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.
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.
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. drzafar.medgen@yahoo.com.|Hematology Oncology and Pharmacogenetic Engineering Sciences (HOPES) Group, Health Sciences/Parasitology Laboratories (HSL), Department of Zoology, University of the Punjab (ZPU), Lahore, Pakistan. drzafar.medgen@yahoo.com.|Department of Biotechnology, University of Sargodha, Sargodha, Pakistan. drzafar.medgen@yahoo.com.|Institute of Molecular Biology and Biotechnology (IMBB), Centre for Research in Molecular Medicine (CRiMM), The University of Lahore, Lahore, Pakistan. drzafar.medgen@yahoo.com.|Pakistan Society for Molecular and Clinical Hematology (PSMH) & Hematology Oncology and Pharmacogenetic Engineering Sciences Group (HOPES), Lahore, Pakistan. drzafar.medgen@yahoo.com.
Zafar
Z
Iqbal
Department of Zoology, Faculty of Biological Sciences, University of the Punjab, Lahore, Pakistan.|Pakistan Society for Molecular and Clinical Hematology, Lahore, Pakistan.|Hematology Oncology and Pharmacogenetic Engineering Sciences (HOPES) Group, Health Sciences/Parasitology Laboratories (HSL), Department of Zoology, University of the Punjab (ZPU), Lahore, Pakistan.|Pakistan Society for Molecular and Clinical Hematology (PSMH) & Hematology Oncology and Pharmacogenetic Engineering Sciences Group (HOPES), Lahore, Pakistan.
Tanveer
T
Akhtar
Hematology Oncology and Pharmacogenetic Engineering Sciences (HOPES) Group, Health Sciences/Parasitology Laboratories (HSL), Department of Zoology, University of the Punjab (ZPU), Lahore, Pakistan.|Pakistan Society for Molecular and Clinical Hematology (PSMH) & Hematology Oncology and Pharmacogenetic Engineering Sciences Group (HOPES), Lahore, Pakistan.
Tashfin
T
Awan
Division of Hematology/Oncology, Department of Medicine, College of Medicine, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia.
Aamer
A
Aleem
Hematology Oncology and Pharmacogenetic Engineering Sciences (HOPES) Group, Health Sciences/Parasitology Laboratories (HSL), Department of Zoology, University of the Punjab (ZPU), Lahore, Pakistan.|Pakistan Society for Molecular and Clinical Hematology (PSMH) & Hematology Oncology and Pharmacogenetic Engineering Sciences Group (HOPES), Lahore, Pakistan.
Noreen
N
Sabir
Centre of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia.
Mahmood
M
Rasool
Hematology Oncology and Pharmacogenetic Engineering Sciences (HOPES) Group, Health Sciences/Parasitology Laboratories (HSL), Department of Zoology, University of the Punjab (ZPU), Lahore, Pakistan.|Pakistan Society for Molecular and Clinical Hematology (PSMH) & Hematology Oncology and Pharmacogenetic Engineering Sciences Group (HOPES), Lahore, Pakistan.
Muhammad
M
Absar
Hematology Oncology and Pharmacogenetic Engineering Sciences (HOPES) Group, Health Sciences/Parasitology Laboratories (HSL), Department of Zoology, University of the Punjab (ZPU), Lahore, Pakistan.|Pakistan Society for Molecular and Clinical Hematology (PSMH) & Hematology Oncology and Pharmacogenetic Engineering Sciences Group (HOPES), Lahore, Pakistan.
Afia M
AM
Akram
Translational Genomic Instability Program, Harvard (Dana-Farber) Cancer Institute, Harvard Medical School, Harvard University, Boston, MA, USA.
Masood A
MA
Shammas
Department of Oncology, Allied Hospital, Punjab Medical College, Faisalabad, Pakistan.
Ijaz H
IH
Shah
Department of Oncology, Allied Hospital, Punjab Medical College, Faisalabad, Pakistan.
Muhammad
M
Khalid
Institute of Radiotherapy and Nuclear Medicine, Peshawar, Pakistan.
Abid S
AS
Taj
Hayatabad Medical Complex, Peshawar, Pakistan.|Department of Oncology, Khyber Teaching Hospital, Peshawar, Pakistan.
Abid
A
Jameel
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.
Abdullah
A
Alanazi
Hematology Oncology and Pharmacogenetic Engineering Sciences (HOPES) Group, Health Sciences/Parasitology Laboratories (HSL), Department of Zoology, University of the Punjab (ZPU), Lahore, Pakistan.|Cox Health System, Springfield, MO, USA.
Ammara T
AT
Gill
Hematology Oncology and Pharmacogenetic Engineering Sciences (HOPES) Group, Health Sciences/Parasitology Laboratories (HSL), Department of Zoology, University of the Punjab (ZPU), Lahore, Pakistan.
Jamil Amjad
JA
Hashmi
Department of Biotechnology, University of Peshawar, Peshawar, Pakistan.|Pakistan Society for Molecular and Clinical Hematology (PSMH) & Hematology Oncology and Pharmacogenetic Engineering Sciences Group (HOPES), Lahore, Pakistan.
Akhtar
A
Hussain
Core DNA Facilities, Centre for Advanced Molecular Biology, University of the Punjab, Lahore, Pakistan.
Muhammad Farooq
MF
Sabar
Hematology Oncology and Pharmacogenetic Engineering Sciences (HOPES) Group, Health Sciences/Parasitology Laboratories (HSL), Department of Zoology, University of the Punjab (ZPU), Lahore, Pakistan.|Department of Biotechnology, University of Sargodha, Sargodha, Pakistan.
Ahmad M
AM
Khalid
Institute of Molecular Biology and Biotechnology (IMBB), Centre for Research in Molecular Medicine (CRiMM), The University of Lahore, Lahore, Pakistan.
Mehmood Hussain
MH
Qazi
Centre of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia.
Sajjad
S
Karim
Hematology Oncology and Pharmacogenetic Engineering Sciences (HOPES) Group, Health Sciences/Parasitology Laboratories (HSL), Department of Zoology, University of the Punjab (ZPU), Lahore, Pakistan.|Pakistan Society for Molecular and Clinical Hematology (PSMH) & Hematology Oncology and Pharmacogenetic Engineering Sciences Group (HOPES), Lahore, Pakistan.
Muhammad Hassan
MH
Siddiqi
Stem Cell Research Group, Department of Anatomy, College of Medicine, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia.
Aamir
A
Mahmood
Hematology Oncology and Pharmacogenetic Engineering Sciences (HOPES) Group, Health Sciences/Parasitology Laboratories (HSL), Department of Zoology, University of the Punjab (ZPU), Lahore, Pakistan.|Asian Medical Institute and National Surgical Centre, Kant, Kyrgyzstan.|Pakistan Society for Molecular and Clinical Hematology (PSMH) & Hematology Oncology and Pharmacogenetic Engineering Sciences Group (HOPES), Lahore, Pakistan.
Mudassar
M
Iqbal
Prince Abdullah Bin Khalid Celiac Disease Research Chair, King Saud University, Riyadh, Saudi Arabia.
Anjum
A
Saeed
Department of Chemistry, University of Sargodha, Sargodha, Pakistan.
Muhammad Imran
MI
Irfan
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D008297:Male; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D010154:Pakistan / Q000208:ethnology; D057285:Precision Medicine; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000208:ethnology / Q000235:genetics* / Q000473:pathology*; D011379:Prognosis; D016019:Survival Analysis; D016896:Treatment Outcome
C113855:MLL-AF4 fusion protein, human; D015514:Oncogene Proteins, Fusion; D051788:Myeloid-Lymphoid Leukemia Protein; D016044:Fusion Proteins, bcr-abl