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Detection of Five Common Fusion Oncogenes in Pakistani Children with Acute Lymphoblastic Leukemia and Their Association with Clinical Pattern and Treatment Outcome

Zafar Iqbal, Sabir Noreen, Aleem Aamer, Awan Tashfeen, Tahir Naeem, Asad Sultan, Ammara H Tahir, Muhammad Absar, Muhammad Azhar Chishti, Muhammad Faiyaz-ul-Haque, Ahmed Mukhtar Khalid, Muhammad Farooq Sabar, Mahmood Rasool, Agha Shabbir Ali, Amer Mahmood, Muhammad Akram, Tariq Saeed, Saleem Arsalan, Danish Mohsin, Ijaz Husssain Shah, Muhammad Khalid, Muhammad Asif, Mudassar Iqbal and Tanveer Akhtar

Abstract

Abstract 5124

Background & Objectives: Acute lymphoblastic leukemia (ALL) is a complex genetic disease involving many fusion oncogenes (FGs) (Xu et al., 2012). The frequency of various FO can vary in different ethnic groups & these FGs have important implications for prognosis & treatment outcome (van-Dongen et al, 1999).

Methods: We studied FGs in 101 pediatric ALL patients using Interphase FISH & RT-PCR (van-Dongen et al, 1999), & their association with clinical features & treatment outcome.

Results: Five most common FGs i. e. BCR-ABL [t(9;22)], TCF3-PBX1 [t(1;19)], ETV6-RUNX1 [t(12;21)], MLL-AF4 [t(4;11)] & SIL-TAL1 (del 1p32) were found in 89/101 (88. 1%) patients. Frequency of BCR-ABL was 44. 5% (45/101) (Table 1). BCR-ABL positive patients had a significantly lower survival (43. 73 ± 4. 24 weeks) (Figure 1)& higher white cell count as compared to others except patients with MLL-AF4. The highest relapse-free survival (RFS) was documented in ETV6-RUNX1 (14. 167 months) followed closely by those cases in which no gene was detected (13/100). RFS in BCR-ABL, MLL-ASF4, TCF-PBX4 & SIL-TAL1 was less than 10 months (7. 994, 3. 559, 5. 500 & 8. 080 months respectively) (Figure 2 & 3).

BCR-ABL: Frequency of occurrence was directly proportional to age (3 less than 2 year age group, 16 in the 2–7 year age group & 26 in the older than 7 group. Total leukocyte count (TLC) was higher when compared to patients with other oncogenes. Organomegaly was not common. BCR-ABL positivity was associated with low remission rates & shortened survival.

ETV6-RUNX1: The median age of the patients was 1. 85 years. The gene frequency was highest in patients younger than 2 years. TLC was not very high & patients had a good prognosis.

MLL-AF4: 17 patients had MLL-AF4 gene rearrangement with a median age of 9 years. Five patients were younger than 2 years, two between 2 & 7 years, & ten patients were in the 7–15 age group. Majority of our patients were older unlike the usual occurrence where most of the patients are infants.

TCF3-PBX1: This FG occurs in around 2% of patients. Only two female patients were diagnosed with this translocation. Both the patients were over 2 years of age. It was associated with an inferior outcome in the context of response to chemotherapy & a higher risk of CNS relapse although small numbers preclude any firm conclusions.

SIL-TAL1: Patients were older than 2 years, with the majority falling in the age range 7 to 15 years. The immunophenotype data were available in all SIL-TAL1 patients showing this fusion gene was associated with T-ALL with organomegaly being observed frequently.

Discussion & Conclusion: This is the first study from Pakistan correlating molecular markers with disease biology & treatment outcome in pediatric ALL. Our study revealed the highest reported frequency of BCR-ABL FO in pediatric ALL, in consistent with various other reports from Pakistan & rest of the world ((Iqbal & Akhtar, 2007; Faiz et al., 2011; (Gaynon et al., 1997; Iacobucci et al., 2012).) which, consequently, was associated with poor overall survival. The data indicates an immediate need for incorporation of tyrosine kinase inhibitors in the treatment of BCR-ABL+ pediatric ALL in this population & the development of facilities for stem cell transplantation.

Clinical & laboratory parametersBCR-ABL No (%) N=45ETV6-RUNX1 No (%) N=18MLL-AF4 No (%) N=17SIL-TAL1 No (%) N=7TCF3-PBX1 No (%) N=2FO not detected No (%) N=12
Male 34 (75)11 (61)12 (70.5)3 (42.8)09 (75)
Female 11 (24.4)7 (38.8)5 (29.4)4 (57.1)2 (100)3 (25)
Age
<23 (6.7)10 (55.5)5 (29.4)000
2-716 (35.6)7 (38.8)2 (11.8)2 (28.6)1 (50)5 (41.6)
8-1526 (57.8)1 (5.5)10 (58.8)5 (71.4)1 (50)7 (58.4)
WBC
<30,00024 (53.3)17 (94.4)10 (58.8)4 (57.1)1 (50)9 (75)
>30,00021 (46.6)1 (5.5)7 (41.1)3 (42.8)1 (50)3 (25)
Hepatomegaly
No23 (51.1)15 (83.3)8 (47.1)3 (42.9)09 (12)
Yes22 (48.9)3 (16.7)9 (53)4 (57.1)2 (100)3 (25)
Splenomegaly
No35 (77.8)15 (83.3)9 (53)5 (71.4)07 (58.3)
Yes10 (23.3)3 (17.7)8 (47.1)2 (28.6)2 (100)5 (41.7)
Lymphadenopathy
No30 (66.7)11 (61.1)5 (29.4)5 (21)2 (100)0
Yes15 (33.3)7 (38.9)12 (70.6)2 (28)02 (16.7)
Platelets
<50,00014 (31.1)6 (33.3)9 (52.9)6 (85.7)2 (100)3 (25)
>50,00031 (68.9)12 (66.7)8 (47.1)1 (14.7)09 (75)
CR
<4weeks13 (28.9)16 (94.4)4 (23.5)5 (71.4)1 (50)8 (66.7)
>4weeks29 (64.4)1 (5.6)10 (82.4)1 (14.2)1 (50)2 (16.6)
No remission3 (6.7)1 (5.6)3 (13.6)1 (14.2)02 (16.6)
Table 1:

Comparison of clinical characteristic of pediatric ALL patients

Figure1

Figure2

Figure3

Disclosures: No relevant conflicts of interest to declare.