Clinical studies using MRD in adult AML
| Trial/study group . | Patients . | MRD technique . | Key finding . |
|---|---|---|---|
| MRD guidance after induction in complete remission in intermediate-risk patients | |||
| GIMEMA 1310, risk-adapted, MRD-directed therapy for young adults with newly diagnosed AML20 | N = 429 ≤60 years | MFC | Similar 2-year survival in MRD-negative intermediate-risk patients receiving autoSCT compared to MRD-positive patients receiving alloSCT. |
| HOVON-SAKK 132: Addition of lenalidomide to intensive treatment in younger and middle-aged adults with newly diagnosed AML21 | N = 780 AML/high-risk MDS ≤65 years | MFC and NPM1 | No difference in outcome between MRD-negative and MRD-positive intermediate-risk patients, while MRD-negative patients were considered eligible for non-alloSCT treatment. |
| ChiCTR-TRC-10001202 and 10001209 NCT03021330: Prognostic effect and clinical application of early MRD by flow cytometry on de novo AML19 | N = 769 <60 years | MFC | Overall survival of MRD-negative patients in favorable and intermediate-risk groups was comparable between transplant and nontransplant patients. |
| Post-remission measurable residual disease directs treatment choice and improves outcomes for patients with intermediate-risk acute myeloid leukemia in CR149 | N = 235 Intermediate risk 14-60 years | MFC | Retrospective analysis of real-world data postremission MRD directs treatment choice and improves outcomes for patients with intermediate-risk AML in CR1. |
| Current retrospective studies showing relevance ofFLT3/ITD as MRD marker | |||
| DNA sequencing to detect residual disease in adults with AML prior to hematopoietic cell transplant15 | N = 1075 AML in CR1 before transplant ≥18 years | NGS | Persistence of FLT3-ITD or NPM1 variants in blood at an allele fraction of 0.01% or higher was associated with increased relapse and worse survival compared with those without variants detected. |
| Prognostic value of FLT3-ITD residual disease in AML23 | N = 161 FLT3-ITD+ AML in CR1 after induction ≥18 years | NGS | FLT3-ITD MRD is prognostic and better identifies patients at risk for relapse compared to MFC or NGS-based NMP1 MRD alone. |
| Pretransplant FLT3-ITD MRD assessed by high-sensitivity PCR-NGS determines posttransplant clinical outcome26 | N = 104 Pretransplant AML 17-68 years | NGS | Pre-HCT detection of FLT3-ITD MRD is related to poor prognosis and can be an indication for future MRD-directed therapeutic strategies. |
| Allogenic stem cell transplantation conditioning/donor selection | |||
| Impact of conditioning intensity of allogeneic transplantation for acute myeloid leukemia with genomic evidence of residual disease (CIBMTR)50 | N = 190 ≥18 years in first CR | NGS: FLT3, NPM1, IDH1, IDH2, and/or KIT variants | MAC rather than RIC in patients with AML with genomic evidence of MRD before alloHCT can result in improved survival. |
| Impact of pre-transplant induction and consolidation cycles on AML allogeneic transplant outcomes: a CIBMTR analysis in 3113 AML patients51 | N = 3113 ≥18 years | MFC, cytogenetics and molecular | Detectable MRD at the time of MAC alloHCT did not impact outcomes while detectable MRD preceding RIC alloHCT was associated with an increased risk of relapse. |
| Measurable residual disease, conditioning regimen intensity, and age predict outcome of allogeneic hematopoietic cell transplantation for acute myeloid leukemia in first remission52 | N = 2292 (EBMT) ≥18 years | MFC and molecular | Patients aged <50 y with AML CR1 MRD-positive status should preferentially be offered MAC alloHCT. Prospective studies are needed to address whether patients who are AML CR1 MRD negative may be spared the toxicity of MAC regimens. |
| Haploidentical allograft is superior to matched sibling donor allograft in eradicating pre-transplantation MRD of AML patients as determined by MFC: a retrospective and prospective analysis53 | N = 339 ≤60 years | MFC | For MRD-positive patients, haploSCT was associated with lower incidence of relapse and better survival, suggesting a stronger antileukemia effect compared to matched sibling donor transplantation. |
| Monitoring during maintenance | |||
| Prospective phase II (NCT00801489): Common kinase mutations do not impact optimal molecular responses in CBF AML treated with fludarabine, cytarabine, and G-CSF based regimens54 | N = 174 ≥18 years | Optimal PCR response FLT3, RAS, and KIT | Attainment of PCR <0.01% during/after consolidation improved RFS and was more important than achieving early optimal PCR response (post C1 PCR <0.1%). |
| Observational cohort: MRD status and FLT3 inhibitor therapy in patients with FLT3/ITD mutated AML following allogeneic hematopoietic cell transplantation55 | N = 34 ≥18 years | NGS: FLT3/ITD | Prognostic significance of NGS-based MRD monitoring for FLT3/ITD and the ability of post-alloSCT maintenance to prevent relapse and death. |
| Measurable residual disease-guided treatment with azacitidine to prevent haematological relapse in patients with myelodysplastic syndrome and acute myeloid leukaemia (RELAZA2): an open-label, multicentre, phase 2 trial56 | N = 53 ≥18 years CR-MRD+ | qPCR: NPM1, DEK-NUP214, RUNX1-RUNX1T1, CBFb-MYH11 | MRD-guided treatment with azacitidine prevented or substantially delayed hematologic relapse with an acceptable safety. |
| Monitoring after treatment | |||
| Posttransplant MRD and T-cell chimerism status predict outcomes in patients allografted with AML/MDS (FIGARO)3 | N = 187 ≥18 years Peri-alloSCT | MFC and T-cell chimerism | Post-alloSCT MRD is an important predictor of outcome and is most informative when combined with T-cell chimerism. |
| Bone marrow CD34+ molecular chimerism as an early predictor of relapse after alloSCT in patients with AML (PROMISE)57 | N = 168 <75 years After alloSCT | Molecular WT1 and CD34+ chimerism | Molecular chimerism and WT1 after alloSCT (first and third months) are useful MRD markers. When considered together at third month, CD34+ molecular chimerism could represent an earlier predictor of relapse compared to WT1. |
| MRD in nonintensively treated patients | |||
| Undetectable measurable residual disease is associated with improved outcomes in AML irrespective of treatment intensity. Retrospective analysis of real world data58 | N = 635 (250 nonintensively treated) ≥18 years | MFC: excluding APL and CBF AML | Achievement of MRD negativity should be the key objective of AML therapy in both high- and low-intensity treatment regimens. |
| Measurable residual disease response and prognosis in treatment-naïve acute myeloid leukemia with venetoclax and azacitidine (VIALE-A)46 | N = 190 (164 in CRc for MRD assessment) ≥18 years | MFC | Patients who achieved CRc and MRD negativity at any time point during treatment with venetoclax and azacitidine had longer duration of response, EFS, and OS than responding MRD-positive patients |
| Ibrutinib added to 10-day decitabine for older patients with AML and higher risk MDS (HOVON-SAKK 135)59 | N = 144 Unfit AML/high-risk MDS >60 years | MFC | After 3 cycles of treatment, 28 (49%) of 57 patients were MRD negative. In this limited number of cases, MRD revealed no apparent impact on outcome. |
| MRD characterization for targeted therapy | |||
| ALLG AMLM26 phase 1B/2 study investigating novel therapies to target early relapse and clonal evolution as pre-emptive therapy in AML (INTERCEPT): a multi-arm, precision-based, recursive, platform trial60 | Patients with MRD-relapse ≥18 years | MFC and molecular | Ongoing study: The primary end point is MRD response (≥1 log10 reduction in molecular MRD or flow MRD <0.1%) within 100 days of the first dose of study drug. |
| Intermediate end point | |||
| Early assessment of clofarabine effectiveness based on measurable residual disease, including AML stem cells (HOVON-SAKK 102)38 | N = 291 ≤65 years | MFC including leukemia stem cells and NPM1 | Lower levels of MRD were found in clofarabine-treated patients than in patients treated without clofarabine in the intermediate-I risk group. |
| Umbrella trial in myeloid malignancies: the MyeloMATCH National Clinical Trials Network Precision Medicine Initiative61 | Older adults, MDS and young adults | MFC and NGS | Ongoing study: Assignment of treatment to patients based on biomarkers related to the disease such as mutations and MRD. |
| Trial/study group . | Patients . | MRD technique . | Key finding . |
|---|---|---|---|
| MRD guidance after induction in complete remission in intermediate-risk patients | |||
| GIMEMA 1310, risk-adapted, MRD-directed therapy for young adults with newly diagnosed AML20 | N = 429 ≤60 years | MFC | Similar 2-year survival in MRD-negative intermediate-risk patients receiving autoSCT compared to MRD-positive patients receiving alloSCT. |
| HOVON-SAKK 132: Addition of lenalidomide to intensive treatment in younger and middle-aged adults with newly diagnosed AML21 | N = 780 AML/high-risk MDS ≤65 years | MFC and NPM1 | No difference in outcome between MRD-negative and MRD-positive intermediate-risk patients, while MRD-negative patients were considered eligible for non-alloSCT treatment. |
| ChiCTR-TRC-10001202 and 10001209 NCT03021330: Prognostic effect and clinical application of early MRD by flow cytometry on de novo AML19 | N = 769 <60 years | MFC | Overall survival of MRD-negative patients in favorable and intermediate-risk groups was comparable between transplant and nontransplant patients. |
| Post-remission measurable residual disease directs treatment choice and improves outcomes for patients with intermediate-risk acute myeloid leukemia in CR149 | N = 235 Intermediate risk 14-60 years | MFC | Retrospective analysis of real-world data postremission MRD directs treatment choice and improves outcomes for patients with intermediate-risk AML in CR1. |
| Current retrospective studies showing relevance ofFLT3/ITD as MRD marker | |||
| DNA sequencing to detect residual disease in adults with AML prior to hematopoietic cell transplant15 | N = 1075 AML in CR1 before transplant ≥18 years | NGS | Persistence of FLT3-ITD or NPM1 variants in blood at an allele fraction of 0.01% or higher was associated with increased relapse and worse survival compared with those without variants detected. |
| Prognostic value of FLT3-ITD residual disease in AML23 | N = 161 FLT3-ITD+ AML in CR1 after induction ≥18 years | NGS | FLT3-ITD MRD is prognostic and better identifies patients at risk for relapse compared to MFC or NGS-based NMP1 MRD alone. |
| Pretransplant FLT3-ITD MRD assessed by high-sensitivity PCR-NGS determines posttransplant clinical outcome26 | N = 104 Pretransplant AML 17-68 years | NGS | Pre-HCT detection of FLT3-ITD MRD is related to poor prognosis and can be an indication for future MRD-directed therapeutic strategies. |
| Allogenic stem cell transplantation conditioning/donor selection | |||
| Impact of conditioning intensity of allogeneic transplantation for acute myeloid leukemia with genomic evidence of residual disease (CIBMTR)50 | N = 190 ≥18 years in first CR | NGS: FLT3, NPM1, IDH1, IDH2, and/or KIT variants | MAC rather than RIC in patients with AML with genomic evidence of MRD before alloHCT can result in improved survival. |
| Impact of pre-transplant induction and consolidation cycles on AML allogeneic transplant outcomes: a CIBMTR analysis in 3113 AML patients51 | N = 3113 ≥18 years | MFC, cytogenetics and molecular | Detectable MRD at the time of MAC alloHCT did not impact outcomes while detectable MRD preceding RIC alloHCT was associated with an increased risk of relapse. |
| Measurable residual disease, conditioning regimen intensity, and age predict outcome of allogeneic hematopoietic cell transplantation for acute myeloid leukemia in first remission52 | N = 2292 (EBMT) ≥18 years | MFC and molecular | Patients aged <50 y with AML CR1 MRD-positive status should preferentially be offered MAC alloHCT. Prospective studies are needed to address whether patients who are AML CR1 MRD negative may be spared the toxicity of MAC regimens. |
| Haploidentical allograft is superior to matched sibling donor allograft in eradicating pre-transplantation MRD of AML patients as determined by MFC: a retrospective and prospective analysis53 | N = 339 ≤60 years | MFC | For MRD-positive patients, haploSCT was associated with lower incidence of relapse and better survival, suggesting a stronger antileukemia effect compared to matched sibling donor transplantation. |
| Monitoring during maintenance | |||
| Prospective phase II (NCT00801489): Common kinase mutations do not impact optimal molecular responses in CBF AML treated with fludarabine, cytarabine, and G-CSF based regimens54 | N = 174 ≥18 years | Optimal PCR response FLT3, RAS, and KIT | Attainment of PCR <0.01% during/after consolidation improved RFS and was more important than achieving early optimal PCR response (post C1 PCR <0.1%). |
| Observational cohort: MRD status and FLT3 inhibitor therapy in patients with FLT3/ITD mutated AML following allogeneic hematopoietic cell transplantation55 | N = 34 ≥18 years | NGS: FLT3/ITD | Prognostic significance of NGS-based MRD monitoring for FLT3/ITD and the ability of post-alloSCT maintenance to prevent relapse and death. |
| Measurable residual disease-guided treatment with azacitidine to prevent haematological relapse in patients with myelodysplastic syndrome and acute myeloid leukaemia (RELAZA2): an open-label, multicentre, phase 2 trial56 | N = 53 ≥18 years CR-MRD+ | qPCR: NPM1, DEK-NUP214, RUNX1-RUNX1T1, CBFb-MYH11 | MRD-guided treatment with azacitidine prevented or substantially delayed hematologic relapse with an acceptable safety. |
| Monitoring after treatment | |||
| Posttransplant MRD and T-cell chimerism status predict outcomes in patients allografted with AML/MDS (FIGARO)3 | N = 187 ≥18 years Peri-alloSCT | MFC and T-cell chimerism | Post-alloSCT MRD is an important predictor of outcome and is most informative when combined with T-cell chimerism. |
| Bone marrow CD34+ molecular chimerism as an early predictor of relapse after alloSCT in patients with AML (PROMISE)57 | N = 168 <75 years After alloSCT | Molecular WT1 and CD34+ chimerism | Molecular chimerism and WT1 after alloSCT (first and third months) are useful MRD markers. When considered together at third month, CD34+ molecular chimerism could represent an earlier predictor of relapse compared to WT1. |
| MRD in nonintensively treated patients | |||
| Undetectable measurable residual disease is associated with improved outcomes in AML irrespective of treatment intensity. Retrospective analysis of real world data58 | N = 635 (250 nonintensively treated) ≥18 years | MFC: excluding APL and CBF AML | Achievement of MRD negativity should be the key objective of AML therapy in both high- and low-intensity treatment regimens. |
| Measurable residual disease response and prognosis in treatment-naïve acute myeloid leukemia with venetoclax and azacitidine (VIALE-A)46 | N = 190 (164 in CRc for MRD assessment) ≥18 years | MFC | Patients who achieved CRc and MRD negativity at any time point during treatment with venetoclax and azacitidine had longer duration of response, EFS, and OS than responding MRD-positive patients |
| Ibrutinib added to 10-day decitabine for older patients with AML and higher risk MDS (HOVON-SAKK 135)59 | N = 144 Unfit AML/high-risk MDS >60 years | MFC | After 3 cycles of treatment, 28 (49%) of 57 patients were MRD negative. In this limited number of cases, MRD revealed no apparent impact on outcome. |
| MRD characterization for targeted therapy | |||
| ALLG AMLM26 phase 1B/2 study investigating novel therapies to target early relapse and clonal evolution as pre-emptive therapy in AML (INTERCEPT): a multi-arm, precision-based, recursive, platform trial60 | Patients with MRD-relapse ≥18 years | MFC and molecular | Ongoing study: The primary end point is MRD response (≥1 log10 reduction in molecular MRD or flow MRD <0.1%) within 100 days of the first dose of study drug. |
| Intermediate end point | |||
| Early assessment of clofarabine effectiveness based on measurable residual disease, including AML stem cells (HOVON-SAKK 102)38 | N = 291 ≤65 years | MFC including leukemia stem cells and NPM1 | Lower levels of MRD were found in clofarabine-treated patients than in patients treated without clofarabine in the intermediate-I risk group. |
| Umbrella trial in myeloid malignancies: the MyeloMATCH National Clinical Trials Network Precision Medicine Initiative61 | Older adults, MDS and young adults | MFC and NGS | Ongoing study: Assignment of treatment to patients based on biomarkers related to the disease such as mutations and MRD. |
alloHCT, allogeneic hematopoietic cell transplantation; APL, acute promyelocytic leukemia; autoSCT, autologous stem cell transplantation; CRc, complete remission rate; EBMT, European Society for Blood and Marrow Transplantation; haploSCT, haploidentical stem cell transplantation; HCT, hematopoietic cell transplantation; MAC, myeloablative conditioning; MDS, myelodysplastic syndrome; RFS, relapse free survival; RIC, reduced intensity conditioning.