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Acute lymphoblastic leukemia


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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Umar Ahmad, M.D.[2] Raviteja Guddeti, M.B.B.S. [3] Carlos A Lopez, M.D. [4]

Synonyms and keywords: Acute lymphocytic leukemia, Acute lymphoid leukemia, ALL

Overview

Overview

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [2] Carlos A Lopez, M.D. [3] Alberto Castro Molina, M.D.

Overview

Prognosis has improved from a 0% to 20-75% survival rate largely due to the continuous development of clinical trials and improvements in bone marrow transplantation (BMT) and stem cell transplantation (SCT) technology. The prognosis for acute lymphoblastic leukemia differs between individuals depending on a wide variety of factors such as gender, ethnicity, age, blood cell count, dissemination and genetic involvement.

Philadelphia chromosome positive acute lymphoblastic leukemia (Ph positive ALL), defined by the BCR ABL1 fusion, is the most common genetic subgroup of ALL in adults and its frequency increases with age.[1] Over the past two decades, outcomes in Ph positive ALL have improved markedly because of the integration of Bcr-abl tyrosine kinase inhibitors (TKIs), response adapted strategies guided by sensitive molecular monitoring (BCR ABL1 transcript levels), and the addition of immunotherapy such as blinatumomab.[2][3]

Natural History, Complications, and Prognosis

Natural history

If left untreated, of patients with acute lymphoblastic leukemia may progress to develop infection, bleeding, infertility, and metastasis to other organs.[4][5][6][7]

Prognosis

  • The overall cure rate in children is 85%, and about 50% of adults have long-term disease-free survival.[8][9]
  • It is worth noting that medical advances in recent years, both through matching the best treatment to the genetic characteristics of the blast cells and through the availability of new drugs, are not fully reflected in statistics that usually refer to five-year survival rates.
  • The prognosis for acute Lymphoblastic leukemia differs between individuals depending on a wide variety of factors:

In Ph positive ALL, long term outcomes have improved substantially with modern TKI based regimens and immunotherapy, and deep molecular responses measured by BCR ABL1 transcript monitoring are strongly prognostic and increasingly guide decisions about treatment intensity and the role of allogeneic transplantation.[2][12][3]

Gender

  • Females tend to fare better than males[13]

Ethnicity

  • Caucasians are more likely to develop acute leukemia than African-Americans, Asians and Hispanics and tend to have a better prognosis than non-Caucasians.

Age

  • Age is a significant factor in children with acute lymphoblastic leukemia and may be an important prognostic factor in adult with acute lympoblastic leukemia as well[14]
  • In one study, overall the prognosis was better in patients younger than 25 years; another study found a better prognosis in patients younger than 35 years
  • These findings may in part, be related to the increased incidence of the Ph1 in older acute lymphoblatic leukemia patients a subgroup associated with poor prognosis[1]
  • Children between 1-10 years of age are most likely to be cured.

Blood cell count

  • White blood cell count at diagnosis of less than 50,000/µl.

Dissemination

Genetic involvement

In Ph positive ALL, the introduction of TKIs and immunotherapy has shifted many treatment strategies toward chemotherapy-reduced or chemotherapy-free regimens in selected adults, with high rates of deep molecular response and decreased dependence on allogeneic transplantation for cure in first remission at some centers.[2][20]

Cytogenetic subtypes with worse prognosis

Central nervous system involvement

  • As in childhood acute lymphoblastic leukemia, adult patients with acute lymphoblastic luekemia are at risk of developing central nervous system involvement during the course of their disease. This is particularly true for patients with L3 (Burkitt) morphology. Both treatment and prognosis are influenced by this complication.

Celular morphology

  • Patients with L3 morphology showed improved outcomes, as evidenced in a completed cancer and Leukemia Group B study, when treated according to specific treatment algorithms.
  • This study found that L3 leukemia can be cured with aggressive, rapidly cycling lymphoma-like chemotherapy regimens.

5 Year survival

  • Between 2004 and 2010, the 5-year relative survival of patients with acute lymphoblastic leukemias was 70%.[21]
  • When stratified by age, the 5-year relative survival of patients with acute lymphoblastic leukemias was 71.3% and 12.2% for patients <65 and ≥ 65 years of age respectively.[21]

Diagnosis

Initial evaluation of ALL includes morphologic assessment, immunophenotyping by flow cytometry, and cytogenetic and molecular testing to define risk and guide therapy. In suspected or confirmed Ph positive ALL, the BCR ABL1 fusion is commonly identified by karyotyping, FISH, and or RT-PCR, and baseline transcript quantification supports subsequent molecular monitoring of treatment response.[3][22]

Molecular monitoring of minimal residual disease in Ph positive ALL is frequently performed by quantitative PCR of BCR ABL1 transcripts, and depth of response is a key prognostic variable that can guide decisions about treatment intensification and transplantation in first remission.[3][12]

At relapse or in cases of molecular or hematologic resistance on TKIs, testing for ABL1 kinase domain mutations may inform selection of subsequent TKIs (including the use of ponatinib for T315I and other resistant mutations).[23]

Treatment

Modern treatment is risk-adapted and increasingly genotype-directed. The discussion below highlights key elements of therapy for Ph positive ALL, one of the most impactful areas of recent therapeutic progress.

Tyrosine kinase inhibitors

The addition of BCR ABL1 TKIs to chemotherapy regimens improved complete remission rates and long-term outcomes in Ph positive ALL compared with historical chemotherapy alone.[24][25] First-generation and second-generation TKIs (imatinib, dasatinib) are used in combination approaches, and third-generation ponatinib is used in selected settings including resistant disease and in frontline strategies at some centers.[26]

Chemo-reduced and chemo-free approaches with immunotherapy

Blinatumomab, a bispecific T-cell engager, has demonstrated activity in B-lineage ALL and has been incorporated into Ph positive ALL regimens to deepen molecular responses and reduce reliance on intensive chemotherapy.[27][28]

A chemotherapy-free strategy of dasatinib followed by blinatumomab produced high rates of molecular response and favorable survival outcomes in adults with newly diagnosed Ph positive ALL in a multicenter study.[2] A similar concept using ponatinib with blinatumomab has shown promising results in single-arm studies, supporting continued clinical development of chemo-reduced strategies.[20][29]

Role of allogeneic stem cell transplantation

Before the TKI era, allogeneic transplantation in first remission was often associated with superior outcomes compared with chemotherapy alone in adults with Ph positive ALL.[30] In current practice, the role of transplantation is increasingly individualized based on depth of molecular response, relapse risk, comorbidities, and treatment strategy, and some patients achieving sustained deep molecular responses may avoid transplantation in first remission.[12][29]

Maintenance and treatment discontinuation

Long-term TKI maintenance is commonly used in Ph positive ALL. In carefully selected patients with prolonged deep molecular remission, discontinuation of maintenance TKI outside of transplant has been reported, highlighting an emerging area of practice that requires close monitoring and careful patient selection.[31]

References

  1. ↑ 1.0 1.1 Burmeister T, Schwartz S, Bartram CR; et al. (2008). “Patients’ age and BCR-ABL frequency in adult B-precursor ALL: a retrospective analysis from the GMALL study group”. Blood. 112: 918–919.
  2. ↑ 2.0 2.1 2.2 2.3 Foà R, Bassan R, Vitale A; et al. (2020). “Dasatinib–blinatumomab for Ph-positive acute lymphoblastic leukemia in adults”. N Engl J Med. 383: 1613–1623.
  3. ↑ 3.0 3.1 3.2 3.3 Ansuinelli M, Della Starza I, Lauretti A; et al. (2021). “Applicability of molecular monitoring in Philadelphia chromosome positive acute lymphoblastic leukemia”. Hematol Oncol. 39: 680–686.
  4. ↑ Ma X, Urayama K, Chang J, Wiemels JL, Buffler PA (2009). “Infection and pediatric acute lymphoblastic leukemia”. Blood Cells Mol. Dis. 42 (2): 117–20. doi:10.1016/j.bcmd.2008.10.006. PMC 2834409. PMID 19064328.
  5. ↑ Byrne J, Fears TR, Mills JL, Zeltzer LK, Sklar C, Meadows AT, Reaman GH, Robison LL (April 2004). “Fertility of long-term male survivors of acute lymphoblastic leukemia diagnosed during childhood”. Pediatr Blood Cancer. 42 (4): 364–72. doi:10.1002/pbc.10449. PMID 14966835.
  6. ↑ Shigeta H, Tasaki N, Kitazumi S, Kitagawa Y, Kanatsuna T, Kondo M (April 1987). “[A case report of Bartter’s syndrome associated with possible pseudohypoparathyroidism type II]”. Nippon Naika Gakkai Zasshi (in Japanese). 76 (4): 549–52. PMID 3611913.
  7. ↑ Harrison’s Principles of Internal Medicine, 16th Edition, Chapter 97. Malignancies of Lymphoid Cells. Clinical Features, Treatment, and Prognosis of Specific Lymphoid Malignancies.
  8. ↑ “National Cancer Institute”.
  9. ↑ Barrett AJ (June 1994). “Bone marrow transplantation for acute lymphoblastic leukaemia”. Baillieres Clin. Haematol. 7 (2): 377–401. PMID 7803908.
  10. ↑ Bishop MR, Logan BR, Gandham S, Bolwell BJ, Cahn JY, Lazarus HM, Litzow MR, Marks DI, Wiernik PH, McCarthy PL, Russell JA, Miller CB, Sierra J, Milone G, Keating A, Loberiza FR, Giralt S, Horowitz MM, Weisdorf DJ (April 2008). “Long-term outcomes of adults with acute lymphoblastic leukemia after autologous or unrelated donor bone marrow transplantation: a comparative analysis by the National Marrow Donor Program and Center for International Blood and Marrow Transplant Research”. Bone Marrow Transplant. 41 (7): 635–42. doi:10.1038/sj.bmt.1705952. PMC 2587442. PMID 18084335.
  11. ↑ 12.0 12.1 12.2 Sasaki K, Kantarjian HM, Short NJ; et al. (2021). “Prognostic factors and outcomes in patients with Philadelphia chromosome positive acute lymphoblastic leukemia treated with tyrosine kinase inhibitors”. Cancer. 127: 2648–2656.
  12. ↑ Pui CH, Boyett JM, Relling MV, Harrison PL, Rivera GK, Behm FG; et al. (1999). “Sex differences in prognosis for children with acute lymphoblastic leukemia”. J Clin Oncol. 17 (3): 818–24. doi:10.1200/JCO.1999.17.3.818. PMID 10071272.
  13. ↑ Foà R (2011). “Acute lymphoblastic leukemia: age and biology”. Pediatr Rep. 3 Suppl 2: e2. doi:10.4081/pr.2011.s2.e2. PMC 3206534. PMID 22053278.
  14. ↑ Mowery CT, Reyes JM, Cabal-Hierro L, Higby KJ, Karlin KL, Wang JH; et al. (2018). “Trisomy of a Down Syndrome Critical Region Globally Amplifies Transcription via HMGN1 Overexpression”. Cell Rep. 25 (7): 1898–1911.e5. doi:10.1016/j.celrep.2018.10.061. PMC 6321629. PMID 30428356.
  15. ↑ Koo HH (2011). “Philadelphia chromosome-positive acute lymphoblastic leukemia in childhood”. Korean J Pediatr. 54 (3): 106–10. doi:10.3345/kjp.2011.54.3.106. PMC 3120995. PMID 21738539.
  16. ↑ Nashed AL, Rao KW, Gulley ML (2003). “Clinical applications of BCR-ABL molecular testing in acute leukemia”. J Mol Diagn. 5 (2): 63–72. doi:10.1016/S1525-1578(10)60454-0. PMC 1907317. PMID 12707370.
  17. ↑ Fielding AK (January 2010). “Current treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia”. Haematologica. 95 (1): 8–12. doi:10.3324/haematol.2009.015974. PMC 2805747. PMID 20065078.
  18. ↑ Mullighan CG (2012). “Molecular genetics of B-precursor acute lymphoblastic leukemia”. J Clin Invest. 122 (10): 3407–15. doi:10.1172/JCI61203. PMC 3461902. PMID 23023711.
  19. ↑ 20.0 20.1 Jabbour E, Short NJ, Jain N; et al. (2023). “Ponatinib and blinatumomab for Philadelphia chromosome-positive acute lymphoblastic leukemia: a single-arm, phase 2 trial”. Lancet Haematol. 10 (1): e24–e34.
  20. ↑ 21.0 21.1 Howlader N, Noone AM, Krapcho M, Garshell J, Miller D, Altekruse SF, Kosary CL, Yu M, Ruhl J, Tatalovich Z,Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer Statistics Review, 1975-2011, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2011/, based on November 2013 SEER data submission, posted to the SEER web site, April 2014.
  21. ↑ de Labarthe A, Rousselot P, Huguet-Rigal F; et al. (2007). “Imatinib combined with induction or consolidation chemotherapy in patients with de novo Philadelphia chromosome-positive acute lymphoblastic leukemia: results of the GRAAPH-2003 study”. Blood. 109: 1408–1413.
  22. ↑ O’Hare T, Shakespeare WC, Zhu X; et al. (2009). “AP24534, a pan-BCR-ABL inhibitor for the treatment of chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance”. Cancer Cell. 16: 401–412.
  23. ↑ Druker BJ, Sawyers CL, Kantarjian H; et al. (2001). “Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome”. N Engl J Med. 344: 1038–1042.
  24. ↑ Ottmann OG, Druker BJ, Sawyers CL; et al. (2002). “A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias”. Blood. 100: 1965–1971.
  25. ↑ Jabbour E, Kantarjian HM, Aldoss I; et al. (2024). “Ponatinib vs imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a randomized clinical trial”. JAMA. 331: 1814–1823.
  26. ↑ Topp MS, Kufer P, Gökbuget N; et al. (2011). “Targeted therapy with the T-cell-engaging antibody blinatumomab of minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival”. J Clin Oncol. 29: 2493–2498.
  27. ↑ Topp MS, Gökbuget N, Stein AS; et al. (2015). “Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study”. Lancet Oncol. 16: 57–66.
  28. ↑ 29.0 29.1 Ribera J-M, García-Calduch O, Ribera J; et al. (2022). “Ponatinib, chemotherapy-free, as first-line treatment for Philadelphia chromosome-positive acute lymphoblastic leukemia”. Blood Adv. 6: 5395–5402.
  29. ↑ Fielding AK, Rowe JM, Richards SM; et al. (2009). “Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the international ALL Trial MRC UKALLXII/ECOG2993”. Blood. 113: 4489–4496.
  30. ↑ Samra B, Kantarjian HM, Sasaki K; et al. (2021). “Discontinuation of maintenance tyrosine kinase inhibitor in Philadelphia chromosome-positive acute lymphoblastic leukemia outside of transplant”. Acta Haematol. 144: 285–292.

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Historical Perspective

Historical Perspective

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Carlos A Lopez, M.D. [2], Kamal Akbar, M.D.[3]

Overview

Leukemia was first described in 1827 by Alfred-Armand-Louis-Marie Velpeau, a French physician.

Historical perspective

  • Velpeau saw that the blood of this patient had a texture that was “like gruel”, and thought that the blood appeared white due to the white corpuscles.[2]
  • In 1845, a number of patients who passed away with enlarged spleens and changes in the “colors and consistencies of their blood” was publicized by the Edinburgh-based pathologist J.H. Bennett; he used the term “leucocythemia” to outline this pathological condition.[1][3]
  • As a visionary in the use of the light microscope in pathology, Virchow was the first to talk about the abnormal overabundance of white blood cells in patients with the clinical syndrome reported by Velpeau and Bennett[1]
  • As Virchow was not certain of the cause of the white blood cell excess, he used the exclusively depictive term “leukemia” (Greek: “white blood”) to refer to the condition.[4]

References

  1. ↑ 1.0 1.1 1.2 Piller, Gordon J. (2001). “Leukaemia – a brief historical review from ancient times to 1950”. British Journal of Haematology. 112 (2): 282–292. doi:10.1046/j.1365-2141.2001.02411.x. ISSN 0007-1048.
  2. ↑ Hoffman, Ronald; et al. (2005). Hematology: Basic Principles and Practice (4th. ed. ed.). St. Louis, Mo.: Elsevier Churchill Livingstone. pp. p. 1071. ISBN 0-443-06629-9.
  3. ↑ Bennett JH. Two cases of hypertrophy of the spleen and liver, where death took place from suppuration of blood. Edinburgh Med Surg J. (1845)64:413.
  4. ↑ Virchow R: Die Leukämie. In Virchow R (ed): Gesammelte Abhandlungen zur Wissenschaftlichen Medizin. Frankfurt, Meidinger, 1856, p 190.
  5. ↑ Ebstein W. Ueber die acute Leukämie und Pseudoleukämie. Deutsch Arch Klin Med. (1889)44:343.
  6. ↑ Mosler F. Klinische Symptome und Therapie der medullären Leukämie. Berl Klin Wochenschr. (1876)13:702.
  7. ↑ Naegeli O. Über rothes Knochenmark und Myeloblasten. Deutsch Med Wochenschr. (1900) 26:287.
  8. ↑ Zhen-yi, Wang (2003). “Ham-Wasserman Lecture: Treatment of Acute Leukemia by Inducing Differentiation and Apoptosis”. Hematology. PMID 14633774.

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Classification

Classification

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [2] Carlos A Lopez, M.D. [3]

Overview

Acute lymphoblastic leukemia may be classified according to either the French-American-British (FAB) classification or World Health Organization (WHO) classification scheme. According to the French-American-British (FAB) classification, acute lymphoblastic leukemia may be classified into 3 subgroups: ALL-L1 (small uniform cells), ALL-L2 (large varied cells) and ALL-L3 (large varied cells with vacuoles). According to the World Health Organization (WHO), acute lymphoblastic leukemia may also be classified into 3 subgroups: B lymphoblastic leukemia/lymphoma, B lymphoblastic leukemia/lymphoma (not organ specific), and B lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities.

Classification

Acute lymphoblastic leukemia may be classified according to either the French-American-British (FAB) classification system or the World Health Organization (WHO) classification system:

French-American-British Classification System

According to the French-American-British classification system, acute lymphoblastic leukemia is classified into 3 subgroups based on the cellular origin of the disease, cellular maturity, and morphology:[1][2]

  • ALL-L1: small uniform cells
  • ALL-L2: large varied cells
  • ALL-L3: large varied cells with vacuoles (bubble-like features)

Each subtype is further classified based on immunophenotyping (the presence of surface markers of the abnormal lymphocytes). There are 2 main immunologic types:

The mature B-cell acute lymphoblastic leukemia (L3) is called Burkitt leukemia/lymphoma.

World Health Organization Classification System

The World Health Organization (WHO) classification of acute lymphoblastic leukemia is based on the prognosis of the disease. According to the WHO classification system, acute lymphoblastic leukemia may be classified into 3 subgroups:[5][6][7]

Group 1

  • B lymphoblastic leukemia/lymphoma

Group 2

  • B lymphoblastic leukemia/lymphoma (Not organ specific)

Group 3

  • B lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities:
  • B lymphoblastic leukemia/lymphoma with t(9;22)(q34;q11.2), BCR-ABL1
  • B lymphoblastic leukemia/lymphoma with t(v;11q23); MLL rearranged
  • B lymphoblastic leukemia/lymphoma with t(12;21)(p13;q22) TEL-AML1 (ETV6-RUNX1)
  • B lymphoblastic leukemia/lymphoma with hyperdiploidy
  • B lymphoblastic leukemia/lymphoma with hypodiploidy
  • B lymphoblastic leukemia/lymphoma with t(5;14)(q31;q32) IL3-IGH
  • B lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3) TCF3-PBX1
Acute lymphoblastic leukemia -L1: Small uniform cells subtype.
Image courtesy of Melih Aktan MD, Istanbul Medical Faculty – Turkey, and Kyoto University – Japan
Acute lymphoblastic leukemia-L1: Large varied cells subtype.
Image courtesy of Melih Aktan MD, Istanbul Medical Faculty – Turkey, and Kyoto University – Japan
Acute lymphoblastic leukemia-L2: Large varied cells (Hand mirror cell).
Image courtesy of Melih Aktan MD, Istanbul Medical Faculty – Turkey, and Kyoto University – Japan
Acute lymphoblastic leukemia-L2: Large varied cells.
Image courtesy of Melih Aktan MD, Istanbul Medical Faculty – Turkey, and Kyoto University – Japan
Acute lymphoblastic leukemia-L2: Large varied cells.
Image courtesy of Melih Aktan MD, Istanbul Medical Faculty – Turkey, and Kyoto University – Japan
Acute lymphoblastic leukemia-L3: Large varied cells with vacuoles (bubble-like features.
Image courtesy of Melih Aktan MD, Istanbul Medical Faculty – Turkey, and Kyoto University – Japan

References

  1. ↑ van Eys J, Pullen J, Head D, Boyett J, Crist W, Falletta J, Humphrey GB, Jackson J, Riccardi V, Brock B (March 1986). “The French-American-British (FAB) classification of leukemia. The Pediatric Oncology Group experience with lymphocytic leukemia”. Cancer. 57 (5): 1046–51. PMID 3484662.
  2. ↑ Lilleyman JS, Hann IM, Stevens RF, Eden OB, Richards SM (September 1986). “French American British (FAB) morphological classification of childhood lymphoblastic leukaemia and its clinical importance”. J. Clin. Pathol. 39 (9): 998–1002. PMC 500200. PMID 3463568.
  3. ↑ Nahar R, Müschen M (2009). “Pre-B cell receptor signaling in acute lymphoblastic leukemia”. Cell Cycle. 8 (23): 3874–7. doi:10.4161/cc.8.23.10035. PMC 4047560. PMID 19901533.
  4. ↑ Han X, Bueso-Ramos CE (2007). “Precursor T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma and acute biphenotypic leukemias”. Am J Clin Pathol. 127 (4): 528–44. doi:10.1309/2QE3A6EKQ8UYDYRC. PMID 17369128.
  5. ↑ Campo E, Swerdlow SH, Harris NL, Pileri S, Stein H, Jaffe ES (2011). “The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications”. Blood. 117 (19): 5019–32. doi:10.1182/blood-2011-01-293050. PMC 3109529. PMID 21300984.
  6. ↑ Chiaretti S, Zini G, Bassan R (2014). “Diagnosis and subclassification of acute lymphoblastic leukemia”. Mediterr J Hematol Infect Dis. 6 (1): e2014073. doi:10.4084/MJHID.2014.073. PMC 4235437. PMID 25408859.
  7. ↑ Kebriaei P, Anastasi J, Larson RA (December 2002). “Acute lymphoblastic leukaemia: diagnosis and classification”. Best Pract Res Clin Haematol. 15 (4): 597–621. PMID 12617866.

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Pathophysiology

Pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [2]Shivali Marketkar, M.B.B.S. [3] Carlos A Lopez, M.D. [4]

Overview

Acute lymphoid leukemia arises from lymphoblasts, which are hematologic white cells that are normally involved in the hematopoiesis. Chromosomal translocations involved in the pathogenesis of acute lymphoid leukemia include translocations between the chromosomes 9 and 22, t(9;22) (q34;q11.2) BCR-ABL1, translocations between the chromosomes 12 and 21, t(12;21)(p13;q22) TEL-AML1, translocations between the chromosomes 5 and 14, t(5;14)(q31;q32)IL3-IGH and translocations between chromosomes 1 and 19 t(1;19)(q23;p13.3) TCF3-PBX1.

Pathophysiology

Physiology

The normal physiology of lymphoblast formation can be understood as follows:[1]

  • Lymphoid cells are formed from pluripotent hematopoietic stem cells in the bone marrow, through a maturation process[2]
  • In the development of B cells, which includes development initiated at the level of the following cells:[3]
    • Lymphoid-primed multipotent progenitors[4]
    • Common lymphoid progenitors[5]
    • Pro–B cells[6]
    • Pre–B cells[7]
    • Mature B cells[8]
  • This maturation process is strictly regulated by the hierarchical activation of transcription factors and selection through functional signal transduction[9]
  • A lymphoblast is a altered naive lymphocyte with recasted cell morphology[10]
  • This happens when the lymphocyte is triggered by an antigen (from antigen-presenting cells) and enlarged in volume by nucleus and cytoplasmic growth as well as new mRNA and protein synthesis[11]
  • The lymphoblast then starts multiplying two to four times every 24-hours for 3-5 days, with a single lymphoblast producing approximately 1000 clones of its original naive lymphocyte, with each embodying the originally unique antigen specificity[12]
  • Finally the dividing cells transforms into effector cells, known as Plasma Cells (for B cells), Cytotoxic T cells, and Helper T cells[13]

Pathogenesis

  • The cause of most acute lymphoblastic leukemia is not known[14]
  • In general, cancer is caused by damage to DNA that leads to uncontrolled cellular growth and spread throughout the body, either by increasing chemical signals that cause growth or interrupting chemical signals that control growth
  • This damage may be caused by environmental factors such as:[15]
    • Chemicals
    • Drugs
    • Radiation
  • In leukemias including acute lymphoblastic leukemia, chromosomal translocation occur regularly
  • It is thought that most translocations occur before birth during fetal development
  • These translocations may trigger oncogenes to “turn on”, causing unregulated mitosis where cells divide too quickly and abnormally, resulting in leukemia.
  • It has been known that acute lymphoblastic leukemia is denoted by gross numerical and structural chromosomal defects, including:
    • Hyperdiploidy (>50 chromosomes)
    • Hypodiploidy (<44 chromosomes)
    • Translocations t{[12;21], [1;19], [9;22], [4;11]}
    • Rearrangements (MYC, MLL)
  • However, several studies have shown that these lesions listed above alone are not enough to cause leukemia and cooperating lesions have to be involved
  • For example, mutations such as t(12;21), ETV6-RUNX1, comprising 22% of pediatric ALL, are present years before the development of leukemia
  • Many of these genes are encoding proteins with key roles in lymphoid development
  • It is advised that the initial event conveys self-renewal coupled with mutation, going into developmental arrest and a secondary cooperative event in cell cycle regulation, tumor suppression and chromatin modification, eventually leading to formation of the leukemic clone
  • Acute lymphoblastic leukemia genomes typically have less structural genetic changes than many solid tumors
  • More than 50 recurring regions of DNA copy number changes have been discovered
  • They are commonly focal deletions, limited to one or few genes that take part in normal lymphoid development:
  • T-lineage acute lymphoblastic leukemia is understood as activated mutations of NOTCH1 and rearrangements of transcription factors which are the follwoing
  • Arrangements of the full range of acute lymphoblastic luekemia subtypes has shown that the alteration of multiple cellular pathways, which includes the following:
  • The disruption of these pathways listed above are typical events in different acute lymphoblastic leukemia subtypes.

BCR-ABL1-like B-ALL and IKZF1 transformation

  • BCR-ABL1-like acute lymphoblastic leukemia has the gene expression signature similar to that of BCR-ABL1 acute lymphoblastic leukemia, while not having the BCR-ABL1 translocation
  • More than 80% of patients with BCR-ABL1-like acute lymphoblastic leukemia have defects in genes that have to do with B-cell development, such as:
  • The prevalence of BCR-ABL1-like acute lymphoblastic leukemia is almost 15% in pediatric B-cell acute lymphoblastic leukemia’s and it known to be associated with an inferior survival rate (5-year event-free-survival <60%), as is BCR-ABL1 acute lymphoblastic leukemia

CRLF2 over expression and JAK mutations

  • Up to half of BCR-ABL1-like cases contain rearrangement of CRLF2 causing an over-expression of CRLF2 on the surface of lymphoblasts that may be picked up by immunophenotyping
  • Additionally, almost half of CRLF2-rearranged cases have concomitant initiating mutations of the JAK genes JAK1 and JAK2
  • The JAK/signal transducers and initiators of transcription (STAT) pathway controls signaling of the following:
    • Cytokine
    • Chemokine
    • Growth factor receptors
  • Signaling is done via the JAK non-receptor tyrosine kinases and the STAT family of transcription factors
  • These changes cause an activation of JAK-STAT signaling that may be responsive to therapy with JAK inhibitors such as ruxolitinib, and this is being explored at the moment as a therapeutic strategy
  • Ongoing next-generation sequencing studies in childhood and adult acute lymphoblastic leukemia are made to define the variety of kinase-activating changes in BCR-ABL1-like acute lymphoblastic leukemia and to develop clinical trials with a goal of leading patients with BCR-ABL1-like acute lymphoblastic leukemia to appropriate tyrosine-kinase inhibitor (TKI) therapy .

Hypodiploid acute lymphoblastic leukemia

Two subtypes of hypodiploid acute lymphoblastic leukemia have been documented according to the intensity of aneuploidy:

  • Near-haploid cases with 24 to 31 chromosomes
  • Low-hypodiploid cases with 32 to 39 chromosomes
  • There has been an analysis recently done of a large cohort of more than 120 hypodiploid pediatric acute lymphoblastic leukemia patients has shown that near-haploid and low-hypodiploid acute lymphoblastic leukemia have different transcriptomic signatures and submicroscopic genetic alterations
  • A large number of near-haploid cases have alteration targeting receptor tyrosine kinase signaling and Ras signaling (71%) and the lymphoid transcription factor gene IKZF3 (13%)
  • In comparison, low-hypodiploid acute lymphoblastic leukemias with 32–39 chromosomes are noted to have changes in the following
    • TP53 (91.2%)
    • IKZF2 (53%)
    • RB1 (41%)
  • Both near-haploid and low-hypodiploid leukemic cells show activation of Ras-signaling and phosphoinositide 3-kinase (PI3K)-signaling pathways and are responsive to PI3K inhibitors, showing that these drugs might be used for this aggressive form of leukemia

T cell acute lymphoblastic leukemia

  • T-lineage acute lymphoblastic leukemia is has been known to have an older age of onset, male sex predominance, and poor outcome in comparison with b cell acute lymphoblastic leukemia
  • As of recent the next-generation sequencing identified sequence mutations and, less common deletion of PHF6 in 16% and 38% of childhood and adult t cell acute lymphoblastic leukemia cases, respectively
  • The role of PHF6 in leukemogenesis is not fully understood, but the loss-of-function alterations have shown that PHF6 is a tumor suppressor
  • Early T-cell precursor of acute lymphoblastic luekemia is an aggressive subtype of immature leukemia that is known for a high proportion of t cell acute lymphoblastic leukemia treatment failures
  • Recent studies found this type of leukemia to be associated with loss-of-function mutations in the following:
    • Hematopoietic regulators (GATA3, IKZF1, RUNX1, ETV6)
    • Gain-of-function mutations in Ras, FLT3, JAK, and IL7R,
    • Inactivating mutations in epigenetic regulators (EZH2, SUZ12, EED, SETD2, DNMT3A)
  • The mutational spectrum of this acute lymphoblastic leukemia subtype is similar to that observed in myeloid leukemias
  • Comparison of its transcriptional profile with those of normal human hematopoietic progenitors showed a great similarity to hematopoietic stem and early myeloid progenitors
  • Thus, the T-cell precursor acute lymphoblastic leukemia is likely to show a part of a spectrum of immature, stem cell-like leukemias
  • Epigenetic modifiers and agents targeting JAK-STAT signaling are currently being investigated

WHO and FAB classification

  • According with the World Health Organization (WHO) classification of acute lymphoblastic leukemia, B lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities include:
  • B lymphoblastic leukemia/lymphoma with t(9;22)(q34;q11.2), BCR-ABL1
  • B lymphoblastic leukemia/lymphoma with t(v;11q23); MLL rearranged
  • B lymphoblastic leukemia/lymphoma with t(12;21)(p13;q22) TEL-AML1 (ETV6-RUNX1)
  • B lymphoblastic leukemia/lymphoma with hyperdiploidy
  • B lymphoblastic leukemia/lymphoma with hypodiploidy
  • B lymphoblastic leukemia/lymphoma with t(5;14)(q31;q32) IL3-IGH
  • B lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3) TCF3-PBX1
  • Malignant, immature white blood cells continuously multiply and are overproduced in the bone marrow
  • Acute lymphoblastic leukemia causes damage and death by crowding out normal cells in the bone marrow, and by spreading (metastasizing) to other organs

Markers

B-cell acute lymphoblastic leukemia:[16]

  • Typically express CD10, CD19, and CD34 on their surface along, with nuclear terminal deoxynucleotide transferase (TdT)

T-cell acute lymphoblastic leukemia:

Genetics

  • Cytogenetics, the study of characteristic large changes in the chromosomes of cancer cells, has been increasingly recognized as an important predictor of outcome in acute lymphoblastic leukemia.[17]
  • It has been recognized for many years that some patients presenting with acute leukemia may have a cytogenetic abnormality that is cytogenetically indistinguishable from the Philadelphia chromosome (Ph1) This occurs in about 20% of adults and a small percentage of children with acute Lymphoblastic leukemia
  • The advances in the conventional cytogenetic techniques, as the fluorescence in situ hybridization, have displayed the chromosomal rearrangements[18]
  • In has been documented that the incidence of chromosomal change is related with the age
  • The translocation t(9;22)(q34;q11) increases with the passage of each consecutive decade, up to 24% between the 40-to 49 years old[18]
  • The t(4;11) (q21;q23) and t(1;19) (q23;q13) are seldomly seen in patients older than 60 years old
  • The t (8;14) (q24;q32) and t(14;18)(q32;q21) translocation rates increase with age
  • The hiperdipoidia is seen in 13% of patients under 20 years old and only 5% of elderly patients
  • The hypodiploidy and complex karyotype (presence of more than 2 chromosomal abnormalities) also increase with age of 4% in the range of 15 to 19 years old to 16% older than 60 years old
Cytogenetic change Target gene Frequency in childhood in % Frequency in adulthood in % Risk category
Philadelphia chromosome BCR-ABL1 3 to 5 25 to 30 Poor prognosis
t(4;11)(q21;q23) MLL-AF4 2 to 3 3 to 7 Poor prognosis
t(8;14)(q24.1;q32) Non-TCR(NOTCH,HOX11,JAK1) 60 Favorable prognosis
Complex karyotype (more than four abnormalities) Poor prognosis
hypodiploidy or near triploidy 5 to 6 3 Poor prognosis
High hyperdiploidy 20 to 30 7 Good prognosis
T cell acute lymphoblastic leukemia TCR

References

  1. ↑ Zuckerman T, Rowe JM (2014). “Pathogenesis and prognostication in acute lymphoblastic leukemia”. F1000Prime Rep. 6: 59. doi:10.12703/P6-59. PMC 4108947. PMID 25184049.
  2. ↑ Weiskopf K, Schnorr PJ, Pang WW, Chao MP, Chhabra A, Seita J; et al. (2016). “Myeloid Cell Origins, Differentiation, and Clinical Implications”. Microbiol Spectr. 4 (5). doi:10.1128/microbiolspec.MCHD-0031-2016. PMC 5119546. PMID 27763252.
  3. ↑ Hoffman W, Lakkis FG, Chalasani G (2016). “B Cells, Antibodies, and More”. Clin J Am Soc Nephrol. 11 (1): 137–54. doi:10.2215/CJN.09430915. PMC 4702236. PMID 26700440.
  4. ↑ Luc, S.; Anderson, K.; Kharazi, S.; Buza-Vidas, N.; Boiers, C.; Jensen, C. T.; Ma, Z.; Wittmann, L.; Jacobsen, S. E. W. (2008). “Down-regulation of Mpl marks the transition to lymphoid-primed multipotent progenitors with gradual loss of granulocyte-monocyte potential”. Blood. 111 (7): 3424–3434. doi:10.1182/blood-2007-08-108324. ISSN 0006-4971.
  5. ↑ Mansson, R.; Zandi, S.; Welinder, E.; Tsapogas, P.; Sakaguchi, N.; Bryder, D.; Sigvardsson, M. (2009). “Single-cell analysis of the common lymphoid progenitor compartment reveals functional and molecular heterogeneity”. Blood. 115 (13): 2601–2609. doi:10.1182/blood-2009-08-236398. ISSN 0006-4971.
  6. ↑ Bertrand, F. E. (2001). “Pro-B-cell to pre-B-cell development in B-lineage acute lymphoblastic leukemia expressing the MLL/AF4 fusion protein”. Blood. 98 (12): 3398–3405. doi:10.1182/blood.V98.12.3398. ISSN 0006-4971.
  7. ↑ Patton, Daniel T.; Plumb, Adam W.; Abraham, Ninan (2014). “The Survival and Differentiation of Pro-B and Pre-B Cells in the Bone Marrow Is Dependent on IL-7Rα Tyr449”. The Journal of Immunology. 193 (7): 3446–3455. doi:10.4049/jimmunol.1302925. ISSN 0022-1767.
  8. ↑ Burger, J. A.; Ghia, P.; Rosenwald, A.; Caligaris-Cappio, F. (2009). “The microenvironment in mature B-cell malignancies: a target for new treatment strategies”. Blood. 114 (16): 3367–3375. doi:10.1182/blood-2009-06-225326. ISSN 0006-4971.
  9. ↑ Gao R, Stock AM (2015). “Temporal hierarchy of gene expression mediated by transcription factor binding affinity and activation dynamics”. MBio. 6 (3): e00686–15. doi:10.1128/mBio.00686-15. PMC 4447250. PMID 26015501.
  10. ↑ Davey, Martin S.; Willcox, Carrie R.; Baker, Alfie T.; Hunter, Stuart; Willcox, Benjamin E. (2018). “Recasting Human Vδ1 Lymphocytes in an Adaptive Role”. Trends in Immunology. 39 (6): 446–459. doi:10.1016/j.it.2018.03.003. ISSN 1471-4906.
  11. ↑ Saitakis, Michael; Dogniaux, Stéphanie; Goudot, Christel; Bufi, Nathalie; Asnacios, Sophie; Maurin, Mathieu; Randriamampita, Clotilde; Asnacios, Atef; Hivroz, Claire (2017). “Different TCR-induced T lymphocyte responses are potentiated by stiffness with variable sensitivity”. eLife. 6. doi:10.7554/eLife.23190. ISSN 2050-084X.
  12. ↑ Haneberg B, Wesenberg F, Aarskog D (1978). “Lymphocyte multiplication in vitro induced by mitogens and antigens”. Scand J Immunol. 8 (1): 9–13. PMID 360370.
  13. ↑ Pennock ND, White JT, Cross EW, Cheney EE, Tamburini BA, Kedl RM (2013). “T cell responses: naive to memory and everything in between”. Adv Physiol Educ. 37 (4): 273–83. doi:10.1152/advan.00066.2013. PMC 4089090. PMID 24292902.
  14. ↑ Wiemels J (2012). “Perspectives on the causes of childhood leukemia”. Chem Biol Interact. 196 (3): 59–67. doi:10.1016/j.cbi.2012.01.007. PMC 3839796. PMID 22326931.
  15. ↑ Inaba H, Greaves M, Mullighan CG (June 2013). “Acute lymphoblastic leukaemia”. Lancet. 381 (9881): 1943–55. doi:10.1016/S0140-6736(12)62187-4. PMC 3816716. PMID 23523389.
  16. ↑ “National Cancer Institute”.
  17. ↑ Moorman A, Harrison C, Buck G, Richards S, Secker-Walker L, Martineau M, Vance G, Cherry A, Higgins R, Fielding A, Foroni L, Paietta E, Tallman M, Litzow M, Wiernik P, Rowe J, Goldstone A, Dewald G (2007). “Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial”. Blood. 109 (8): 3189–97. PMID 17170120.
  18. ↑ 18.0 18.1 P., M.; Borjas-Gutierrez, C.; M., G.; E., L.; M., A.; R., J. (2013). “Pathophysiology of Acute Lymphoblastic Leukemia”. doi:10.5772/54652.

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Causes

Causes

Differentiating Acute lymphoblastic leukemia from other Diseases

Differentiating Acute lymphoblastic leukemia from other Diseases

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

Overview

Acute lymphoblastic leukemia must be differentiated from other diseases such as acute myelogenous leukemia, hairy cell leukemia and malignant lymphoma.[1]

Differential diagnosis

The following table differentiates acute lymphoblastic leukemia from other leukemias that may present with similar clinical features such as fever, fatigue, weight loss, recurrent infections and elevated leukocyte counts. The following are the differentials:

Disease Etiology Clinical Manifestation Laboratory Findings Gold standard diagnosis Associated findings
Demography History Symptoms Signs
Constitutional symptoms Weight Bleeding Abdominal Pain Vital sign Jaundice LAP Hepatosplenomegaly Other CBC Histopathology Other
Acute myelogenous leukemia[2][3]
  • Clonal proliferation of malignant myeloid blast cells in the marrow
  • Genetic abnormalities t(8;21), inv(16), and t(15;17)
 ↓ + – – Rare Mild and asymptomatic NA
  • Persistent or frequent infections
  • Fatal within weeks or months if left untreated
Acute lymphoblastic leukemia[4][5]
  • Arrest of lymphoblasts
  • Chromosomal translocations: t(9;22) , t(12;21), t(5;14), t(1;19)
  • The most common form of cancer in children
  • Peak 2-5 years of age
  • Boys > girls
  • History of cancer
  • History of drug exposure
 ↓ + – – + + NA
  • CNS involvement
Chronic myelogenous leukemia[6][7]
  • Median age 50 years old
 ↓ + Abdominal fullness
  • Normal
 – – +
Disease Etiology Demography History Constitutional symptoms Weight Bleeding Abdominal Pain Vital sign Jaundice LAP Hepatosplenomegaly Other CBC Histopathology Other Gold standard diagnosis Associated findings
Chronic lymphocytic leukemia[8]
  • The most common leukemia in adults in western countries
  • M > F
  • Median age 70 years old
 ↓ + + – +

The most common abnormal finding

+
Hairy cell leukemia[9][10]
  • Accumulation of small mature B cell lymphoid cells with abundant cytoplasm and “hairy” projections
  • BRAF mutation
  • Uncommon
  • Median age 50 to 55 years old
  • M >> F
  • More common in Caucasians than Blacks
 ↓ + Abdominal fullness
  • Normal
 – ± +

Splenomegaly

Large granular lymphocytic leukemia[11][12]​
  • Clonal proliferation of cytotoxic T cells
  • Dysregulation of apoptosis through abnormalities in the Fas/Fas ligand pathway
  • Rare
  • Median age 60 years
  • M = F
  • Autoimmune diseases
  • Lymphoproliferative disorders
 ↓ – – – ± +
  • Mostly asymptomatic
  • Modest lymphocytosis
  • Neutropenia
  • Anemia
  • Thrombocytopenia
  • Large lymphocytes with a condensed round or oval nucleus, abundant pale basophilic cytoplasm, and small azurophilic granules
  • Multiple serological abnormalities including rheumatoid factor, antinuclear antibody, antiplatelet antibodies, antineutrophil antibodies, positive direct Coombs test, hyper- or hypogammaglobulinemia, monoclonal gammopathies, and elevated β2-microglobulin
  • Biopsy and flow cytometry + T-cell receptor gene rearrangement studies
  • Recurrent bacterial infection
Chronic neutrophilic leukemia[13]
  • Mature granulocytic proliferation in the blood and marrow
  • Point mutations in the CSF3R gene
  • Very rare
  • M = F
  • Multiple myeloma
 ↓ – – – – +

The most common clinical finding

  • Pruritus
  • Gout
  • Peripheral blood neutrophilia (> 25 x 109/L) with myeloid precursors (promyelocytes, myelocytes, metamyelocytes)
  • Toxic granulation in the neutrophils
  • Nuclear hypersegmentation
  • Increased myeloid:erythroid ratio > 20:1
  • WHO diagnostic criteria include leukocytosis of ≥ 25 x 109/L
  • More than 80% neutrophils,
  • Less than 10% circulating neutrophil precursors with blasts
  • Poor prognosis
  • Absence of the Philadelphia chromosome or a BCR/ABL fusion gene
Disease Etiology Demography History Constitutional symptoms Weight Bleeding Abdominal Pain Vital sign Jaundice LAP Hepatosplenomegaly Other CBC Histopathology Other Gold standard diagnosis Associated findings

References

  1. ↑ “National Cancer Institute”.
  2. ↑ Saif A, Kazmi S, Naseem R, Shah H, Butt MO (August 2018). “Acute Myeloid Leukemia: Is That All There Is?”. Cureus. 10 (8): e3198. doi:10.7759/cureus.3198. PMID 30410824. Vancouver style error: initials (help)
  3. ↑ Estey EH (April 2013). “Acute myeloid leukemia: 2013 update on risk-stratification and management”. Am. J. Hematol. 88 (4): 318–27. doi:10.1002/ajh.23404. PMID 23526416.
  4. ↑ Sawalha Y, Advani AS (March 2018). “Management of older adults with acute lymphoblastic leukemia: challenges & current approaches”. Int J Hematol Oncol. 7 (1): IJH02. doi:10.2217/ijh-2017-0023. PMC 6176956. PMID 30302234.
  5. ↑ Portell CA, Advani AS (April 2014). “Novel targeted therapies in acute lymphoblastic leukemia”. Leuk. Lymphoma. 55 (4): 737–48. doi:10.3109/10428194.2013.823493. PMID 23841506.
  6. ↑ Saußele S, Silver RT (April 2015). “Management of chronic myeloid leukemia in blast crisis”. Ann. Hematol. 94 Suppl 2: S159–65. doi:10.1007/s00277-015-2324-0. PMID 25814082.
  7. ↑ Eden RE, Coviello JM. PMID 30285354. Missing or empty |title= (help)
  8. ↑ Rai KR, Jain P (March 2016). “Chronic lymphocytic leukemia (CLL)-Then and now”. Am. J. Hematol. 91 (3): 330–40. doi:10.1002/ajh.24282. PMID 26690614.
  9. ↑ Troussard X, Cornet E (December 2017). “Hairy cell leukemia 2018: Update on diagnosis, risk-stratification, and treatment”. Am. J. Hematol. 92 (12): 1382–1390. doi:10.1002/ajh.24936. PMC 5698705. PMID 29110361.
  10. ↑ Wierda WG, Byrd JC, Abramson JS, Bhat S, Bociek G, Brander D, Brown J, Chanan-Khan A, Coutre SE, Davis RS, Fletcher CD, Hill B, Kahl BS, Kamdar M, Kaplan LD, Khan N, Kipps TJ, Lancet J, Ma S, Malek S, Mosse C, Shadman M, Siddiqi T, Stephens D, Wagner N, Zelenetz AD, Dwyer MA, Sundar H (November 2017). “Hairy Cell Leukemia, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology”. J Natl Compr Canc Netw. 15 (11): 1414–1427. doi:10.6004/jnccn.2017.0165. PMID 29118233.
  11. ↑ Matutes E (March 2017). “Large granular lymphocytic leukemia. Current diagnostic and therapeutic approaches and novel treatment options”. Expert Rev Hematol. 10 (3): 251–258. doi:10.1080/17474086.2017.1284585. PMID 28128670.
  12. ↑ Oshimi K (2017). “Clinical Features, Pathogenesis, and Treatment of Large Granular Lymphocyte Leukemias”. Intern. Med. 56 (14): 1759–1769. doi:10.2169/internalmedicine.56.8881. PMC 5548667. PMID 28717070.
  13. ↑ Elliott MA, Tefferi A (August 2018). “Chronic neutrophilic leukemia: 2018 update on diagnosis, molecular genetics and management”. Am. J. Hematol. 93 (4): 578–587. doi:10.1002/ajh.24983. PMID 29512199.

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Epidemiology and Demographics

Epidemiology and Demographics

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [2]; Rim Halaby, M.D. [3] Carlos A Lopez, M.D. [4]

Overview

In 2015, the incidence of acute lymphoblastic leukemia was approximately 2 per 100,000 individuals with a case-fatality rate of approximately 20% in the United States. Males are more commonly affected with acute lymphoblastic leukemia compared to females.

Epidemiology and Demographics

Incidence and Mortality 2015

  • In 2015, the incidence of acute lymphoblastic leukemia was estimated to be 2 per 100,000 individuals in the United States.[1]
  • The case fatality rate of acute lymphoblastic leukemia is approximately 20% in the United States.

Prevalence

  • In the United States, the age-adjusted prevalence of acute lymphoblastic leukemia is 17.4 per 100,000 in 2011.[2]

Incidence

  • The number of annual acute lymphoblastic leukemia cases in the United States is roughly 4000, 3000 of which inflict children.[3]

Age

  • Acute lymphoblastic leukemia has been reported at 80 percent of all childhood leukemia cases, making it the most prevalent type of childhood cancer.[4]
  • It has a peak incident rate of 2-5 years old, going down in incidence with increasing age before going up again at around 50 years old.[5]
  • While the overall age-adjusted incidence of acute lymphoblastic leukemia in the United States between 2007 and 2011 is 1.7 per 100,000, the age-adjusted incidence of acute lymphoblastic leukemia by age category is:[2]
    • Under 65 years: 1.7 per 100,000
    • 65 and over: 1.6 per 100,000

Gender

  • Acute lymphoblastic leukemia is slightly more common in males than females.[6]
  • In the United States, the age-adjusted prevalence of acute lymphoblastic leukemia by gender in 2011 is:[2]
    • In males: 19.3 per 100,000
    • In females: 15.4 per 100,000
  • In the United States, the age-adjusted incidence of acute lymphoblastic leukemia by gender on 2011 is:[2]
    • In males: 1.9 per 100,000 persons
    • In females: 1.63 per 100,000 persons
  • Shown below is an image depicting the observed incidence of lymphocytic leukemia by gender in the United States between 1975 and 2011. These graphs are adapted from SEER: The Surveillance, Epidemiology, and End Results Program of the National Cancer Institute.[2]

Race

  • Shown below is a table depicting the age-adjusted prevalence of acute lymphoblastic leukemia by race in 2011 in the United States.[2]
All Races White Black Asian/Pacific Islander Hispanic
Age-adjusted 17.4 per 100,000 20 per 100,000 7.6 per 100,000 13.2 per 100,000 20.8 per 100,000

References

  1. ↑ “National Cancer Institute”.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 Howlader N, Noone AM, Krapcho M, Garshell J, Miller D, Altekruse SF, Kosary CL, Yu M, Ruhl J, Tatalovich Z,Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer Statistics Review, 1975-2011, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2011/, based on November 2013 SEER data submission, posted to the SEER web site, April 2014.
  3. ↑ Guru Murthy, Guru Subramanian; Pondaiah, Satish Kumar; Abedin, Sameem; Atallah, Ehab (2018). “Incidence and survival of T-cell acute lymphoblastic leukemia in the United States”. Leukemia & Lymphoma: 1–8. doi:10.1080/10428194.2018.1522442. ISSN 1042-8194.
  4. ↑ Bhojwani D, Howard SC, Pui CH (2009). “High-risk childhood acute lymphoblastic leukemia”. Clin Lymphoma Myeloma. 9 Suppl 3: S222–30. doi:10.3816/CLM.2009.s.016. PMC 2814411. PMID 19778845.
  5. ↑ Barrington-Trimis JL, Cockburn M, Metayer C, Gauderman WJ, Wiemels J, McKean-Cowdin R (2017). “Trends in childhood leukemia incidence over two decades from 1992 to 2013”. Int J Cancer. 140 (5): 1000–1008. doi:10.1002/ijc.30487. PMC 5550103. PMID 27778348.
  6. ↑ Esparza SD, Sakamoto KM (2005). “Topics in pediatric leukemia–acute lymphoblastic leukemia”. MedGenMed. 7 (1): 23. PMC 1681386. PMID 16369328.

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Risk Factors

Risk Factors

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [2] Carlos A Lopez, M.D. [3]

Overview

Common risk factors in the development of acute lymphoblastic leukemia are Down syndrome, ataxia telangiectasia, Bloom syndrome, X-linked agammaglobulinemia, Fanconi’s anemia and severe combined immunodeficiency.

Risk Factors

Common risk factors in the development of acute lymphoblastic leukemia are Down syndrome, ataxia telangiectasia, Bloom syndrome, X-linked agammaglobulinemia, Fanconi’s anemia severe combined immunodeficiency, radiation exposure, exposure to benzene, and smoking.

Common risk factors

Acute lymphoblastic leukemia risk factors may include the following:[1]

Less common risk factors

References

  1. ↑ Belson M, Kingsley B, Holmes A (January 2007). “Risk factors for acute leukemia in children: a review”. Environ. Health Perspect. 115 (1): 138–45. doi:10.1289/ehp.9023. PMC 1817663. PMID 17366834.
  2. ↑ 2.0 2.1 Greaves MF (1997). “Aetiology of acute leukaemia”. Lancet. 349 (9048): 344–9. PMID 9024390.
  3. ↑ Khalade A, Jaakkola MS, Pukkala E, Jaakkola JJ (2010). “Exposure to benzene at work and the risk of leukemia: a systematic review and meta-analysis”. Environ Health. 9: 31. doi:10.1186/1476-069X-9-31. PMC 2903550. PMID 20584305.
  4. ↑ Guan H, Miao H, Ma N, Lu W, Luo B (2017). “Correlations between Epstein-Barr virus and acute leukemia”. J Med Virol. 89 (8): 1453–1460. doi:10.1002/jmv.24797. PMID 28225168.
  5. ↑ Metayer C, Zhang L, Wiemels JL, Bartley K, Schiffman J, Ma X; et al. (2013). “Tobacco smoke exposure and the risk of childhood acute lymphoblastic and myeloid leukemias by cytogenetic subtype”. Cancer Epidemiol Biomarkers Prev. 22 (9): 1600–11. doi:10.1158/1055-9965.EPI-13-0350. PMC 3769478. PMID 23853208.
  6. ↑ Farioli A, Legittimo P, Mattioli S, Miligi L, Benvenuti A, Ranucci A; et al. (2014). “Tobacco smoke and risk of childhood acute lymphoblastic leukemia: findings from the SETIL case-control study”. Cancer Causes Control. 25 (6): 683–92. doi:10.1007/s10552-014-0371-9. PMID 24699944.
  7. ↑ Mowery CT, Reyes JM, Cabal-Hierro L, Higby KJ, Karlin KL, Wang JH; et al. (2018). “Trisomy of a Down Syndrome Critical Region Globally Amplifies Transcription via HMGN1 Overexpression”. Cell Rep. 25 (7): 1898–1911.e5. doi:10.1016/j.celrep.2018.10.061. PMC 6321629. PMID 30428356.
  8. ↑ Bielorai B, Fisher T, Waldman D, Lerenthal Y, Nissenkorn A, Tohami T; et al. (2013). “Acute lymphoblastic leukemia in early childhood as the presenting sign of ataxia-telangiectasia variant”. Pediatr Hematol Oncol. 30 (6): 574–82. doi:10.3109/08880018.2013.777949. PMID 23509889.
  9. ↑ Adams M, Jenney M, Lazarou L, White R, Birdsall S, Staab T; et al. (2013). “Acute myeloid leukaemia after treatment for acute lymphoblastic leukaemia in girl with Bloom syndrome”. J Genet Syndr Gene Ther. 4 (8). doi:10.4172/2157-7412.1000177. PMC 4052885. PMID 24932421.
  10. ↑ Conley, Mary Ellen (2015). “Are Patients with X-Linked Agammaglobulinemia at Increased Risk of Developing Acute Lymphoblastic Leukemia?”. Journal of Clinical Immunology. 35 (2): 98–99. doi:10.1007/s10875-015-0132-x. ISSN 0271-9142.
  11. ↑ Mushtaq N, Wali R, Fadoo Z, Saleem AF (2012). “Acute lymphoblastic leukemia in a child with Fanconi’s anaemia”. J Coll Physicians Surg Pak. 22 (7): 458–60. doi:07.2012/JCPSP.558560 Check |doi= value (help). PMID 22747869.
  12. ↑ Cesano A, O’Connor R, Lange B, Finan J, Rovera G, Santoli D (1991). “Homing and progression patterns of childhood acute lymphoblastic leukemias in severe combined immunodeficiency mice”. Blood. 77 (11): 2463–74. PMID 2039829.
  13. ↑ Bailey HD, Metayer C, Milne E, Petridou ET, Infante-Rivard C, Spector LG; et al. (2015). “Home paint exposures and risk of childhood acute lymphoblastic leukemia: findings from the Childhood Leukemia International Consortium”. Cancer Causes Control. 26 (9): 1257–70. doi:10.1007/s10552-015-0618-0. PMC 5257283. PMID 26134047.
  14. ↑ Tabrizi MM, Hosseini SA (2015). “Role of Electromagnetic Field Exposure in Childhood Acute Lymphoblastic Leukemia and No Impact of Urinary Alpha- Amylase–a Case Control Study in Tehran, Iran”. Asian Pac J Cancer Prev. 16 (17): 7613–8. PMID 26625771.
  15. ↑ Orgel, E.; Tucci, J.; Alhushki, W.; Malvar, J.; Sposto, R.; Fu, C. H.; Freyer, D. R.; Abdel-Azim, H.; Mittelman, S. D. (2014). “Obesity is associated with residual leukemia following induction therapy for childhood B-precursor acute lymphoblastic leukemia”. Blood. 124 (26): 3932–3938. doi:10.1182/blood-2014-08-595389. ISSN 0006-4971.

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Screening

Screening

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [2] Carlos A Lopez, M.D. [3]

Overview

According to the National cancer institute, screening for acute lymphoblastic leukemia is not recommended.

Acute lymphoblastic leukemia screening

According to the National cancer institute, screening for acute lymphoblastic leukemia is not recommended.[1]

References

  1. ↑ “National Cancer Institute”.

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Natural History, Complications and Prognosis

Natural History, Complications and Prognosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [2] Carlos A Lopez, M.D. [3]

Overview

Prognosis has improved from a 0% to 20-75% survival rate largely due to the continuous development of clinical trials and improvements in bone marrow transplantation (BMT) and stem cell transplantation (SCT) technology. The prognosis for acute lymphoblastic leukemia differs between individuals depending on a wide variety of factors such as gender, ethnicity, age, blood cell count, dissemination and genetic involvement.

Natural History, Complications, and Prognosis

Natural history

If left untreated, of patients with acute lymphoblastic leukemia may progress to develop infection, bleeding, infertility, and metastasis to other organs.[1][2][3][4]

Prognosis

  • The overall cure rate in children is 85%, and about 50% of adults have long-term disease-free survival.[5][6]
  • It is worth noting that medical advances in recent years, both through matching the best treatment to the genetic characteristics of the blast cells and through the availability of new drugs, are not fully reflected in statistics that usually refer to five-year survival rates.
  • The prognosis for acute Lymphoblastic leukemia differs between individuals depending on a wide variety of factors:

Gender

  • Females tend to fare better than males[9]

Ethnicity

  • Caucasians are more likely to develop acute leukemia than African-Americans, Asians and Hispanics and tend to have a better prognosis than non-Caucasians.

Age

  • Age is a significant factor in children with acute lymphoblastic leukemia and may be an important prognostic factor in adult with acute lympoblastic leukemia as well[10]
  • In one study, overall the prognosis was better in patients younger than 25 years; another study found a better prognosis in patients younger than 35 years
  • These findings may in part, be related to the increased incidence of the Ph1 in older acute lymphoblatic leukemia patients a subgroup associated with poor prognosis
  • Children between 1-10 years of age are most likely to be cured.

Blood cell count

  • White blood cell count at diagnosis of less than 50,000/µl.

Dissemination

Genetic involvement

Cytogenetic subtypes with worse prognosis

Central nervous system involvement

  • As in childhood acute lymphoblastic leukemia, adult patients with acute lymphoblastic luekemia are at risk of developing central nervous system involvement during the course of their disease. This is particularly true for patients with L3 (Burkitt) morphology. Both treatment and prognosis are influenced by this complication.

Celular morphology

  • Patients with L3 morphology showed improved outcomes, as evidenced in a completed cancer and Leukemia Group B study, when treated according to specific treatment algorithms.
  • This study found that L3 leukemia can be cured with aggressive, rapidly cycling lymphoma-like chemotherapy regimens.

5 Year survival

  • Between 2004 and 2010, the 5-year relative survival of patients with acute lymphoblastic leukemias was 70%.[16]
  • When stratified by age, the 5-year relative survival of patients with acute lymphoblastic leukemias was 71.3% and 12.2% for patients <65 and ≥ 65 years of age respectively.[16]

References

  1. ↑ Ma X, Urayama K, Chang J, Wiemels JL, Buffler PA (2009). “Infection and pediatric acute lymphoblastic leukemia”. Blood Cells Mol. Dis. 42 (2): 117–20. doi:10.1016/j.bcmd.2008.10.006. PMC 2834409. PMID 19064328.
  2. ↑ Byrne J, Fears TR, Mills JL, Zeltzer LK, Sklar C, Meadows AT, Reaman GH, Robison LL (April 2004). “Fertility of long-term male survivors of acute lymphoblastic leukemia diagnosed during childhood”. Pediatr Blood Cancer. 42 (4): 364–72. doi:10.1002/pbc.10449. PMID 14966835.
  3. ↑ Shigeta H, Tasaki N, Kitazumi S, Kitagawa Y, Kanatsuna T, Kondo M (April 1987). “[A case report of Bartter’s syndrome associated with possible pseudohypoparathyroidism type II]”. Nippon Naika Gakkai Zasshi (in Japanese). 76 (4): 549–52. PMID 3611913.
  4. ↑ Harrison’s Principles of Internal Medicine, 16th Edition, Chapter 97. Malignancies of Lymphoid Cells. Clinical Features, Treatment, and Prognosis of Specific Lymphoid Malignancies.
  5. ↑ “National Cancer Institute”.
  6. ↑ Barrett AJ (June 1994). “Bone marrow transplantation for acute lymphoblastic leukaemia”. Baillieres Clin. Haematol. 7 (2): 377–401. PMID 7803908.
  7. ↑ Bishop MR, Logan BR, Gandham S, Bolwell BJ, Cahn JY, Lazarus HM, Litzow MR, Marks DI, Wiernik PH, McCarthy PL, Russell JA, Miller CB, Sierra J, Milone G, Keating A, Loberiza FR, Giralt S, Horowitz MM, Weisdorf DJ (April 2008). “Long-term outcomes of adults with acute lymphoblastic leukemia after autologous or unrelated donor bone marrow transplantation: a comparative analysis by the National Marrow Donor Program and Center for International Blood and Marrow Transplant Research”. Bone Marrow Transplant. 41 (7): 635–42. doi:10.1038/sj.bmt.1705952. PMC 2587442. PMID 18084335.
  8. ↑ Pui CH, Boyett JM, Relling MV, Harrison PL, Rivera GK, Behm FG; et al. (1999). “Sex differences in prognosis for children with acute lymphoblastic leukemia”. J Clin Oncol. 17 (3): 818–24. doi:10.1200/JCO.1999.17.3.818. PMID 10071272.
  9. ↑ Foà R (2011). “Acute lymphoblastic leukemia: age and biology”. Pediatr Rep. 3 Suppl 2: e2. doi:10.4081/pr.2011.s2.e2. PMC 3206534. PMID 22053278.
  10. ↑ Mowery CT, Reyes JM, Cabal-Hierro L, Higby KJ, Karlin KL, Wang JH; et al. (2018). “Trisomy of a Down Syndrome Critical Region Globally Amplifies Transcription via HMGN1 Overexpression”. Cell Rep. 25 (7): 1898–1911.e5. doi:10.1016/j.celrep.2018.10.061. PMC 6321629. PMID 30428356.
  11. ↑ Koo HH (2011). “Philadelphia chromosome-positive acute lymphoblastic leukemia in childhood”. Korean J Pediatr. 54 (3): 106–10. doi:10.3345/kjp.2011.54.3.106. PMC 3120995. PMID 21738539.
  12. ↑ Nashed AL, Rao KW, Gulley ML (2003). “Clinical applications of BCR-ABL molecular testing in acute leukemia”. J Mol Diagn. 5 (2): 63–72. doi:10.1016/S1525-1578(10)60454-0. PMC 1907317. PMID 12707370.
  13. ↑ Fielding AK (January 2010). “Current treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia”. Haematologica. 95 (1): 8–12. doi:10.3324/haematol.2009.015974. PMC 2805747. PMID 20065078.
  14. ↑ Mullighan CG (2012). “Molecular genetics of B-precursor acute lymphoblastic leukemia”. J Clin Invest. 122 (10): 3407–15. doi:10.1172/JCI61203. PMC 3461902. PMID 23023711.
  15. ↑ 16.0 16.1 Howlader N, Noone AM, Krapcho M, Garshell J, Miller D, Altekruse SF, Kosary CL, Yu M, Ruhl J, Tatalovich Z,Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer Statistics Review, 1975-2011, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2011/, based on November 2013 SEER data submission, posted to the SEER web site, April 2014.

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