Prognostic and therapeutic implications of minimal residual disease detection in acute myeloid leukemia

Buccisano, Francesco; Maurillo, Luca; Principe, Maria Ilaria Del; Poeta, Giovanni Del; Sconocchia, Giuseppe; Lo‐Coco, Francesco; Arcese, William; Amadori, Sergio; Venditti, Adriano

doi:10.1182/blood-2011-08-363291

Cited by 234 publications

(182 citation statements)

References 96 publications

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“…Plausibly as a result of these interventions results were superior to those observed in historical controls. Analogous results have been reported in adults [16]. Particularly valuable information is likely to come from the MRC/NCRI AML17 study in the UK in which patients are being randomized to MRD monitoring or not.…”

Section: Minimal Residual Disease (Mrd)supporting

confidence: 62%

“…Patients with the best prognoses can be treated with standard therapy emphasizing higher doses of ara-C post CR (HiDAC) [10], although (a) it remains unknown if the same is true in patients considered best risk based on NPM1/ FLT32 rather than cytogenetics and (b) the exact dose of HiDAC is not clear; however, doses of 1.021.5 g/m 2 seems as effective as 3 g/m 2 [52]. Patients who have inv [16] or t(8;21) together with a CKIT mutation have worse prognoses than patients without a CKIT mutation [7] and thus might be candidates for HCT from a matched sibling donor or for clinical trials involving the CKIT inhibitor dasatinib. The choice of 317 rather than a clinical trial for induction in the intermediate-1 and intermediate-2 groups depends on whether patients see their prognosis with the former as good enough to be reluctant to undertake a clinical trial, which might produce a worse outcome.…”

Section: Summary Of Treatment Recommendationsmentioning

confidence: 99%

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Acute myeloid leukemia: 2013 update on risk‐stratification and management

2013

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Disease overviewAcute myeloid leukemia (AML) results from accumulation of abnormal blasts in the marrow. These cells interfere with normal hematopoiesis, can escape into the peripheral blood, and infiltrate CSF and lung. It is likely that many different mutations, epigenetic aberrations, or abnormalities in micro RNA expression can produce the same morphologic disease with these differences responsible for the very variable response to therapy, which is AMLs principal feature.DiagnosisThis rests on demonstration that the marrow or blood has > 20% blasts of myeloid lineage. Blast lineage is assessed by multiparameter flow cytometry, with CD33 and CD13 being surface markers typically expressed by myeloid blasts. It should be realized that clinical/prognostic considerations, not the blast % per se, should be the main factor determining how a patient is treated.Risk StratificationTwo features determine risk: the probability of treatment‐related mortality (TRM) and, more important, even in patients aged >75 with Zubrod performance status 1, the probability of resistance to standard therapy despite not incurring TRM. The chief predictor of resistance is cytogenetics, with a monosomal karyotype (MK) denoting the disease is essentially incurable with standard therapy even if followed by a standard allogeneic transplant (HCT). The most common cytogentic finding is a normal karyotype(NK) and those of such patients with an NPM1 mutation but no FLT3 internal tandem duplication (ITD), or with a CEBPA mutation, have a prognosis similar to that of patients with the most favorable cytogenetics (inv 16 or t[8;21]) (60–70% cure rate). In contrast, NK patients with a FLT3 ITD have only a 30–40% chance of cure even after HCT. Accordingly analyses of NPM1, FLT3, and CEBPA should be part of routine evaluation, much as is cytogenetics. Risk is best assessed considering several variables simultaneously rather than, for example, only age. Increasing evidence indicates that other mutations and abnormalities in microRNA (miRNA) expression also affect resistance as do post treatment factors, in particular the presence of minimal residual disease. These newer mutations and MRD are discussed in this update.Risk‐adapted therapyPatients with inv (16) or t(8;21) or who are NPM1+/FLT3ITD—can receive standard therapy (daunorubicin + cytarabine) and should not receive HCT in first CR. It seems likely that use of a daily daunorubicin dose of 90 mg/m2 will further improve outcome in these patients. There appears no reason to use doses of cytarabine > 1 g/m2 (for example bid X 6 days), as opposed to the more commonly used 3 g/m2. Patients with an unfavorable karyotype (particularly MK) are unlikely to benefit from standard therapy (even with dose escalation) and are thus prime candidates for clinical trials of new drugs or new approaches to HCT; the latter should be done in first CR. Patients with intermediate prognoses (for example NK and NPM and FLT3ITD negative) should also receive HCT in first CR and can plausibly receive either investigational or standard induction therapy, with the same prognostic information about standard therapy leading one patient to choose the standard and another an investigational option. This update discusses results with newer agents: quizartinib and crenolanib, gemtuzumab ozogamicin, clofarabine and cladribine, azacitidine and decitabine, volasertib, and means to prevent relapse after allogeneic transplant.The diagnosis of AML essentially is made as it was in 2012. Thus this review will emphasize new developments in risk stratification and treatment using as references many papers published in 2012. Am. J. Hematol. 88:318–327, 2013. © 2013 Wiley Periodicals, Inc.

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Section: Minimal Residual Disease (Mrd)supporting

confidence: 62%

Section: Summary Of Treatment Recommendationsmentioning

confidence: 99%

Acute myeloid leukemia: 2013 update on risk‐stratification and management

2013

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“…As previously demonstrated [17,19,21,23], achieving MRD-negative status post-consolidation, regardless of ARA-C schedule, translates into significant RFS and OS prolongations, especially in SDACtreated patients who are MRD negative. The lack of a clear advantage for MRD-negative HDAC recipients is likely due to the small sample size (nine patients) and unusually high TRM, with 30% mortality during stem cell transplantation.…”

Section: Discussionmentioning

confidence: 70%

“…Genetic/cytogenetic abnormalities were classified according to the European LeukemiaNet criteria [22]. LAIP-expressing patients were selected and re-assessed through relevant combinations of antibodies in polychromatic assays [23], that also enabled identification of 2 antibody combinations for each patient, thus minimizing pitfalls due to potential phenotypic changes upon relapse [24,25]. As previously reported, MRD negativity was set at <3.5 3 10 24 residual leukemic cells (RLCs) [16,17,19,23].…”

Section: Methodsmentioning

confidence: 99%

Minimal residual disease as biomarker for optimal biologic dosing of ARA‐C in patients with acute myeloid leukemia

et al. 2014

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We assessed by flow cytometry minimal residual disease (MRD) in patients with acute myeloid leukemia (AML) given standard-dose (SDAC) and high-dose ARA-C (HDAC) regimens. Of 163 patients enrolled, 130 (median age, 45 years; range, 18-59 years) qualified for analysis, all achieving complete remission after treatment with SDAC (n 5 78) or HDAC (n 5 52) plus etoposide and daunorubicin. Consolidation consisted of intermediate-dose ARA-C and daunorubicin. MRD negativity was significantly more frequent in the SDAC vs. HDAC arm after both induction (37% vs. 15%, P 5 0.007) and consolidation (44% vs. 18%, P 5 0.002).Respective median residual leukemic cell counts with SDAC and HDAC use were 1.5 3 10 23 and 4 3 10 23 (P 5 0.033) after induction and 5.7 3 10 24 and 2.9 3 10 23 (P 5 0.008) after consolidation. Based on ARA-C schedule and post-consolidation MRD status, the four patient groups (SDAC-MRD 2 , HDAC-MRD 2 , SDAC-MRD 1 , and HDAC-MRD 1 ) displayed 5-year overall survival rates of 60%, 33%, 24%, and 42% (P 5 0.007), respectively, with 24%, 35%, 74%, and 48% (P < 0.0001) respective cumulative incidence of relapse estimates. MRD may serve as a biomarker for optimal biologic dosing of ARA-C, and SDAC regimen appears to yield more frequent MRD negativity.

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“…RQ-PCR amplifies leukemia-associated genetic abnormalities, while flow cytometric profiling detects leukemiaassociated immunophenotypes (LAIPs). [173][174][175] Both methods have a higher sensitivity than conventional morphology. RQ-PCR has a detection range of 1 in 1000 to 1 in 100,000, while flow cytometry has sensitivity between 10 -4 to 10 -5 .…”

Section: Role Of Mrd Monitoringmentioning

confidence: 99%