A phase 3 trial of azacitidine versus a semi‐intensive fludarabine and cytarabine schedule in older patients with untreated acute myeloid leukemia

Vives, Susana; Martínez‐Cuadrón, David; Burgues, Juan Miguel Bergua; Algarra, Lorenzo; Tormo, Mar; Martínez-Sánchez, María P.; Serrano, Josefina; Herrera, Pilar; Ramos, Fernando; Salamero, Olga; Lavilla, Esperanza; López-Lorenzo, José Luis; Gil, Cristina; Vidriales, B; Falantes, José; Serrano, Alfons; Labrador, Jorge; Sayas, María José; Foncillas, María Ángeles; Barciela, María L. Amador; Olave, María T.; Colorado, Mercedes; Gascón, Adriana; Fernández, María Á.; Simiele, Adriana; Pérez‐Encinas, Manuel; Rodríguez‐Veiga, Rebeca; García, Olga; Martínez‐López, Joaquín; Barragán, Eva; Sanz, Miguel Á.; Montesinos, Pau

doi:10.1002/cncr.33403

Cited by 21 publications

(17 citation statements)

References 33 publications

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“…43,44 Interestingly, we show 30% CR/CRi after non-IC for unfit patients (i.e, FLUGA regimen or similar), but this was not accompanied by improved survival compared to HMA. 45 We reproduce significantly poorer median OS in sAML (5.6 months) as compared to de novo AML (10.9 months). 3,4,28,5,16,19,21,[24][25][26][27] We can affirm that median OS in different studies is affected by the proportion of IC treated patients in each series.…”

Section: Discussionmentioning

confidence: 63%

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Treatment patterns and outcomes of 2310 patients with secondary acute myeloid leukemia: a PETHEMA registry study

et al. 2022

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Secondary acute myeloid leukemia (sAML) comprises a heterogeneous group of patients, and is associated with poor overall survival (OS). We analyze the characteristics, treatment patterns and outcomes of sAML adult patients of the Programa Español de Tratamientos en Hematología (PETHEMA) registry. Overall, 6211 (72.9%) were de novo and 2310 (27.1%) sAML, divided into myelodysplastic syndrome (MDS-AML, 44%), MDS/myeloproliferative (MDS/MPN-AML, 10%), MPN-AML (11%), therapy-related (t-AML, 25%), and antecedent neoplasia without prior chemotherapy/radiotherapy (neo-AML, 9%). Compared to de novo, sAML were older (median age 69 years old), had more ECOG ≥2 (35%) or high-risk cytogenetics (40%), less FLT3-ITD (11%) and NPM1 mutations (21%), and received less intensive chemotherapy regimens (38%) (all P<0.001). Median OS was higher in de novo than in sAML (10.9 vs 5.6 months, P<0.001); and shorter in sAML after hematologic disorder (MDS, MDS/MPN or MPN) as compared to t-AML and neo-AML (5.3 vs 6.1 vs 5.7 months, respectively, P=0.04). After intensive chemotherapy, median OS was better among de novo and neo-AML patients (17.2 and 14.6 months). No OS differences were observed after hypomethylating agents according to type of AML. sAML was as an independent adverse prognostic factor for OS. We confirm high prevalence and adverse features of sAML and we establish its independent adverse prognostic value. This study was registered at www.clinicaltrials.gov as #NCT02607059.

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Section: Discussionmentioning

confidence: 63%

“… 43,44 Interestingly, we show 30% CR/CRi after non-IC for unfit patients (ie, FLUGA regimen or similar), but this was not accompanied by improved survival compared with HMA. 45 …”

Section: Discussionmentioning

confidence: 99%

Treatment patterns and outcomes of 2310 patients with secondary acute myeloid leukemia: a PETHEMA registry study

et al. 2022

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“…All patients provided written informed consent, and the trial was approved by the appropriate institutional review boards or ethics committees of the participating institutions. The study was registered at www.ClinicalTrials.gov as NCT02319135 (accessed on 6 April 2020), and the results of the FLUGAZA trial have been published elsewhere [10,11].…”

Section: Identification Cohortmentioning

confidence: 99%

The Mutational Landscape of Acute Myeloid Leukaemia Predicts Responses and Outcomes in Elderly Patients from the PETHEMA-FLUGAZA Phase 3 Clinical Trial

Ayala

Rapado

Onecha

et al. 2021

Cancers

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We sought to predict treatment responses and outcomes in older patients with newly diagnosed acute myeloid leukemia (AML) from our FLUGAZA phase III clinical trial (PETHEMA group) based on mutational status, comparing azacytidine (AZA) with fludarabine plus low-dose cytarabine (FLUGA). Mutational profiling using a custom 43-gene next-generation sequencing panel revealed differences in profiles between older and younger patients, and several prognostic markers that were useful in young patients were ineffective in older patients. We examined the associations between variables and overall responses at the end of the third cycle. Patients with mutated DNMT3A or EZH2 were shown to benefit from azacytidine in the treatment-adjusted subgroup analysis. An analysis of the associations with tumor burden using variant allele frequency (VAF) quantification showed that a higher overall response was associated with an increase in TET2 VAF (odds ratio (OR), 1.014; p = 0.030) and lower TP53 VAF (OR, 0.981; p = 0.003). In the treatment-adjusted multivariate survival analyses, only the NRAS (hazard ratio (HR), 1.9, p = 0.005) and TP53 (HR, 2.6, p = 9.8 × 10−7) variants were associated with shorter overall survival (OS), whereas only mutated BCOR (HR, 3.6, p = 0.0003) was associated with a shorter relapse-free survival (RFS). Subgroup analyses of OS according to biological and genomic characteristics showed that patients with low–intermediate cytogenetic risk (HR, 1.51, p = 0.045) and mutated NRAS (HR, 3.66, p = 0.047) benefited from azacytidine therapy. In the subgroup analyses, patients with mutated TP53 (HR, 4.71, p = 0.009) showed a better RFS in the azacytidine arm. In conclusion, differential mutational profiling might anticipate the outcomes of first-line treatment choices (AZA or FLUGA) in older patients with AML. The study is registered at ClinicalTrials.gov as NCT02319135.

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“…TET2 mutant patients over 65 years of age with newly diagnosed TET2 mutant AML (UPN31-80) were from the Programa para el Estudio de la Terapeutica en Hemopatias Malignas (PETHEMA) phase 3 FLUGAZA clinical trial (NCT02319135) 6 , which was approved by the Institutional Review Board of Hospital Le Fe, Valencia, Spain (Eudract=2014-000319-15).…”

Section: Patientsmentioning

confidence: 99%

“…Having described a single patient with biallelic TET2 mutation (UPN01) who responded very well to 5-Aza we sought to determine whether biallelic TET2 mutation affected response in other patients treated with 5-Aza. AML patients over the age of 65 years were recruited to the PETHEMA FLUGAZA phase 3 clinical trial and were randomized to receive either 5-Aza or low-dose Ara-C plus fludarabine (FLUGA) 6 . Fifty patients had a TET2 mutation identified by targeted sequencing which included 6 patients with a mutant allele frequency >85% indicative of biallelic TET2 mutation (Table S8).…”

Section: Biallelic Tet2 Alterations In Aml Patients Treated With 5-azamentioning

confidence: 99%

Biallelic TET2 mutation sensitizes to 5’-azacitidine in acute myeloid leukemia

Stölzel

Fordham

Lin

et al. 2021

Preprint

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Precision medicine can significantly improve outcomes for cancer patients, but implementation requires comprehensive characterization of tumor cells to identify therapeutically exploitable vulnerabilities. Here we describe somatic biallelic TET2 mutation (focal deletion and nonsense mutation) in an elderly patient with acute myeloid leukemia (AML) that was chemoresistant to anthracycline and cytarabine, but acutely sensitive to 5-azacitidine (5-Aza) hypomethylating monotherapy, resulting in long-term morphological remission (overall survival (OS) 850 days). Given the role of TET2 as a regulator of genomic methylation, we hypothesized that mutant TET2 allele dosage affects response to 5-Aza. Using an isogenic cell model system and an orthotopic mouse xenograft, we demonstrate that biallelic TET2 mutations confer sensitivity to 5-Aza compared to cells with monoallelic mutation. We subsequently identified 29 additional patients from the Study Alliance Leukemia biobank with chromosome 4 abnormalities and identified two further patients with complex biallelic TET2 mutations, including one with trisomy 4, homozygosity across the long arm and an inactivating point mutation. We also screened patients recruited to the PETHEMA FLUGAZA phase 3 clinical trial and identified three patients with biallelic TET2 mutations, two of whom had responded very well to single agent 5-Aza (OS 767 and 579 days) despite having adverse risk AML and poor performance status. Our data argue in favor of using hypomethylating agents for chemoresistant disease or as first line therapy in patients with biallelic TET2-mutated AML and demonstrate the importance of considering mutant allele dosage in the implementation of precision medicine for cancer patients.

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A phase 3 trial of azacitidine versus a semi‐intensive fludarabine and cytarabine schedule in older patients with untreated acute myeloid leukemia

Cited by 21 publications

References 33 publications

Treatment patterns and outcomes of 2310 patients with secondary acute myeloid leukemia: a PETHEMA registry study

Treatment patterns and outcomes of 2310 patients with secondary acute myeloid leukemia: a PETHEMA registry study

The Mutational Landscape of Acute Myeloid Leukaemia Predicts Responses and Outcomes in Elderly Patients from the PETHEMA-FLUGAZA Phase 3 Clinical Trial

Biallelic TET2 mutation sensitizes to 5’-azacitidine in acute myeloid leukemia

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