Selected MRD studies for assessment of treatment response in adult ALL
| Study . | No. and risk group of patients . | Treatment . | MRD assessment/prognostic significance of MRD/conclusions . | Retaining prognostic significance of classic risk factors/comments . |
|---|---|---|---|---|
| Ph-negative ALL* | ||||
| Vidriales22 (2003) | 102 patients | According to clinical risk factors: | FCM (3 colors) during (d+14) and after (d+35) induction: | MRD most relevant independent prognostic factor |
| B- and T-lineage | Chemo (n = 65) | Prognostic influence of MRD at both time points | Additional independent prognostic factors: age, WBC, Ph positivity | |
| CR after induction | Plus auto-SCT (n = 14) | Poor prognosis in patients with MRD persistence ≥ 5 × 10−3 d+14 and/or ≥ 5 × 10−4 d+35 Excellent prognosis in small subgroup of patients with early MRD clearance (< 3 × 10−4, d+14) | ||
| Plus allo-SCT (n = 23) | ||||
| Brüggemann3 (2006) | 196 patients B- and T-lineage SR ALL | Chemo† | RQ-PCR (Ig/TCR) at 9 time points (d+11, d+24, d+44, d+71, wk+16, wk+22, wk+30, wk+41, wk+52) | Study population homogeneous concerning other prognostic factors MRD only variable with significant impact on outcome No prognostic impact of remaining variables (age, WBC, T- vs B-lineage) |
| Prognostic influence of MRD at all time points Excellent prognosis in small subgroup of patients with early MRD clearance (MRD negativity at d+14) Poor prognosis in patients with MRD persistence (MRD > 1 × 10−4 from d+71 onwards) | ||||
| Holowiecki48 (2008) | 116 patients B- and T-lineage SR (n = 34) and HR (n = 82) ALL | Chemo (n = 54) Auto-SCT (n = 27) Allo-SCT (n = 35) | FCM (3 colors) after induction and Cons Poor prognosis in SR and HR patients with MRD > 10−3 after induction and being treated with Chemo alone Higher proportion of patients with MRD > 10−3 in HR patients than in SR patients No prognostic impact of MRD on T-ALL No significant impact of MRD after Cons | MRD after induction most relevant independent prognostic factor Additional independent prognostic factors: age and WBC |
| Bassan1 (2009) | 112 patients B- and T-lineage All risk groups | According to MRD and clinical risk factors‡ Chemo (n = 51) Allo-SCT (n = 25) Auto-SCT (n = 21) No additional treatment (relapse, toxicity: (n = 15) | RQ-PCR (Ig/TCR and/or fusion genes) at 3 time points (wk+10, wk+16, wk+22) | Combined MRD information at wk+16 and wk+22 most relevant independent prognostic factor |
| Good prognosis in patients with MRD < 10−4 (wk+16) and any MRD negativity (wk+22) irrespective of classic risk group Poor outcome in patients with MRD persistence without differences related to original clinical risk class Early MRD (wk+10) predicted late MRD (wk+16/wk+22) | Additional independent prognostic factor: WBC Allo-SCT not needed in HR patients with MRD LR profile | |||
| Patel47 (2010)§ | 159 patients B-lineage ALL | Irrespective of risk group Chemotherapy (n = 94) Auto-SCT (n = 25) Allo-SCT (n = 40) | DNA fingerprinting/RQ-PCR (Ig/TCR) at 3(-5) time points (wk+5, wk+10, wk+17, for patients without SCT: also wk+28, wk+39): Prognostic influence of MRD in patients receiving Chemo or auto-SCT as postremission treatment Most discriminative time points: wk+10, wk+17 No significant impact of MRD in patients with allo-SCT | No multivariate analysis performed |
| Gökbuget46 (2012) | 580 patients B- and T-lineage ALL SR (n = 434) and HR (n = 146) patients) | According to MRD (only SR ALL) and clinical risk factors: Chemo (n = 425) Allo-SCT (n = 155) | RQ-PCR (Ig/TCR) at 2 time points (d+71, wk+16) Prognostic influence of MRD at d+71 and wk+16 Complete MRD response rate higher in SR vs HR patients (d+71: 77% vs 51%), clinical benefit of complete response comparable for SR and HR patients | Multivariate analysis: MRD only parameter with significant prognostic impact |
| MRD-based allo-SCT in MRD-HR patients | ||||
| SCT performed in half of the patients | ||||
| Improved DFS and OS for patients with SCT | ||||
| Ph-positive ALL | ||||
| Pane10 (2005) | 45 Ph+ patients | Chemo followed by allo-SCT (in case of available donor, n = 20) | RT-PCR (BCR-ABL) at 2 time points (end of induction, end of first Cons) | Age and WBC did not differ between both MRD groups |
| No TKI | Heterogeneous sensitivity to treatment | |||
| Better DFS and OS in good molecular responders ( > 2 log reduction after induction + > 3 log reduction after Cons 1) compared with poor molecular responders | ||||
| Ottmann97 (2007) | 49 Ph+ patients | Randomized induction: Chemo vs TKI | RT- and qualitative nested PCR (BCR-ABL) after end of induction, each Cons/reinduction cycle | Lower WBC at diagnosis in MRD negative patients |
| Elderly patients (54-79 y) | Cons: Chemo + TKI | Heterogeneous sensitivity to treatment | ||
| MRD response in patients with TKI induction compared to Chemo: | ||||
| Better initial MRD response in TKI group | ||||
| No difference in median MRD level after Cons | ||||
| MRD negativity at any time associated with more favorable outcome | ||||
| Yanada53 (2008) | 100 Ph+ patients‖ | Induction Chemo + TKI | RT-PCR (BCR-ABL) at d+28, d+63 (end of induction), | |
| Donor: allo-SCT in CR1 (n = 60) | end of Cons 1 (+later time points) | |||
| No donor: Cons Chemo + TKI (n = 37) | No impact of rapid MRD clearance (MRD negativity at d+28, d+62 or after Cons 1) on relapse-free survival | |||
| Lee51 (2009) | 52 Ph+ patients | Treatment sequence: Induction Chemo 4 wk TKI Cons Chemo 4 wk TKI Allo-SCT in CR1 (n = 48) or non-CR (n = 4) | RT-PCR (BCR-ABL) after induction Chemo, first TKI, after Cons Chemo, after second course TKI No prognostic impact of MRD after induction Chemo before TKI Better DFS and lower relapse rate in patients with ≥ 3 log reduction after first imatinib course | MRD after TKI most significant independent prognostic factor Chronic GVHD only additional variable with an independent prognostic impact |
| Study . | No. and risk group of patients . | Treatment . | MRD assessment/prognostic significance of MRD/conclusions . | Retaining prognostic significance of classic risk factors/comments . |
|---|---|---|---|---|
| Ph-negative ALL* | ||||
| Vidriales22 (2003) | 102 patients | According to clinical risk factors: | FCM (3 colors) during (d+14) and after (d+35) induction: | MRD most relevant independent prognostic factor |
| B- and T-lineage | Chemo (n = 65) | Prognostic influence of MRD at both time points | Additional independent prognostic factors: age, WBC, Ph positivity | |
| CR after induction | Plus auto-SCT (n = 14) | Poor prognosis in patients with MRD persistence ≥ 5 × 10−3 d+14 and/or ≥ 5 × 10−4 d+35 Excellent prognosis in small subgroup of patients with early MRD clearance (< 3 × 10−4, d+14) | ||
| Plus allo-SCT (n = 23) | ||||
| Brüggemann3 (2006) | 196 patients B- and T-lineage SR ALL | Chemo† | RQ-PCR (Ig/TCR) at 9 time points (d+11, d+24, d+44, d+71, wk+16, wk+22, wk+30, wk+41, wk+52) | Study population homogeneous concerning other prognostic factors MRD only variable with significant impact on outcome No prognostic impact of remaining variables (age, WBC, T- vs B-lineage) |
| Prognostic influence of MRD at all time points Excellent prognosis in small subgroup of patients with early MRD clearance (MRD negativity at d+14) Poor prognosis in patients with MRD persistence (MRD > 1 × 10−4 from d+71 onwards) | ||||
| Holowiecki48 (2008) | 116 patients B- and T-lineage SR (n = 34) and HR (n = 82) ALL | Chemo (n = 54) Auto-SCT (n = 27) Allo-SCT (n = 35) | FCM (3 colors) after induction and Cons Poor prognosis in SR and HR patients with MRD > 10−3 after induction and being treated with Chemo alone Higher proportion of patients with MRD > 10−3 in HR patients than in SR patients No prognostic impact of MRD on T-ALL No significant impact of MRD after Cons | MRD after induction most relevant independent prognostic factor Additional independent prognostic factors: age and WBC |
| Bassan1 (2009) | 112 patients B- and T-lineage All risk groups | According to MRD and clinical risk factors‡ Chemo (n = 51) Allo-SCT (n = 25) Auto-SCT (n = 21) No additional treatment (relapse, toxicity: (n = 15) | RQ-PCR (Ig/TCR and/or fusion genes) at 3 time points (wk+10, wk+16, wk+22) | Combined MRD information at wk+16 and wk+22 most relevant independent prognostic factor |
| Good prognosis in patients with MRD < 10−4 (wk+16) and any MRD negativity (wk+22) irrespective of classic risk group Poor outcome in patients with MRD persistence without differences related to original clinical risk class Early MRD (wk+10) predicted late MRD (wk+16/wk+22) | Additional independent prognostic factor: WBC Allo-SCT not needed in HR patients with MRD LR profile | |||
| Patel47 (2010)§ | 159 patients B-lineage ALL | Irrespective of risk group Chemotherapy (n = 94) Auto-SCT (n = 25) Allo-SCT (n = 40) | DNA fingerprinting/RQ-PCR (Ig/TCR) at 3(-5) time points (wk+5, wk+10, wk+17, for patients without SCT: also wk+28, wk+39): Prognostic influence of MRD in patients receiving Chemo or auto-SCT as postremission treatment Most discriminative time points: wk+10, wk+17 No significant impact of MRD in patients with allo-SCT | No multivariate analysis performed |
| Gökbuget46 (2012) | 580 patients B- and T-lineage ALL SR (n = 434) and HR (n = 146) patients) | According to MRD (only SR ALL) and clinical risk factors: Chemo (n = 425) Allo-SCT (n = 155) | RQ-PCR (Ig/TCR) at 2 time points (d+71, wk+16) Prognostic influence of MRD at d+71 and wk+16 Complete MRD response rate higher in SR vs HR patients (d+71: 77% vs 51%), clinical benefit of complete response comparable for SR and HR patients | Multivariate analysis: MRD only parameter with significant prognostic impact |
| MRD-based allo-SCT in MRD-HR patients | ||||
| SCT performed in half of the patients | ||||
| Improved DFS and OS for patients with SCT | ||||
| Ph-positive ALL | ||||
| Pane10 (2005) | 45 Ph+ patients | Chemo followed by allo-SCT (in case of available donor, n = 20) | RT-PCR (BCR-ABL) at 2 time points (end of induction, end of first Cons) | Age and WBC did not differ between both MRD groups |
| No TKI | Heterogeneous sensitivity to treatment | |||
| Better DFS and OS in good molecular responders ( > 2 log reduction after induction + > 3 log reduction after Cons 1) compared with poor molecular responders | ||||
| Ottmann97 (2007) | 49 Ph+ patients | Randomized induction: Chemo vs TKI | RT- and qualitative nested PCR (BCR-ABL) after end of induction, each Cons/reinduction cycle | Lower WBC at diagnosis in MRD negative patients |
| Elderly patients (54-79 y) | Cons: Chemo + TKI | Heterogeneous sensitivity to treatment | ||
| MRD response in patients with TKI induction compared to Chemo: | ||||
| Better initial MRD response in TKI group | ||||
| No difference in median MRD level after Cons | ||||
| MRD negativity at any time associated with more favorable outcome | ||||
| Yanada53 (2008) | 100 Ph+ patients‖ | Induction Chemo + TKI | RT-PCR (BCR-ABL) at d+28, d+63 (end of induction), | |
| Donor: allo-SCT in CR1 (n = 60) | end of Cons 1 (+later time points) | |||
| No donor: Cons Chemo + TKI (n = 37) | No impact of rapid MRD clearance (MRD negativity at d+28, d+62 or after Cons 1) on relapse-free survival | |||
| Lee51 (2009) | 52 Ph+ patients | Treatment sequence: Induction Chemo 4 wk TKI Cons Chemo 4 wk TKI Allo-SCT in CR1 (n = 48) or non-CR (n = 4) | RT-PCR (BCR-ABL) after induction Chemo, first TKI, after Cons Chemo, after second course TKI No prognostic impact of MRD after induction Chemo before TKI Better DFS and lower relapse rate in patients with ≥ 3 log reduction after first imatinib course | MRD after TKI most significant independent prognostic factor Chronic GVHD only additional variable with an independent prognostic impact |
Only MRD studies being published as peer reviewed papers are listed.
Chemo indicates chemotherapy; Cons, consolidation; CR, complete remission; D, day; DFS, disease free survival; FCM, flow cytometry; HR, high risk; Ind, induction; LR, low risk; OS, overall survival; Ph, Philadelphia chromosome; RQ-PCR, real-time quantitative PCR; RT-PCR, reverse transcriptase-PCR; SCT, stem cell transplantation; SR, standard risk; TKI, tyrosine kinase inhibitors; TP(s), time-point(s); Wk, week; and WBC, white blood cell count.
Only study of Bassan et al includes Ph-positive patients.1
Eleven patients with SCT censored at time of SCT.
Clinical risk factors for assignment to allo-SCT independent of MRD: presence of t(9;22) or t(4;11).
Update from an interim report of Mortuza et al.9