Detection of minimal residual disease identifies differences in treatment response between T-ALL and precursor B-ALL

Abstract

We performed sensitive polymerase chain reaction-based minimal residual disease (MRD) analyses on bone marrow samples at 9 follow-up time points in 71 children with T-lineage acute lymphoblastic leukemia (T-ALL) and compared the results with the precursor B-lineage ALL (B-ALL) results (n ‫؍‬ 210) of our previous study. At the first 5 follow-up time points, the frequency of MRD-positive patients and the MRD levels were higher in T-ALL than in precursor-B-ALL, reflecting the more frequent occurrence of resistant disease in T-ALL. Subsequently, patients were classified according to their MRD level at time point 1 (TP1), taken at the end of induction treatment (5 weeks), and at TP2 just before the start of consolidation treatment (3 months). Patients were considered at low risk if TP1 and TP2 were MRD negative and at high risk if MRD levels at TP1 and TP2 were 10 ؊3 or higher; remaining patients were considered at intermediate risk. The relative distribution of patients with T-ALL (n ‫؍‬ 43) over the MRDbased risk groups differed significantly from that of precursor B-ALL (n ‫؍‬ 109). Twenty-three percent of patients with T-ALL and 46% of patients with precursor B-ALL were classified in the low-risk group (P ‫؍‬ .01) and had a 5-year relapsefree survival (RFS) rate of 98% or greater.In contrast, 28% of patients with T-ALL were classified in the MRD-based highrisk group compared to only 11% of patients with precursor B-ALL (P ‫؍‬ .02), and the RFS rates were 0% and 25%, respectively (P ‫؍‬ .03). Not only was the distribution of patients with T-ALL different over the MRD-based risk groups, the prognostic value of MRD levels at TP1 and TP2 was higher in T-ALL (larger RFS gradient), and consistently higher RFS rates were found for MRD-negative T-ALL patients at the first 5 follow-up time points. IntroductionChildhood acute lymphoblastic leukemia (ALL) has a B-lineage origin in approximately 85% of patients and a T-lineage origin in the remaining approximately 15% of patients. 1 Typical T-lineage ALL (T-ALL) is diagnosed in male adolescents and is frequently characterized by hyperleukocytosis, mediastinal mass, and central nervous system involvement. 2,3 Children with T-ALL generally have a poorer prognosis than those with precursor B-lineage ALL (B-ALL). 1,4 In T-ALL, the following characteristics were shown to have a negative effect on treatment outcome: patient age 15 years or older, L2 blast morphology, karyotype other than hyperdiploidy, and CD3 ϩ . 2,3 The most immature T-ALLs (CD1 Ϫ / CD3 Ϫ ) are also associated with unfavorable outcome, whereas CD1 ϩ T-ALL forms a distinct subgroup with an excellent prognosis on intensive high-risk treatment. [4][5][6][7] Early in vivo response has been identified as one of the strongest prognostic factors in childhood ALL. [8][9][10][11][12] Patients with T-ALL frequently have a poor in vivo steroid response 9,12,13 and are resistant to many drugs, as demonstrated by in vitro assays. 14 Nevertheless, treatment outcome has significantly improved, and the sustained relapse-free s...

Minimal residual disease (MRD) analysis in the non-MRD-based ALL IC-BFM 2002 protocol for childhood ALL: is it possible to avoid MRD testing?

“…BCP-ALL patients showed a better response at d15 and d33, while the difference between the two groups was no longer distinct at w12. This finding is in agreement with a previous study comparing BCP-ALL and T-ALL patients treated according to the ALL-BFM 90 protocol 25 and implies the potential benefit available to T-ALL patients from treatment modalities used later in the treatment. As most of the T-ALL patients were positive at d33 and negative at w12, another time point in between the two might be beneficial for risk stratification of T-ALL patients in BFM-based protocols.…”

Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: Report of the BIOMED-2 Concerted Action BMH4-CT98-3936

“…195,196 Labeling of J primers is not regarded to be informative for IGH (VH-JH or DH-JH), IGK (Vk-Jk), or IGL (Vl-Jl). For rapid identification of IGK-Kde rearrangements, it might be interesting to discriminate between Vk-Kde and intronRSS-Kde rearrangements by differential labeling of the Kde and intronRSS primers (see Figure 6b).…”

“…MRD techniques should preferably reach at least sensitivities of 10 À4 (one malignant cell in 10 4 normal cells). Such MRD information appears to have high prognostic value, particularly in ALL, for example, during and after induction therapy [196][197][198][199][200] and before stem cell transplantation. [201][202][203] In lymphoid malignancies, sensitive and quantitative detection of MRD can be achieved by real-time quantitative PCR analysis of patient-specific junctional regions of rearranged Ig/TCR genes.…”

Optimization of PCR-based minimal residual disease diagnostics for childhood acute lymphoblastic leukemia in a multi-center setting

“…Within the International BFM Study Group (I-BFM-SG), patients were classified according to MRD levels at day 33 and day 78 of therapy, and three risk groups could be distinguished: low-risk patients (LR), having MRD negativity at both time points (about 45% of patients; 5-year relapse rate of 2%); patients at high-risk (HR), having high (X10 À3 ) MRD levels at both time points (about 15% of patients; 5-year relapse rate of 80%); and the remaining patients at intermediate risk (IR; 5-year relapse rate of 22%). 3,9 Of note, for recognition of LR patients, the MRD assay had to reach a sensitivity of at least 10 À4 . 3,9 On the basis of these results, MRD diagnostics for treatment stratification is currently applied in many childhood ALL treatment protocols, including the ongoing AIEOP/BFM ALL-2000 and DCOG-ALL10 protocols.…”