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Abstract
Minimal residual disease (MRD) enables reliable assessment of risk in acute lymphoblastic leukemia (ALL). However, little is known on association between MRD status and germline genetic variation. We examined 159 Caucasian (Slavic) patients with pediatric ALL, treated according to ALL-IC-BFM 2002/2009 protocols, in search for association between 23 germline polymorphisms and MRD status at day 15, day 33 and week 12, with adjustment for MRD-associated clinical covariates. Three variants were significantly associated with MRD: rs1544410 in VDR (MRD-day15); rs1051266 in RFC (MRD-day33, MRD-week12), independently and in an additive effect with rs10519613 in IL15 (MRD-day33). The risk alleles for MRD-positivity were: A allele of VDR (OR = 2.37, 95%CI = 1.07–5.21, P = 0.03, MRD-day15); A of RFC (OR = 1.93, 95%CI = 1.05–3.52, P = 0.03, MRD-day33 and MRD-week12, P < 0.01); A of IL15 (OR = 2.30, 95%CI = 1.02–5.18, P = 0.04, MRD-day33). The risk for MRD-day33-positive status was higher in patients with risk alleles in both RFC and IL15 loci than in patients with risk alleles in one locus or no risk alleles: 2 vs. 1 (OR = 3.94, 95% CI = 1.28–12.11, P = 0.024), 2 vs. 0 (OR = 6.75, 95% CI = 1.61–28.39, P = 0.012). Germline variation in genes related to pharmacokinetics/pharmacodynamics of anti-leukemic drugs and to anti-tumor immunity of the host is associated with MRD status and might help improve risk assessment in ALL.
Highlights
Of therapeutic regimens, introduction of more efficient chemotherapeutic drugs, and treatment diversification in the risk-stratified patient groups
The study group did not consist of consecutive patients, their distribution into high risk (HR), intermediate (IR) and standard risk (SR) groups (Table 1) did not differ from that reported for a cohort of 5060 patients treated according to the Acute lymphoblastic leukemia (ALL) IC-BFM 2002 protocol[19] (P = 0.2265)
Our results indicate associations of polymorphic variants in three genes with the MRD-status in pediatric ALL patents: rs1544410 in VDR with MRD at day 15; rs1051266 in RFC, independently and in combination with rs10519613 in IL15 with MRD at day 33; and rs1051266 in RFC with MRD at week 12
Summary
Of therapeutic regimens, introduction of more efficient chemotherapeutic drugs, and treatment diversification in the risk-stratified patient groups. Quantitative assessment of the level of residual leukemic cells (minimal residual disease, MRD) in patients undergoing treatment for ALL is an important indicator of the efficiency of a therapy. Several clinical studies carried out in the late 1990s demonstrated that monitoring MRD during the first three months of treatment holds the most prognostic value for risk assessment in pediatric ALL; generally, the presence of residual leukemic cells at the specified time points is associated with inferior survival[3,4,5]. The use of MRD status as an indicator of the treatment response enables rapid assessment of the prognostic potential of genetic polymorphisms in association studies, with no need for a long-term follow-up that is necessary when such studies are based on survival analysis[15]. The group of patients was ethnically uniform (all were Caucasian of Slavic origin), and MRD was assessed, by flow cytometry (FC) and/or real-time polymerase chain reaction (RQ-PCR), at three uniformly chosen time points after the beginning of treatment
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