An Outcome Analysis of Childhood Acute Promyelocytic Leukemia Treated with Atra and Arsenic Trioxide, and Limited Dose Anthracycline

Abstract

The overall survival of Acute Promyelocytic Leukemia (APL), reported in recent studies, is approaching to 90% wherein, arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) are used as the mainstay of treatment with either limited or no use of anthracycline and cytarabine. This study is aimed to ascertain the outcome of children with APL using similar approach. A total of 30 patients with APL, registered from January 2015 to December 2018, were reviewed. Diagnosis was established on bone marrow aspirate and confirmed by the presence of PML-RARA translocation. Treatment protocol was based on Australian APML 4 study performed by Australian Leukemia Lymphoma Group (ALLG). Lumbar puncture was not performed as it was not part of the protocol due to the risk of bleeding. The mean age in current cohort was 9 years with 53% males. Seven (23.3%) patients died and three (10%) abandoned treatment during induction. Twenty patients completed the intensive phase of chemotherapy and all (100%) of them attained molecular remission (MR). One patient dropped out after MR whereas, 19 remain on follow up with no evidence of disease, reflecting disease free survival (DFS) of 95%. With a median follow up of 2.5 years (range 2.1–4.8 years) the 5 years Kaplan–Meier estimate of OS was 63% and 73%, with and without abandonment, respectively. Analysis of outcome according to risk groups revealed inferior outcome of high risk (HR) group (38% and 50% with and without abandonment, respectively) in contrast to standard risk (SR) group which showed better outcome (82% and 88% with and without abandonment, respectively). The attainment of 100% molecular remission and absence of relapse supports the effectiveness of this regimen. Moreover, it is found to be less toxic and therefore, can be conveniently managed in day-care settings.

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Fig. 1

Abbreviations

APL:

Acute promyelocytic leukemia

AML:

Acute myeloid leukemia

FAB:

French American British

RARA:

Retinoic acid receptor alpha

PML:

Promyelocytic leukemia

ATRA:

All-trans retinoic acid

CR:

Complete remission

MRC:

Medical Research Council

TIH:

The Indus hospital

EMR:

Electronic medical record

CRF:

Case report form

BMA:

Bone marrow aspirate

WHO:

World Health Organization

FISH:

Fluorescence in-situ hybridization

ALLG:

Australian leukemia lymphoma group

WCC:

White cell count

CNS:

Central nervous system

MR:

Molecular remission

PCR:

Polymerase chain reaction

NGO:

Non-government organization

CBC:

Complete blood count

PT:

Prothrombin time

G-CSF:

Granulocyte colony stimulating factor

SPSS:

Statistical package for social studies

IBM:

International business machines

SD:

Standard deviation

IQR:

Interquartile range

OS:

Overall survival

EFS:

Event free survival

DFS:

Disease free survival

ED:

Early death

LR:

Low risk

HR:

High risk

References

  1. 1.

    Gregory J, Feusner J (2009) Acute promyelocyticleukemia in childhood. CurrOncol Rep 11(6):439–445

    Google Scholar 

  2. 2.

    Stein EM, Tallman MS (2014) Acute promyelocyticleukemia in children and adolescents. ActaHaematol 132:307–312

    CAS  Google Scholar 

  3. 3.

    Swerdlow S, Campo E, Harris NL, Jaffe E, Pileri S, Stein H et al (2017) WHO classification of tumours of haematopoietic and lymphoid tissues (revised 4th edition). Lyon, IARC, p 421

    Google Scholar 

  4. 4.

    Melnick A, Licht JD (1999) Deconstructing a disease: RARalpha, its fusion partners, and their roles in the pathogenesis of acute promyelocyticleukemia. Blood 93(10):3167–3215

    CAS  Article  Google Scholar 

  5. 5.

    Lo-Coco F, Ammatuna E, Montesinos P, Sanz MA (2008) Acute promyelocyticleukemia: recent advances in diagnosis and management. SeminOncol 35(4):401–409

    CAS  Google Scholar 

  6. 6.

    Redner RL (2002) Variations on a theme: the alternate translocations in APL. Leukemia 16(10):1927–1932

    CAS  Article  Google Scholar 

  7. 7.

    Shen ZX, Shi ZZ, Fang J, Gu BW, Li JM, Zhu YM et al (2004) All-trans retinoic acid/As2O3 combination yields a high-quality remission and survival in newly diagnosed acute promyelocyticleukemia. ProcNatlAcadSci U S A 101(15):5328–5335

    CAS  Article  Google Scholar 

  8. 8.

    Breen KA, Grimwade D, Hunt BJ (2011) The pathogenesis and management of the coagulopathy of acute promyelocytic leukaemia. Br J Haematol 156:24–36

    Article  Google Scholar 

  9. 9.

    Wang ZY, Chen Z (2008) Acute promyelocyticleukemia: from highly fatal to highly curable. Blood 111:2505–2515

    CAS  Article  Google Scholar 

  10. 10.

    Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S et al (2013) Retinoic acid and arsenic trioxide for acute promyelocyticleukemia. N Engl J Med 369:111–121

    CAS  Article  Google Scholar 

  11. 11.

    Bally C, Fadlallah J, Leverger G, Bertrand Y, Robert A, Baruchel A et al (2012) Outcome of acute promyelocyticleukemia (APL) in children and adolescents: an analysis in two consecutive trials of the European APL Group. J ClinOncol 30(14):1641–1646

    CAS  Article  Google Scholar 

  12. 12.

    Testi AM, Biondi A, Lo Coco F, Moleti ML, Giona F, Vignetti M et al (2005) GIMEMA-AIEOPAIDA protocol for the treatment of newly diagnosed acute promyelocyticleukemia (APL) in children. Blood 106(2):447–453

    CAS  Article  Google Scholar 

  13. 13.

    Pellicori P, Calicchia A, Lococo F, Cimino G, Torromeo C (2012) Subclinical anthracyclinecardiotoxicity in patients with acute promyelocyticleukemia in long-term remission after the AIDA protocol. Congest Heart Fail 18(4):217–221

    CAS  Article  Google Scholar 

  14. 14.

    Creutzig U, Zimmermann M, Dworzak M, Urban C, Henze G, Kremens B et al (2020) Favourable outcome of patients with childhood acute promyelocytic leukaemia after treatment with reduced cumulative anthracycline doses: report from the AML-BFM Study Group. Br J Haematol 149(3):399–409

    Article  Google Scholar 

  15. 15.

    Iland HJ, Bradstock K, Supple SG, Catalano A, Collins M, Hertzberg M et al (2012) All-trans-retinoic acid, Idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocyticleukemia (APML4). Blood 120(8):1570–1580

    CAS  Article  Google Scholar 

  16. 16.

    Burnett AK, Hills RK, Grimwade D, Goldstone AH, Hunter A, Milligan D et al (2007) Idarubicin and ATRA is as effective as MRC chemotherapy in patients with acutepromyelocytic leukaemia with lower toxicity and resource usage: preliminaryresults of the MRC AML15 Trial. Blood 110(11):589

    Article  Google Scholar 

  17. 17.

    Ades L, Chevret S, Raffoux E, de Botton S, Guerci A, Pigneux A et al (2006) Iscytarabine useful in the treatment of acute promyelocyticleukemia@ Results of a randomized trial from the European Acute PromyelocyticLeukemia Group. J ClinOncol. 24:5703–5710

    CAS  Article  Google Scholar 

  18. 18.

    Estey E, Garcia-Manero G, Ferrajoli A, Faderl S, Verstovsek S, Jones D et al (2006) Use of all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocyticleukemia. Blood 107:3469–3473

    CAS  Article  Google Scholar 

  19. 19.

    Ades L, Raffoux E, Chevret S, de Botton S, Guerci A, Pigneux A et al (2010) Is AraC required in the treatment of standard risk APL? Long term results of arandomized trial (APL 2000) from the French Belgian Swiss APL Group. Blood 116(21):13

    Article  Google Scholar 

  20. 20.

    Kutny MA, Alonzo TA, Gerbing RB, Wang YC, Fu C, Meshinchiet S et al (2015) Results of a phase III trial including arsenic trioxide consolidation for pediatric patients with acute promyelocyticleukemia (APL): a report from the children’s oncology group study AAML0631. Blood 126(23):219

    Article  Google Scholar 

  21. 21.

    Ortega JJ, Madero L, Martín G, Verdeguer A, García P, Parody R et al (2005) Treatment with all-trans retinoic acid and anthracyclinemonochemotherapy for children with acute promyelocyticleukemia: a multicenter study by the PETHEMA Group. J ClinOncol 23(30):7632–7640

    CAS  Article  Google Scholar 

  22. 22.

    Kim MH, Choi CS, Lee JW, Jang PS, Chung NG, Bin C et al (2010) Outcome of childhood acute promyelocytic leukemia treated using a modified AIDA protocol. Korean J Hematol 45(4):236–241

    CAS  Article  Google Scholar 

  23. 23.

    Ribeiro RC, Rego E (2006) Management of APL in developing countries: epidemiology, challenges, and opportunities for international collaboration. ASH Edu Program Book 1:162–168

    Google Scholar 

  24. 24.

    Li EQ, Xu L, Zhang ZQ, Xiao Y, Guo HX, Luo XQ et al (2012) Retrospective analysis of 119 cases of pediatric acute promyelocyticleukemia: Comparisons of four treatment regimes. ExpTher Med 4(1):93–98

    CAS  Article  Google Scholar 

  25. 25.

    Jastaniah W, Alsultan A, Al Daama S, Ballourah W, Bayoumy M, Anzi FA et al (2018) Clinical characteristics and outcome of childhood acute promyelociticleukemia (APL) in Saudi Arabia: a multicenter SAPHOS leukemia group study. Hematology 23(6):316–323

    Article  Google Scholar 

  26. 26.

    Testi AM, D’Angiò M, Locatelli F, Pession A, Lo CF (2014) Acute PromyelocyticLeukemia (APL): comparison between children and adults. Mediterr J Hematol Infect Dis 6(1):e2014032

    Article  Google Scholar 

  27. 27.

    Rego EM, Kim HT, Ruiz-Argüelles GJ, Undurraga MS, Uriarte MR, Jacomo HR et al (2013) Improving acute promyelocyticleukemia (APL) outcome in developing countries through networking, results of the International Consortium on APL. Blood 121(11):1935–1943

    CAS  Article  Google Scholar 

  28. 28.

    Abla O, Ribeiro RC, Testi AM, Montesinos P, Creutzig U, Sung L et al (2017) Predictors of thrombohemorrhagic early death in children and adolescents with t(15;17)-positive acute promyelocyticleukemia treated with ATRA and chemotherapy. Ann Hematol 96(9):1449–1456

    Article  Google Scholar 

  29. 29.

    Serna J, Montesinos P, Vellenga E, Rayón C, Parody R, León A et al (2008) Causes and prognostic factors of remission induction failure in patients with acute promyelocyticleukemia treated with all-trans retinoic acid and idarubicin. Blood 111(7):3395–3402

    Article  Google Scholar 

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Correspondence to Naeem Jabbar.

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Jabbar, N., Khayyam, N., Arshad, U. et al. An Outcome Analysis of Childhood Acute Promyelocytic Leukemia Treated with Atra and Arsenic Trioxide, and Limited Dose Anthracycline. Indian J Hematol Blood Transfus (2021). https://doi.org/10.1007/s12288-021-01404-1

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Keywords

  • Acute promyelocytic leukemia
  • Acute myeloid leukemia
  • Chemotherapy
  • Molecular remission
  • Survival outcome