Table 4.
MRDpos-based results (risk stratification, risk-oriented therapy and clinical outcome) in AYA and adult Ph− ALL trials.
| Trial/Study (Ref.) | Patient Age (Years), Median (Range) | MRD Analysis | Favorable MRD Response | Comparative Outcomes: Favorable MRD Cut-Offs Vs. Not |
||
|---|---|---|---|---|---|---|
| Evaluable/CR, No. (%) | Method 1 | Cut-Off 2 | No. (%) | |||
| AYA only (maximum age 40 years) | ||||||
| MRC-UKALL2003 [11] | NR (16–24) | 223/229 (97) | Mol | Negative/<0.01% d29, negative at EOC | 54 (24) | 5-y EFS 93% vs. 63–71% (p = 0.0001) 3 |
| PETHEMA ALL08 [35] | 20 (15–30) | 61/68 (90) | MFC | <0.1% w5–6, <0.05% w19–20 |
48 (77) | NR |
| GIMEMA LAL1308 [39] | NR (18–35) | 64/68 (94)/ 66/68 (97) 49/68 (72)/ 50/68 (73) |
MFC Mol |
<0.1% d33/78 | 37 (58)/54 (82) 28 (57)/38 (76) |
4-y OS by d33 MRD 67–75% vs. 27–41% (p = 0.002) 4 4-y RFS by d33 MRD 67–73% vs. 27–43% (p ≤ 0.025) 4 4-y OS by d78 MRD 74–77% vs. 31–39% (p ≤ 0.01) 4 4-y RFS by d78 MRD 71–72% vs. 26–34% (p ≤ 0.01) 4 |
| MDACC (aBFM/HyperCVAD) * [36] | 22 (13–39) | 93/199 (47) | MFC | <0.01% d29/d84 | 58 (62) | 5-y OS by d29 MRD 75% vs. 40% (p = 0.004) 5-y OS by d84 MRD 75% vs. 22% (p = 0.0004) |
| CALGB 10,403 [37] | 24 (17–39) | 80/237 (34) | Mol | Negative at EOI | 35 (44) | 3-y RFS 85% vs. 54% (p = 0.0006) |
| AYA and adults (maximum age > 40 years) | ||||||
| NOPHO 2008 [14] | 26 (18–45) | NR/218 | Mol | <0.1% d29/d79 | (56–64) 5 | NR |
| GRAALL 2003–2005 [26] | 31 (15–59) | 423/860 (49) | Mol | Negative/<0.01% w6 | 265 (63) | 5-y CIR 23–31% vs. 60% (p ≤ 0.01) |
| GMALL 07/03 [74] | 34 (16–65) | 1057/1857 (57) | Mol | Negative w16 | 625 (59) | 5-y OS 83% vs. 43–68% (p < 0.0001) 6 |
| MDACC [75] | 37 (15–86) | 215/394 (55) | MFC | <0.01% d24/d108 | 147 (68)/194 (90) | 3-y OS by d24 MRD 76% vs. 49–61% (p = 0.001) 7 3-y EFS by d24 MRD 65% vs.16–46% (p < 0.001) 7 |
| PETHEMA ALL-HR11 [49] | 40 (15–60) | 286/289 (99) | MFC | <0.1% w5–6 | 220 (82) | 5-y OS 59% vs. 38% (p < 0.001) |
| NILG 10/07 [51] | 41 (18–65) | 109/140 (78) | Mol | <0.01% w10–16/negative w22 | 68 (62) | 5-y OS 78% vs. 34% (p < 0.0001) 5-y RFS 66% vs. 29% (p < 0.0001) |
| HOVON-100 ** [41] | 42 (18–70) | 168/297 (56) | Mol/MFC | <0.01% after consolidation 1 | 126 (75) | NR |
Abbreviations: CALGB, Cancer and Leukemia Group B; GIMEMA, Gruppo Italiano Malattie Ematologiche dell’Adulto; GMALL, German Multicenter Study Group for Adult ALL; GRAALL, Group for Research on Adult Acute Lymphoblastic Leukemia; HOVON, Hemato-Oncology Foundation for Adults in the Netherlands; MDACC, M.D. Anderson Cancer Center; NILG, Northern Italy Leukemia Study Group; NOPHO, Nordic Society of Pediatric Hematology and Oncology; PETHEMA, Programa Español de Tratamientos en Hematología; RALL, Russian ALL Study Group; MRC-UKALL, Medical Research Council-United Kingdom ALL Study Group; EFS, event-free survival; OS, overall survival; RFS, relapse-free survival; CIR, cumulative incidence of relapse; NR, not reported (or not available); 1 Mol, molecular assays; MFC, multiparametric flow cytometry; 2 d, day; w, week; EOC, end of consolidation; EOI, end of induction; 3 observed ranges in MRD positive (>0.01% d29) or indeterminate (<0.01% at EOC); 4 observed ranges according to MRD timepoint by MFC or Mol method; 5 d29 MRD response rates according to ALL subset (BCP ALL < 100 WBC, B-ALL > 100 WBC, T-ALL); 6 observed range > vs. ≤ 10−4; 7 observed ranges according to d108 MRD status; * cumulative MRD-based results from both treatment regimens; ** update on all study patients (personal communication by Dr. A.J. Rjineveld, Rotterdam, The Netherlands).