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Abstract 5115

Abstract 5124

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).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.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).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.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.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.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.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.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.No relevant conflicts of interest to declare.

Acute lymphoblastic leukemia (ALL) is a heterogeneous lymphoid disorder with many genetic abnormalities of which fusion oncogenes (FGs) are very common with a known role in leukemogenesis (Harrison & Foroni, 2002). Although prognostic significance of FGs is well characterized in pediatric ALL, the role of FGs in adult ALL is not well established (Moorman et al., 2007).We studied the frequency and association of five most common FGs namely BCR-ABL, MLL-AF4, ETV6-RUNX11, E2A-PBX1 and SIL-TAL1 with disease biology and treatment outcome in adult ALL. FGs were studied at diagnosis in 104 adult ALL patients using RT-PCR (Van-Dongen et al, 1999) and Interphase FISH.FGs were found in 78. 8% (82/104) subjects (Table 1). Overall survival (OS) and relapse free survival (RFS) were 26. 17 and 11. 147 months, respectively (Figures 1–2). Patients with MLL-AF4 (12. 19%) showed an elevated total leukocyte count (TLC), prominent organomegaly, frequent central nervous system (CNS) involvement, and a poor clinical outcome (OS=8. 8 months). SIL-TAL1 (35. 36%) was associated with lymphadenopathy, frequent organomegaly, low platelets count and poor survival. Patients with BCR-ABL (20. 3%) had high TLC (p-value <0. 001), splenomegaly (p-value <0. 001), low platelets count (p-value <0. 001), poor outcome (OS=9. 3 & RFS=6. 3 months) and 10% less chances of CR as compared to BCR-ABL negative cases. ETV6-RUNX1 (4. 8 %) was mostly associated with low TLC, less common organomegaly, high CR rates and higher OS (30. 2 months), but their long term survival negatively affected by late relapses. Patients with TCF3-PBX1 (16. 3%) were associated with younger age (10/17, 59%), lower TLC (14/17, 82%), platelet count higher than 50×109/l (12/17, 71%), less common hepatomegaly (2/17, 12%), less common splenomegaly (3/17, 18%), early CR (11/17, 65%) but high relapse rate (13/17, 76. 1%) and shorter OS (11. 6 months).High relapse rates and shorter OS despite favorable prognosis manifested by clinical features and high early CR rates in TCF3-PBX1 highlights the need for their identification at presentation and intensified treatment protocols to manage high relapse rate (Foa et al., 2003). Association of SIL-TAL1 with lymphadenopathy can help in better identification of this adult ALL subgroup at low resource centers. We found much higher frequency of TCF3-PBX1 and lower frequency of ETV6-RUNX1 than previously reported (Van Dongen et al, 1999). Although MLL-AF4 positive ALL is rarely observed in adult ALL, its frequency was 9. 7% in our adult ALL patients, which added to overall poor outcome of adult ALL in our population. Characterization of TCF3-PBX1 as poor prognostic molecular entity in our adult ALL population, low frequency of favorably prognostic ETV6-RUNX1, high frequency of poor prognostic MLL-AF4 and TCF3-PBX1 reflects ethnic and geographic differences in the biology and treatment of adult ALL (Burmeister et al., 2010). Therefore, it identifies the need for molecular testing in routine clinical settings at diagnosis and its implication in molecular prognostication and differential treatment. It also indicates the need for in-depth molecular analysis using advanced techniques and their implication in understanding the leukemogenesis and clinical management of adult ALL.No relevant conflicts of interest to declare.