Genotype-specific MRD interpretation improves stratification in paediatric acute lymphoblastic leukaemia
<strong>Purpose</strong> Minimal residual disease (MRD) and genetic abnormalities are important risk factors for outcome in acute lymphoblastic leukemia. Current risk algorithms dichotomize MRD data and do not assimilate genetics when assigning MRD risk, which reduces predictive accuracy...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Formato: | Journal article |
| Publicado em: |
American Society of Clinical Oncology
2017
|
| _version_ | 1826270953703735296 |
|---|---|
| author | O'Connor, D Enshaei, A Bartram, J Hancock, J Harrison, C Hough, R Samarasinghe, S Schwab, C Vora, A Wade, R Moppett, J Moorman, A Goulden, N |
| author_facet | O'Connor, D Enshaei, A Bartram, J Hancock, J Harrison, C Hough, R Samarasinghe, S Schwab, C Vora, A Wade, R Moppett, J Moorman, A Goulden, N |
| author_sort | O'Connor, D |
| collection | OXFORD |
| description | <strong>Purpose</strong> Minimal residual disease (MRD) and genetic abnormalities are important risk factors for outcome in acute lymphoblastic leukemia. Current risk algorithms dichotomize MRD data and do not assimilate genetics when assigning MRD risk, which reduces predictive accuracy. The aim of our study was to exploit the full power of MRD by examining it as a continuous variable and to integrate it with genetics. <strong>Patients and Methods</strong> We used a population-based cohort of 3,113 patients who were treated in UKALL2003, with a median follow-up of 7 years. MRD was evaluated by polymerase chain reaction analysis of Ig/TCR gene rearrangements, and patients were assigned to a genetic subtype on the basis of immunophenotype, cytogenetics, and fluorescence in situ hybridization. To examine response kinetics at the end of induction, we log-transformed the absolute MRD value and examined its distribution across subgroups. <strong>Results</strong> MRD was log normally distributed at the end of induction. MRD distributions of patients with distinct genetic subtypes were different (P < .001). Patients with good-risk cytogenetics demonstrated the fastest disease clearance, whereas patients with high-risk genetics and T-cell acute lymphoblastic leukemia responded more slowly. The risk of relapse was correlated with MRD kinetics, and each log reduction in disease level reduced the risk by 20% (hazard ratio, 0.80; 95% CI, 0.77 to 0.83; P < .001). Although the risk of relapse was directly proportional to the MRD level within each genetic risk group, absolute relapse rate that was associated with a specific MRD value or category varied significantly by genetic subtype. Integration of genetic subtype–specific MRD values allowed more refined risk group stratification. <strong>Conclusion</strong> A single threshold for assigning patients to an MRD risk group does not reflect the response kinetics of the different genetic subtypes. Future risk algorithms should integrate genetics with MRD to accurately identify patients with the lowest and highest risk of relapse. |
| first_indexed | 2024-03-06T21:48:59Z |
| format | Journal article |
| id | oxford-uuid:4a972813-f7b6-4f4f-8f55-5bc3c8c7dabd |
| institution | University of Oxford |
| last_indexed | 2024-03-06T21:48:59Z |
| publishDate | 2017 |
| publisher | American Society of Clinical Oncology |
| record_format | dspace |
| spelling | oxford-uuid:4a972813-f7b6-4f4f-8f55-5bc3c8c7dabd2022-03-26T15:38:26ZGenotype-specific MRD interpretation improves stratification in paediatric acute lymphoblastic leukaemiaJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:4a972813-f7b6-4f4f-8f55-5bc3c8c7dabdSymplectic Elements at OxfordAmerican Society of Clinical Oncology2017O'Connor, DEnshaei, ABartram, JHancock, JHarrison, CHough, RSamarasinghe, SSchwab, CVora, AWade, RMoppett, JMoorman, AGoulden, N<strong>Purpose</strong> Minimal residual disease (MRD) and genetic abnormalities are important risk factors for outcome in acute lymphoblastic leukemia. Current risk algorithms dichotomize MRD data and do not assimilate genetics when assigning MRD risk, which reduces predictive accuracy. The aim of our study was to exploit the full power of MRD by examining it as a continuous variable and to integrate it with genetics. <strong>Patients and Methods</strong> We used a population-based cohort of 3,113 patients who were treated in UKALL2003, with a median follow-up of 7 years. MRD was evaluated by polymerase chain reaction analysis of Ig/TCR gene rearrangements, and patients were assigned to a genetic subtype on the basis of immunophenotype, cytogenetics, and fluorescence in situ hybridization. To examine response kinetics at the end of induction, we log-transformed the absolute MRD value and examined its distribution across subgroups. <strong>Results</strong> MRD was log normally distributed at the end of induction. MRD distributions of patients with distinct genetic subtypes were different (P < .001). Patients with good-risk cytogenetics demonstrated the fastest disease clearance, whereas patients with high-risk genetics and T-cell acute lymphoblastic leukemia responded more slowly. The risk of relapse was correlated with MRD kinetics, and each log reduction in disease level reduced the risk by 20% (hazard ratio, 0.80; 95% CI, 0.77 to 0.83; P < .001). Although the risk of relapse was directly proportional to the MRD level within each genetic risk group, absolute relapse rate that was associated with a specific MRD value or category varied significantly by genetic subtype. Integration of genetic subtype–specific MRD values allowed more refined risk group stratification. <strong>Conclusion</strong> A single threshold for assigning patients to an MRD risk group does not reflect the response kinetics of the different genetic subtypes. Future risk algorithms should integrate genetics with MRD to accurately identify patients with the lowest and highest risk of relapse. |
| spellingShingle | O'Connor, D Enshaei, A Bartram, J Hancock, J Harrison, C Hough, R Samarasinghe, S Schwab, C Vora, A Wade, R Moppett, J Moorman, A Goulden, N Genotype-specific MRD interpretation improves stratification in paediatric acute lymphoblastic leukaemia |
| title | Genotype-specific MRD interpretation improves stratification in paediatric acute lymphoblastic leukaemia |
| title_full | Genotype-specific MRD interpretation improves stratification in paediatric acute lymphoblastic leukaemia |
| title_fullStr | Genotype-specific MRD interpretation improves stratification in paediatric acute lymphoblastic leukaemia |
| title_full_unstemmed | Genotype-specific MRD interpretation improves stratification in paediatric acute lymphoblastic leukaemia |
| title_short | Genotype-specific MRD interpretation improves stratification in paediatric acute lymphoblastic leukaemia |
| title_sort | genotype specific mrd interpretation improves stratification in paediatric acute lymphoblastic leukaemia |
| work_keys_str_mv | AT oconnord genotypespecificmrdinterpretationimprovesstratificationinpaediatricacutelymphoblasticleukaemia AT enshaeia genotypespecificmrdinterpretationimprovesstratificationinpaediatricacutelymphoblasticleukaemia AT bartramj genotypespecificmrdinterpretationimprovesstratificationinpaediatricacutelymphoblasticleukaemia AT hancockj genotypespecificmrdinterpretationimprovesstratificationinpaediatricacutelymphoblasticleukaemia AT harrisonc genotypespecificmrdinterpretationimprovesstratificationinpaediatricacutelymphoblasticleukaemia AT houghr genotypespecificmrdinterpretationimprovesstratificationinpaediatricacutelymphoblasticleukaemia AT samarasinghes genotypespecificmrdinterpretationimprovesstratificationinpaediatricacutelymphoblasticleukaemia AT schwabc genotypespecificmrdinterpretationimprovesstratificationinpaediatricacutelymphoblasticleukaemia AT voraa genotypespecificmrdinterpretationimprovesstratificationinpaediatricacutelymphoblasticleukaemia AT wader genotypespecificmrdinterpretationimprovesstratificationinpaediatricacutelymphoblasticleukaemia AT moppettj genotypespecificmrdinterpretationimprovesstratificationinpaediatricacutelymphoblasticleukaemia AT moormana genotypespecificmrdinterpretationimprovesstratificationinpaediatricacutelymphoblasticleukaemia AT gouldenn genotypespecificmrdinterpretationimprovesstratificationinpaediatricacutelymphoblasticleukaemia |