Bone Marrow Lymphocytes: can they be an alternative for Bone Marrow Lymphoblasts as early predictors of relapse and remission in Acute Lymphoblastic Leukemia at the post-Induction chemotherapy phase?

Authors

  • Nethmi Viranya Warnakulsuriya
  • Dilini Nimeshi Wanigasinghe
  • Priyanka Herath
  • Darshana Kottahachchi

DOI:

https://doi.org/10.34117/bjdv10n4-041

Keywords:

Acute Lymphoblastic Leukemia, complete blood count, induction chemotherapy, bone marrow lymphoblast, bone marrow lymphocytes

Abstract

Background: Acute Lymphoblastic Leukemia (ALL) is a hematological malignancy that arises due to unusual proliferation of lymphoid precursor cells in bone marrow. Induction chemotherapy is vital for achieving complete remission in ALL, but accurately predicting relapse risk and identifying patients likely to sustain remission remains challenging. Conventionally, bone marrow lymphoblasts have been used as the gold standard for assessing treatment response and predicting relapse in ALL. However, emerging evidence suggests that bone marrow lymphocytes may serve as alternative predictive biomarkers. Aim: This study aims to review the utility of bone marrow lymphocytes as early predictors of relapse and remission in ALL during the post-induction chemotherapy phase. It will explore the advantages and limitations of assessing lymphocytes compared to lymphoblasts and discuss the potential mechanisms underlying their prognostic significance. Patients and Methods: Total of 105 newly diagnosed ALL patients; 75 with B ALL and 30 with T ALL was selected to the study. Laboratory investigations included Complete Blood Count (CBC) with the manual differential count analysis and obtaining bone marrow parameters from myelogram reports. The patients were followed until the end of the induction phase and, the laboratory parameters were taken. Correlation bivariate analysis, Paired sample t-Test was performed to establish the associations between peripheral blood parameters with the bone marrow parameters. Receiver operating characteristic (ROC) curve analysis was performed to establish cutoff values for peripheral blood parameters and the bone marrow lymphocytes with aiming to investigate bone marrow response. All the analysis was performed using Microsoft Excel 2013.12 SPSS version 26. Results: In B ALL at Day 8, Lymphocytes% in Bone Marrow (L%_BM) showed a significant strong negative correlation (r =-0.357, p<0.05) with NLR. ROC curve analysis showed cut off values for Lymphocytes; NLR =<0.400 indicates the presence of L%_BM >10% in B ALL. When considering T ALL D8, the ALC>=1756/mm3 suggests the presence of >10% L%_BM in D8. Conclusion: Our research demonstrated strong correlations to predict the Lymphoblasts% in Bone Marrow (BL%_BM) & L%_BM by using peripheral blood parameters which is straight forward and easily obtainable. Moreover, we were successfully able to set up cut off peripheral blood parameter values to monitor the response of the Lymphocytes of the bone marrow. Before implementing the results, further studies could be carried out by increasing the sample size for both B & T ALL with the accurate monitoring of the patients.

References

BHAT, S., SHAH, S. and HUSSAIN, S. (2019). Single Circulating Blast in the Peripheral Blood Film in Normal Individuals and Patients of Non-neoplastic Haematological Disorders and Non-Hematological Neoplasms/Disorders- A Study at a Tertiary Care Centre. International Journal of Contemporary Medical Research [IJCMR], 6(1). doi:https://doi.org/10.21276/ijcmr.2019.6.1.9.

BRISCO, M.J., CONDON, J.J., HUGHES, E., NEOH, S.H., SYKES, P.J., SESHADRI, R., ANTHONY Keith Morley, TOOGOOD, I., WATERS, K.E., TAURO G and EKERT, H. (1994). Outcome prediction in childhood acute lymphoblastic leukaemia by molecular quantification of residual disease at the end of induction. 343(8891), pp.196–200. doi:https://doi.org/10.1016/s0140-6736(94)90988-1.

BUCHMANN, S. et al. (2022) “Remission, treatment failure, and relapse in pediatric all:An international consensus of the ponte-di-legno consortium,” Blood, 139(12), pp. 1785–1793. Available at: https://doi.org/10.1182/blood.2021012328.

CAMPANA, D. and COUSTAN-SMITH, E. (2002). Detection of Minimal Residual Disease in Acute Leukemia by Flow Cytometry. Copyright © 1999 Wiley-Liss, Inc.

CONTER, V., ARICÒ, M., VALSECCHI, M., BASSO, G., BIONDI, A., MADON, E., MANDELLI, F., PAOLUCCI, G., PESSION, A., RIZZARI, C., RONDELLI, R., ZANESCO, L. and MASERA, G. (2000). Long-term results of the Italian Association of Pediatric Hematology and Oncology (AIEOP) Acute Lymphoblastic Leukemia Studies, 1982–1995. Leukemia, 14(12), pp.2196–2204. doi:https://doi.org/10.1038/sj.leu.2401963.

CHIARETTI, S., ZINI, G. and BASSAN, R., 2014. DIAGNOSIS AND SUBCLASSIFICATION OF ACUTE LYMPHOBLASTIC LEUKEMIA. Mediterranean Journal of Hematology and Infectious Diseases, 6(1), p. e2014073.

COUSTAN-SMITH, E., SANCHO, J., HANCOCK, M., RAZZOUK, B., RIBEIRO, R., RIVERA, G., RUBNITZ, J., SANDLUND, J., PUI, C. and CAMPANA, D., 2002. Use of peripheral blood instead of bone marrow to monitor residual disease in children with acute lymphoblastic leukemia. Blood, 100(7), pp.2399-2402.

DAI, Q., ZHANG, G., YANG, H., WANG, Y., YE, L., PENG, L., SHI, R., GUO, S., HE, J. and JIANG, Y., 2021. Clinical features and outcome of pediatric acute lymphoblastic leukemia with low peripheral blood blast cell count at diagnosis. Medicine, 100(4), p.e24518.

FARIA, S.S., FERNANDES, P.C., SILVA, M.J.B., LIMA, V.C., FONTES, W., FREITAS-JUNIOR, R., ETEROVIC, A.K. and FORGET, P. (2016). The neutrophil-to-lymphocyte ratio: a narrative review. ecancermedicalscience, [online] 10. doi:https://doi.org/10.3332/ecancer.2016.702.

GAJJAR, A., RIBEIRO, R., HANCOCK, M., RIVERA, G., MAHMOUD, H., SANDLUND, J., CRIST, W. and PUI, C. (1995). Persistence of circulating blasts after 1 week of multiagent chemotherapy confers a poor prognosis in childhood acute lymphoblastic leukemia. Blood, 86(4), pp.1292–1295. doi:https://doi.org/10.1182/blood.v86.4.1292.bloodjournal8641292.

GALLEGOS-ARREOLA, M., BORJAS-GUTIERREZ, C., M., G., E., L., M., A. and R., J., 2013. Pathophysiology of Acute Lymphoblastic Leukemia. [online] intechopen.com. Available at: <http://dx.doi.org/10.5772/54652> [Accessed 2 May 2022].

GUNASEKERA, S., VINDULA, G., COMBS, R. and HOWARD, S., 2020. Protocol concordance and impact of protocol deviations on selected outcomes in delivery of high-dose methotrexate in acute lymphoblastic leukemia in Sri Lanka. Journal of Clinical Oncology, 38(29_suppl), pp.17-17.

GUPTA, A. et al. (2015) “Absolute lymphocyte count recovery independently predicts outcome in childhood acute lymphoblastic leukemia,” Journal of Pediatric Hematology/Oncology,37(3).Availableat :https://doi.org/10.1097/mph.0000000000000249.

HOFFBRAND, A. and MOSS, P., 2015. Essential haematology. 7th ed. Chichester, West Sussex: Wiley Blackwell, pp.190- 195.

HUANG, Y.-M., WANG, Y.-N., ZHENG, Y., PAN, L.-L., LI, Y., LI, J.-G. and WANG, S.-Y. (2021). The prognostic value of the peripheral blood cell counts changes during induction chemotherapy in Chinese patients with adult acute myeloid leukemia. Medicine, [online] 100(8), pp.e24614–e24614. doi:https://doi.org/10.1097/md.0000000000024614.

JANG, J., KIM, Y.R., CHO, H., CHUNG, H., KIM, S.-J., KIM, J.S., CHEONG, J.-W. and MIN, Y.H. (2019). Peripheral Blood Absolute Lymphocyte Count at Diagnosis As a New Prognostic Factor in Acute Myeloid Leukemia with t(8;21) Patients. Blood, 134(Supplement_1), pp.5178–5178. doi:https://doi.org/10.1182/blood-2019-128027.

JI WON LEE, JOON SEOL BAE, JIN HO KIM, HEE WON CHO, HEE YOUNG JU, KEON HEE YOO, HONG HOE KOO, WOO, S.-Y., KIM, S. and KI WOONG SUNG (2022). Absolute Neutrophil Count after the First Chemotherapy Cycle as a Surrogate Marker for Treatment Outcomes in Patients with Neuroblastoma. Cancer Research and Treatment, [online] 54(1), pp.259–268. doi:https://doi.org/10.4143/crt.2021.010.

KROBER, S.M. et al. (1999) “Reactive and neoplastic lymphocytes in human bone marrow: Morphological, immunohistological, and molecular biological investigations on biopsy specimens,” Journal of Clinical Pathology, 52(7), pp. 521–526. Available at: https://doi.org/10.1136/jcp.52.7.521.

LOCATELLI, F., SCHRAPPE, M., BERNARDO, M.E. and RUTELLA, S. (2012). How I treat relapsed childhood acute lymphoblastic leukemia. Blood, [online] 120(14), pp.2807–2816. doi:https://doi.org/10.1182/blood-2012-02-265884.

NGUYEN, T., MELVILLE, A., NATH, S., STORY, C., HOWELL, S., SUTTON, R., ZANNETTINO, A. and REVESZ, T., 2015. Bone Marrow Recovery by Morphometry during Induction Chemotherapy for Acute Lymphoblastic Leukemia in Children. PLOS ONE, 10(5), p. e0126233.

PIERRO, J., HOGAN, L., BHATLA, T. and CARROLL, W., 2017. New targeted therapies for relapsed pediatric acute lymphoblastic leukemia. Expert Review of Anticancer Therapy, 17(8), pp.725-736.

PIOTR STEFANIUK, SZYMCZYK, A. and PODHORECKA, M. (2020). The Neutrophil to Lymphocyte and Lymphocyte to Monocyte Ratios as New Prognostic Factors in Hematological Malignancies – A Narrative Review. Cancer management and research, Volume 12, pp.2961–2977. doi:https://doi.org/10.2147/cmar.s245928.

PUI, C.-H., RELLING, M.V., CAMPANA, D. and EVANS, W.E. (2002). Childhood acute lymphoblastic leukemia. Reviews in Clinical and Experimental Hematology, 6(2), pp.161–180. doi:https://doi.org/10.1046/j.1468-0734.2002.00067.x.

RABIN, K.R. et al. (2011) “Absolute lymphocyte counts refine minimal residual disease-based risk stratification in childhood acute lymphoblastic leukemia,” Pediatric Blood & Cancer, 59(3), pp. 468–474. Available at: https://doi.org/10.1002/pbc.23395.

RABIZADEH, E., PICKHOLTZ, I., BARAK, M., ISAKOV, E., ZIMRA, Y. and FROOM, P. (2014). Acute leukemia detection rate by automated blood count parameters and peripheral smear review. International Journal of Laboratory Hematology, 37(1), pp.44–49. doi:https://doi.org/10.1111/ijlh.12225.

RAETZ, E, M.J., DEVIDAS, M., HUNGER, S.P., CARROLL, W.L. and. (2004). Minimal Residual Disease(MRD) in Childhood Acute Lymphoblastic Leukemia(ALL) in Relapse. A Children’s Oncology Group (COG) Study. Blood, 104(11), pp.324–324. doi:https://doi.org/10.1182/blood. v104.11.324.324.

ROCHET, N.M., MARKOVIC, S.N. and PORRATA, L.F. (2012) “The role of complete blood cell count in prognosis—watch this space,” Oncology & Hematology Review (US), 08(01), p. 76. Available at: https://doi.org/10.17925/ohr.2012.08.1.76.

RUBNITZ, J.E., CAMPBELL, P., ZHOU, Y., SANDLUND, J.T., JEHA, S., RIBEIRO, R.C., INABA, H., BHOJWANI, D., RELLING, M.V., HOWARD, S.C., CAMPANA, D. and PUI, C.-H. (2013). Prognostic impact of absolute lymphocyte counts at the end of remission induction in childhood acute lymphoblastic leukemia. Cancer, 119(11), pp.2061–2066. doi:https://doi.org/10.1002/cncr.28026.

STEENBERGEN EJ, VERHAGEN OJ, VAN LEEUWEN EF, et al. Prolonged persistence of PCR-detectable minimal residual disease after diagnosis or first relapse predicts poor outcome in childhood B-precursor acute lymphoblastic leukemia. Leukemia. 1995 Oct;9(10):1726-1734. PMID: 7564517.

TERWILLIGER, T. and ABDUL-HAY, M., 2017. Acute lymphoblastic leukemia: a comprehensive review and 2017 update. Blood Cancer Journal, 7(6), pp. e577-e577.

TRAUSTI OSKARSSON, SÖDERHÄLL, S., ARVIDSON, J., FORESTIER, E., THOMAS LETH FRANDSEN, MARIT HELLEBOSTAD, Päivi LÄHTEENMÄKI, Jónsson, Ó.G., IDA HED MYRBERG and HEYMAN, M. (2017). Treatment‐related mortality in relapsed childhood acute lymphoblastic leukemia. Pediatric Blood & Cancer, 65(4). doi:https://doi.org/10.1002/pbc.26909.

WASSERMAN, R., N GALILI, ITO, Y., SILBER, J.H., REICHARD, B.A., SHANE, S., WOMER, R.B., LANGE, B. and G ROVERA (1992). Residual disease at the end of induction therapy as a predictor of relapse during therapy in childhood B-lineage acute lymphoblastic leukemia. Journal of Clinical Oncology, 10(12), pp.1879–1888. doi:https://doi.org/10.1200/jco.1992.10.12.1879.

WHITESIDE, T.L. (2022). Tumor-Infiltrating Lymphocytes and Their Role in Solid Tumor Progression. Experientia Supplementum, pp.89–106. doi:https://doi.org/10.1007/978-3-030-91311-3_3.

YOUSSEF, M.K. et al. (2022) “Predictive value of neutrophil-to-lymphocyte, lymphocyte-to-monocyte, and platelet-to-lymphocyte ratios in adult and pediatric acute lymphoblastic leukemia patients,” The Egyptian Journal of Haematology, 47(4), p. 239. Available at: https://doi.org/10.4103/ejh.ejh_19_22.

Downloads

Published

2024-04-18

How to Cite

Warnakulsuriya, N. V., Wanigasinghe, D. N., Herath, P., & Kottahachchi, D. (2024). Bone Marrow Lymphocytes: can they be an alternative for Bone Marrow Lymphoblasts as early predictors of relapse and remission in Acute Lymphoblastic Leukemia at the post-Induction chemotherapy phase?. Brazilian Journal of Development, 10(4), e69027. https://doi.org/10.34117/bjdv10n4-041

Issue

Section

Original Papers