B Cell Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) is a heterogeneous condition that affected 64,200 people worldwide in 2017.1 It is divided into two subcategories – B cell ALL (B-ALL) and T cell ALL (T-ALL) – with B-ALL representing approximately 75% of cases,2 and is the most common pediatric cancer.3 Pediatric patients generally respond well to treatment and have a good prognosis, but adult patients fare less well,2 with a higher relapse rate after remission and a poorer overall survival rate.4 This difference has been attributed to the presence of chromosomal anomalies in adult patients – such as the Philadelphia chromosome – higher resistance to treatment, and an increased likelihood of having pre-existing comorbidities.2 Recent advances in treatment protocols and testing have significantly improved outcomes for all patients with B-ALL.2, 5

Formation

Lymphoid cells develop from hematopoietic stem cells in the bone marrow, which then mature into lymphocytes. Maturation is a stepwise procedure, and is normally well managed by cell signaling, activating transcription factors, and positive/negative selection.6 B-ALL arises from genetic abnormalities that block lymphoid differentiation, driving aberrant cell proliferation and survival by evading apoptosis.6, 7 Normal lymphoid cells are replaced by malignant ones with clonality, which accumulate in the bone marrow, peripheral blood, and extramedullary sites,2, 6 reducing the proportion of healthy leukocytes, erythrocytes, and platelets.8

Diagnosis and treatment assessment

Initial diagnosis is made by the detection of at least 20% lymphoblasts in the bone marrow, which normally only constitute 5% of total cell count. Further diagnostic testing, and guidance for tailoring treatments, may include detailed morphology, flow cytometry, immunophenotyping, and cytogenetics.2

B-ALL treatment is generally divided into four stages: induction, consolidation, intensification, and maintenance. Treatment evaluation has drastically evolved in recent times, and measurable residual disease (MRD) monitoring is now routinely used alongside various stages to gauge therapy effectiveness and guide ongoing treatment decisions.9 MRD monitoring methods include multi-parametric flow cytometry (FCM), PCR, and next generation sequencing (NGS), which all offer the required sensitivity and specificity. FCM is usually performed on bone marrow samples, and it is important to establish the patient’s baseline immunophenotype before therapy initation.9 This way, if the patient relapses, bone marrow can be analyzed again through FCM and compared to pretreatment cell panels.9

Cell markers

CD19, CD10, CD20, CD34, CD38, and CD45 have been identified in multiple studies as important cell markers in FCM for MRD detection.10 In addition to these backbone markers increased sensitivity was seen when either CD66c and CD123, or CD73 with CD304.10 CD22 and CD58 have also been studied and used in combination with other markers.9

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References

  1. Dong Y, Shi O et al. (2020) Leukemia incidence trends at the global, regional, and national level between 1990 and 2017. Exp Hematol Oncol. 9 (14). https://doi.org/10.1186/s40164-020-00170-6
  2. Terwilliger T, Abdul-Hay M. (2017) Acute lymphoblastic leukemia: a comprehensive review and 2017 update. Blood Cancer J. 7 (6). https://doi.org/10.1038/bcj.2017.53
  3. Hunger SP, Mullighan CG. (2015) Acute Lymphoblastic Leukemia in Children. N Engl J Med. 373(16):1541-1552. doi:10.1056/NEJMra1400972
  4. Rowe JM. (2010) Prognostic factors in adult acute lymphoblastic leukaemia. Br J Haematol. 150(4):389-405. doi:10.1111/j.1365-2141.2010.08246.x
  5. Gökbuget N, Hoelzer D. (2009) Treatment of adult acute lymphoblastic leukemia. Semin Hematol. 46(1):64-75. doi:10.1053/j.seminhematol.2008.09.003
  6. Huang F, Liao E et al. (2020) Pathogenesis of pediatric B cell acute lymphoblastic leukemia: Molecular pathways and disease treatments (Review). Oncol Lett, 20(1): 448-454. https://doi.org/10.3892/ol.2020.11583
  7. Zuckerman T, Rowe JM. (2014) Pathogenesis and prognostication in acute lymphoblastic leukemia. F1000Prime Rep. 6:59. doi:10.12703/P6-59
  8. National Cancer Institute. (October 2021) Childhood Acute Lymphoblastic Leukemia Treatment. https://www.cancer.gov/types/leukemia/patient/child-all-treatment-pdq#section/all Accessed December 2, 2021
  9. Kruse A, Abdel-Azim N et al. (2020) Minimal Residual Disease Detection in Acute Lymphoblastic Leukemia. Int J Mol Sci. 21(3):1054. doi:10.3390/ijms21031054
  10. Theunissen P, Mejstrikova E et al on behalf of the EuroFlow Consortium. (2017) Standardized flow cytometry for highly sensitive MRD measurements in B-cell acute lymphoblastic leukemia. Blood. 129 (3): 347–357. doi: https://doi.org/10.1182/blood-2016-07-726307

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