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ASSOCIATION OF HYPERDIPLOIDY WITH REMISSION STATUS IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA AFTER INDUCTION THERAPY.

Byline: Saqib Hussain Korejo, Ch Altaf Hussain, Tariq Ghafoor, Hamid Saeed Malik, Ayesha Khurshid and Rafia Mahmood

Keywords: Acute Lymphoblastic Leukemia, Complete Haematological Remission (CHR), Hyperdiploidy.

INTRODUCTION

Most common type of malignancy in children is acute lymphoblastic leukemia (ALL). It constitutes around 75% to 80% of pediatric leukemias. Increase in the early lymphoid precursors in bone marrow is the typical feature of childhood ALL1,2. Fever, bruises and bone pains are the frequent presentations of childhood ALL3. Diagnosis of childhood ALL is based on morphology, immunophenotyping, karyotyping and gene expression1. Cytogenetic studies have a major role in establishing diagnosis and determining the optimal therapy2. Some of the cytogenetic abnormalities have established prognostic impact. Cytogenetic abnormalities with favourable prognosis are hyperdiploidy, t (12:21) (p13;q22) ETV6-RUNX1 and those with poor prognosis are 11q23 (MLL gene rearrangement) and Ph + ALL. Other prognostic indicators are age, WBC count, flow cytometry and induction response4,5. Hyperdiploidy is defined as having more than diploid number of chromosomes i.e >46 chromosomes.

Hyper-diploidy in general has good prognosis6-9. Hyperdiploidy is self-sufficient indicator of good prognosis9,10. Present management of ALL of childhood cures about 80% of patients. Main cause of relapse is treatment failure or may be due to inadequate treatment. Some of the patients do not achieve complete haematological remission (CHR) after induction therapy and are considered as high risk having poor prognosis. Such patients are candidates for allogenic stem cell transplantation11,12. Remission induction is a multiagent therapy which attains complete remission in about >95% of cases. Three to four drugs (prednisolone, vincristine, asparaginase with or without daunorubicin) are used for the treatment of childhood ALL depending upon the risk groups of patients13. Complete haematological remission is defined as absolute neutrophil count (ANC) 1.0 x 109/L, platelet count 100,000/ul and bone marrow blast 20% blasts, Sudan black negativity of the blast cells and characteristic immunophenotype (for B-ALL >20% of Blast cells express tdt, CD10, CD 19, CD 22, cCD79a and for T-ALL, cCD 3, CD 5, CD 7). Cytogenetic studies were also carried out. On the basis of cytogenetics two groups were made one with hyperdiploidy and other group without hyperdiploidy. Chromosome analysis was done by metaphase chromosome banding using conventional Giemsa banding technique. Bone marrow samples (5ml) were collected in sodium heparin tubes and were processed immediately, cultured by standard methods and harvested (by mitotic inhibitor and addition of hypotonic solution). Fixation was done by methanol and glacial acetic acid in a ratio of 3:1, after fixation was treated with trypsin and stained with Giemsa.

Slides were examined under light microscopy and minimum of 20 metaphases were analyzed and interpreted according to the international system of cytogenetic nomenclature (ISCN). Risk stratification of patients was done according to National Cancer Institute's criteria. Standard risk was defined as age <10 years and WBC count of <50,000 x 109/L and high risk was defined as age [greater than or equal to]10 years of age and WBC count of [greater than or equal to]50,000 x 109/L. Patients having high risk cytogenetics i.e. (t(9:22 and t(11q23; variable)) and patients of T-ALL were also included in high risk category. Patients of ALL included in the study were treated with 'UK ALL 2011' protocol. Standard risk group received regimen-A chemotherapy and high risk group received regimen-B chemotherapy.

Regimen-A included three drugs (dexamethasone, vincristine and asparaginase) and Regimen-B included four drugs (dexa-methasone, vincristine, asparaginase and daunorubicin) Remission status was assessed after 1 month of induction chemotherapy by blood complete counts and bone marrow examination. Complete haematological remission (CHR) was defined as absolute neutrophil count (ANC) of 1.0 x 109/L, Platelet count of [greater than or equal to]100,000/ul, bone marrow aspirate with <05% blasts and no extramedullary disease after 1 month of induction therapy. Data were analyzed by using SPSS 24. Quantitative variables were represented by mean +- SD and qualitative variables were measured as frequencies and percentages. Comparison of remission status between the 2 groups (with or without hyperdiploidy) was done by using chi square/Fisher's exact test. A p-value less than or equal to 0.05 considered as a significant p-value.

Table-I. Characteristics of the patients of acute lymphoblastic leukaemia included in the study (N = 62).

Patients characteristics###Hyperdiploidy###Without hyperdiploidy

###n=19(30.6%)###n=43(69.4%)

Gender###Male###16(84.2%)###28(65.1%)

distribution###Female###03(15.8%)###15(34.9%)

Age###<10 years###17(89.5%)###37(86.0%)

###10 years###02(10.5%)###06(14.0%)

Risk groups###Standard###16(84.2%)###26(60.5%)

###High###03(15.8%)###17(39.5%)

Table-II: Remission status between 2 groups with and without hyperdiploidy.

###Hyperdiploidy###Other group without###p-value

###hyperdiploidy

Remission###18(94.7%)###29(67.4%)###0.02

Not in remission###01(5.26%)###14(32.6%)

RESULTS

Out of total 80 patients of ALL, 62 patients yielded successful cytogenetic culture and were included in the study. Of them, 54 (87%) patients were between 1-9 years of age and 8 (13%) patients were [greater than or equal to]10 years of age. Mean age at diagnosis was 5.6 +- 2.9 years. There were 44 (71%) boys and 18 (29%) girls with a male to female ratio of 2.4:1 (M: F 2.4:1). Nineteen patients (30.64%) had WBC [greater than or equal to]50 x 109/L while 43 (69.35%) had WBC 50 chromosomes). J Clin Oncol 2000; 18(9): 1876-87.

7. Raimondi SC, Roberson PK, Pui CH, Behm FG, Rivera GK. Hyperdiploid (47-50) acute lymphoblastic leukemia in children. Blood 1992; 79(12): 3245-52.

8. Abdi SI, Saleem M, Ahmad M. Chromosomal pattern in acute lymphoblastic leukaemia. J Pak Med Assoc 1990; 40(1): 9-11.

9. Carroll WL. Safety in numbers: hyperdiploidy and prognosis. Blood 2013; 121(13): 2374-6.

10. Ito C, Kumagai M, Manabe A, Coustan-Smith E, Raimondi SC, Behm FG, et al. Hyperdiploid acute lymphoblastic leukemia with 51 to 65 chromosomes: a distinct biological entity with a marked propensity to undergo apoptosis. Blood 1999; 93(1): 315-20.

11. Schrappe M, Hunger SP, Pui CH, Saha V, Gaynon PS, Baruchel A, et al. Outcomes after induction failure in childhood acute lymphoblastic leukemia. N Engl J Med 2012; 366(15): 1371-81.

12. Teachey DT, Hunger SP. Predicting relapse risk in childhood acute lymphoblastic leukaemia. Br J Haematol 2013; 162(5): 606-20.

13. Oudot C, Auclerc MF, Levy V, Porcher R, Piguet C, Perel Y, et al. Prognostic factors for leukemic induction failure in children with acute lymphoblastic leukemia and outcome after salvage therapy: the FRALLE 93 study. J Clin Oncol 2008; 26(9): 1496-503.

14. Silverman LB, Gelber RD, Young ML, Dalton VK, Barr RD, Sallan SE. Induction failure in acute lymphoblastic leukemia of childhood. Cancer 1999; 85(6): 1395-404.

15. Yasmeen N, Ashraf S. Childhood acute lymphoblastic leukaemia; epidemiology and clinicopathological features. J Pak Med Assoc 2009; 59(3): 150-3.

16. Rana ZA, Rabbani MW, Sheikh MA, Khan AA. Outcome of childhood acute lymphoblastic leukaemia after induction therapy - 3 years experience at a single paediatric oncology centre. J Ayub Med Coll Abbot 2009; 21(4): 150-3.

17. Kulkarni K, Marwaha R, Trehan A, Bansal D. Survival outcome in childhood ALL: experience from a tertiary care centre in North India. Pediatr Blood and Cancer 2009; 53(2): 168-73.

18. Dastugue N, Suciu S, Plat G, Speleman F, Cave H, Girard S, et al. Hyperdiploidy with 58-66 chromosomes in childhood B-acute lymphoblastic leukemia is highly curable: 58951 CLG-EORTC results. Blood 2013; 121(13): 2415-23.

19. Moorman AV, Richards SM, Martineau M, Cheung KL, Robinson HM, Jalali GR, et al. Outcome heterogeneity in childhood highhyperdiploid acute lymphoblastic leukemia. Blood 2003; 102(8): 2756-62.

20. Pui CH, Yang JJ, Hunger SP, Pieters R, Schrappe M, Biondi A, et al. Childhood acute lymphoblastic leukemia: progress through collaboration. J Clin Oncol 2015; 33(27): 2938.
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Publication:Pakistan Armed Forces Medical Journal
Date:Jun 30, 2019
Words:1431
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