26069331 | doi = 10.1182/blood-2015-04-641704 | doi-access = free }}</ref><ref>Seiter K, Harris JE. Acute Lymphoblastic Leukemia Treatment Protocols. emedicine; Medscape. {{cite web |url=http://emedicine.medscape.com/article/2004705-overview |title=Acute Lymphoblastic Leukemia Treatment Protocols: Treatment Protocols |access-date=16 August 2015 |url-status=live |archive-url=https://web.archive.org/web/20150901110601/http://emedicine.medscape.com/article/2004705-overview |archive-date=1 September 2015  }}</ref>
|-
| '''Consolidation/intensification'''
|Use high doses of chemotherapy to further reduce tumor burden
| Typical protocols use the following given as blocks (varies from 1–3 blocks depending on a person's risk category) in different multi-drug combinations:
* vincristine
* [[cyclophosphamide]]
* cytarabine
* daunorubicin
* [[etoposide]]
* [[thioguanine]]
* [[mercaptopurine]]

Central nervous system relapse is treated with intrathecal administration of [[hydrocortisone]], methotrexate, and cytarabine.
|-
| '''Maintenance therapy'''
|Kill any residual cell that was not killed by remission induction and intensification regimens
* Can sometimes start immediately after remission induction and be interrupted by bursts of consolidation/intensification therapy
* Although such residual cells are few, they will cause relapse if not eradicated
* Length of maintenance therapy is three years for boys, two years for girls and adults
|Typical protocol would include:
* daily oral [[mercaptopurine]]
* weekly oral [[methotrexate]]
* monthly 5-day course of intravenous vincristine and oral corticosteroids
|}

Adult chemotherapy regimens mimic those of childhood ALL; however, are linked with a higher risk of disease relapse with chemotherapy alone. Two subtypes of ALL (B-cell ALL and T-cell ALL) require special considerations when it comes to selecting an appropriate treatment regimen in adults with ALL. B-cell ALL is often associated with cytogenetic abnormalities (specifically, t(8;14), t (2;8), and t(8;22)), which require aggressive therapy consisting of brief, high-intensity regimens. T-cell ALL responds to cyclophosphamide-containing agents the most.<ref name=":2">{{cite web|url=https://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq|title=Adult Acute Lymphoblastic Leukemia Treatment|website=National Cancer Institute|access-date=6 December 2017}}</ref>

Recent updates on the treatment of adult acute lymphoblastic leukemia (ALL) include advancements in immunotherapy, particularly the use of monoclonal antibodies like blinatumomab and inotuzumab ozogamicin, which target specific cancer cells and are used alongside stem cell transplantation. Additionally, tyrosine kinase inhibitors (TKIs) such as imatinib and dasatinib are incorporated for Philadelphia chromosome-positive ALL, improving treatment outcomes.<ref>{{Cite web |title=Adult Acute Lymphoblastic Leukemia Treatment (PDQ®)–Health Professional Version |url=https://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq |website=National Cancer Institute |access-date=July 12, 2024}}</ref>

=== 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). In the past, physicians commonly utilized radiation in the form of whole-brain radiation for central nervous system prophylaxis, to prevent the occurrence and/or recurrence of leukemia in the brain. Recent studies showed that CNS chemotherapy provided results as favorable but with fewer 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.<ref name=":1">{{cite book|title=Hoffbrand's Essential Haematology| vauthors = Hoffbrand AV, Moss PA |isbn=978-1-118-40867-4|edition=Seventh|location=Chichester, West Sussex|oclc=909538759|date = 26 October 2015}}</ref><ref name="Paul 1645–1666"/>

=== Biological therapy ===

Selection of biological targets based on their combinatorial effects on the leukemic lymphoblasts can lead to clinical trials for improvement in the effects of ALL treatment.<ref name="pmid22273806">{{cite journal | vauthors = Lambrou GI, Papadimitriou L, Chrousos GP, Vlahopoulos SA | title = Glucocorticoid and proteasome inhibitor impact on the leukemic lymphoblast: multiple, diverse signals converging on a few key downstream regulators | journal = Molecular and Cellular Endocrinology | volume = 351 | issue = 2 | pages = 142–51 | date = April 2012 | pmid = 22273806 | doi = 10.1016/j.mce.2012.01.003 | s2cid = 28749125 }}</ref> [[Tyrosine-kinase inhibitor]]s (TKIs), such as [[imatinib]], are often incorporated into the treatment plan for people with ''Bcr-Abl1+ (Ph+)'' ALL.<ref>{{Cite journal |last1=Foà |first1=Robin |last2=Chiaretti |first2=Sabina |date=2022-06-23 |editor-last=Longo |editor-first=Dan L. |title=Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia |url=https://www.nejm.org/doi/10.1056/NEJMra2113347 |journal=New England Journal of Medicine |language=en |volume=386 |issue=25 |pages=2399–2411 |doi=10.1056/NEJMra2113347 |pmid=35731654 |issn=0028-4793|url-access=subscription }}</ref><ref>{{Cite journal |last1=Dragani |first1=Matteo |last2=Ansuinelli |first2=Michela |last3=Papayannidis |first3=Cristina |last4=Fracchiolla |first4=Nicola |last5=Cardinali |first5=Valeria |last6=Cedrone |first6=Michele |last7=Guolo |first7=Fabio |last8=Perrone |first8=Salvatore |last9=Salutari |first9=Prassede |last10=Todisco |first10=Elisabetta |last11=Foà |first11=Robin |last12=Chiaretti |first12=Sabina |date=2025-01-09 |title=Tyrosine kinase inhibitor discontinuation in non-allografted Philadelphia-positive acute lymphoblastic leukemia patients: a Campus ALL real-life study |journal=Haematologica |volume=110 |issue=5 |pages=1177–1181 |doi=10.3324/haematol.2024.286325 |pmid=39781617 |issn=1592-8721|doi-access=free |pmc=12050923 }}</ref> However, this subtype of ALL is frequently resistant to the combination of chemotherapy and TKIs, and allogeneic stem cell transplantation is often recommended upon relapse.<ref name=":1" />

[[Blinatumomab]] is not only a promising add-on to chemotherapy in infant ALL,<ref>{{cite journal|title=Blinatumomab added to upfront chemotherapy in infant lymphoblastic leukemia |year=2023|volume=388|issue=17|pages=1572–1581|doi=10.1056/NEJMoa2214171 |pmid=37099340|s2cid=258332506 |last1=Van Der Sluis |first1=I. M. |last2=De Lorenzo |first2=P. |last3=Kotecha |first3=R. S. |last4=Attarbaschi |first4=A. |last5=Escherich |first5=G. |last6=Nysom |first6=K. |last7=Stary |first7=J. |last8=Ferster |first8=A. |last9=Brethon |first9=B. |last10=Locatelli |first10=F. |last11=Schrappe |first11=M. |last12=Scholte-Van Houtem |first12=P. E. |last13=Valsecchi |first13=M. G. |last14=Pieters |first14=R. |journal=The New England Journal of Medicine }}</ref> it is also a promising standalone therapy in children.<ref>{{cite journal|title=Blinatumomab for First-Line Treatment of Children and Young Persons With B-ALL |journal=[[Journal of Clinical Oncology]]|year=2024|volume=42|issue=8|pages=907–914 |doi=10.1200/JCO.23.01392 |pmid=37967307 |last1=Hodder |first1=Angus |last2=Mishra |first2=Avijeet K. |last3=Enshaei |first3=Amir |last4=Baird |first4=Susan |last5=Bhuller |first5=Kaljit |last6=Elbeshlawi |first6=Ismail |last7=Bonney |first7=Denise |last8=Clesham |first8=Katherine |last9=Cummins |first9=Michelle |last10=Vedi |first10=Aditi |last11=Gibson |first11=Brenda |last12=George |first12=Lindsay |last13=Ingham |first13=Danielle |last14=Jigoulina |first14=Galina |last15=Lancaster |first15=Donna |last16=Lindsay |first16=Katherine |last17=Madni |first17=Majid |last18=Malone |first18=Andrea |last19=Mitchell |first19=Bethany |last20=Moppett |first20=John |last21=Motwani |first21=Jayashree |last22=Moorman |first22=Anthony V. |last23=Patrick |first23=Katharine |last24=Samrin |first24=Lamia |last25=Tewari |first25=Sanjay |last26=Thakur |first26=Indu |last27=O'Connor |first27=David |last28=Samarasinghe |first28=Sujith |last29=Vora |first29=Ajay |url=https://discovery.ucl.ac.uk/id/eprint/10181934/ }}</ref>

=== Immunotherapy ===

[[Chimeric antigen receptor]]s (CARs) have been developed as a promising [[Cancer immunotherapy|immunotherapy]] 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 this therapy, mice are immunized with the CD19 antigen and produce anti-CD19 antibodies. [[Hybridoma technology|Hybridomas]] developed from mouse spleen cells fused to a myeloma cell line can be developed as a source for the cDNA encoding the CD19-specific antibody.<ref name="pmid23527958">{{cite journal | vauthors = Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, Teachey DT, Chew A, Hauck B, Wright JF, Milone MC, Levine BL, June CH | title = Chimeric antigen receptor-modified T cells for acute lymphoid leukemia | journal = The New England Journal of Medicine | volume = 368 | issue = 16 | pages = 1509–1518 | date = April 2013 | pmid = 23527958 | pmc = 4058440 | doi = 10.1056/NEJMoa1215134 }}{{Erratum|doi=10.1056/NEJMx160005|pmid=26962747|http://retractionwatch.com/2016/03/15/nejm-corrects-3-papers-after-prominent-cancer-scientist-left-off-credit-for-breakthrough/ ''Retraction Watch''|checked=yes}}</ref> 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. Varying arrangements of subunits serve 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 (immunology)|CD3]]-zeta containing [[Immunoreceptor tyrosine-based activation motif|ITAM]] repeats. Other sequences frequently included are: [[CD137|4-1bb]] and [[CD134|OX40]].<ref name="Barrett_2014">{{cite journal | vauthors = Barrett DM, Singh N, Porter DL, Grupp SA, June CH | title = Chimeric antigen receptor therapy for cancer | journal = Annual Review of Medicine | volume = 65 | pages = 333–47 | year = 2014 | pmid = 24274181 | pmc = 4120077 | doi = 10.1146/annurev-med-060512-150254 }}</ref> The final transgene sequence, containing the scFv and endodomain sequences is then inserted into immune effector cells that are obtained from the person and expanded ''[[in vitro]]''. In trials these have been a type of [[T cell|T-cell]] capable of [[cytotoxicity]].<ref name="pmid23695536">{{cite journal | vauthors = Alonso-Camino V, Sánchez-Martín D, Compte M, Nuñez-Prado N, Diaz RM, Vile R, Alvarez-Vallina L | title = CARbodies: Human Antibodies Against Cell Surface Tumor Antigens Selected From Repertoires Displayed on T Cell Chimeric Antigen Receptors | journal = Molecular Therapy: Nucleic Acids | volume = 2 | article-number = e93 | date = May 2013 | issue = 5 | pmid = 23695536 | pmc = 4817937 | doi = 10.1038/mtna.2013.19 }}</ref>

Inserting the DNA into the effector cell can be accomplished by several methods. Most commonly, this is done using a [[lentivirus]] that encodes the transgene. Pseudotyped, self-inactivating lentiviruses are an effective method for the stable insertion of a desired transgene into the target cell.<ref name="pmid9811723">{{cite journal | vauthors = Zufferey R, Dull T, Mandel RJ, Bukovsky A, Quiroz D, Naldini L, Trono D | title = Self-inactivating lentivirus vector for safe and efficient in vivo gene delivery | journal = Journal of Virology | volume = 72 | issue = 12 | pages = 9873–80 | date = December 1998 | pmid = 9811723 | pmc = 110499 | doi = 10.1128/JVI.72.12.9873-9880.1998 }}</ref> Other methods include [[electroporation]] and [[transfection]], but these are limited in their efficacy as transgene expression diminishes over time.{{medical citation needed|date=August 2023}}

The gene-modified effector cells are then transplanted back into the person. Typically this process is done in conjunction with a conditioning regimen such as [[cyclophosphamide]], which has been shown to potentiate the effects of infused T-cells. This effect has been attributed to making an immunologic space within which the cells populate.<ref name="Barrett_2014" /> The process as a whole results in an [[effector cell]], typically a T-cell, that can recognize a tumor cell [[antigen]] in a manner that is independent of the [[major histocompatibility complex]] and which can initiate a cytotoxic response.{{medical citation needed|date=August 2023}}

In 2017, [[tisagenlecleucel]] was approved by the [[Food and Drug Administration|FDA]] as a [[Chimeric antigen receptor|CAR-T]] therapy for people with acute B-cell lymphoblastic leukemia who did not respond adequately to other treatments or have relapsed.<ref name="FDA2017">{{cite web|url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm574058.htm|title=Press Announcements—FDA approval brings first gene therapy to the United States |author1= Office of the Commissioner |website=www.fda.gov|archive-url=https://web.archive.org/web/20170903080825/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm574058.htm|archive-date=3 September 2017|access-date=12 September 2017}}</ref> In a 22-day process, the "drug" is customized for each person. T cells purified from each person are modified by a virus that inserts genes that encode a chimaeric antigen receptor into their DNA, one that recognizes leukemia cells.<ref>{{cite journal | vauthors = Ledford H | title = Engineered cell therapy for cancer gets thumbs up from FDA advisers | journal = Nature | volume = 547 | issue = 7663 | page = 270 | date = July 2017 | pmid = 28726836 | doi = 10.1038/nature.2017.22304 | doi-access = free | bibcode = 2017Natur.547..270L }}</ref>

[[Obecabtagene autoleucel]] (Aucatzyl) was approved for medical use in the United States in November 2024.<ref name="FDA Aucatzyl">{{cite web | title=FDA approves obecabtagene autoleucel for acute lymphoblastic leukemia | website=U.S. [[Food and Drug Administration]] (FDA) | date=8 November 2024 | url=https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-obecabtagene-autoleucel-adults-relapsed-or-refractory-b-cell-precursor-acute | archive-url=https://web.archive.org/web/20241108230826/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-obecabtagene-autoleucel-adults-relapsed-or-refractory-b-cell-precursor-acute | archive-date=8 November 2024 | access-date=10 November 2024}}</ref><ref>{{cite press release | title=Autolus Therapeutics Announces FDA Approval of Aucatzyl (obecabtagene autoleucel – obe-cel) for adults with relapsed/refractory B-cell acute lymphoblastic leukemia (r/r B-ALL) | publisher=Autolus Therapeutics | via=GlobeNewswire | date=8 November 2024 | url=https://www.globenewswire.com/news-release/2024/11/08/2977884/0/en/index.html| access-date=10 November 2024}}</ref>

=== Relapsed ALL ===
Typically, people who experience a relapse in their ALL after initial treatment have a poorer prognosis than those who remain in complete remission after induction therapy. It is unlikely that recurrent leukemia will respond favorably to the standard chemotherapy regimen that was initially implemented, and instead, these people should be trialed on reinduction chemotherapy followed by [[allogeneic bone marrow transplantation]]. These people in relapse may also receive [[blinatumomab]], as it has shown to increase remission rates and overall survival rates, without increased toxic effects.<ref>{{cite journal | vauthors = Kantarjian H, Stein A, Gökbuget N, Fielding AK, Schuh AC, Ribera JM, Wei A, Dombret H, Foà R, Bassan R, Arslan Ö, Sanz MA, Bergeron J, Demirkan F, Lech-Maranda E, Rambaldi A, Thomas X, Horst HA, Brüggemann M, Klapper W, Wood BL, Fleishman A, Nagorsen D, Holland C, Zimmerman Z, Topp MS | title = Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia | language = EN | journal = The New England Journal of Medicine | volume = 376 | issue = 9 | pages = 836–847 | date = March 2017 | pmid = 28249141 | pmc = 5881572 | doi = 10.1056/nejmoa1609783 }}</ref>

Low-dose [[Palliative care|palliative]] radiation may also help reduce the burden of tumors inside or outside the central nervous system and alleviate some symptoms.{{medical citation needed|date=August 2023}}

There has also been evidence and approval of use for [[dasatinib]], a [[tyrosine kinase inhibitor]]. It has shown efficacy in cases of people with Ph1-positive and [[imatinib]]-resistant ALL, but more research needs to be done on long-term survival and time to relapse.<ref name=":2"/>

=== Side effects ===
Chemotherapies or stem cell transplantations may require a [[platelet transfusion]] to prevent bleeding.<ref>{{cite journal | vauthors = Estcourt L, Stanworth S, Doree C, Hopewell S, Murphy MF, Tinmouth A, Heddle N | title = Prophylactic platelet transfusion for prevention of bleeding in patients with haematological disorders after chemotherapy and stem cell transplantation | journal = The Cochrane Database of Systematic Reviews | issue = 5 | article-number = CD004269 | date = May 2012 | pmid = 22592695 | doi = 10.1002/14651858.CD004269.pub3 | editor-last = Cochrane Haematological Malignancies Group | pmc = 11972837 }}</ref><ref>{{cite journal | vauthors = Estcourt LJ, Stanworth SJ, Doree C, Hopewell S, Trivella M, Murphy MF | title = Comparison of different platelet count thresholds to guide administration of prophylactic platelet transfusion for preventing bleeding in people with haematological disorders after myelosuppressive chemotherapy or stem cell transplantation | journal = The Cochrane Database of Systematic Reviews | issue = 11 | article-number = CD010983 | date = November 2015 | volume = 2015 | pmid = 26576687 | doi = 10.1002/14651858.CD010983.pub2 | editor-last = Cochrane Haematological Malignancies Group | pmc = 4717525 }}</ref> Moreover, patients undergoing a stem cell transplantation can develop a [[graft-versus-host disease]] (GvHD). It was evaluated whether mesenchymal stromal cells can be used to prevent a GvHD. The evidence is very uncertain about the therapeutic effect of mesenchymal stromal cells to treat graft-versus-host diseases after a stem cell transplantation on the all-cause mortality and complete disappearance of chronic acute graft-versus-host diseases. Mesenchymal stromal cells may result in little to no difference in the all-cause mortality, relapse of malignant disease, and incidence of acute and chronic graft-versus-host diseases if they are used for prophylactic reasons.<ref>{{cite journal | vauthors = Fisher SA, Cutler A, Doree C, Brunskill SJ, Stanworth SJ, Navarrete C, Girdlestone J | title = Mesenchymal stromal cells as treatment or prophylaxis for acute or chronic graft-versus-host disease in haematopoietic stem cell transplant (HSCT) recipients with a haematological condition | journal = The Cochrane Database of Systematic Reviews | volume = 1 | article-number = CD009768 | date = January 2019 | issue = 1 | pmid = 30697701 | doi = 10.1002/14651858.CD009768.pub2 | editor-last = Cochrane Haematological Malignancies Group | pmc = 6353308 }}</ref>

=== Supportive therapy ===
Adding physical exercises to the standard treatment for adult patients with haematological malignancies like ALL may result in little to no difference in mortality, quality of life, and physical functioning. These exercises may result in a slight reduction in depression. Furthermore, aerobic physical exercises probably reduce fatigue. The evidence is very uncertain about the effect on anxiety and serious adverse events.<ref>{{cite journal | vauthors = Knips L, Bergenthal N, Streckmann F, Monsef I, Elter T, Skoetz N | title = Aerobic physical exercise for adult patients with haematological malignancies | journal = The Cochrane Database of Systematic Reviews | volume = 1 | article-number = CD009075 | date = January 2019 | issue = 1 | pmid = 30702150 | doi = 10.1002/14651858.CD009075.pub3 | editor-last = Cochrane Haematological Malignancies Group | pmc = 6354325 }}</ref>

=== Cell therapy ===
[[Brexucabtagene autoleucel]] (Tecartus) was approved by the FDA in October 2021 for the treatment of adults with relapsed or refractory B-cell precursor ALL, and later by the EMA in December 2021.<ref name="FDA 20210101">{{cite web | title=FDA approves brexucabtagene autoleucel for relapsed or refractory B-cell precursor acute lymphoblastic leukemia | website=U.S. [[Food and Drug Administration]] (FDA) | date=1 October 2021 | url=https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-brexucabtagene-autoleucel-relapsed-or-refractory-b-cell-precursor-acute-lymphoblastic | archive-url=https://web.archive.org/web/20211002190129/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-brexucabtagene-autoleucel-relapsed-or-refractory-b-cell-precursor-acute-lymphoblastic | archive-date=2 October 2021 | access-date=2 October 2021}} {{PD-notice}}</ref><ref name="Kite PR 20211001">{{cite web | title=U.S. FDA Approves Kite's Tecartus as the First and Only Car T for Adults With Relapsed or Refractory B-cell Acute Lymphoblastic Leukemia | website=Kite | via=Business Wire | date=1 October 2021 | url=https://www.businesswire.com/news/home/20211001005719/en/U.S.-FDA-Approves-Kite%E2%80%99s-Tecartus%C2%AE-as-the-First-and-Only-Car-T-for-Adults-With-Relapsed-or-Refractory-B-cell-Acute-Lymphoblastic-Leukemia | access-date=1 October 2021}}</ref><ref>{{Cite web |date=2020-10-15 |title=Summary of opinion (initial authorisation) - Tecartus |url=https://www.ema.europa.eu/en/documents/smop-initial/chmp-summary-positive-opinion-tecartus_en.pdf |access-date=2025-01-10 |website=[[European Medicines Agency]]}}</ref>

Each dose of brexucabtagene autoleucel is a customized treatment created using the recipient's immune system to help fight the leukaeamia.<ref name="FDA Tecartus PR">{{cite web | title=FDA Approves First Cell-Based Gene Therapy For Adult Patients with Relapsed or Refractory MCL | website=U.S. [[Food and Drug Administration]] (FDA) | date=24 July 2020 | url=https://www.fda.gov/news-events/press-announcements/fda-approves-first-cell-based-gene-therapy-adult-patients-relapsed-or-refractory-mcl | archive-url=https://web.archive.org/web/20200725050713/https://www.fda.gov/news-events/press-announcements/fda-approves-first-cell-based-gene-therapy-adult-patients-relapsed-or-refractory-mcl | archive-date=25 July 2020 | access-date=24 July 2020}} {{PD-notice}}</ref> The recipient's [[T cell]]s, a type of white blood cell, are collected and genetically modified to include a new gene that facilitates the targeting and killing of the lymphoma cells.<ref name="FDA Tecartus PR" /> These modified T cells are then infused back into the recipient.<ref name="FDA Tecartus PR" />

=== Helminthic Therapy ===

[[Helminthic therapy]] could be an interesting avenue to explore, according to the following study: 
"Impact of pinworm infection on the development of murine B-cell leukemia/lymphoma in the presence and absence of ETV6::RUNX1"<ref>{{cite journal | vauthors = Fitch BA, Situ J, Wiemels JL, Kogan SC, Zhou M | title = Impact of pinworm infection on the development of murine B-cell leukemia/lymphoma in the presence and absence of ETV6::RUNX1 | language = en | journal = Haematologica | volume = 108 | issue = 12 | pages = 3480–3484 | date = 1 December 2023 | pmid = 37345483 | pmc = 10690896 | doi = 10.3324/haematol.2022.282591 }}</ref>

== Prognosis ==

Before the development of chemotherapy regimens and hematopoietic stem cell transplants, children were surviving a median length of 3 months, largely due to either infection or bleeding. Since the advent of chemotherapy, the prognosis for childhood leukemia has improved greatly and children with ALL are estimated to have a 95% probability of achieving a successful remission after 4 weeks of initiating treatment. People in pediatric care with ALL in developed countries have a greater than 80% five-year survival rate. It is estimated that 60–80% of adults undergoing induction chemotherapy achieve complete remission after 4 weeks, and those over the age of 70 have a cure rate of 5%.<ref name="HoffbrandMoss2006" /><ref>{{cite journal | vauthors = Hutter JJ | title = Childhood leukemia | journal = Pediatrics in Review | volume = 31 | issue = 6 | pages = 234–41 | date = June 2010 | pmid = 20516235 | doi = 10.1542/pir.31-6-234 | s2cid = 207170780 }}</ref>
[[File:Overall survival rates in pediatric and adult ALL patients.png|thumb|Graphs of overall survival rates at 5 years and 10 years in people in pediatric care and adults with ALL]]

However, there are differing prognoses for ALL among individuals depending on a variety of factors:
* Gender: Females tend to fare better than males.
* Ethnicity: [[Whites|Caucasians]] are more likely to develop acute leukemia than [[African American|African-Americans]], [[Asian American|Asians]], or [[Hispanics in the United States|Hispanics]]. However, they also tend to have a better prognosis than non-Caucasians.
* Age at diagnosis: children 1–10 years of age are most likely to develop ALL and to be cured of it. Cases in older people are more likely to result from chromosomal abnormalities (e.g., the Philadelphia chromosome) that make treatment more difficult and prognoses poorer. Older people are also likely to have co-morbid medical conditions that make it even more difficult to tolerate ALL treatment.
* White blood cell count at diagnosis of greater than 30,000 (B-ALL) or 100,000 (T-ALL) is associated with worse outcomes
* Cancer spreading into the [[central nervous system]] ([[brain]] or [[spinal cord]]) has worse outcomes.
* Morphological, immunological, and genetic subtypes
* Person's response to initial treatment and longer length of time required (greater than 4 weeks) to reach complete remission
* Early relapse of ALL
* [[Minimal residual disease]]
* [[Genetic disorder]]s, such as [[Down syndrome]], and other chromosomal abnormalities (aneuploidy and translocations)<ref>{{cite web|url=http://www.cancer.ca/en/cancer-information/cancer-type/leukemia-acute-lymphocytic-all/prognosis-and-survival/?region=on|title=Prognosis and survival for acute lymphocytic leukemia - Canadian Cancer Society|website=www.cancer.ca|access-date=6 December 2017|archive-date=7 December 2017|archive-url=https://web.archive.org/web/20171207014817/http://www.cancer.ca/en/cancer-information/cancer-type/leukemia-acute-lymphocytic-all/prognosis-and-survival/?region=on}}</ref>

{| class="wikitable"
|+ In children<ref>Nelson Essentials of Pediatrics By Karen Marcdante, Robert M. Kliegman, Richard E. Behrman, Hal B. Jenson p597</ref><ref>The Guide Paediatrics. {{ISBN|978-978-917-9909}}. p51</ref><ref>{{cite book|title=Hoffbrand's Essential Haematology | vauthors = Hoffbrand AV, Moss PA |isbn=978-1-118-40867-4|edition=Seventh|location=Chichester, West Sussex|page=194|oclc=909538759|date = 26 October 2015}}</ref>
|-
! Factor !! Unfavorable !! Favorable
|-
|Age || <2 or >10 years ||3–5 years
|-
|Sex || Male || Female
|-
| Race || Black || Caucasian
|-
| Organomegaly || Present || Absent
|-
| Mediastinal mass || Present || Absent
|-
| CNS involvement || Present || Absent
|-
| Leukocyte count || B-ALL >30,000mm<sup>3</sup> T-ALL >100,000mm<sup>3</sup>
| Low
|-
| Hemoglobin concentration || >10g/dl || <10g/dl
|-
| Cell type || Non Lymphoid || Lymphoid
|-
| Cell lineage ||Pre B cell +
T-ALL (children)
| Early Pre B cell
|-
| Karyotype || Translocation || Hyperdiploidy
|-
|Response to treatment || Slow
>1 week to clear blasts from blood
| Rapid
<1 week to clear blasts from blood
|-
|Time to remission
|>4 weeks
|<4 weeks
|-
|Minimal residual disease
|Positive at 3 – 6 months
|Negative at 1 month (children) or 3 months (adults)
|}

Cytogenetics, the study of characteristic large changes in the [[chromosomes]] of [[cancer cell]]s, is an important predictor of outcome.<ref name="pmid17170120">{{cite journal | vauthors = 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 | title = 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 | journal = Blood | volume = 109 | issue = 8 | pages = 3189–97 | date = April 2007 | pmid = 17170120 | doi = 10.1182/blood-2006-10-051912 | s2cid = 1038016 | doi-access = free }}</ref> Some cytogenetic subtypes have a worse prognosis than others. These include:<ref name=Seiter2014/>
* Person with t(9,22) positive-ALL (30% of adult ALL cases) and other ''Bcr-abl-''rearranged leukemias are more likely to have a poor prognosis, but survival rates may rise with treatment consisting of chemotherapy and ''Bcr-abl'' tyrosine kinase inhibitors.<ref name=":2"/>
* A translocation between chromosomes 4 and 11 occurs in about 4% of cases and is most common in infants under 12 months.{{medical citation needed|date=August 2023}}

{| class="wikitable"
|-
! 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
|-
|Deletion of chromosome 7
|Poor prognosis
|-
|Trisomy 8
|Poor prognosis
|-
| High [[hyperdiploidy]] (trisomy 4, 10, 17)
| Good prognosis
|-
| del(9p)
| Good prognosis
|}
* Hyperdiploidy (>50 chromosomes) and t(12;21) are good prognostic factors and also makeup 50% of pediatric ALL cases.
{| class="wikitable"
|+ Based on bone marrow cytogenetics
|-
! 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 risk,<ref name="pmid19138562">{{cite journal | vauthors = Den Boer ML, van Slegtenhorst M, De Menezes RX, Cheok MH, Buijs-Gladdines JG, Peters ST, Van Zutven LJ, Beverloo HB, Van der Spek PJ, Escherich G, Horstmann MA, Janka-Schaub GE, Kamps WA, Evans WE, Pieters R | title = A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study | journal = The Lancet. Oncology | volume = 10 | issue = 2 | pages = 125–34 | date = February 2009 | pmid = 19138562 | pmc = 2707020 | doi = 10.1016/S1470-2045(08)70339-5 }}</ref> somewhere in-between the good and poor risk categories.

== Epidemiology ==

Acute lymphoblastic leukemia affected about 876,000 people and resulted in 111,000 deaths globally in 2015.<ref name=GBD2015Pre/><ref name=GBD2015De/> It occurs in both children and adults with the highest rates seen between the ages three and seven years. Around 75% of cases occur before the age of 6 with a secondary rise after the age of 40.<ref name="HoffbrandMoss2006" /> It is estimated to affect 1 in 1500 children.<ref name=Boer2017>{{cite journal | vauthors = Boer JM, den Boer ML | title = BCR-ABL1-like acute lymphoblastic leukaemia: From bench to bedside | journal = European Journal of Cancer | volume = 82 | pages = 203–218 | date = September 2017 | pmid = 28709134 | doi = 10.1016/j.ejca.2017.06.012 }}</ref>

Accounting for the broad age profiles of those affected, ALL newly occurs in about 1.7 per 100,000 people annually.<ref name="MDAnd2016" /> Acute lymphoblastic leukemia represents approximately 20% of adults and 80% of childhood leukemias, making it the most common childhood cancer.<ref name="MDAnd2016" /> Although 80 to 90% of children will have a long-term complete response with treatment,<ref name="Nathan_2014_8" />{{rp|1527}} it remains the leading cause of cancer-related deaths among children.<ref name="Guo2014" /> 85% of cases are of B-cell lineage and have an equal number of cases in both males and females. The remaining 15% of T-cell lineage have a male predominance.

Globally, ALL typically occurs more often in Caucasians, Hispanics, and Latin Americans than in Africans.<ref name=Wintrobe_2013_13 />{{rp|1617}}<ref name="pmid25297793">{{cite journal | vauthors = Urayama KY, Manabe A | title = Genomic evaluations of childhood acute lymphoblastic leukemia susceptibility across race/ethnicities | journal = [Rinsho Ketsueki] the Japanese Journal of Clinical Hematology | volume = 55 | issue = 10 | pages = 2242–8 | date = October 2014 | pmid = 25297793 }}</ref> In the US, ALL is more common in children from Caucasian (36 cases/million) and Hispanic (41 cases/million) descent when compared to those from African (15 cases/million) descent.<ref>{{cite book|title=Cancer Incidence and Survival among Children and Adolescents: United States SEER Program 1975–1995.| vauthors = Ries LA, Smith MA, Gurney JG, Linet M, Tamra T, Young JL, Bunin GR |publisher=National Cancer Institute, SEER Program|year=1999|location=Bethesda, MD}}</ref>

== Pregnancy ==
Leukemia is rarely associated with pregnancy, affecting only about 1 in 10,000 pregnant women.<ref name="Shapira2008" /> The management of leukemia in a pregnant woman depends primarily on the type of leukemia. Acute leukemias normally require prompt, aggressive treatment, despite significant risks of [[miscarriage|pregnancy loss]] and [[birth defect]]s, especially if chemotherapy is given during the developmentally sensitive [[first trimester]].<ref name="Shapira2008" />

== References ==

<references>
<!-- This reference list uses [[WP:LDR]] and is organized alphanumerically by arbitrary ref name -->

<ref name="DeAngelo2013">DeAngelo DJ, Pui C. Acute lymphoblastic leukemia and lymphoblastic lymphoma. Chapter 19 of American Society of Hematology Self-Assessment Program. 2013. {{ISBN|9780982843512}}</ref>

<ref name="Guo2014">{{cite journal | vauthors = Guo LM, Xi JS, Ma Y, Shao L, Nie CL, Wang GJ | title = ARID5B gene rs10821936 polymorphism is associated with childhood acute lymphoblastic leukemia: a meta-analysis based on 39,116 subjects | journal = Tumour Biology | volume = 35 | issue = 1 | pages = 709–13 | date = January 2014 | pmid = 23975371 | doi = 10.1007/s13277-013-1097-0 | s2cid = 12601034 }}</ref>

<ref name="Nathan_2014_8">{{cite book | vauthors = Orkin SH, Nathan DG, Ginsburg D |title = Nathan and Oski's Hematology and Oncology of Infancy and Childhood |publisher = Saunders |year = 2014 |edition = 8th |isbn = 978-1-4557-5414-4 |display-authors = et al }}</ref>

<ref name="Shapira2008">{{cite journal | vauthors = Shapira T, Pereg D, Lishner M | title = How I treat acute and chronic leukemia in pregnancy | journal = Blood Reviews | volume = 22 | issue = 5 | pages = 247–59 | date = September 2008 | pmid = 18472198 | doi = 10.1016/j.blre.2008.03.006 }}</ref>

<ref name=Wintrobe_2013_13>{{cite book | vauthors = Greer JP, Arber DA, Glader B |title = Wintrobe's Clinical Hematology |publisher = Lippincott Williams & Wilkins |year = 2013 |edition = 13th |isbn = 978-1-4511-7268-3 |display-authors = etal }}</ref>{{rp|1617}}
</references>

== External links ==

{{Medical resources
|  DiseasesDB      = 195
|  ICD10           = {{ICD10|C|91|0|c|81}}
|  ICD9            = {{ICD9|204.0}}
|  ICDO            = {{ICDO|9835|3}}
|  OMIM            =
|  MedlinePlus     =
|  eMedicineSubj   = med
|  eMedicineTopic  = 3146
|  eMedicine_mult  = {{eMedicine2|ped|2587}}
|  MeshID          = D054198
}}

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[[Category:Acute lymphocytic leukemia]]
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[[Category:Pediatric cancers]]
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