Treatment response and residual-disease monitoring in initial and relapsed TEL-AML1 positive childhood ALL

Abstract In vivo response to initial therapy, as assessed by determination of minimal residual disease after five and 12 weeks of treatment, has evolved as one of strong prognostic factors in children with acute lymphoblastic leukemia (ALL) treated according to the BFM regime. It is currently not known if the individual treatment response might be influenced by copy number alterations (CNA) leading to altered gene expression. We compared leukemic genomic profiles of 25 treatment sensitive (MRD-SR) and 25 resistant (MRD-HR) childhood ALL patients by means of high-resolution array-CGH. CNA were found in 46 patients (92%) of both treatment response groups. Microscopic alterations affecting the whole or nearly whole chromosome arm were frequently found, e.g. gain of 21 in 11/50, loss of 9p in 5/50, loss of 8p in 3/50, loss of 20q in 3/50 and loss of 7p in 2/50 or gain of 1q in 2/50. The most significant difference was a gain of chromosome 1q23-qter due to an unbalanced t(1;19), found in 10/25 MRD-SR patients, but in none of the MRD-HR patients (p<0.002). The most frequent CNA in the MRD-HR group were deletions of genomic regions harboring the immunoglobulin genes (Ig), e.g. 2p11.2 in 15 of 25 cases (60%) compared to 7 of 25 in the MRD-SR group (28%) (p=0.045). Combining all Ig loci, significantly more MRD-HR than MRD-SR patients were affected with deletions (17 versus 8 patients, p=0.02). The frequency of other CNA, like loss of 9p21 or gains of 21q, did not differ strongly between the two patient groups. This is the first study evaluating the clinical significance of CNA as detected by array-CGH in childhood ALL and may lead to improved risk classification.

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Thiopurine Methyltransferase Genotype Modulates Early Treatment Response to 6-Mercaptopurine as Measured by Minimal Residual Disease in Childhood Acute Lymphoblastic Leukemia.

Blood ◽

10.1182/blood.v104.11.321.321 ◽

2004 ◽

Vol 104 (11) ◽

pp. 321-321

Author(s):

Martin Stanulla ◽

Elke Schaffeler ◽

Thomas Flohr ◽

Gunnar Cario ◽

Karl Welte ◽

...

Keyword(s):

Relative Risk ◽

Treatment Response ◽

Residual Disease ◽

Tpmt Activity ◽

Wild Type Allele ◽

Wild Type ◽

Childhood All ◽

Consolidation Treatment ◽

Type Allele ◽

Minimal Residual

Abstract Thiopurine S-methyltransferase (TPMT) is a cytosolic enzyme that catalyzes the S-methylation of thiopurines. The TPMT locus is subject to genetic polymorphism, with heterozygous individuals (about 10% of Caucasians) having intermediate, and homozygous individuals (about 0.33% of Caucasians) having low TPMT activity. More than 95% of defective TPMT activity can be explained by the most frequent variant alleles TPMT*2, TPMT*3A, TPMT*3B, TPMT*3C and TPMT*3D. In the present study, we analyzed the association TPMT of genotype with minimal residual disease (MRD), before and after application of a four week cycle of 6-mercaptopurine (6-MP; 60 mg/m2/d) during induction consolidation treatment. Samples were derived from patients enrolled in our ongoing Berlin-Frankfurt-Muenster (BFM) trial on treatment of childhood ALL (ALL-BFM 2000) from 10/1999 to 03/2002. Routine bone-marrow samples were taken at diagnosis and after completion of induction (treatment day 33) and induction consolidation (treatment day 78). Semiquantitative estimation of MRD was performed by standardized PCR analysis of leukemia clone-specific immunoglobulin and T-cell receptor gene rearrangements and TAL1 deletions. In order to be included in the study presented here, patients had to have at least one MRD marker with a sensitivity of 10−4 and successful MRD monitoring at both follow-up time points (day 33 and day 78); MRD loads smaller than 10−4 were defined as negative. Genotyping was performed by a DHPLC method. We were able to analyze 814 patients with childhood ALL. 755 (92.8%) patients were homozygous for the TPMT wild-type allele, 55 (6.8%) were heterozygous, and 4 (0.5%) homozygous for a variant TPMT allele. Except for immunophenotype, no major differences with regard to characteristics known to be associated with treatment response were observed between patients homozygous for the wild-type allele and those being heterozygous. The four patients homozygous for a variant TPMT allele were already MRD negative after completion of remission induction on treatment day 33. Therefore, they were not included in further analyses. In patients homozygous for the wild-type allele or heterozygous, MRD levels on day 33 were equally distributed between the groups. However, when MRD levels were assessed on day 78, after administration of induction consolidation treatment, including a 4-week cycle of 6-MP, significant differences with regard to clearance of MRD were observed between patients homozygous for the TPMT wild-type allele and heterozygotes. For heterozygous patients, this distribution translated into a 2.4-fold reduction in risk of having measurable MRD after induction consolidation treatment (relative risk = 0.42; 95% confidence interval = 0.16–0.99; P = 0.047). This effect remained significant in multivariate analysis including immunophenotype (relative risk = 0.36; 95% confidence interval = 0.15–0.87; P = 0.023). Our results indicate that TPMT genotype has a substantial influence on MRD after administration of 6-MP during induction consolidation treatment of childhood ALL, most likely through modulation of 6-MP dose intensity. In addition, our data support a role for MRD in the assessment of treatment response to specific drugs.

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