Thiopurine Methyltransferase Genetics Is Associated with Treatment Outcome and Hepatic Toxicity in Pediatric Patients with Acute Lymphoblastic Leukemia: a Report From the ALL-BFM Study Group.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2625-2625
Author(s):  
Martin Stanulla ◽  
Elke Schäffeler ◽  
Silke Pohlschmidt ◽  
Martin Zimmermann ◽  
Anja Möricke ◽  
...  
Keyword(s):  
Enzyme Activity ◽  
Acute Lymphoblastic Leukemia ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Thiopurine Methyltransferase ◽  
Wild Type ◽  
Childhood All ◽  
Genotype 2 ◽  
Minimal Residual

Abstract Abstract 2625 Poster Board II-601 The thiopurines 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) play an essential role in treatment protocols for acute lymphoblastic leukemia (ALL). Thiopurine methyltransferase (TPMT) is a key enzyme in the metabolism of thiopurines and underlies phenotypically relevant genetic variation. Heterozygotes or homozygotes for TPMT genotypes conferring lower enzyme activity demonstrate thiopurine drug metabolic patterns distinct from those of TPMT wild-type individuals. Underlining its clinical importance, several studies have demonstrated a relationship between low TPMT enzyme activity and thiopurine-associated toxicity as well as decreased relapse risk. Here we report on a prospective evaluation of the role of TPMT genetics for survival and treatment-related toxicity in a cohort of 814 pediatric ALL patients. These 814 patients were initially selected based on availability of DNA and represent 85.1% of the entire patient population (n=956) enrolled in the German-Austrian-Swiss multi-center trial ALL-BFM 2000 from October 1999 to September 2002. Genotyping for TPMT was performed by a denaturing HPLC method and subsequent sequencing of variant alleles using DNA prepared from either leukemic or remission bone marrows. This analysis revealed 755 (92.8%) patients with TPMT wild-type, 55 (6.8%) with a heterozygous, and 4 (0.5%) with a homozygous variant genotype (*2/*3A, *3A/*3A [n=2], *3A/*11), respectively. Genotype frequencies were in Hardy-Weinberg equilibrium. Allele frequencies were as follows: TPMT*1 = 96.12%, TPMT*2 = 0.25%, TPMT*3A = 2.95%, TPMT*3C = 0.56%, TPMT*9 = 0.06%, and TPMT*11 = 0.06%. Patients (n=55) heterozygous for allelic variants of TPMT conferring lower enzyme activity demonstrated significantly better event-free survival (EFS) and a lower relapse rate compared to homozygous wild-type patients (n=755) (six-years pEFS; heterozygotes vs. wild-type, 95% (SE 3%) vs. 84% (SE 1%), p(log-rank) = 0.04; p(point estimate difference) = <0.001, relapse incidence at six years, 4% (SE 3%) vs. 12% (SE 3%), p = 0.07). In a Cox regression analysis, adjusting for sex, age, presenting leukocyte count, immunophenotype and minimal residual disease the effect of TPMT genotype was still detectable, but lost statistical significance (hazard ratio for TPMT heterozygosity = 0.38, p = 0.10). An analysis stratified by minimal residual disease-defined risk groups will be presented. While TPMT heterozygotes did not demonstrate statistically significant differences when their toxicity data collected according to the National Cancer Institute's Common Toxicity Criteria were compared with wild-type patients for 6-MP-containing treatment phases, they had an increased risk of developing hepatic veno-occlusive disease associated with a two-week exposure towards 6-TG given during re-intensification. In conclusion, TPMT genotyping may contribute important information for clinical decision making in childhood ALL that goes beyond the prevention of toxicity in TPMT deficient patients. Disclosures: No relevant conflicts of interest to declare.

Importance of Minimal Residual Disease Testing During the Second Year of Therapy for Children With Acute Lymphoblastic Leukemia

2003 ◽  
Vol 21 (4) ◽  
pp. 704-709 ◽  
Author(s):  
Glenn M. Marshall ◽  
Michelle Haber ◽  
Edward Kwan ◽  
Ling Zhu ◽  
Daniella Ferrara ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Univariate Analysis ◽  
Prognostic Significance ◽  
Maintenance Chemotherapy ◽  
Childhood All ◽  
Second Year ◽  
Minimal Residual

Purpose: A high level of minimal residual disease (MRD) after induction chemotherapy in children with acute lymphoblastic leukemia (ALL) is an indicator of relative chemotherapy resistance and a risk factor for relapse. However, the significance of MRD in the second year of therapy is unclear. Moreover, it is unknown whether treatment intervention can alter outcome in patients with detectable MRD. Patients and Methods: We assessed the prognostic value of MRD testing in bone marrow samples from 85 children at 1, 12, and 24 months from diagnosis using clone-specific polymerase chain reaction primers designed to detect clonal antigen receptor gene rearrangements. These children were part of a multicenter, randomized clinical trial, which, in the second year of treatment, compared a 2-month reinduction-reintensification followed by maintenance chemotherapy with standard maintenance chemotherapy alone. Results: MRD was detected in 69% of patients at 1 month, 25% at 12 months, and 28% at 24 months from diagnosis. By univariate analysis, high levels of MRD at 1 month, or the presence of any detectable MRD at 12 or 24 months from diagnosis, were highly predictive of relapse. Multivariate analysis showed that MRD testing at 1 and 24 months each had independent prognostic significance. Intensified therapy at 12 months from diagnosis did not improve prognosis in those patients who were MRD positive at 12 months from diagnosis. Conclusion: Clinical outcome in childhood ALL can be predicted with high accuracy by combining the results of MRD testing at 1 and 24 months from diagnosis.

Sequence analysis of clonal immunoglobulin and T-cell receptor gene rearrangements in children with acute lymphoblastic leukemia at diagnosis and at relapse: implications for pathogenesis and for the clinical utility of PCR-based methods of minimal residual disease detection

Blood ◽  
2003 ◽  
Vol 102 (13) ◽  
pp. 4520-4526 ◽  
Author(s):  
Aihong Li ◽  
Jianbiao Zhou ◽  
David Zuckerman ◽  
Montse Rue ◽  
Virginia Dalton ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Minimal Residual Disease ◽  
T Cell Receptor ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Cell Receptor ◽  
Gene Rearrangements ◽  
Childhood All ◽  
Minimal Residual

AbstractImmunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangements provide clonal markers useful for diagnosis and measurement of minimal residual disease (MRD) in acute lymphoblastic leukemia (ALL). We analyzed the sequences of Ig and TCR gene rearrangements obtained at presentation and relapse in 41 children with ALL to study clonal stability, which has important implications for monitoring MRD, during the course of the disease. In 42%, all original Ig and/or TCR sequences were conserved. In 24%, one original sequence was preserved but the other lost, and in 14% the original sequences were conserved with new sequences identified at relapse. In 20% only new sequences were found at relapse. Using primers designed from the novel relapse sequences, the relapse clone could be identified as subdominant clones in the diagnostic sample in 8 of 14 patients. Alteration of these clonal gene rearrangements is a common feature in childhood ALL. MRD detection should include multiple gene targets to minimize false-negative samples or include also multicolor flow cytometry. In some cases the leukemic progenitor cell might arise earlier in lineage before DHJH recombination but retain the capacity to further differentiate into cells capable of altering the pattern of Ig and/or TCR rearrangements. (Blood. 2003;102:4520-4526)

Integrated Use of Minimal Residual Disease Classification and IKZF1 Alteration Status Accurately Predicts 79% of Relapses In Pediatric Acute Lymphoblastic Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 272-272 ◽  
Author(s):  
Esmé Waanders ◽  
Vincent H.J. van der elden ◽  
Ellen van der Schoot ◽  
Frank N. van Leeuwen ◽  
Simon V. van Reijmersdal ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Risk Stratification ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Risk Group ◽  
Lymphoblastic Leukemia ◽  
Wild Type ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Minimal Residual

Abstract Abstract 272 The response to therapy as determined by minimal residual disease (MRD) is currently used for stratification in treatment protocols for pediatric acute lymphoblastic leukemia (ALL). Even though MRD classification clearly identifies patients at low or at high risk for relapse, it also results in a large intermediate group (50 to 60% of patients), which still contains approximately half of all relapse cases. To improve risk stratification, we evaluated the added value of the IKZF1 alteration status, recently identified as a prognostic factor, in precursor-B-ALL patients. In an unbiased cohort of 131 uniformly treated precursor-B-ALL patients, we determined MRD levels at 42 and 84 days after treatment initiation using RQ-PCR analysis of Ig/TCR rearrangements. Based on these levels, patients were divided into three groups: MRD-Low (MRD-L), MRD-Medium (MRD-M) and MRD-High (MRD-H). IKZF1 alterations at diagnosis were determined using multiplex ligation-dependent probe amplification and genomic sequencing. We confirmed the strong prognostic significance of MRD classification, which was independent of IKZF1 status. Importantly, in the large MRD-M group (n=81; 62% of patients) containing 46% of the relapsed patients, IKZF1 alteration status identified 8 out of 11 relapsed patients (72%). The 9 year relapse-free survival (RFS) for IKZF1 mutated patients in this MRD-M group was 27% compared to 96% for patients wild-type for IKZF1 (P<0.001). Based on these results, we defined a new parameter integrating both MRD and IKZF1 status. The favorable risk group included patients classified as MRD-L or MRD-M with IKZF1 wild-type (n=104; 5 relapses), whereas the high risk group consisted of MRD-H patients or MRD-M patients with IKZF1 alterations (n=27; 19 relapses). This parameter showed stronger prognostic value than each of the established risk factors alone (Hazard Ratio[95%CI]: 24.98[8.29-75.31]). Importantly, whereas MRD and IKZF1 status alone identified only 46% and 54% of relapses, respectively, their integrated use allowed prediction of 79% of all relapses with 93% specificity. In conclusion: The use of a new parameter integrating MRD and IKZF1 status results in an unprecedented sensitivity in upfront relapse prediction and has a high potential for future risk stratification, particularly for patients originally classified as non-high-risk, such as the large group of MRD-M patients. Disclosures: No relevant conflicts of interest to declare.

scholarly journals New markers for minimal residual disease detection in acute lymphoblastic leukemia

Blood ◽  
2011 ◽  
Vol 117 (23) ◽  
pp. 6267-6276 ◽  
Author(s):  
Elaine Coustan-Smith ◽  
Guangchun Song ◽  
Christopher Clark ◽  
Laura Key ◽  
Peixin Liu ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Acute Lymphoblastic Leukemia ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Differentially Expressed ◽  
Molecular Testing ◽  
Childhood All ◽  
B Lineage ◽  
Minimal Residual

Abstract To identify new markers for minimal residual disease (MRD) detection in acute lymphoblastic leukemia (ALL), we compared genome-wide gene expression of lymphoblasts from 270 patients with newly diagnosed childhood ALL to that of normal CD19+CD10+ B-cell progenitors (n = 4). Expression of 30 genes differentially expressed by ≥ 3-fold in at least 25% of cases of ALL (or 40% of ALL subtypes) was tested by flow cytometry in 200 B-lineage ALL and 61 nonleukemic BM samples, including samples containing hematogones. Of the 30 markers, 22 (CD44, BCL2, HSPB1, CD73, CD24, CD123, CD72, CD86, CD200, CD79b, CD164, CD304, CD97, CD102, CD99, CD300a, CD130, PBX1, CTNNA1, ITGB7, CD69, CD49f) were differentially expressed in up to 81.4% of ALL cases; expression of some markers was associated with the presence of genetic abnormalities. Results of MRD detection by flow cytometry with these markers correlated well with those of molecular testing (52 follow-up samples from 18 patients); sequential studies during treatment and diagnosis-relapse comparisons documented their stability. When incorporated in 6-marker combinations, the new markers afforded the detection of 1 leukemic cell among 105 BM cells. These new markers should allow MRD studies in all B-lineage ALL patients, and substantially improve their sensitivity.

scholarly journals Postinduction Minimal Residual Disease Monitoring by Polymerase Chain Reaction in Children With Acute Lymphoblastic Leukemia

2014 ◽  
Vol 32 (31) ◽  
pp. 3553-3558 ◽  
Author(s):  
Maddalena Paganin ◽  
Giulia Fabbri ◽  
Valentino Conter ◽  
Elena Barisone ◽  
Katia Polato ◽  
...  
Keyword(s):  
Polymerase Chain Reaction ◽  
Acute Lymphoblastic Leukemia ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Individual Risk ◽  
Chain Reaction ◽  
Childhood All ◽  
Polymerase Chain ◽  
Minimal Residual

Purpose Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer. Monitoring minimal residual disease (MRD) by using real-time quantitative polymerase chain reaction (RQ-PCR) provides information for patient stratification and individual risk-directed treatment. Cooperative studies have documented that measurement of blast clearance from the bone marrow during and after induction therapy identifies patient populations with different risk of relapse. We explored the possible contribution of measurements of MRD during the course of treatment. Patients and Methods We used RQ-PCR to detect MRD in 110 unselected patients treated in Italy in the International Collaborative Treatment Protocol for Children and Adolescents With Acute Lymphoblastic Leukemia (AIEOP-BFM ALL 2000). The trial took place in AIEOP centers during postinduction chemotherapy. Results were categorized as negative, low positive (below the quantitative range [< 5 × 10−4]), or high positive (≥ 5 × 10−4). Patients with at least one low-positive or high-positive result were assigned to the corresponding subgroup. Results Patients who tested high positive, low positive, or negative had significantly different cumulative incidences of leukemia relapse: 83.3%, 34.8%, and 8.6%, respectively (P < .001). Two thirds of positive cases were identified within 4 months after induction-consolidation therapy, suggesting that this time frame may be most suitable for cost-effective MRD monitoring, particularly in patients who did not clear their disease at the end of consolidation. Conclusion These findings provide further insights into the dynamic of MRD and the ongoing effort to define molecular relapse in childhood ALL.

scholarly journals Clinical significance of low levels of minimal residual disease at the end of remission induction therapy in childhood acute lymphoblastic leukemia

Blood ◽  
2010 ◽  
Vol 115 (23) ◽  
pp. 4657-4663 ◽  
Author(s):  
Patricia Stow ◽  
Laura Key ◽  
Xiaohua Chen ◽  
Qiulu Pan ◽  
Geoffrey A. Neale ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Minimal Residual Disease ◽  
Clinical Significance ◽  
Induction Therapy ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Remission Induction ◽  
Childhood All ◽  
Low Levels ◽  
Minimal Residual

Abstract Minimal residual disease (MRD) at the end of remission-induction therapy predicts relapse in acute lymphoblastic leukemia (ALL). We examined the clinical significance of levels below the usual threshold value for MRD positivity (0.01%) in 455 children with B-lineage ALL, using polymerase chain reaction amplification of antigen-receptor genes capable of detecting at least 1 leukemic cell per 100 000 normal mononucleated cells (0.001%). Of the 455 clinical samples studied on day 46 of therapy, 139 (30.5%) had MRD 0.001% or more with 63 of these (45.3%) showing levels of 0.001% to less than 0.01%, whereas 316 (69.5%) had levels that were either less than 0.001% or undetectable. MRD measurements of 0.001% to less than 0.01% were not significantly related to presenting characteristics but were associated with a poorer leukemia cell clearance on day 19 of remission induction therapy. Patients with this low level of MRD had a 12.7% (± 5.1%; SE) cumulative risk of relapse at 5 years, compared with 5.0% (± 1.5%) for those with lower or undetectable MRD (P < .047). Thus, low levels of MRD (0.001%-< 0.01%) at the end of remission induction therapy have prognostic significance in childhood ALL, suggesting that patients with this finding should be monitored closely for adverse events.

Sign in / Sign up

Export Citation Format

Share Document