Prognostic significance of minimal residual disease in infants with acute lymphoblastic leukemia treated within the Interfant-99 protocol

Abstract

Acute lymphoblastic leukemia (ALL) in infants younger than 1 year is a rare but relatively homogeneous disease ( approximately 80% MLL gene rearranged, approximately 70% CD10-negative) when compared with childhood and adult ALL. Several studies in children and adults with ALL have shown that minimal residual disease (MRD) status is a strong and independent prognostic factor. We therefore evaluated the prognostic significance of MRD in infant ALL. Ninety-nine infant patients treated according to the Interfant-99 protocol were included in this study. MRD was analyzed by real-time quantitative PCR analysis of rearranged immunoglobulin genes, T-cell receptor genes and MLL genes at various time points (TP) during therapy. Higher MRD levels at the end of induction (TP2) and consolidation (TP3) were significantly associated with lower disease-free survival. Combined MRD information at TP2 and TP3 allowed recognition of three patients groups that significantly differed in outcome. All MRD-high-risk patients (MRD levels > or =10(-4) at TP3; 26% of patients) relapsed. MRD-low-risk patients (MRD level <10(-4) at both TP2 and TP3) constituted 44% of patients and showed a relapse-rate of only 13%, whereas remaining patients (MRD-medium-risk patients; 30% of patients) had a relapse rate of 31%. Comparison between the current Interfant-06 stratification at diagnosis and the here presented MRD-based stratification showed that both stratifications recognized different subgroups of patients. These data indicate that MRD diagnostics has added value for recognition of risk groups in infant ALL and that MRD diagnostics can be used for treatment intervention in infant ALL as well.

Standardized MRD quantification in European ALL trials: Proceedings of the Second International Symposium on MRD assessment in Kiel, Germany, 18–20 September 2008

“…In addition, genomic break points of some leukemiaspecific translocations, such as MLL gene rearrangements or SIL-TAL1 fusion genes, represent alternative DNA targets; however, they are applicable only to a minority of patients. 41,42 Clone-specific Ig/TCR PCR generally reaches sensitivities of 10 À4 -10 À5 . These high sensitivities require the precise identification of junctional region sequences of Ig and TCR genes in each ALL, because these sequences are required to design clone-specific oligonucleotides.…”

High frequency of IKZF1 deletions in Chinese adult patients with acute lymphoblastic leukemia detected by multiplex real-time quantitative PCR

“…Two DNA MRD markers with high sensitivity (at least 10 -4 ) are generally required in MRD intervention clinical trials [29][30], and in a large cohort of 2854 pediatric precursor B-cell ALL patients, 20% of patients had only one sensitive marker and 8% had none [30]. At present the concept of using disease-related markers for MRD testing has been already established for fusion transcripts such as BCR-ABL and for gene rearrangements such as for SIL-TAL1 in T-ALL and for MLL rearrangements in infant ALLs [31]. The use of oncogenic lesions for MRD monitoring has been limited by the fact that recurrent chromosomal translocations are not found in all ALL and are usually studied at the RNA level, so that IKZF1 gene deletions will provide a useful addition to the repertoire of MRD markers currently available for monitoring MRD in ALL and inclusion of this marker in standard screening for MRD targets would be an easy way to provide more patients with two sensitive markers.…”

Flow cytometric detection of minimal residual disease in B-lineage acute lymphoblastic leukemia by using “MRD lite” panel

“…Prospective studies in large series of patients have demonstrated a strong correlation between MRD levels during clinical remission and treatment outcome. 10,11 For MRD studies, leukemia-associated immunophenotypes (LAIP)…”

“…Prospective studies in large series of patients have demonstrated a strong correlation between MRD levels during clinical remission and treatment outcome. 10,11 For MRD studies, leukemia-associated immunophenotypes (LAIP) Methods: Fifteen cases of B-ALL were studied for MRD at Day 19 of remission-induction therapy by employing a simplified MRD detection protocol using a 3-color fluorochrome conjugated antibody panel (CD19, CD10, and CD34) on bone marrow aspirate samples.…”