Impact of cytogenetics on outcomes in pediatric acute lymphoblastic leukemia

Rachana Chennamaneni; Sadashivudu Gundeti; Meher Lakshmi Konatam; Stalin Bala; Ashok Kumar; Lakshmi Srinivas

doi:10.4103/sajc.sajc_13_18

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ORIGINAL ARTICLE: Hematolymphoid Malignancies

07 (

); 263-266

doi:

10.4103/sajc.sajc_13_18

Impact of cytogenetics on outcomes in pediatric acute lymphoblastic leukemia

Rachana Chennamaneni¹, Sadashivudu Gundeti¹, Meher Lakshmi Konatam^1,, Stalin Bala¹, Ashok Kumar¹, Lakshmi Srinivas¹

1 Department of Medical Oncology, Nizam’s Institute of Medical Sciences, Hyderabad, Telangana, India

*Corresponding author: Dr. Meher Lakshmi. drrachanach@gmail.com

Published: 2020-12-21

MedIntel Services Pvt Ltd. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/.)

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Abstract

Context: In acute lymphoblastic leukemia (ALL), the most important prognostic factors are age, leukocyte count at presentation, immunophenotype, and cytogenetic abnormalities. The cytogenetic abnormalities are associated with distinct immunologic phenotypes of ALL and characteristic outcomes. Aims: The present study was primarily aimed at analyzing the impact of cytogenetics on postinduction responses and event-free survival (EFS) in pediatric patients with ALL. The secondary objective was to study the overall survival (OS). Subjects and Methods: A total of 240 patients with age <18 years and diagnosed with ALL between January 2011 and June 2016 were retrospectively analyzed. Cytogenetics was evaluated with conventional karyotyping or reverse transcriptase polymerase chain reaction. Based on cytogenetic abnormalities, the patients were grouped into five categories, and the outcomes were analyzed. Results: Of the 240 patients, 125 (52%) patients had evaluable cytogenetics. Of these, 77 (61.6%) patients had normal cytogenetics, 19 (15.2%) had t(9;22) translocation, 10 (8%) had unfavorable cytogenetics which included t(9;11), hypodiploidy, and complex karyotype, 10 (8%) had favorable cytogenetics which included t(12;21), t(1;19), and high hyperdiploidy, 9 (7.2%) had miscellaneous cytogenetics. Seventy-one percent of patients were treated with MCP 841 protocol, while 29% of patients received BFM-ALL 95 protocol. The 3-year EFS and OS of the entire group were 52% and 58%, respectively. On univariate analysis, EFS and OS were significantly lower in t(9;22) compared to normal cytogenetics (P = 0.033 and P = 0.0253, respectively) and were not significant for other subgroups compared to normal cytogenetics. On multivariate analysis, EFS was significantly lower for t(9;22) and unfavorable subgroups. Conclusions: Cytogenetics plays an important role in the molecular characterization of ALL defining the prognostic subgroups. Patients with unfavorable cytogenetics and with t(9;22) have poorer outcomes.

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References

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Kulkarni KP, Arora RS, Marwaha RK. Survival outcome of childhood acute lymphoblastic leukemia in India: A resource-limited perspective of more than 40 years. J Pediatr Hematol Oncol 2011;33:475-9.
Cytogenetic abnormalities in adult acute lymphoblastic leukemia: Correlations with hematologic findings outcome. A Collaborative Study of the Group Français de Cytogénétique Hématologique. Blood 1996;87:3135-42.
Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the world health organization classification of myeloid neoplasms and acute leukemia. Blood 2016;127:2391-405.
Mrózek K, Harper DP, Aplan PD. Cytogenetics and molecular genetics of acute lymphoblastic leukemia. Hematol Oncol Clin North Am 2009;23:991-1010, v.
Magrath I, Shanta V, Advani S, Adde M, Arya LS, Banavali S, et al. Treatment of acute lymphoblastic leukaemia in countries with limited resources; lessons from use of a single protocol in India over a twenty year period [corrected]. Eur J Cancer 2005;41:1570-83.
Möricke A, Reiter A, Zimmermann M, Gadner H, Stanulla M, Dördelmann M, et al. Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: Treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95. Blood 2008;111:4477-89.
GraphPad Prism version 7.00 for Windows. GraphPad Software. La Jolla, California, USA. Available from: http://www.graphpad.com. [Last accessed on 2017 Dec 23].
Kaplan EL, Maier P. Non-parametric estimation from incomplete observations. J Am Stat Assoc 1965;53:457-81.
Fletcher JA, Kimball VM, Lynch E, Donnelly M, Pavelka K, Gelber RD, et al. Prognostic implications of cytogenetic studies in an intensively treated group of children with acute lymphoblastic leukemia. Blood 1989;74:2130-5.
Pullarkat V, Slovak ML, Kopecky KJ, Forman SJ, Appelbaum FR. Impact of cytogenetics on the outcome of adult acute lymphoblastic leukemia: Results of southwest oncology group 9400 study. Blood 2008;111:2563-72.
Pandita A, Harish R, Digra SK, Raina A, Sharma AA, Koul A, et al. Molecular cytogenetics in childhood acute lymphoblastic leukemia: A hospital-based observational study. Clin Med Insights Oncol 2015;9:39-42.
Settin A, Al Haggar M, Al Dosoky T, Al Baz R, Abdelrazik N, Fouda M, et al. Prognostic cytogenetic markers in childhood acute lymphoblastic leukemia. Indian J Pediatr 2007;74:255-63.
Safaei A, Shahryari J, Farzaneh MR, Tabibi N, Hosseini M. Cytogenetic findings of patients with acute lymphoblastic leukemia in Fars province. Iran J Med Sci 2013;38:301-7.
Chessels JM, Swansbury GJ, Reeves B, Bailey CC, Richards SM. Cytogenetics and prognosis in childhood lymphoblastic leukaemia: Results of MRC UKALL X. Medical research council working party in childhood leukaemia. Br J Haematol 1997;99:93-100.
Forestier E, Johansson B, Gustafsson G, Borgström G, Kerndrup G, Johannsson J, et al. Prognostic impact of karyotypic findings in childhood acute lymphoblastic leukaemia: A Nordic series comparing two treatment periods. For the Nordic Society of Paediatric Haematology and Oncology (NOPHO) leukaemia cytogenetic study group. Br J Haematol 2000;110:147-53.
Shanta V, Maitreyan V, Sagar TG, Gajalakshmi CK, Rajalekshmy KR. Prognostic variables and survival in pediatric acute lymphoblastic leukemias: Cancer institute experience. Pediatr Hematol Oncol 1996;13:205-16.
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Chessells JM, Harrison CJ, Kempski H, Webb DK, Wheatley K, Hann IM, et al. Clinical features, cytogenetics and outcome in acute lymphoblastic and myeloid leukaemia of infancy: Report from the MRC childhood leukaemia working party. Leukemia 2002;16:776-84.
Pui CH, Campana D, Pei D, Bowman WP, Sandlund JT, Kaste SC, et al. Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med 2009;360:2730-41.
Goldberg JM, Silverman LB, Levy DE, Dalton VK, Gelber RD, Lehmann L, et al. Childhood T-cell acute lymphoblastic leukemia: The Dana-Farber cancer institute acute lymphoblastic leukemia consortium experience. J Clin Oncol 2003;21:3616-22.
Bhutani M, Kochupillai V, Bakshi S. Childhood acute lymphoblastic leukemia: Indian experience. Indian J Med Paediatr Oncol 2004;20:3-8.
Moorman AV, Harrison CJ, Buck GA, Richards SM, Secker-Walker LM, Martineau M, et al. 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 2007;109:3189-97.

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[1] Ward E, DeSantis C, Robbins A, Kohler B, Jemal A. Childhood and adolescent cancer statistics, 2014. CA Cancer J Clin 2014;64:83-103.

[2] Kulkarni KP, Arora RS, Marwaha RK. Survival outcome of childhood acute lymphoblastic leukemia in India: A resource-limited perspective of more than 40 years. J Pediatr Hematol Oncol 2011;33:475-9.

[3] Cytogenetic abnormalities in adult acute lymphoblastic leukemia: Correlations with hematologic findings outcome. A Collaborative Study of the Group Français de Cytogénétique Hématologique. Blood 1996;87:3135-42.

[4] Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the world health organization classification of myeloid neoplasms and acute leukemia. Blood 2016;127:2391-405.

[5] Mrózek K, Harper DP, Aplan PD. Cytogenetics and molecular genetics of acute lymphoblastic leukemia. Hematol Oncol Clin North Am 2009;23:991-1010, v.

[6] Magrath I, Shanta V, Advani S, Adde M, Arya LS, Banavali S, et al. Treatment of acute lymphoblastic leukaemia in countries with limited resources; lessons from use of a single protocol in India over a twenty year period [corrected]. Eur J Cancer 2005;41:1570-83.

[7] Möricke A, Reiter A, Zimmermann M, Gadner H, Stanulla M, Dördelmann M, et al. Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: Treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95. Blood 2008;111:4477-89.

[8] GraphPad Prism version 7.00 for Windows. GraphPad Software. La Jolla, California, USA. Available from: http://www.graphpad.com. [Last accessed on 2017 Dec 23].

[9] Kaplan EL, Maier P. Non-parametric estimation from incomplete observations. J Am Stat Assoc 1965;53:457-81.

[10] Fletcher JA, Kimball VM, Lynch E, Donnelly M, Pavelka K, Gelber RD, et al. Prognostic implications of cytogenetic studies in an intensively treated group of children with acute lymphoblastic leukemia. Blood 1989;74:2130-5.

[11] Pullarkat V, Slovak ML, Kopecky KJ, Forman SJ, Appelbaum FR. Impact of cytogenetics on the outcome of adult acute lymphoblastic leukemia: Results of southwest oncology group 9400 study. Blood 2008;111:2563-72.

[12] Pandita A, Harish R, Digra SK, Raina A, Sharma AA, Koul A, et al. Molecular cytogenetics in childhood acute lymphoblastic leukemia: A hospital-based observational study. Clin Med Insights Oncol 2015;9:39-42.

[13] Settin A, Al Haggar M, Al Dosoky T, Al Baz R, Abdelrazik N, Fouda M, et al. Prognostic cytogenetic markers in childhood acute lymphoblastic leukemia. Indian J Pediatr 2007;74:255-63.

[14] Safaei A, Shahryari J, Farzaneh MR, Tabibi N, Hosseini M. Cytogenetic findings of patients with acute lymphoblastic leukemia in Fars province. Iran J Med Sci 2013;38:301-7.

[15] Chessels JM, Swansbury GJ, Reeves B, Bailey CC, Richards SM. Cytogenetics and prognosis in childhood lymphoblastic leukaemia: Results of MRC UKALL X. Medical research council working party in childhood leukaemia. Br J Haematol 1997;99:93-100.

[16] Forestier E, Johansson B, Gustafsson G, Borgström G, Kerndrup G, Johannsson J, et al. Prognostic impact of karyotypic findings in childhood acute lymphoblastic leukaemia: A Nordic series comparing two treatment periods. For the Nordic Society of Paediatric Haematology and Oncology (NOPHO) leukaemia cytogenetic study group. Br J Haematol 2000;110:147-53.

[17] Shanta V, Maitreyan V, Sagar TG, Gajalakshmi CK, Rajalekshmy KR. Prognostic variables and survival in pediatric acute lymphoblastic leukemias: Cancer institute experience. Pediatr Hematol Oncol 1996;13:205-16.

[18] Radhakrishnan V, Gupta S, Ganesan P, Rajendranath R, Ganesan TS, Rajalekshmy KR, et al. Acute lymphoblastic leukemia: A single center experience with Berlin, Frankfurt, and munster-95 protocol. Indian J Med Paediatr Oncol 2015;36:261-4.

[19] Advani S, Pai S, Venzon D, Adde M, Kurkure PK, Nair CN, et al. Acute lymphoblastic leukemia in India: An analysis of prognostic factors using a single treatment regimen. Ann Oncol 1999;10:167-76.

[20] Hunger SP, Lu X, Devidas M, Camitta BM, Gaynon PS, Winick NJ, et al. Improved survival for children and adolescents with acute lymphoblastic leukemia between 1990 and 2005: A report from the children's oncology group. J Clin Oncol 2012;30:1663-9.

[21] Chessells JM, Harrison CJ, Kempski H, Webb DK, Wheatley K, Hann IM, et al. Clinical features, cytogenetics and outcome in acute lymphoblastic and myeloid leukaemia of infancy: Report from the MRC childhood leukaemia working party. Leukemia 2002;16:776-84.

[22] Pui CH, Campana D, Pei D, Bowman WP, Sandlund JT, Kaste SC, et al. Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med 2009;360:2730-41.

[23] Goldberg JM, Silverman LB, Levy DE, Dalton VK, Gelber RD, Lehmann L, et al. Childhood T-cell acute lymphoblastic leukemia: The Dana-Farber cancer institute acute lymphoblastic leukemia consortium experience. J Clin Oncol 2003;21:3616-22.

[24] Bhutani M, Kochupillai V, Bakshi S. Childhood acute lymphoblastic leukemia: Indian experience. Indian J Med Paediatr Oncol 2004;20:3-8.

[25] Moorman AV, Harrison CJ, Buck GA, Richards SM, Secker-Walker LM, Martineau M, et al. 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 2007;109:3189-97.

Impact of cytogenetics on outcomes in pediatric acute lymphoblastic leukemia

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Abstract

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