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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 5) cytogenetics 6) serum calcium: hypercalcemia [3] 7) lumbar pucture: CSF analysis 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
  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. Acute Lymphoblastic Leukemia in Children http://www.nci.nih.gov/newscenter/all3
  18. 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