Longitudinal minimal residual disease (MRD) evaluation in acute myeloid leukaemia with <i>NPM1</i> mutation: from definition of molecular relapse to MRD‐driven salvage approach

Guolo, Fabio; Minetto, Paola; Clavio, Marino; Miglino, Maurizio; Colombo, Nicoletta; Cagnetta, Antonia; Cea, Michele; Marcolin, R; Todiere, Andrea; Ballerini, Filippo; Gobbi, Marco; Lemoli, Roberto M.

doi:10.1111/bjh.16116

Cited by 11 publications

(15 citation statements)

References 10 publications

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“…Two elderly patients considered unfit for HSCT remain alive at 6 and 12 months respectively. As detectable NPM1 mut ‐MRD levels prior to HSCT are associated with inferior outcomes, 6–8 it would seem reasonable to consider venetoclax‐based therapy to try to attain a molecular CR before transplantation 9,15 …”

Section: Discussionmentioning

confidence: 99%

Venetoclax induces rapid elimination of NPM1 mutant measurable residual disease in combination with low‐intensity chemotherapy in acute myeloid leukaemia

et al. 2020

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Summary Based on promising results in older adults with acute myeloid leukaemia (AML), we treated patients with NPM1mut measurable residual disease (MRD) using off‐label venetoclax in combination with low‐dose cytarabine or azacitidine. Twelve consecutive patients were retrospectively identified, including five with molecular persistence and seven with molecular relapse/progression. All patients with molecular persistence achieved durable molecular complete remission (CRMRD‐) without transplantation. Six of seven patients with molecular relapse/progression achieved CRMRD‐ after 1–2 cycles of venetoclax. This paper highlights the promising efficacy of venetoclax‐based therapy to reduce the relapse risk in patients with persistent or rising NPM1mut MRD.

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Section: Discussionmentioning

confidence: 99%

Venetoclax induces rapid elimination of NPM1 mutant measurable residual disease in combination with low‐intensity chemotherapy in acute myeloid leukaemia

et al. 2020

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“…Varying lead times have also been reported in studies of NPM1-mutated AML. Guolo et al 45 reported a median lead time from NPM1 BM MRD re-occurrence to overt clinical relapse of 4Á5 months, but with a rather wide range of 1-8Á4 months. This is in agreement with results reported by Chou et al 26 [median (range) lead time of 4Á9 (1-12Á3) months] and Dvorakova et al 48 [median (range) lead time 97 days].…”

Section: Relapse Kinetics Molecular Relapse Definition and Resulting Lead Timesmentioning

confidence: 99%

“…Likewise, the ability of rising NPM1 mutant transcript levels in PB and/or BM to predict relapse has been reported in numerous studies. 14,16,18,20,26,40,41,[45][46][47][48][49] Loss of mutated NPM1 at relapse has been observed with variable frequency ranging from 1% to 12%. 14,17,[50][51][52][53] However, as a founder genetic lesion, mutated NPM1 is generally considered a stable marker, invariably present at relapse in numerous studies.…”

Section: Persistent Low-level Qpcr Mrd During Longterm Remissionmentioning

confidence: 99%

“…During recent decades, several studies have investigated the feasibility and effect of qPCR MRD-directed therapy using a variety of treatment regimens (Table III). 45,64,[70][71][72][73][74][75]88 Doubek et al 70,71 investigated frequent MRD monitoring in two small series of patients and found that the majority of those treated with pre-emptive chemotherapy, gemtuzumab or immunotherapy after SCT showed a molecular response (12/15 patients in total), albeit CR was sustained in only four patients. In recent studies of NPM1-mutated AML, patients with rising qPCR MRD levels were allocated to SCT with or without prior salvage chemotherapy, which resulted in long-term survival in 60-80% of the patients.…”

Section: Relapse and Pre-emptive Treatment Strategies Of Molecular Mrdmentioning

confidence: 99%

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Peripheral blood molecular measurable residual disease is sufficient to identify patients with acute myeloid leukaemia with imminent clinical relapse

et al. 2021

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Longitudinal molecular measurable residual disease (MRD) sampling after completion of therapy serves as a refined tool for identification of imminent relapse of acute myeloid leukaemia (AML) among patients in long-term haematological complete remission. Tracking of increasing quantitative polymerase chain reaction MRD before cytomorphological reappearance of blasts may instigate individual management decisions and has paved the way for development of preemptive treatment strategies to substantially delay or perhaps even revert leukaemic regrowth. Traditionally, MRD monitoring is performed using repeated bone marrow aspirations, albeit the current European LeukemiaNet MRD recommendations acknowledge the use of peripheral blood as an alternative source for MRD assessment. Persistent MRD positivity in the bone marrow despite continuous morphological remission is frequent in both core binding factor leukaemias and nucleophosmin 1-mutated AML. In contrast, monthly assessment of MRD in peripheral blood superiorly separates patients with imminent haematological relapse from longterm remitters and may allow pre-emptive therapy of AML relapse.

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“…This is probably of highest relevance when the aim of monitoring is early detection of pending relapse, a situation where RT‐qPCR may be superior, at least in cases with fast relapse kinetics. However, in patients with NPM1 mutation without FLT3 ‐ITD, molecular progression often occur over several months before hematological relapse 40,41 …”

Section: Discussionmentioning

confidence: 99%

Comparison of RNA‐ and DNA‐based methods for measurable residual disease analysis in NPM1‐mutated acute myeloid leukemia

Pettersson

Alm

Almstedt³

et al. 2021

Int J Lab Hematology

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Introduction Reverse transcriptase quantitative PCR (RT‐qPCR) is considered the method of choice for measurable residual disease (MRD) assessment in NPM1‐mutated acute myeloid leukemia (AML). MRD can also be determined with DNA‐based methods offering certain advantages. We here compared the DNA‐based methods quantitative PCR (qPCR), droplet digital PCR (ddPCR), and targeted deep sequencing (deep seq) with RT‐qPCR. Methods Of 110 follow‐up samples from 30 patients with NPM1‐mutated AML were analyzed by qPCR, ddPCR, deep seq, and RT‐qPCR. To select DNA MRD cutoffs for bone marrow, we performed receiver operating characteristic analyses for each DNA method using prognostically relevant RT‐qPCR cutoffs. Results The DNA‐based methods showed strong intermethod correlation, but were less sensitive than RT‐qPCR. A bone marrow cutoff at 0.1% leukemic DNA for qPCR or 0.05% variant allele frequency for ddPCR and deep seq offered optimal sensitivity and specificity with respect to 3 log10 reduction of NPM1 transcripts and/or 2% mutant NPM1/ABL. With these cutoffs, MRD results agreed in 95% (191/201) of the analyses. Although more sensitive, RT‐qPCR failed to detect leukemic signals in 10% of samples with detectable leukemic DNA. Conclusion DNA‐based MRD techniques may complement RT‐qPCR for assessment of residual leukemia. DNA‐based methods offer high positive and negative predictive values with respect to residual leukemic NPM1 transcripts at levels of importance for response to treatment. However, moving to DNA‐based MRD methods will miss a proportion of patients with residual leukemic RNA, but on the other hand some MRD samples with detectable leukemic DNA can be devoid of measurable leukemic RNA.

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Longitudinal minimal residual disease (MRD) evaluation in acute myeloid leukaemia with NPM1 mutation: from definition of molecular relapse to MRD‐driven salvage approach

Cited by 11 publications

References 10 publications

Venetoclax induces rapid elimination of NPM1 mutant measurable residual disease in combination with low‐intensity chemotherapy in acute myeloid leukaemia

Venetoclax induces rapid elimination of NPM1 mutant measurable residual disease in combination with low‐intensity chemotherapy in acute myeloid leukaemia

Peripheral blood molecular measurable residual disease is sufficient to identify patients with acute myeloid leukaemia with imminent clinical relapse

Comparison of RNA‐ and DNA‐based methods for measurable residual disease analysis in NPM1‐mutated acute myeloid leukemia

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