Individualized Tumor Response Testing (ITRT) Profile Has a Prognostic Value in Childhood Acute Lymphoblastic Leukemia (ALL) and Acute Non-Lymphoblastic Leukemia (ANLL): The Multicenter Non-Interventional Long-Term Follow-up Study of Polish Pediatric Leukemia Study Group

Individualized tumor response testing (ITRT) is a recently accepted term for ex vivo drug resistance profile testing in cancer patients. Previous studies have shown that ITRT results in children correspond with clinical response in initial acute lymphoblastic leukemia (iALL), but not in initial acute myeloid leukemia (iAML). ITRT combined profile to prednisolone, vincristine, and L-asparaginase (PVA score) showed a strong association with clinical outcome in iALL (Den Boer et al JCO; Hollemann et al, NEJM). OBJECTIVE: Polish Pediatric Leukemia Study Group carried out between 1999–2010 a multi-institutional, non-interventional study on correlation between ITRT profile and clinical response in long-term follow-up. The objective of the study was to assess the role of ITRT profile as prognostic factor in childhood iALL and iAML. MATERIALS AND METHODS: A total number of 998 children (median age 6.5 yrs, range 3 days - 21 yrs) were enrolled into the study, including 817 with initial ALL (iALL) and 181 children with initial AML (iAML). The median follow-up was 4.6 yrs (range 0–10,4). ITRT (ex vivo drug resistance profile) was determined by the MTT assay. Following drugs were tested: prednisolone (P), vincristine (V), L-asparaginase (A), daunorubicin (D), doxorubicin (Dox), idarubicin (I), mitoxantrone (M), cytarabine (C), busulfan (B) and etoposide (E). Apart from ITRT to single drugs, combined ex vivo drug resistance profiles PVA, PVADC, PVADoxC in iALL and CVIDM in iAML were also determined. Probability of DFS was estimated by the Kaplan-Meier method and compared by the log-rank test. Univariate and multivariate analyses were performed in Cox regression model. RESULTS: (1) For iALL patients, neither single drug nor 3-drugs PVA combined ITRT profile had prognostic value for pDFS. 5-drug PVADC and PVADoxC profiles had predictive values, with p-values 0.049 and 0.017, respectively. For 295 iALL patients with ITRT-sensitive PVADC profile, 5-year pDFS=0.892. No ITRT factor was discriminative between very early, early and late ALL relapses. In univariate analysis in Cox model, following factors had prognostic value for pDFS in iALL: steroid resistance by day 8 (p=0.002), bone marrow (BM) response by day 15 (p=0.005), BM response by day 33 (p=0.001) and PVADC ITRT profile (p=0.052). In multivariate analysis in Cox model, only BM response by day 33 (p=0.001) had prognostic value for pDFS in iALL, while bone marrow BM by day 15 had borderline significance (p=0.055). (2) For iAML patients, ITRT to cytarabine had an impact on pDFS (0.81 vs 0.63, p=0.047). For 55 iAML patients with ITRT-sensitive to cytarabine, 5-year pDFS=0.816. 5-drug CVIDM profile had also predictive values, with p-value 0.020. No ITRT factor was discriminative between very early, and late AML relapses. In univariate analysis in Cox model, no factor had prognostic value for pDFS in iAML, while ITRT to cytarabine almost reached significance (p=0.054). Multivariate analysis for iAML was not performed. CONCLUSION: Ex vivo drug resistance profile (ITRT) can be regarded as a risk factor in childhood acute leukemias. Combined ITRT profile to prednisolone, vincristine, L-asparaginase, daunorubicin and cytarabine (PVADC) has predictive value in pediatric iALL, while ITRT profile to cytarabine has prognostic value in pediatric iAML. ACKNOWLEDGEMENTS: Supported by grants: EFS-POKL.04.01.01-00-191/08-00 nr 1/2010; MNiSW Nr N N407 541339; MNiSW Nr N407 078 32/2964; UMK 09/2009; UMK 10/2009.

No relevant conflicts of interest to declare.