NGS-MRD in the context of MFC and qPCR MRD: approaches and interventions
| NGS-MRD pediatric and adult studies in HCT . | Other MRD approaches and comparative studies . | Interventions based upon MRD pre-/post-HCT . |
|---|---|---|
| Pulsipher et al3,(n = 56): in children pre-HCT NGS-MRD negativity vs positivity led to a 2-y relapse rate of 0% vs 53% and 2-y OS 96% vs 48% in pre-HCT MRD-negative vs MRD-positive. Post-HCT NGS-MRD was highly sensitive in predicting relapse. Abdel-Azim et al21,(n = 87): NGS-MRD–negative children pre-HCT had EFS/OS >90% whether treated with TBI or non-TBI. NGS MRD-positive: 2-year EFS of 50%. Liang et al6,(n = 158): adult multicenter, n = 158. Pre-HCT NGS-MRD was undetectable (0), low (<10–4), high (≥10–4 and ≤10–3), and very high (>10–3) in 82 (67%), 24 (20%), 11 (9%), and 5 (4%), respectively. Any level of NGS-MRD detected pre-HCT increased relapse (HR, 6.31; P < .001). Muffly et al9 (n = 62): strong correlation between PB and BM NGS-MRD. Sensitivity and specificity of NGS-MRD was 87% and 90% in PB. Median time from detection of PB MRD to relapse was 90 d after HCT and 60 d after CART. Short et al8 (n = 44, in retrospective cohort; n = 65, in prospective cohort): NGS-MRD clarifies multilineage BCR::ABL ALL in adults; 32% discordance between BCR::ABL and NGS-MRD; and 11 of 65 patients achieved NGS-MRD negativity and did not relapse despite detection of BCR::ABL by PCR. | MFC (n = 105, 146): multiparameter flow cytometry (MFC) MRD highly predictive of relapse, EFS, and OS before HCT; poor sensitivity early after HCT but increased by 8-12 mo after HCT. Acute GVHD improves EFS/OS due to lower relapse, chronic GVHD does not due to higher treatment-related mortality.27,32, IgH/TCR PCR/qPCR MRD (n = 64, 71, 17, 91, 113): highly predictive of relapse, EFS, and OS before HCT; high risk >10–3, intermediate risk 10–3 to 10–4, low risk <10–4. High sensitivity for relapse prediction both early and late after HCT.33-37, Comparative studies: MFC vs PCRpediatric(N = 616): PCR has improved sensitivity compared to MFC-MRD, doubling the number of patients detected at risk in similar populations.31, MFC vs NGS-MRD pediatric(n = 184): NGS-MRD improved predictive power for relapse, EFS, and OS before HCT compared with MFC. NGS-MRD highly predictive of relapse at any time after HCT.3, MFC vs NGS-MRD adult (n = 25): in 17% of cases, MRD detected by NGS but not MFC.38 There was >80% relapse-free survival in NGS-MRD-negative patients.38 | Balduzzi et al39,(n = 82): pre-HCT MRD >10–4 associated with 9.2 hazard of relapse. Additional chemotherapy to reduce MRD associated with fivefold reduction in risk of relapse. Pre-HCT MRD >10–4 + no GVHD post-HCT: IS tapered at month 2, relapse rate 46%. Post-HCT MRD associated with 2.5-fold risk of relapse in the first 100 d; rose to 7.8-fold risk if detected after 6 mo. All patients with MRD >10–3 after HCT relapsed. Rettinger et al40 (n = 58): withdrawal of IS ± DLI given to some patients with mixed chimerism (MC) and/or MRD+ early after. Those with MC/MRD+ not getting intervention relapsed, but those with MC/MRD+ getting intervention had similar 3-y EFS to those who were MRD-negative and did not have MC. Lancaster et al41 (n = 48): pediatric patients with >10−4 MRD by PCR pre-HCT had early withdrawal of IS ± DLI. EFS in the group remained low at 19%, but relapses were delayed up to 3 y. |
| NGS-MRD pediatric and adult studies in HCT . | Other MRD approaches and comparative studies . | Interventions based upon MRD pre-/post-HCT . |
|---|---|---|
| Pulsipher et al3,(n = 56): in children pre-HCT NGS-MRD negativity vs positivity led to a 2-y relapse rate of 0% vs 53% and 2-y OS 96% vs 48% in pre-HCT MRD-negative vs MRD-positive. Post-HCT NGS-MRD was highly sensitive in predicting relapse. Abdel-Azim et al21,(n = 87): NGS-MRD–negative children pre-HCT had EFS/OS >90% whether treated with TBI or non-TBI. NGS MRD-positive: 2-year EFS of 50%. Liang et al6,(n = 158): adult multicenter, n = 158. Pre-HCT NGS-MRD was undetectable (0), low (<10–4), high (≥10–4 and ≤10–3), and very high (>10–3) in 82 (67%), 24 (20%), 11 (9%), and 5 (4%), respectively. Any level of NGS-MRD detected pre-HCT increased relapse (HR, 6.31; P < .001). Muffly et al9 (n = 62): strong correlation between PB and BM NGS-MRD. Sensitivity and specificity of NGS-MRD was 87% and 90% in PB. Median time from detection of PB MRD to relapse was 90 d after HCT and 60 d after CART. Short et al8 (n = 44, in retrospective cohort; n = 65, in prospective cohort): NGS-MRD clarifies multilineage BCR::ABL ALL in adults; 32% discordance between BCR::ABL and NGS-MRD; and 11 of 65 patients achieved NGS-MRD negativity and did not relapse despite detection of BCR::ABL by PCR. | MFC (n = 105, 146): multiparameter flow cytometry (MFC) MRD highly predictive of relapse, EFS, and OS before HCT; poor sensitivity early after HCT but increased by 8-12 mo after HCT. Acute GVHD improves EFS/OS due to lower relapse, chronic GVHD does not due to higher treatment-related mortality.27,32, IgH/TCR PCR/qPCR MRD (n = 64, 71, 17, 91, 113): highly predictive of relapse, EFS, and OS before HCT; high risk >10–3, intermediate risk 10–3 to 10–4, low risk <10–4. High sensitivity for relapse prediction both early and late after HCT.33-37, Comparative studies: MFC vs PCRpediatric(N = 616): PCR has improved sensitivity compared to MFC-MRD, doubling the number of patients detected at risk in similar populations.31, MFC vs NGS-MRD pediatric(n = 184): NGS-MRD improved predictive power for relapse, EFS, and OS before HCT compared with MFC. NGS-MRD highly predictive of relapse at any time after HCT.3, MFC vs NGS-MRD adult (n = 25): in 17% of cases, MRD detected by NGS but not MFC.38 There was >80% relapse-free survival in NGS-MRD-negative patients.38 | Balduzzi et al39,(n = 82): pre-HCT MRD >10–4 associated with 9.2 hazard of relapse. Additional chemotherapy to reduce MRD associated with fivefold reduction in risk of relapse. Pre-HCT MRD >10–4 + no GVHD post-HCT: IS tapered at month 2, relapse rate 46%. Post-HCT MRD associated with 2.5-fold risk of relapse in the first 100 d; rose to 7.8-fold risk if detected after 6 mo. All patients with MRD >10–3 after HCT relapsed. Rettinger et al40 (n = 58): withdrawal of IS ± DLI given to some patients with mixed chimerism (MC) and/or MRD+ early after. Those with MC/MRD+ not getting intervention relapsed, but those with MC/MRD+ getting intervention had similar 3-y EFS to those who were MRD-negative and did not have MC. Lancaster et al41 (n = 48): pediatric patients with >10−4 MRD by PCR pre-HCT had early withdrawal of IS ± DLI. EFS in the group remained low at 19%, but relapses were delayed up to 3 y. |
DLI, donor lymphocyte infusion; EFS, event-free survival; IS, immunosuppression; OS, overall survival; PB, peripheral blood; qPCR, quantitative PCR.