When Less Is Good, Is None Better? The Prognostic and Therapeutic Significance of Peri-Transplant Minimal Residual Disease Assessment in Pediatric Acute Lymphoblastic Leukemia
Abstract
:1. Introduction
2. MRD Assays in Pediatric ALL
2.1. Multicolor Flow Cytometry
2.2. Molecular/Allele-Specific Oligonucleotide PCR-Based
2.3. High Throughput Sequencing PCR
3. Prognostic Significance of MRD
3.1. Pre-HSCT MRD
3.2. Post-HSCT MRD
4. Therapeutic Implications Based on Peri-HSCT MRD
4.1. Pre-HSCT MRD to Minimize Therapy
4.2. Approaches to Eliminate Pre- and Post-HSCT MRD
4.3. Immune Suppression Modulation
4.4. Donor Leukocyte Infusion
5. Conclusions
Acknowledgments
Author Contributions
Conflict of Interest
References
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Modality | Target | Sensitivity | Turnaround | Standardization | Diagnostic Sample | Patient-Specific Assays |
---|---|---|---|---|---|---|
MFC | Aberrant immunophenotype | 10−4 | Fast | Non-standardized (unless on study) | No | No |
ASO-PCR | Ig/TCR variable junctional region | 10−4–10−5 | Slow | Standardized | Yes | Yes |
HTS-PCR | Ig/TCR V-D-J gene | 10−6 | Medium | Non-standardized | Ideally | No |
Author | Year | Study Type | Technique | Sensitivity | N | Age, Years, Median (Range) | Remission | Results |
---|---|---|---|---|---|---|---|---|
Knechtli [32] | 1998 | R | PCR | <10−3–10−5 | 64 | <18 | CR1, CR2 | 2-year EFS 73% MRD− vs. 0% MRD+ p < 0.001 |
Van der Velden [33] | 2001 | R | PCR | <10−4 | 17 | <15 | CR1, CR2 | 5-year RFS 80% MRD− vs. 33% MRD+ |
Sanchez [34] | 2002 | P | MCF | <10−4 | 24 | 18 (3–49) | ≥CR1 | 2-year RFS 73% MRD− vs. 33% MRD+ p = 0.03 |
Bader [35] | 2002 | R | PCR | <10−4 | 41 | 9.8 (1.5–17.8) | ≥CR1 | 5-year EFS 78% MRD− vs. 32% MRD+ p = 0.011 |
Krejci [36] | 2003 | R | PCR | <10−4 | 140 | <19 | ≥CR1 | 5-year EFS 75.2% MRD− vs. 29.8% MRD+ |
Imashuku [37] | 2003 | P | PCR | <10−4 | 95 | 9 (0.3–20) | Not remission, ≥CR1 | Available data in 19 relapses, all 19 were MRD+ |
Goulden [38] | 2003 | R | PCR | <10−4 | 64 | Pediatric | ≥CR1 | 3-year EFS 73% MRD− vs. 17% MRD+ p < 0.001 |
Sramkova [39] | 2007 | P | PCR | <10−4 | 25 | 1.1–19 | Partial remission, CR1, CR2 | EFS 94% MRD− vs. 13% MRD+ p < 0.001 |
Paganin [40] | 2008 | P | PCR | <10−4 | 60 | 5 (0.6–17) | CR2 | 3-year EFS 73% MRD− vs. 19% MRD+ p < 0.05 |
Bader [41] | 2009 | P | PCR | 10−4 | 91 | 11.1 (3–22.6) | CR2, CR3 | 3-year EFS 60% MRD− vs. 27% MRD+ |
Elorza [42] | 2010 | P | MCF | 10−4 | 31 | 7 (<1–16) | ≥CR1 | 2-year EFS 74% MRD− vs. 20% MRD+ |
Leung [43] | 2012 | R | MFC | 10−4 | 64 | 11.3 (0.6–25.1) | ≥CR1 | 5-year OS 87.5% MRD− vs. 48.5% MRD+ |
Ruggeri [44] | 2012 | R | PCR/MFC | 10−3−5 | 170 | 6.5 (<1–17) | CR1,CR2, CR3 | 4-year CIR 24% MRD− vs. 39% MRD+ |
Bachanova [45] | 2012 | P | MFC | 10−3 | 86 | 20 (6–63) | CR1, CR2, CR3 | 2-year RR 26% MRD− vs. 30% MRD+ |
Shah [46] | 2014 | R | MFC | 10−4 | 34 | <21 | CR2 | RR 35% MRD− vs. 64% MRD+ |
Balduzzi [47] | 2014 | P | PCR | 10−4 | 82 | 8 (<1–20) | CR1, CR2, CR3 | 5-year EFS 77.7% MRD− vs. 30.8% MRD+ p < 0.001 |
Bar [48] | 2014 | R | MCF | 10−3–10−4 | 153 (62 ped) | 24.6 (0.6–61.8) | ≥CR1 | 3-year EOR 17% MRD− vs. 38% MRD+ |
Pulsipher [49] | 2015 | R | HTS-PCR | 10−6 | 41 | 1–21 | CR1, CR2 | 2-year RR 0% MRD− vs. 53% MRD+ |
Sutton [50] | 2015 | P | PCR | 10−4 | 69 | Pediatric | CR1, CR2, CR3 | LFS 83% MRD− vs. 41% MRD+ |
Eckert [51] | 2015 | P | PCR | 10−3 | 71 | Pediatric | CR1 | DFS 58% MRD− vs. 26% MRD+ |
Author | Year | Study Type | Technique | Sensitivity | N | Age, Years, Median (Range) | Remission | Results |
---|---|---|---|---|---|---|---|---|
Sanchez [34] | 2002 | P | MCF | <10−4 | 40 | 18 (3–49) | ≥CR1 | RR3% MRD− vs. 88% MRD+ |
Imashuku [37] | 2003 | P | PCR | <10−4 | 95 | 9 (0.3–20) | Active disease, ≥CR1 | RR 26% MRD− vs. 27% MRD+ (p = 1) |
Zhao [52] | 2012 | P | MFC | <10−4 | 139 (35 ped) | 24 (4–55) | ≥CR1 | EFS 80% MRD− vs. 54% MRD+ (p = 0.001) |
Balduzzi [47] | 2014 | P | PCR | 10−4 | 82 | 8 (<1–20) | CR1, CR2, CR3 | 5-yr EFS 40.3% MRD+ |
Bar [48] | 2014 | R | MCF | 10−3–10−4 | 144 | 24.6 (0.6–61.8) | ≥CR1 | HR 7.47 risk of relapse if MRD+ |
Bader [53] | 2015 | P | PCR | 10−4 | 113 | Pediatric | No remission and ≥CR2 | MRD inversely correlated with EFS at all time points (p = 0.004) |
Pulsipher [49] | 2015 | R | HTS | 10−6 | 53 | 1–21 | CR1, CR2 | RR 13% MRD− vs. 73% MRD+ |
Sutton [50] | 2015 | P | PCR | 10−4 | 47 | Pediatric | CR1, CR2, CR3 | LFS 67% MRD− vs. 36% MRD+ |
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Lamble, A.; Phelan, R.; Burke, M. When Less Is Good, Is None Better? The Prognostic and Therapeutic Significance of Peri-Transplant Minimal Residual Disease Assessment in Pediatric Acute Lymphoblastic Leukemia. J. Clin. Med. 2017, 6, 66. https://doi.org/10.3390/jcm6070066
Lamble A, Phelan R, Burke M. When Less Is Good, Is None Better? The Prognostic and Therapeutic Significance of Peri-Transplant Minimal Residual Disease Assessment in Pediatric Acute Lymphoblastic Leukemia. Journal of Clinical Medicine. 2017; 6(7):66. https://doi.org/10.3390/jcm6070066
Chicago/Turabian StyleLamble, Adam, Rachel Phelan, and Michael Burke. 2017. "When Less Is Good, Is None Better? The Prognostic and Therapeutic Significance of Peri-Transplant Minimal Residual Disease Assessment in Pediatric Acute Lymphoblastic Leukemia" Journal of Clinical Medicine 6, no. 7: 66. https://doi.org/10.3390/jcm6070066