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High Frequency and Poor Prognosis of Late Childhood BCR-ABL-Positive and MLL-AF4-Positive ALL Define the Need for Advanced Molecular Diagnostics and Improved Therapeutic Strategies in Pediatric B-ALL in Pakistan

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Abstract

Background

Fusion oncogenes (FOs) resulting from chromosomal abnormalities have an important role in leukemogenesis in pediatric B cell acute lymphoblastic leukemia (ALL). The most common FOs are BCR-ABL, MLL-AF4, ETV6-RUNX1, and TCF3-PBX1, all of which have important prognostic and drug selection implications. Moreover, frequencies of FOs have ethnic variations. We studied Pakistani frequencies of FOs, clinical pattern, and outcome in pediatric B-ALL.

Methods

FOs were studied in 188 patients at diagnosis using reverse transcriptase-polymerase chain reaction (RT-PCR) and interphase fluorescent in situ hybridization (FISH). Data were analyzed using SPSS version 17 (SPSS Inc., Chicago, IL, USA).

Results

FOs were detected in 87.2 % of patients. Mean overall survival was 70.9 weeks, 3-year survival was 31.9 %, and 3-year relapse-free survival was 18.1 %. Four patients died of drug toxicities. ETV6-RUNX1 (19.14 %) had better survival (110.9 weeks; p = 0.03); TCF3-PBX1 (2.1 %) was associated with inferior outcome and higher central nervous system (CNS) relapse risk; MLL-AF4 (18.1 %) was more common in the 8- to 15-year age group (24/34; p = 0.001) and was associated with organomegaly, low platelet count, and poor survival; and BCR-ABL (47.9 %) was associated with older age (7–15 years, 52/90), lower remission rates, shorter survival (43.73 ± 4.24 weeks) and higher white blood cell count. Overall, MLL-AF4 and BCR-ABL were detected in 66 % of B-ALL, presented in later childhood, and were associated with poor prognosis and inferior survival.

Conclusions

This study reports the highest ethnic frequency of BCR-ABL FO in pediatric ALL, and is consistent with previous reports from our region. Poor prognosis BCR-ABL and MLL-AF4 was detected in two-thirds of pediatric B-ALL and is likely to be the reason for the already reported poor survival of childhood ALL in South-East Asia. Furthermore, MLL-AF4, usually most common in infants, presented in later childhood in most of the ALL patients, which was one of the unique findings in our study. The results presented here highlight the need for mandatory inclusion of molecular testing for pediatric ALL patients in clinical decision making, together with the incorporation of tyrosine kinase inhibitors, as well as hematopoietic stem cell transplantation facilities, to improve treatment outcome for patients in developing countries.

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Author contributions

Zafar Iqbal, Ammara T. Gill and Mudassar Iqbal performed experiments, analyzed the data, and wrote the manuscript. Tanveer Akhtar, Mahmood Rasool, Aamir Mahmood and Muhammad Imran Irfan analyzed the data and critically reviewed the manuscript. Tashfin Awan, Noreen Sabir and Muhammad Farooq Sabar performed experiments and analyzed the data. Aamer Aleem and Muhammad Absar analyzed the data and wrote the manuscript. Afia M. Akram and Muhammad Hassan Siddiqi performed experiments. Masood A. Shammas, Abdullah Alanazi, Ahmad M. Khalid, Mehmood Hussain Qazi and Sajjad Karim critically reviewed the manuscript. Ijaz H. Shah, Muhammad Khalid, Abid S. Taj, Abid Jameel, Jamil Amjad Hashmi, Akhtar Hussain and Anjum Saeed analyzed the clinical data. Zafar Iqbal is guarantor of the overall content.

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Authors and Affiliations

  1. Medical Genetics/Hematology and Oncology, CLS, CAMS, King Saud Bin Abdulaziz University for Health Sciences/KAIMRC, King Abdulaziz Medical City, National Guard Health Affairs, Riyadh, 11426, Saudi Arabia

    Zafar Iqbal & Abdullah Alanazi

  2. Department of Zoology, Faculty of Biological Sciences, University of the Punjab, Lahore, Pakistan

    Tanveer Akhtar

  3. Pakistan Society for Molecular and Clinical Hematology, Lahore, Pakistan

    Tanveer Akhtar

  4. Hematology Oncology and Pharmacogenetic Engineering Sciences (HOPES) Group, Health Sciences/Parasitology Laboratories (HSL), Department of Zoology, University of the Punjab (ZPU), Lahore, Pakistan

    Zafar Iqbal, Tanveer Akhtar, Tashfin Awan, Noreen Sabir, Muhammad Absar, Afia M. Akram, Ammara T. Gill, Jamil Amjad Hashmi, Ahmad M. Khalid, Muhammad Hassan Siddiqi & Mudassar Iqbal

  5. Division of Hematology/Oncology, Department of Medicine, College of Medicine, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia

    Aamer Aleem

  6. Centre of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia

    Mahmood Rasool & Sajjad Karim

  7. Translational Genomic Instability Program, Harvard (Dana-Farber) Cancer Institute, Harvard Medical School, Harvard University, Boston, MA, USA

    Masood A. Shammas

  8. Department of Oncology, Allied Hospital, Punjab Medical College, Faisalabad, Pakistan

    Ijaz H. Shah & Muhammad Khalid

  9. Institute of Radiotherapy and Nuclear Medicine, Peshawar, Pakistan

    Abid S. Taj

  10. Hayatabad Medical Complex, Peshawar, Pakistan

    Abid Jameel

  11. Department of Oncology, Khyber Teaching Hospital, Peshawar, Pakistan

    Abid Jameel

  12. Cox Health System, Springfield, MO, USA

    Ammara T. Gill

  13. Department of Biotechnology, University of Peshawar, Peshawar, Pakistan

    Akhtar Hussain

  14. Core DNA Facilities, Centre for Advanced Molecular Biology, University of the Punjab, Lahore, Pakistan

    Muhammad Farooq Sabar

  15. Department of Biotechnology, University of Sargodha, Sargodha, Pakistan

    Zafar Iqbal & Ahmad M. Khalid

  16. Institute of Molecular Biology and Biotechnology (IMBB), Centre for Research in Molecular Medicine (CRiMM), The University of Lahore, Lahore, Pakistan

    Zafar Iqbal & Mehmood Hussain Qazi

  17. Stem Cell Research Group, Department of Anatomy, College of Medicine, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia

    Aamir Mahmood

  18. Asian Medical Institute and National Surgical Centre, Kant, Kyrgyzstan

    Mudassar Iqbal

  19. Pakistan Society for Molecular and Clinical Hematology (PSMH) & Hematology Oncology and Pharmacogenetic Engineering Sciences Group (HOPES), Lahore, Pakistan

    Zafar Iqbal, Tanveer Akhtar, Tashfin Awan, Noreen Sabir, Muhammad Absar, Afia M. Akram, Akhtar Hussain, Muhammad Hassan Siddiqi & Mudassar Iqbal

  20. Prince Abdullah Bin Khalid Celiac Disease Research Chair, King Saud University, Riyadh, Saudi Arabia

    Anjum Saeed

  21. Department of Chemistry, University of Sargodha, Sargodha, Pakistan

    Muhammad Imran Irfan

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  1. Zafar Iqbal
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Correspondence to Zafar Iqbal.

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Conflicts of interest

Zafar Iqbal, Tanveer Akhtar, Tashfin Awan, Aamer Aleem, Noreen Sabir, Mahmood Rasool, Muhammad Absar, Afia M. Akram, Masood A. Shammas, Ijaz H. Shah, Muhammad Khalid, Abid S. Taj, Abid Jameel, Abdullah Alanazi, Ammara T. Gill, Jamil Amjad Hashmi, Akhtar Hussain, Muhammad Farooq Sabar, Ahmad M. Khalid, Mehmood Hussain Qazi, Sajjad Karim, Muhammad Hassan Siddiqi, Aamir Mahmood, Mudassar Iqbal, Anjum Saeed, and Muhammad Imran Irfan have no conflicts of interest to disclose.

Funding

This study was partially supported by the College of Medicine Research Center, Deanship of Scientific Research, King Saud University, Riyadh, Saudi Arabia.

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Iqbal, Z., Akhtar, T., Awan, T. et al. High Frequency and Poor Prognosis of Late Childhood BCR-ABL-Positive and MLL-AF4-Positive ALL Define the Need for Advanced Molecular Diagnostics and Improved Therapeutic Strategies in Pediatric B-ALL in Pakistan. Mol Diagn Ther 19, 277–287 (2015). https://doi.org/10.1007/s40291-015-0149-0

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