Early minimal residual disease assessment after AML induction with fludarabine, cytarabine and idarubicin (<scp>FLAI</scp>) provides the most useful prognostic information

Minetto, Paola; Guolo, Fabio; Clavio, Marino; Kunkl, Annalisa; Colombo, Nicoletta; Carminati, Enrico; Fugazza, Giuseppina; Matarese, Simona; Guardo, Daniela; Ballerini, Filippo; Grazia, Carmen Di; Raiola, Anna Maria; Cagnetta, Antonia; Cea, Michele; Miglino, Maurizio; Lemoli, Roberto M.; Gobbi, Marco

doi:10.1111/bjh.15106

Cited by 12 publications

(11 citation statements)

References 9 publications

(14 reference statements)

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“…Notably, 51% (54/106) of patients that obtained a cytological CR after induction, reached complete molecular remission, as assessed by WT1 expression. These findings highlight the ability of the FLAI‐GO regimen to induce a good debulking effect and a deep response, supporting the value of WT1 as a marker of MRD, although WT1 is not still worldwide considered a standard tool for MRD assessment . Furthermore, in the present study both univariate and multivariate analysis showed that the achievement of a molecular response after FLAI‐GO (WT1 less than 70 copies) significantly improved OS and DFS (Table ).…”

Section: Discussionsupporting

confidence: 76%

Flai (fludarabine, cytarabine, idarubicin) plus low‐dose Gemtuzumab Ozogamicin as induction therapy in CD33‐positive AML: Final results and long term outcome of a phase II multicenter clinical trial

et al. 2018

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The aim of this prospective clinical trial was to evaluate the efficacy and safety of a combination of Gemtuzumab-Ozogamicin (GO) and FLAI scheme (fludarabine, cytarabine, idarubicin) as a first-line therapy in CD33 positive AML. We treated 130 patients, aged <65, with a median age of 52 years. FLAI-GO induction regimen included fludarabine (30 mg/sqm) and cytarabine (2 g/sqm) on days 1-5; idarubicin (10 mg/sqm) on days 1, 3, and 5; and GO (3 mg/sqm) on day 6. SCT was planned for all high-risk AML patients, after consolidation with intermediate doses of cytarabine and idarubicin and a high dose of cytarabine. CD33 expression exceeded 20% in all cases. Primary endpoints of the study included feasibility, overall response rate (ORR) and toxicity. Secondary endpoints included the evaluation of MRD by WT1 expression, feasibility and outcome of consolidation with SCT, overall survival (OS) and disease-free survival (DFS). After induction with FLAI-GO, complete remission (CR) rate was 82%. Four patients achieved partial remission (PR) and 12% were resistant (ORR 85%); death during induction (DDI) was 3%. The hematological and extra hematological toxicity of FLAI-GO was manageable; 45% of patients experienced transient and reversible GO infusion related adverse events. In the setting of patients who achieved a cytological CR after FLAI-GO, the mean of WT1 copies dropped from 8337±9936 copies/10 ABL (diagnosis) to 182 ± 436 copies after induction therapy (p = 0.0001) showing a very good disease debulking. After a median follow-up of 54 months, 67/130 (52%) patients were alive. The probability of 1, 2, and 5-year OS was 80%, 63%, and 52%, respectively. The probability of 1, 2, and 5-year DFS was 77%, 58%, and 52%, respectively. Allogeneic and autologous SCT was performed in 60 (46%) and 23 (18%) patients, respectively. In summary, the final results of this trial confirm that FLAI-GO is an active and safe treatment strategy for CD33-positive AML patients aged ≤ 65 years, allowing a high ORR, a good disease debulking, favorable safety profile, low DDI, and subsequent high SCT rate. The encouraging results of this trial, consolidated by a long follow-up, support the reintroduction of GO in clinical practice.

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Section: Discussionsupporting

confidence: 76%

Flai (fludarabine, cytarabine, idarubicin) plus low‐dose Gemtuzumab Ozogamicin as induction therapy in CD33‐positive AML: Final results and long term outcome of a phase II multicenter clinical trial

et al. 2018

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“…Minetto and colleagues addressed the issue of the best time-point of MRD assessment by flow cytometry. In a cohort of AML patients treated with a fludarabine-based induction regimen, they showed that early MRD assessment (after induction) is the strongest predictor of outcome [8]. Moreover, they confirmed their previous observation that the integration MRD monitoring by flow cytometry and molecular biology on WT1 leads to an improvement in prognostic stratification.…”

Section: Discussionsupporting

confidence: 60%

“…This was previously demonstrated in their paper on the impact of MRD status before allo-SCT. Thanks to the combination of the high positive predictive value of WT1 MRD and the high negative predictive value of flow cytometry MRD, three cohorts of patients could be identified according to MRD status before transplant, showing worsening outcome: negative by WT1 and flow cytometry, positive by flow cytometry and negative by WT1, and positive by WT1 and flow cytometry [8]. In this complex scenario, allo-SCT should be offered to those patients who have less than 20–30% of expected long-term overall survival with conventional chemotherapy (usually high-risk AML) [7].…”

Section: Discussionmentioning

confidence: 99%

“…In the era of the next generation sequencing, many more data on molecular markers of AML will be available [10]. Moreover, the dynamic monitoring of MRD either by flow cytometry or by molecular biology is becoming a useful tool for early allocation of patients in different risk categories and, for example, for addressing patients who do not clear MRD to intensive treatments or new target drugs before allo-SCT [8, 9]. As a consequence, clinicians have to be very skillful in combining these data with the clinical prognostic factors.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Biological versus Clinical Risk Factors in Acute Myeloid Leukemia: Is There a Winner?

Malagola

Polverelli

Cancelli

et al. 2019

Case Reports in Hematology

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We present a case of a patient with a three-month history of peripheral blood cytopenia without a confirmed diagnosis of myelodysplastic syndrome, who developed a favourable-risk acute myeloid leukemia (AML), according to the European Leukemia Net (ELN) criteria. The patient achieved a complete remission with incomplete platelet recovery (CRi) after induction. The patient achieved the morphological CR after the first consolidation and completed the first-line treatment with a syngeneic stem cell transplantation (SCT). A disease relapse occurred after one year of CR (blast cell count in the bone marrow 15%), and the patient was offered a haplo-SCT, which he refused due to personal reasons. In this paper, we discuss the interplay between clinical and biological risk factors in non-high-risk AML patients and speculate that some old clinical risk factors (e.g., age of the patient, achievement of CR after induction, and previous history of myelodysplastic syndrome) may still impact on the treatment decision algorithm of some of these patients.

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“…It should be mentioned that the controversial interpretation of the prognostic value of MRD in different studies may be attributed to the number of induction and consolidation courses completed at the time of MFC MRD monitoring, and the modality and intensity of induction regimens, as reported by Minetto et al. for fludarabine plus high dose cytarabine-based induction, an earlier timepoint of MRD assessment may provide the most significant information on outcome ( 26 ).…”

Section: Discussionmentioning

confidence: 99%

Measurable Residual Disease Detected by Multiparameter Flow Cytometry and Sequencing Improves Prediction of Relapse and Survival in Acute Myeloid Leukemia

et al. 2021

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The clinically ideal time point and optimal approach for the assessment of measurable residual disease (MRD) in patients with acute myeloid leukemia (AML) are still inconclusive. We investigated the clinical value of multiparameter flow cytometry-based MRD (MFC MRD) after induction (n = 492) and two cycles of consolidation (n = 421). The latter time point was proved as a superior indicator with independent prognostic significance for both relapse-free survival (RFS, HR = 3.635, 95% CI: 2.433–5.431, P <0.001) and overall survival (OS: HR = 3.511, 95% CI: 2.191–5.626, P <0.001). Furthermore, several representative molecular MRD markers were compared with the MFC MRD. Both approaches can establish prognostic value in patients with NPM1 mutations, and FLT3, C-KIT, or N-RAS mutations involved in kinase-related signaling pathways, while the combination of both techniques further refined the risk stratification. The detection of RUNX1–RUNX1T1 fusion transcripts achieved a considerable net reclassification improvement in predicting the prognosis. Conversely, for patients with biallelic CEBPA or DNMT3A mutations, only the MFC method was recommended due to the poor prognostic discriminability in tracking mutant transcripts. In conclusion, this study demonstrated that the MFC MRD after two consolidation cycles independently predicted clinical outcomes, and the integration of MFC and molecular MRD should depend on different types of AML-related genetic lesions.

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Early minimal residual disease assessment after AML induction with fludarabine, cytarabine and idarubicin (FLAI) provides the most useful prognostic information

Cited by 12 publications

References 9 publications

Flai (fludarabine, cytarabine, idarubicin) plus low‐dose Gemtuzumab Ozogamicin as induction therapy in CD33‐positive AML: Final results and long term outcome of a phase II multicenter clinical trial

Flai (fludarabine, cytarabine, idarubicin) plus low‐dose Gemtuzumab Ozogamicin as induction therapy in CD33‐positive AML: Final results and long term outcome of a phase II multicenter clinical trial

Biological versus Clinical Risk Factors in Acute Myeloid Leukemia: Is There a Winner?

Measurable Residual Disease Detected by Multiparameter Flow Cytometry and Sequencing Improves Prediction of Relapse and Survival in Acute Myeloid Leukemia

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