Studies reporting on MRD detection and monitoring in FL
| Study . | Advanced disease . | Patients . | Therapy . | Tissue . | Method . | Marker . | Tumor burden . | MRD− % . | Clinical impact . | Follow-up . |
|---|---|---|---|---|---|---|---|---|---|---|
| Rambaldi et al13 | BCL2/IGH + FL, untreated | 128 (79 received R) | CHOP × 6 4 weeks R in PCR + patients | BM ± PB | Nested PCR | Enrolled PCR + patients (BCL2/IGH 100%) | — | End of CHOP: BM MRD− 36% (43/118) PB MRD− 35% (43/121) After R: MRD− 59 % at week 12, 74 % at week 28, and 63% at week 44 | 3-year FFR BM MRD− after CHOP 52% BM MRD− after R at week 44, 3-year FFR 57% vs 20% MRD+ | 17 months (8-39) |
| Rambaldi et al14 | BCL2/IGH + FL, untreated | 86 (same series) | BM | RQ-PCR | Enrolled PCR + patients (BCL2/IGH 100%) | At baseline: Low (1 cell in 103–105): 43 %; intermediate (1 cell in 102–103): 34 %; high (>1 cell in 102): 23 % CR: 71 % in low vs 26 % in high EFS: 59 % in low/intermediate vs 32% in high | See above | FFR: 64 % MRD− vs 32 % MRD + (P < .006) | 56 months (40-75) | |
| Ladetto et al15 | High-risk FL untreated <60 years | 134 | Phase 3 R-HDS vs CHOP × 6 + R × 4 (GITMO/IIL) | BM | Nested PCR | 73/104 (70 %) BCL2/IGH (65) + IGH (8) | — | Overall, 65 % (39/60) MRD− After CHOP-R: MRD− 44% After R-HDS: MRD− 80% (P < .002) | PFS MRD− vs MRD + (P < .001), regardless of treatment arm | 51 months |
| Bruna et al16 | High-risk FL untreated <60 years | 134 | Update of the phase 3 R-HDS vs CHOP × 6 + R × 4 (GITMO/IIL) | BM | Nested PCR | — | Overall, 65% (39/60) MRD− | 13-year OS R-HDS 64.5 % vs 68.5 % CHOP-R 13-year OS BM MRD− 82.1 % vs BM MRD + 51.9 % (P =.030) 20/24 (83 %) patients with 4-year long-term MRD− in first CR | 13 years | |
| Ladetto et al17 | FL >60 years, untreated | 227 | ML17638 R-FND × 4 + 4R ± 4R every 2 months | BM | RQ-PCR | 116/227 (BCL2/IGH 51 %) | PFS: 80 % in low vs 75 % in intermediate vs 66 % in high PFS: 61% at month + 42 in both PCR + and PCR − at baseline | At EOI: MRD− 70 % End of consolidation: MRD− 84 % | 3-year PFS: at end of consolidation: 72 % MRD− vs 39 % MRD + (16 %) (P <.007) Median PFS: 12 months MRD− (RQ-PCR); 75 % of MRD− free of PD at 36 months (P < .001) PFS maintenance arm: 83 % PCR− vs 60 % PCR + (P = .007) PFS observation arm: 71 % PCR− vs 50 % PCR + (P < .001) | 42 months |
| Galimberti et al18 | FL untreated | 415 | Phase 3 FOLL05 trial R-CHOP, R- CVP, R-FN | BM | Nested PCR; RQ-PCR | 220/415 (BCL2/IGH 53%) RQ-PCR in 105 cases | At diagnosis: 61.9% PCR+ non-CR vs 38.1% PCR− (P = .027) BM biopsy+ 32% non-CR vs 21.8% in BM− cases (P = .021) 3-year PFS: 74% in PCR−/BM− at diagnosis vs 55% in PCR+/BM+ (P = .04) ORR 38.9% in high RQ vs 76.6% in low (P = .006) Relapses: 22% in <1 × 10–4 copies vs 78% in >1 × 10–4 copies (P = .033) at baseline 3-year PFS: 80% in low vs 59% in high (P = .015) | EOI MRD− (qPCR): 109/154 (70.8%) (no difference between arms) R-CHOP 39% R-FN 36% R-CVP 25% RQ decrease >3 log: R-CHOP 42.1% R-FN 36.8% R-CVP 21.1% (P = .07) | Relapse rate: 33% for MRD− vs 41% for MRD+ at EOI (P = .363) 3-year PFS 64.3% for MRD− vs 53.1 for MRD+ at EOI (P= .08) 3-year PFS 66% for 63 MRD− vs 41% for 24 MRD+ at 12 months from EOI (P = .015) 3-year PFS 84% for 46 MRD− vs 50% for 19 MRD+ at 24 months (P = .014) | NA |
| Zohren et al19 | FL, untreated | 114 | Phase 3 NHL1-2003 trial R-CHOP vs R-B | PB | RQ-PCR | 114/173 (BCL2/IGH 66%) | Median PFS: 22 months in high BCL2/IGH (ratio >1, n = 28) vs NR in intermediate (ratio 0.1-1, n = 24) vs NR in low (<0.1, n = 55) High vs intermediate: HR, 4.28; 95% CI, 1.70-10.77 (P = .002) High vs low: HR, 3.02; 95% CI, 1.55-5.86 (P = .001) | Overall MRD− 78/92 (85%) After R-B MRD− 43/48 (89.6%) After R-CHOP MRD− 35/44 (79.5%) | 3-year PFS 63% overall | 41 months (0-69) |
| Pott et al20,21 | FL, untreated | 1101 | Phase 3 Gallium trial R vs G (CVP, B, CHOP) + maintenance | PB ± BM | RQ-PCR Nested PCR | 968/1101 (BCL2/IGH + IGH 88%) 815 (74%) suitable for RQ-PCR | Clonal marker vs no marker at baseline: stage IV 61% vs 34%; BM biopsy infiltration 58.2% vs 14.3%; high-risk FLIPI 44.5% vs 30.8%; extranodal involvement 70% vs 40% | MI PB MRD−: G-vs R-based treatment (94% vs 89%, P =.013) EOI PB ± BM MRD−: G- vs R-based treatment (92% vs 85%, P = .0041) EOI BM MRD−: G- vs R-based treatment (93% vs 83%, P =.0014), NS in the PB EOI MRD− PB ± BM: R-CVP 76% vs G-CVP 91.4%; R-CHOP 77.8% vs G-CHOP 91.3%; R-B 89.6% vs G-B 92.5% EOI PB MRD−: R-CVP 79% vs G-CVP 94%; R-CHOP 93% vs G-CHOP 96%; R-B 96% vs G-B 96% EOI BM MRD−: R-CHOP 74% vs G-CHOP 93%; R-B 87% vs G-B 93% EOI MRD+: 22/24 (92%) patients in the G-chemo arm and 36/46 (78%) patients in the R-chemo arm achieved MRD negativity early during maintenance | 4-year PFS: 80% early responders (PB MI MRD−/EOI MRD−) vs 30% PB MI MRD +/EOI MRD + (P < .0001) vs 60% late responders, PB MI MRD +/EOI MRD− (P = .0133) EOI MRD− significantly affected PFS (HR, 0.38; 95% CI, 0.26-0.56; P < .0001) and OS (HR, 0.35; 95% CI, 0.17-0.72; P = .0027) | 57 months |
| Delfau-Larue et al22 | FL untreated | 440 | Phase 3 Relevance trial R2 (18 cycles of lenalidomide plus R, followed by R maintenance therapy every 8 weeks for 12 cycles) vs R-chemo (CHOP) followed by R-maintenance every 8 weeks for 12 cycles | PB ± BM | ddPCR | 222/440 (BCL2/IGH 50.45%) BCL2/IGH+ patients: stage III-IV disease (96% vs 90%, P = .004), FLIPI score >1 (91% vs 83%, P = .002), BM involvement (62% vs 48%, P = .003) | Tumor burden 10 times higher in PB and BM of patients with week 24 MRD+, compared to patients with week 24 MRD− (P = .03 and .02) | At EOI (week 24): PB MRD− 98%, BM MRD− 78% R2 arm: MRD− 105/117; 90% vs R-chemo MRD− 70/90; 77% (P = .022) | 3-year PFS: 84% for MRD− (in PB and/or BM) vs 55% for MRD+ (P = .015) 3-year PFS: 85% for BM MRD− vs 54% for BM MRD+ (P = .011) MRD+ at EOI: R-chemo arm (HR, 3.3; 95% CI, 1.2-9.2; P = .02) vs R2 arm (HR, 2; 95% CI, 0.6-6.8; P = .27) | NA |
| Pott et al23 | R refractory FL | Phase 3 GADOLIN trial G-B + G maintenance vs B | PB ± BM | RQ-PCR (and subsequent nested) | 71% (228/319) (63% BCL2/IGH+ [MBR, mcr, 3′MBR] and 72% IGH) 52% (166/319) suitable for RQ-PCR ≤10-4 | At MI: PB MRD− 79% (41/52) in G-B vs 47% (17/36) in B (P = .0029) At EOI, PB or BM MRD− 86% (54/63) in G-B vs 55% (30/55) in B (P = .0002) | PFS (HR, 0.33; P < .0001) and OS (HR, 0.39; P = .008) for MRD− PFS in MRD +3.3 months in both arms in MRD− 8.54 B vs 35.71 G-B | 31.8 months | ||
| Study . | Localized disease . | Patients . | Therapy . | Tissue . | Method . | Marker . | Tumor burden . | MRD− % . | Clinical impact . | Follow-up . |
| Pulsoni et al24 | Stage I (78%) Stage II (22%) untreated FL | 67 | IFRT (24-30 Gy) (+4 weeks R in MRD+ from 2005 in 19 patients) | PB ± BM | Nested PCR RQ-PCR ddPCR | 72% | 84-month PFS: 75% for BCL2/IGH- vs 59% for BCL2/IGH+ at baseline (P = .26) 84-month PFS: 90.9% in 11patients with MRD <10−5 vs 38% in 19 patients with MRD ≥10−5 by ddPCR at baseline (P = .015) | After RT: MRD −50% After R: 16/19 (84%) MRD− | Different PFS in MRD+ patients post-IFRT: between untreated patients vs patients treated with R after 2005 (P = .049) Different PFS of MRD+ patients during the follow-up vs persistently MRD− patients (P = .038) | 82 months (17-196) |
| Herfarth et al25 | Stage I (56%) Stage II (44%) untreated FL | 85 (60 long term) | MIR trial R × 8 cycles + IFRT (30-40 Gy) | 83 (64 PB, 13 BM) | Overall 24/64 (38%; PB 35%, BM 46%) Stage II > stage I (P = .0038) | 57% below 10−4 | MRD−: 20/21 (95%) at week 18 | 15/19 patients MRD− with no progression; 3 patients relapsed, in 2 associated or predicted by MRD+ sample | 29.6 months |
| Study . | Advanced disease . | Patients . | Therapy . | Tissue . | Method . | Marker . | Tumor burden . | MRD− % . | Clinical impact . | Follow-up . |
|---|---|---|---|---|---|---|---|---|---|---|
| Rambaldi et al13 | BCL2/IGH + FL, untreated | 128 (79 received R) | CHOP × 6 4 weeks R in PCR + patients | BM ± PB | Nested PCR | Enrolled PCR + patients (BCL2/IGH 100%) | — | End of CHOP: BM MRD− 36% (43/118) PB MRD− 35% (43/121) After R: MRD− 59 % at week 12, 74 % at week 28, and 63% at week 44 | 3-year FFR BM MRD− after CHOP 52% BM MRD− after R at week 44, 3-year FFR 57% vs 20% MRD+ | 17 months (8-39) |
| Rambaldi et al14 | BCL2/IGH + FL, untreated | 86 (same series) | BM | RQ-PCR | Enrolled PCR + patients (BCL2/IGH 100%) | At baseline: Low (1 cell in 103–105): 43 %; intermediate (1 cell in 102–103): 34 %; high (>1 cell in 102): 23 % CR: 71 % in low vs 26 % in high EFS: 59 % in low/intermediate vs 32% in high | See above | FFR: 64 % MRD− vs 32 % MRD + (P < .006) | 56 months (40-75) | |
| Ladetto et al15 | High-risk FL untreated <60 years | 134 | Phase 3 R-HDS vs CHOP × 6 + R × 4 (GITMO/IIL) | BM | Nested PCR | 73/104 (70 %) BCL2/IGH (65) + IGH (8) | — | Overall, 65 % (39/60) MRD− After CHOP-R: MRD− 44% After R-HDS: MRD− 80% (P < .002) | PFS MRD− vs MRD + (P < .001), regardless of treatment arm | 51 months |
| Bruna et al16 | High-risk FL untreated <60 years | 134 | Update of the phase 3 R-HDS vs CHOP × 6 + R × 4 (GITMO/IIL) | BM | Nested PCR | — | Overall, 65% (39/60) MRD− | 13-year OS R-HDS 64.5 % vs 68.5 % CHOP-R 13-year OS BM MRD− 82.1 % vs BM MRD + 51.9 % (P =.030) 20/24 (83 %) patients with 4-year long-term MRD− in first CR | 13 years | |
| Ladetto et al17 | FL >60 years, untreated | 227 | ML17638 R-FND × 4 + 4R ± 4R every 2 months | BM | RQ-PCR | 116/227 (BCL2/IGH 51 %) | PFS: 80 % in low vs 75 % in intermediate vs 66 % in high PFS: 61% at month + 42 in both PCR + and PCR − at baseline | At EOI: MRD− 70 % End of consolidation: MRD− 84 % | 3-year PFS: at end of consolidation: 72 % MRD− vs 39 % MRD + (16 %) (P <.007) Median PFS: 12 months MRD− (RQ-PCR); 75 % of MRD− free of PD at 36 months (P < .001) PFS maintenance arm: 83 % PCR− vs 60 % PCR + (P = .007) PFS observation arm: 71 % PCR− vs 50 % PCR + (P < .001) | 42 months |
| Galimberti et al18 | FL untreated | 415 | Phase 3 FOLL05 trial R-CHOP, R- CVP, R-FN | BM | Nested PCR; RQ-PCR | 220/415 (BCL2/IGH 53%) RQ-PCR in 105 cases | At diagnosis: 61.9% PCR+ non-CR vs 38.1% PCR− (P = .027) BM biopsy+ 32% non-CR vs 21.8% in BM− cases (P = .021) 3-year PFS: 74% in PCR−/BM− at diagnosis vs 55% in PCR+/BM+ (P = .04) ORR 38.9% in high RQ vs 76.6% in low (P = .006) Relapses: 22% in <1 × 10–4 copies vs 78% in >1 × 10–4 copies (P = .033) at baseline 3-year PFS: 80% in low vs 59% in high (P = .015) | EOI MRD− (qPCR): 109/154 (70.8%) (no difference between arms) R-CHOP 39% R-FN 36% R-CVP 25% RQ decrease >3 log: R-CHOP 42.1% R-FN 36.8% R-CVP 21.1% (P = .07) | Relapse rate: 33% for MRD− vs 41% for MRD+ at EOI (P = .363) 3-year PFS 64.3% for MRD− vs 53.1 for MRD+ at EOI (P= .08) 3-year PFS 66% for 63 MRD− vs 41% for 24 MRD+ at 12 months from EOI (P = .015) 3-year PFS 84% for 46 MRD− vs 50% for 19 MRD+ at 24 months (P = .014) | NA |
| Zohren et al19 | FL, untreated | 114 | Phase 3 NHL1-2003 trial R-CHOP vs R-B | PB | RQ-PCR | 114/173 (BCL2/IGH 66%) | Median PFS: 22 months in high BCL2/IGH (ratio >1, n = 28) vs NR in intermediate (ratio 0.1-1, n = 24) vs NR in low (<0.1, n = 55) High vs intermediate: HR, 4.28; 95% CI, 1.70-10.77 (P = .002) High vs low: HR, 3.02; 95% CI, 1.55-5.86 (P = .001) | Overall MRD− 78/92 (85%) After R-B MRD− 43/48 (89.6%) After R-CHOP MRD− 35/44 (79.5%) | 3-year PFS 63% overall | 41 months (0-69) |
| Pott et al20,21 | FL, untreated | 1101 | Phase 3 Gallium trial R vs G (CVP, B, CHOP) + maintenance | PB ± BM | RQ-PCR Nested PCR | 968/1101 (BCL2/IGH + IGH 88%) 815 (74%) suitable for RQ-PCR | Clonal marker vs no marker at baseline: stage IV 61% vs 34%; BM biopsy infiltration 58.2% vs 14.3%; high-risk FLIPI 44.5% vs 30.8%; extranodal involvement 70% vs 40% | MI PB MRD−: G-vs R-based treatment (94% vs 89%, P =.013) EOI PB ± BM MRD−: G- vs R-based treatment (92% vs 85%, P = .0041) EOI BM MRD−: G- vs R-based treatment (93% vs 83%, P =.0014), NS in the PB EOI MRD− PB ± BM: R-CVP 76% vs G-CVP 91.4%; R-CHOP 77.8% vs G-CHOP 91.3%; R-B 89.6% vs G-B 92.5% EOI PB MRD−: R-CVP 79% vs G-CVP 94%; R-CHOP 93% vs G-CHOP 96%; R-B 96% vs G-B 96% EOI BM MRD−: R-CHOP 74% vs G-CHOP 93%; R-B 87% vs G-B 93% EOI MRD+: 22/24 (92%) patients in the G-chemo arm and 36/46 (78%) patients in the R-chemo arm achieved MRD negativity early during maintenance | 4-year PFS: 80% early responders (PB MI MRD−/EOI MRD−) vs 30% PB MI MRD +/EOI MRD + (P < .0001) vs 60% late responders, PB MI MRD +/EOI MRD− (P = .0133) EOI MRD− significantly affected PFS (HR, 0.38; 95% CI, 0.26-0.56; P < .0001) and OS (HR, 0.35; 95% CI, 0.17-0.72; P = .0027) | 57 months |
| Delfau-Larue et al22 | FL untreated | 440 | Phase 3 Relevance trial R2 (18 cycles of lenalidomide plus R, followed by R maintenance therapy every 8 weeks for 12 cycles) vs R-chemo (CHOP) followed by R-maintenance every 8 weeks for 12 cycles | PB ± BM | ddPCR | 222/440 (BCL2/IGH 50.45%) BCL2/IGH+ patients: stage III-IV disease (96% vs 90%, P = .004), FLIPI score >1 (91% vs 83%, P = .002), BM involvement (62% vs 48%, P = .003) | Tumor burden 10 times higher in PB and BM of patients with week 24 MRD+, compared to patients with week 24 MRD− (P = .03 and .02) | At EOI (week 24): PB MRD− 98%, BM MRD− 78% R2 arm: MRD− 105/117; 90% vs R-chemo MRD− 70/90; 77% (P = .022) | 3-year PFS: 84% for MRD− (in PB and/or BM) vs 55% for MRD+ (P = .015) 3-year PFS: 85% for BM MRD− vs 54% for BM MRD+ (P = .011) MRD+ at EOI: R-chemo arm (HR, 3.3; 95% CI, 1.2-9.2; P = .02) vs R2 arm (HR, 2; 95% CI, 0.6-6.8; P = .27) | NA |
| Pott et al23 | R refractory FL | Phase 3 GADOLIN trial G-B + G maintenance vs B | PB ± BM | RQ-PCR (and subsequent nested) | 71% (228/319) (63% BCL2/IGH+ [MBR, mcr, 3′MBR] and 72% IGH) 52% (166/319) suitable for RQ-PCR ≤10-4 | At MI: PB MRD− 79% (41/52) in G-B vs 47% (17/36) in B (P = .0029) At EOI, PB or BM MRD− 86% (54/63) in G-B vs 55% (30/55) in B (P = .0002) | PFS (HR, 0.33; P < .0001) and OS (HR, 0.39; P = .008) for MRD− PFS in MRD +3.3 months in both arms in MRD− 8.54 B vs 35.71 G-B | 31.8 months | ||
| Study . | Localized disease . | Patients . | Therapy . | Tissue . | Method . | Marker . | Tumor burden . | MRD− % . | Clinical impact . | Follow-up . |
| Pulsoni et al24 | Stage I (78%) Stage II (22%) untreated FL | 67 | IFRT (24-30 Gy) (+4 weeks R in MRD+ from 2005 in 19 patients) | PB ± BM | Nested PCR RQ-PCR ddPCR | 72% | 84-month PFS: 75% for BCL2/IGH- vs 59% for BCL2/IGH+ at baseline (P = .26) 84-month PFS: 90.9% in 11patients with MRD <10−5 vs 38% in 19 patients with MRD ≥10−5 by ddPCR at baseline (P = .015) | After RT: MRD −50% After R: 16/19 (84%) MRD− | Different PFS in MRD+ patients post-IFRT: between untreated patients vs patients treated with R after 2005 (P = .049) Different PFS of MRD+ patients during the follow-up vs persistently MRD− patients (P = .038) | 82 months (17-196) |
| Herfarth et al25 | Stage I (56%) Stage II (44%) untreated FL | 85 (60 long term) | MIR trial R × 8 cycles + IFRT (30-40 Gy) | 83 (64 PB, 13 BM) | Overall 24/64 (38%; PB 35%, BM 46%) Stage II > stage I (P = .0038) | 57% below 10−4 | MRD−: 20/21 (95%) at week 18 | 15/19 patients MRD− with no progression; 3 patients relapsed, in 2 associated or predicted by MRD+ sample | 29.6 months |
Only trials including anti-CD20 monoclonal antibodies have been included.
FN, fludarabine and mitoxantrone; FND, fludarabine, mitoxantrone, and dexamethasone; IFRT, involved field radiotherapy; MIR, Mabthera and Involved field Radiotherapy (NCT00509184); NA, not available; NS, not significant; ORR, overall response rate; qPCR, quantitative PCR.