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acute lymphoblastic leukemia (ALL)

See precursor B-lymphoblastic leukemia/lymphoma or precursor T-lymphoblastic leukemia/lymphoma. Etiology: 1) unknown (most cases) 2) risk factors a) trisomy 21, Klinefelter syndrome, Bloom syndome, ataxia telangiectasia b) viral infections - T-cell lymphotrophic virus 1 - Epstein Barr virus - human immunodeficiency virus Epidemiology: 1) 1-1.5/100,000 2) more common in children, ~75% occur before age 6 3) secondary increased incidence occurs after age 50 Pathology: 1) maturation arrest in committed stem cells - proliferation of immature lymphoblasts - disease of precursor B-cells or T-cells [1] 2) 25% of adults have the Philadelphia chromosome t(9,22) -> poor prognostic indicator 3) meningeal involvement occurs more commonly in children 4) infections associated with neutropenia 5) infection with Pneumocystis carinii a) steroid chemotherapy b) T-cell & B-cell dysfunction 6) skin & mucous membrane lesions [2] Genetics: 1) chromosomal translocation t9q34.1:22q11 (Philadelphia chromsome, bcr/abl) in 25% of adults - up to 50% of patients > 70 years of age [1] 2) childhood ALL associated with mutation in nibrin gene (putative) 3) chromosomal insertion ins(5;11)(q31;q13q23) resulting in MLL-AFF4 fusion protein 4) translocation t(1;14)(q25;q32) involving LHX4 with IGHG1 5) translocation t(1;14)(p32;q11) involving TAL1 with TCRA 6) translocation t(4;11)(p12;q23) involving FRYL with MLL is found in treatment-related acute lymphoblastic leukemia (ALL), forms a MLL-FRYL fusion protein 7) translocation t(9;18)(p13;q11.2) involving ZNF521 with PAX5 translocation generates the PAX5-ZNF521 oncogene consisting of N-terminus of PAX5 & C-terminus of ZNF521 8) rearrangements of KMT2A occur in ~80% of infants with ALL &in up to 15% of children & adults with ALL [14] 9) other implicated genes - DHX32, RGS2, HOX11 Clinical manifestations: 1) non specific - fatigue, easy bruising, bleeding, dizziness, infections, pallor, echymoses, petechiae 2) lympadenopathy (especially mediastinal lympadenopathy), splenomegaly, 20%, rarely symptomatic 3) fever, night sweats, weight loss can occur 4) extremity & joint pains may be only presenting symptoms in children 5) symptoms related to very high leukocytosis is rare (more common with AML) 6) cranial nerve palsies & meningitis in 5-8% of B-cell ALL 7) abdominal masses & spontaneous tumor lysis syndrome more common with B-cell ALL Laboratory: 1) complete blood count with differential, > 20% blasts 2) peripheral smear a) myeloperoxidase negative b) TdT positive or negative c) >= 25% lymphoblasts is diagnostic d) cytopenias secondary to bone marrow involvement 3) bone marrow biopsy - >= 25% lymphoblasts is diagnostic 4) immunophenotyping by flow cytometry - CD10 & CD20-positive B-cell precursors (necessary & confirmatory) [1] 5) cytogenetics 6) serum calcium: hypercalcemia [3] 7) lumbar pucture: CSF analysis - assess CNS involvement in patients with newly diagnosed ALL [1,17] - cell count, differential, flow cytometry testing - intrathecal chemotherapy (usually cytarabine or methotrexate) is routinely employed in all patients with ALL, & most patients receive one or two doses of prophylactic intrathecal chemotherapy with each cycle of systemic chemotherapy 8) PCR/ISH for acute lymphoblastic leukemia - chromosomal translocation t9q34.1:22q11 (Philadelphia chromosome, bcr/abl) 9) see ARUP consult [5] Radiology: - radiographs or bone scan may show lytic bone lesions Complications: - frequent involvement of the central nervous system - survivors are at high risk of secondary cancer & metabolic syndrome Management: 1) chemotherapy a) induction with anthracycline, vincristine, L-asparaginase & glucocorticoid [1] - (daunorubicin, vincristine, L-asparaginase & prednisone) - antibiotic prophylaxis routine in adults - antibiotic prophylaxis with levofloxacin reduces incidence of C difficle colitis in children [8] b) consolidation - high-dose methotrexate for B-cell lineage ALL - cyclophosphamide & cytarabine for T-cell lineage ALL c) dasatinib + glucocorticoid for Philadelphia chromosome-positive ALL [1,7] d) adults > 30 years of age may not respond well to combination chemotherapy containing asparaginase [1] e) blinatumomab (Blincyto) FDA-approved for relapsed or refractory disease or minimal residual disease [9] 2) intrathecal chemotherapy with or without cranial irradiation - prophylactic cranial irradiation not indicated [4] 3) maintenance: - 6-mercapropurine, methotrexate, vincristine, corticosteroids 4) monoclonal antibody therapy improves response rates & long-term survival a) rituximab b) alemtuzumab c) blinatumomab (Blincyto) d) inotuzumab ozogamicin (Besponsa) + dexamethasone induction therapy can result in complete remission in older adults with Philadelphia chromosome- negative precursor B-cell ALL [16] 5) revumenib, an investigational menin inhibitor, shows promsign responses in infants & children with KMT2A-rearranged ALL [14] 6) hematopoietic stem-cell transplantation - myeloablative conditioning with cyclophosphamide + busulfan or total body radiation [13] - CAR T-cell therapy: tisagenlecleucel (Kymria) - CAR T-cell therapy: brexucabtagene autoleucel (Tecartus) FDA approved for adult ALL with relapsed or refractory B-cell leukemia 7) prognosis a) complete remission >90% b) relapse is a problem c) in adults, cure rate is 30-40% [1] 8) predictors of poor prognosis a) age > 60 years b) poor performance status c) high leukocyte count at presentation 1] > 30,000/uL B-cell ALL 2] > 100,000/uL T-cell ALL d) B-cell ALL vs T-cell ALL e) cytogenetic abnormalities t(9:22), +8, t(4,11), -7, hypodiploid karyotypes f) lack of HOX11 gene expression g) Philadelphia chromosome positive: - treatment with imatinib or dasatinib in addition to chemotherapy & hematopoietic stem-cell transplantation favorably changes prognosis [1] h) inability to achieve complete remission [1] 8) follow-up - screening for dyslipidemia, diabetes & hypertension in survivors - echocardiography periodically if anthracycline exposure [1] - annual history & physical examination focused on endocrine dysfunction [15]

Interactions

disease interactions

Related

cytogenetic abnormalities in ALL

Specific

acute lymphoblastic leukemia, L1 acute lymphoblastic leukemia, L2 acute lymphoblastic leukemia, L3 (Burkitt type, mature B-cell ALL) mature B-cell acute lymphocytic leukemia (ALL) Philadelphia chromosome positive acute lymphoblastic leukemia (ALL) precursor B-lymphoblastic leukemia/lymphoblastic lymphoma (B-cell ALL) precursor T-lymphoblastic leukemia/lymphoma

General

acute leukemia lymphoid leukemia

References

  1. Medical Knowledge Self Assessment Program (MKSAP) 11, 15, 16, 17, 18. American College of Physicians, Philadelphia 1998, 2009, 2012, 2015, 2018. - Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022 - Medical Knowledge Self Assessment Program (MKSAP) 20 American College of Physicians, Philadelphia 2025
  2. Harrison's Principles of Internal Medicine, 14th ed. Fauci et al (eds), McGraw-Hill Inc. NY, 1998, pg 539
  3. Jobbour EJ et al, Adult acute lymphoblastic leukemia, Mayo Clin Proc 80(11):1517, 2005
  4. Pui C-H et al Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med 2009 Jun 25; 360:2730. PMID: 19553647
  5. ARUP Consult: Acute Lymphoblastic Leukemia - ALL The Physician's Guide to Laboratory Test Selection & Interpretation https://www.arupconsult.com/content/acute-lymphoblastic-leukemia
  6. Pui CH, Evans WE. Treatment of acute lymphoblastic leukemia. N Engl J Med. 2006 Jan 12;354(2):166-78. PMID: 16407512
  7. Foa R, Vitale A, Vignetti M et al Dasatinib as first-line treatment for adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood. 2011 Dec 15;118(25):6521-8 PMID: 21931113
  8. Wolf J et al Levofloxacin prophylaxis during induction therapy for pediatric acute lymphoblastic leukemia. Clin Infect Dis. 2017 Sep 14. PMID: 29020310
  9. FDA News Release. December 3, 2014. FDA approves Blincyto to treat a rare form of acute lymphoblastic leukemia. First anti-CD19 drug to receive agency approval. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm425549.htm - Ingram I. Blincyto OK'd for MRD-Positive Acute Lymphoblastic Leukemia. Residual disease undetectable in 70 of 86 patients treated. MedPage Today. March 29, 2018 https://www.medpagetoday.com/hematologyoncology/leukemia/72073 - FDA News Release. March 29, 2018 FDA expands approval of Blincyto for treatment of a type of leukemia in patients who have a certain risk factor for relapse. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm603151.htm
  10. Minerd J, expert critique by Taylor J New Immunotherapies for Relapsed/Refractory ALL. Explaining the data, mechanisms, and side effects. MedPage Today. ASCO Reading Room 05.09.2018 https://www.medpagetoday.com/reading-room/asco/hematologic-malignancies/72774 - Leonard J, Stock W Progress in adult ALL: Incorporation of new agents to frontline treatment. American Society of Hematology (ASH) Education Book 2017: 28-36. - Man LM, Morris AL, Keng M. New therapeutic strategies in acute lymphocytic leukemia. Curr Hematol Malig Rep. 2017 Jun;12(3):197-206 PMID: 28353016
  11. Diller L. Clinical practice. Adult primary care after childhood acute lymphoblastic leukemia. N Engl J Med. 2011 Oct 13;365(15):1417-24. PMID: 21995389
  12. Mulcahy N FDA Approves First CAR T-Cell for Adult ALL. For Patients With R/R B-Cell Disease. Medscape. October 4, 2021 https://www.medscape.com/viewarticle/960191
  13. Jenkins K Busulfan-Based Myeloablative Conditioning in ALL. Potential alternative to TBI-based regimen showed similar survival, toxicity, late effects. MedPage Today October 11, 2022 https://www.medpagetoday.com/reading-room/asco/hematologic-malignancies/101155
  14. Brooks M Novel Drug Leads to 'Impressive' Responses in Advanced Leukemia. Medscape. March 20, 2023 https://www.medscape.com/viewarticle/989871
  15. NEJM Knowledge+ Hematology
  16. Stelljes M et al. Inotuzumab ozogamicin as induction therapy for patients older than 55 years with Philadelphia chromosome-negative B-precursor ALL. J Clin Oncol 2024 Jan 20; 42:273 PMID: 37883727 https://ascopubs.org/doi/10.1200/JCO.23.00546 - Logan A. Innovating simpler and less toxic frontline management for adults with ALL. J Clin Oncol 2024 Jan 20; 42:250. PMID: 37883737 https://ascopubs.org/doi/10.1200/JCO.23.01726
  17. Kopmar NE, Cassaday RD. How I prevent and treat central nervous system disease in adults with acute lymphoblastic leukemia. Blood. 2023;141:1379-1388. PMID: 36548957
  18. Acute Lymphoblastic Leukemia in Children http://www.nci.nih.gov/newscenter/all3
  19. Childhood Acute Lymphoblastic Leukemia (PDQ): Treatment http://www.cancer.gov/cancertopics/pdq/treatment/childALL/HealthProfessional - Adult Acute Lymphoblastic Leukemia (PDQ): Treatment http://www.cancer.gov/cancertopics/pdq/treatment/adultALL/HealthProfessional