Clinical importance of minimal residual disease in childhood acute lymphoblastic leukemia

Blood ◽  
2000 ◽  
Vol 96 (8) ◽  
pp. 2691-2696 ◽  
Author(s):  
Elaine Coustan-Smith ◽  
Jose Sancho ◽  
Michael L. Hancock ◽  
James M. Boyett ◽  
Frederick G. Behm ◽  
...  

By using rapid flow cytometric techniques capable of detecting one leukemic cell in 104 normal cells, we prospectively studied minimal residual disease (MRD) in 195 children with newly diagnosed acute lymphoblastic leukemia (ALL) in clinical remission. Bone marrow aspirates (n = 629) were collected at the end of remission induction therapy and at 3 intervals thereafter. Detectable MRD (ie, ≥0.01% leukemic mononuclear cells) at each time point was associated with a higher relapse rate (P < .001); patients with high levels of MRD at the end of the induction phase (≥1%) or at week 14 of continuation therapy (≥0.1%) had a particularly poor outcome. The predictive strength of MRD remained significant even after adjusting for adverse presenting features, excluding patients at very high or very low risk of relapse from the analysis, and considering levels of peripheral blood lymphoblasts at day 7 and day 10 of induction therapy. The incidence of relapse among patients with MRD at the end of the induction phase was 68% ± 16% (SE) if they remained with MRD through week 14 of continuation therapy, compared with 7% ± 7% if MRD became undetectable (P = .035). The persistence of MRD until week 32 was highly predictive of relapse (all 4 MRD+patients relapsed vs 2 of the 8 who converted to undetectable MRD status; P = .021). Sequential monitoring of MRD by the method described here provides highly significant, independent prognostic information in children with ALL. Recent improvements in this flow cytometric assay have made it applicable to more than 90% of all new patients.

Blood ◽  
2000 ◽  
Vol 96 (8) ◽  
pp. 2691-2696 ◽  
Author(s):  
Elaine Coustan-Smith ◽  
Jose Sancho ◽  
Michael L. Hancock ◽  
James M. Boyett ◽  
Frederick G. Behm ◽  
...  

Abstract By using rapid flow cytometric techniques capable of detecting one leukemic cell in 104 normal cells, we prospectively studied minimal residual disease (MRD) in 195 children with newly diagnosed acute lymphoblastic leukemia (ALL) in clinical remission. Bone marrow aspirates (n = 629) were collected at the end of remission induction therapy and at 3 intervals thereafter. Detectable MRD (ie, ≥0.01% leukemic mononuclear cells) at each time point was associated with a higher relapse rate (P &lt; .001); patients with high levels of MRD at the end of the induction phase (≥1%) or at week 14 of continuation therapy (≥0.1%) had a particularly poor outcome. The predictive strength of MRD remained significant even after adjusting for adverse presenting features, excluding patients at very high or very low risk of relapse from the analysis, and considering levels of peripheral blood lymphoblasts at day 7 and day 10 of induction therapy. The incidence of relapse among patients with MRD at the end of the induction phase was 68% ± 16% (SE) if they remained with MRD through week 14 of continuation therapy, compared with 7% ± 7% if MRD became undetectable (P = .035). The persistence of MRD until week 32 was highly predictive of relapse (all 4 MRD+patients relapsed vs 2 of the 8 who converted to undetectable MRD status; P = .021). Sequential monitoring of MRD by the method described here provides highly significant, independent prognostic information in children with ALL. Recent improvements in this flow cytometric assay have made it applicable to more than 90% of all new patients.


Blood ◽  
2010 ◽  
Vol 115 (23) ◽  
pp. 4657-4663 ◽  
Author(s):  
Patricia Stow ◽  
Laura Key ◽  
Xiaohua Chen ◽  
Qiulu Pan ◽  
Geoffrey A. Neale ◽  
...  

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.


2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 9554-9554
Author(s):  
Eloy Perez ◽  
Primo Cruz-Borja ◽  
Silvia Chavez-Gallegos

9554 Background: The presence of minimal residual disease (MDR) following therapy for acute lymphoblastic leukemia (ALL) has been shown to be an important prognostic marker in many studies. MRD is typically detected either by polymerase chain reaction amplification or by flow cytometry. Flow-based MRD assessment has the potential for rapidly identifying patients at increased risk of relapsed, allowing for prompt changes in therapy, including earlier intensification. There are not many information about the response by MRD in countries with limited resources. Methods: The patients included were 90 ALL patients treated at the Hospital Infantil de Morelia from June 1, 2009 to January 5, 2012. MRD positivity (+) was defined as >0.01% of the gated population. Results: MRD was obtained in 90 patients, 38 males and 36 females. The median age was 7 years (10 months to 15 years). The levels of MRD were: <0.01, 74 (82.2%), 0.01-1%, 9 (10%), ≥1%, 7 (7.7%). There was not a statistically significant association between the most important ALL prognostic factors (Gender, Age at diagnosis, White blood cell count at diagnosis, Central Nervous System disease, Prednisone response, DNA Index, Immunophenotype). Conclusions: The good response found is similar to that reported by international groups, a situation which suggests that the response to chemotherapy is appropriate. However, cure rates are still not equal making it necessary to review institutional treatment protocols and social characteristics of the population to achieve cure rates reported by international groups.


2014 ◽  
Vol 32 (27) ◽  
pp. 3012-3020 ◽  
Author(s):  
Kathryn G. Roberts ◽  
Deqing Pei ◽  
Dario Campana ◽  
Debbie Payne-Turner ◽  
Yongjin Li ◽  
...  

Purpose BCR-ABL1–like acute lymphoblastic leukemia (ALL) is a recently identified B-cell ALL (B-ALL) subtype with poor outcome that exhibits a gene expression profile similar to BCR-ABL1-positive ALL but lacks the BCR-ABL1 fusion protein. We examined the outcome of children with BCR-ABL1–like ALL treated with risk-directed therapy based on minimal residual disease (MRD) levels during remission induction. Patients and Methods Among 422 patients with B-ALL enrolled onto the Total Therapy XV study between 2000 and 2007, 344 had adequate samples for gene expression profiling. Next-generation sequencing and/or analysis of genes known to be altered in B-ALL were performed in patients with BCR-ABL1–like ALL who had available material. Outcome was compared between patients with and those without BCR-ABL1–like ALL. Results Forty (11.6%) of the 344 patients had BCR-ABL1–like ALL. They were significantly more likely to be male, have Down syndrome, and have higher MRD levels on day 19 and at the end of induction than did other patients with B-ALL. Among 25 patients comprehensively studied for genetic abnormalities, 11 harbored a genomic rearrangement of CRLF2, six had fusion transcripts responsive to ABL tyrosine kinase inhibitors or JAK inhibitors, and seven had mutations involving the Ras signaling pathway. There were no significant differences in event-free survival (90.0% ± 4.7% [SE] v 88.4% ± 1.9% at 5 years; P = .41) or in overall survival (92.5% ± 4.2% v 95.1% ± 1.3% at 5 years; P = .41) between patients with and without BCR-ABL1–like ALL. Conclusion Patients who have BCR-ABL1–like ALL with poor initial treatment response can be salvaged with MRD-based risk-directed therapy and may benefit from identification of kinase-activating lesions for targeted therapies.


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