Minimal residual disease evaluation by flow cytometry is a complementary tool to cytogenetics for treatment decisions in acute myeloid leukaemia

For PETHEMA Programa para el Estudio de la Terapéutica en Hemopatías Malignas Cooperative Study Group.The clinical utility of minimal residual disease (MRD) analysis in acute myeloid leukaemia (AML) is not yet defined. We analysed the prognostic impact of MRD level at complete remision after induction therapy using multiparameter flow cytometry in 306 non-APL AML patients. First, we validated the prognostic value of MRD-thresholds we have previously proposed (≥0.1%; ≥0.01-0.1%; and <0.01), with a 5-year RFS of 38%, 50% and 71%, respectively (p = 0.002). Cytogenetics is the most relevant prognosis factor in AML, however intermediate risk cytogenetics represent a grey zone that require other biomarkers for risk stratification, and we show that MRD evaluation discriminate three prognostic subgroups (p = 0.03). Also, MRD assessments yielded relevant information on favourable and adverse cytogenetics, since patients with favourable cytogenetics and high MRD levels have poor prognosis and patients with adverse cytogenetics but undetectable MRD overcomes the adverse prognosis. Interestingly, in patients with intermediate or high MRD levels, intensification with transplant improved the outcome as compared with chemotherapy, while the type of intensification therapy did not influenced the outcome of patients with low MRD levels. Multivariate analysis revealed age, MRD and cytogenetics as independent variables. Moreover, a scoring system, easy in clinical practice, was generated based on MRD level and cytogenetics.This work was supported in part by Spanish grants from Fondo de Investigación Sanitaria-ISCIII (FIS 00/0023-03, PI12/02321), DGCYT (SAF 94- 0308, SAF2001-1687), Conserjería de Educación de Castilla y León (HUS416A12), and Red Temática de Investigación Cooperativa en Cáncer (RTICC-ISCIII) (RD12/0036/0069).Peer Reviewe

Differences in ex-vivo Chemosensitivity to Anthracyclines in First Line Acute Myeloid Leukemia

Induction schedules in acute myeloid leukemia (AML) are based on combinations of cytarabine and anthracyclines. The choice of the anthracycline employed has been widely studied in multiple clinical trials showing similar complete remission rates. Using an ex vivo test we have analyzed if a subset of AML patients may respond differently to cytarabine combined with idarubicin, daunorubicin or mitoxantrone. Bone marrow (BM) samples of 198 AML patients were incubated for 48 hours in 96 well plates, each well containing different drugs or drug combinations at different concentrations. Ex vivo drug sensitivity analysis was made using the PharmaFlow platform maintaining the BM microenvironment. Drug response was evaluated as depletion of AML blast cells in each well after incubation. Annexin V-FITC was used to quantify the ability of the drugs to induce apoptosis, and pharmacological responses were calculated using pharmacokinetic population models. Similar dose-respond graphs were generated for the three anthracyclines, with a slight decrease in EC with idarubicin (p=1.462E-06), whereas the interpatient variability of either drug was large. To identify those cases of selective sensitivity to anthracyclines, potency was compared, in terms of area under the curve. Differences in anthracycline monotherapy potency greater than 30% from 3 pairwise comparisons were identified in 28.3% of samples. Furthermore, different sensitivity was detected in 8.2% of patients comparing combinations of cytarabine and anthracyclines. A third of the patients could benefit from the use of this test in the first line induction therapy selection, although it should be confirmed in a clinical trial specifically designed

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

PETHEMA Group.[Background] Options to treat elderly patients (≥65 years old) newly diagnosed with acute myeloid leukemia (AML) include intensive and attenuated chemotherapy, hypomethylating agents with or without venetoclax, and supportive care. This multicenter, randomized, open-label, phase 3 trial was designed to assess the efficacy and safety of a fludarabine, cytarabine, and filgrastim (FLUGA) regimen in comparison with azacitidine (AZA).[Methods] Patients (n = 283) were randomized 1:1 to FLUGA (n = 141) or AZA (n = 142). Response was evaluated after cycles 1, 3, 6, and 9. Measurable residual disease (MRD) was assessed after cycle 9. When MRD was ≥0.01%, patients continued with the treatment until relapse or progressive disease. Patients with MRD < 0.01% suspended treatment to enter the follow-up phase. [Results] The complete remission (CR) rate after 3 cycles was significantly better in the FLUGA arm (18% vs 9%; P = .04), but the CR/CR with incomplete recovery rate at 9 months was similar (33% vs 29%; P = .41). There were no significant differences between arms in early mortality at 30 or 60 days. Hematologic toxicities were more frequent with FLUGA, especially during induction. The 1-year overall survival (OS) rate and the median OS were superior with AZA versus FLUGA: 47% versus 27% and 9.8 months (95% confidence interval [CI], 5.6-14 months) versus 4.1 months (95% CI, 2.7-5.5 months; P = .005), respectively. The median event-free survival was 4.9 months (95% CI, 2.8-7 months) with AZA and 3 months (95% CI, 2.5-3.5 months) with FLUGA (P = .001). [Conclusions] FLUGA achieved more remissions after 3 cycles, but the 1-year OS rate was superior with AZA. However, long-term outcomes were disappointing in both arms (3-year OS rate, 10% vs 5%). This study supports the use of an AZA backbone for future combinations in elderly patients with AML.This study was supported by the Spanish Biomedical Research Centre in Cancer of the Carlos III Health Institute (CB16/12/00369) and by the Carlos III Health Institute/Subdirectorate General for Health Research (FIS No. PI16/01661). Celgene provided the azacitidine and financial support for this study

Genomics improves risk stratifi cation of adults with T-cell acute lymphoblastic leukemia enrolled in measurable residual disease-oriented trials

Genetic information has been crucial to understand the pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL) at diagnosis and at relapse, but still nowadays has a limited value in a clinical context. Few genetic markers are associated with the outcome of T-ALL patients, independently of measurable residual disease (MRD) status after therapy. In addition, the prognostic relevance of genetic features may be modulated by the specific treatment used. We analyzed the genetic profile of 145 T-ALL patients by targeted deep sequencing. Genomic information was integrated with the clinical -biological and survival data of a subset of 116 adult patients enrolled in two consecutive MRD-oriented trials of the Spanish PETHEMA (Programa Espanol de Tratamientos en Hematologia) group. Genetic analysis revealed a mutational profile defined by DNMT3A/ N/KRAS/ MSH2/ U2AF1 gene mutations that identified refractory/resistant patients. Mutations in the DMNT3A gene were also found in the non-leukemic cell fraction of patients with T-ALL, revealing a possible mutational-driven clonal hematopoiesis event to prime T-ALL in elderly. The prognostic impact of this adverse genetic profile was independent of MRD status on day +35 of induction therapy. The combined worse-outcome genetic signature and MRD on day +35 allowed risk stratification of T-ALL into standard or high-risk groups with significantly different 5 -year overall survival (OS) of 52% (95% confidence interval: 37-67) and 17% (95% confidence interval: 1-33), respectively. These results confirm the relevance of the tumor genetic profile in predicting patient outcome in adult T-ALL and highlight the need for novel gene-targeted chemotherapeutic schedules to improve the OS of poor-prognosis T-ALL patients

Long-Term Outcomes After Autologous Versus Allogeneic Stem Cell Transplantation in Molecularly-Stratified Patients With Intermediate Cytogenetic Risk Acute Myeloid Leukemia: A PETHEMA Study

PETHEMA (Programa Español de Tratamientos en Hematología) and GETH (Grupo Espa~nol de Trasplante Hematopoyético y Terapia Celular) Cooperative GroupsAcute myeloid leukemia (AML) with intermediate risk cytogenetics (IRcyto) comprises a variety of biological entities with distinct mutational landscapes that translate into differential risks of relapse and prognosis. Optimal postremission therapy choice in this heterogeneous patient population is currently unsettled. In the current study, we compared outcomes in IRcyto AML recipients of autologous (autoSCT) (n = 312) or allogeneic stem cell transplantation (alloSCT) (n = 279) in first complete remission (CR1). Molecular risk was defined based on CEBPA, NPM1, and FLT3-ITD mutational status, per European LeukemiaNet 2017 criteria. Five-year overall survival (OS) in patients with favorable molecular risk (FRmol) was 62% (95% confidence interval [CI], 50-72) after autoSCT and 66% (95% CI, 41-83) after matched sibling donor (MSD) alloSCT (P = .68). For patients of intermediate molecular risk (IRmol), MSD alloSCT was associated with lower cumulative incidence of relapse (P < .001), as well as with increased nonrelapse mortality (P = .01), as compared to autoSCT. The 5-year OS was 47% (95% CI, 34-58) after autoSCT and 70% (95% CI, 59-79) after MSD alloSCT (P = .02) in this patient subgroup. In a propensity-score matched IRmol subcohort (n = 106), MSD alloSCT was associated with superior leukemia-free survival (hazard ratio [HR] 0.33, P = .004) and increased OS in patients alive 1 year after transplantation (HR 0.20, P = .004). These results indicate that, within IRcyto AML in CR1, autoSCT may be a valid option for FRmol patients, whereas MSD alloSCT should be the preferred postremission strategy in IRmol patients.Supported by a Río Hortega academic clinical fellowship (CM19/00194) from the Instituto de Salud Carlos III, Spain (E.R.A.). Additional funding has been provided by CIBERONC grants to J.P.S. (CB16/12/00480), M.M.S. (CB16/12/00369) and B.V. (CB16/12/00233)

Chemotherapy or allogeneic transplantation in high-risk Philadelphia chromosome–negative adult lymphoblastic leukemia

The need for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in adults with Philadelphia chromosome–negative (Ph−) acute lymphoblastic leukemia (ALL) with high-risk (HR) features and adequate measurable residual disease (MRD) clearance remains unclear. The aim of the ALL-HR-11 trial was to evaluate the outcomes of HR Ph− adult ALL patients following chemotherapy or allo-HSCT administered based on end-induction and consolidation MRD levels. Patients aged 15 to 60 years with HR-ALL in complete response (CR) and MRD levels (centrally assessed by 8-color flow cytometry) <0.1% after induction and <0.01% after early consolidation were assigned to receive delayed consolidation and maintenance therapy up to 2 years in CR. The remaining patients were allocated to allo-HSCT. CR was attained in 315/348 patients (91%), with MRD <0.1% after induction in 220/289 patients (76%). By intention-to-treat, 218 patients were assigned to chemotherapy and 106 to allo-HSCT. The 5-year (±95% confidence interval) cumulative incidence of relapse (CIR), overall survival (OS), and event-free survival probabilities for the whole series were 43% ± 7%, 49% ± 7%, and 40% ± 6%, respectively, with CIR and OS rates of 45% ± 8% and 59% ± 9% for patients assigned to chemotherapy and of 40% ± 12% and 38% ± 11% for those assigned to allo-HSCT, respectively. Our results show that avoiding allo-HSCT does not hamper the outcomes of HR Ph− adult ALL patients up to 60 years with adequate MRD response after induction and consolidation. Better postremission alternative therapies are especially needed for patients with poor MRD clearance

Tratamiento adaptado al riesgo de la leucemia promielocítica aguda con ATRA y quimioterapia

El tratamiento actual de la leucemia promielocítica aguda (LPA) con la combinación de ácido trans-retinóico (ATRA) y quimioterapia proporciona una tasa muy elevada de curaciones. No obstante, aunque estrecho, hay un margen de mejora mediante la reducción de cada una de las diferentes causas de fracaso terapéutico. Dada la heterogeneidad de estas causas de fracaso, planteamos la hipótesis de que un análisis de dichas causas y la identificación de las variables ligadas al paciente, a su enfermedad y al propio tratamiento, podrían ser de ayuda en la implementación de las medidas apropiadas para mejorar dichos resultados. Así, la identificación de diferentes variables pronósticas podría ayudar a diseñar esquemas de tratamiento adaptado al riesgo. El análisis pormenorizado, a corto y a largo plazo, de las diferentes complicaciones y de los resultados de los esquemas quimioterápicos en sus diferentes fases, deberían ayudar a refinar el manejo de las complicaciones y optimizar los futuros protocolos con el fin de ofrecer una menor toxicidad, pero al mismo tiempo manteniendo una elevada eficacia antileucémica. Esta Tesis recoge los resultados de 3 estudios publicados en 2 revistas internacionales de alto impacto especializadas en hematología. Todos ellos comparten un nexo común; el análisis de una serie de pacientes tratados con dos protocolos consecutivos del grupo cooperativo Español PETHEMA (LPA96 y LPA99) para el tratamiento de la LPA. El primer estudio evalúa los resultados a largo plazo del protocolo LPA99, con consolidaciones adaptadas al riesgo de recaída según el índice pronóstico desarrollado conjuntamente en el año 2000 por los grupos PETHEMA y GIMEMA. Este trabajo ofreció unos resultados robustos sobre el impacto positivo de las modificaciones realizadas en la intensidad de la dosificación de las antraciclinas y del ATRA en aquellos pacientes con riesgo intermedio y alto de recaída. Éste sirvió de base para los siguientes protocolos de tratamiento de la LPA del grupo PETHEMA. El segundo estudio se centró en el análisis detallado de una complicación propia del tratamiento de inducción: el síndrome de diferenciación. Este estudio se planteó identificar los factores de riesgo para el desarrollo de este síndrome, con el fin de adaptar la profilaxis y el manejo del mismo según el riesgo de presentar formas graves del mismo. Gracias a este trabajo, la prevención del síndrome de diferenciación se implementó de forma adaptada al riesgo en los siguientes protocolos PETHEMA. El tercer trabajo analizó el impacto pronóstico de un marcador molecular presente en la LPA, las mutaciones de FLT3. Existiendo controversia sobre el valor pronóstico independiente de FLT3, y por tanto de su posible incorporación a estrategias terapéuticas adaptadas al riesgo, desde el grupo PETHEMA se realizó este estudio de marcado carácter traslacional. Los resultados ayudaron a establecer la incidencia y las características clínicas y biológicas asociadas a la presencia de FLT3, y sirvieron para tomar la decisión de no realizar modificaciones en los algoritmos terapéuticos basados en la presencia de ese marcador. Este conjunto de estudios ha permitido un conocimiento profundo y un avance en el manejo de la LPA en sus sucesivas fases de tratamiento. Sin embargo, los hallazgos reportados aquí tendrán que ser validados en diferentes contextos terapéuticos.Current treatment of acute promyelocytic leukemia (APL) with all trans-retinoic acid (ATRA) and chemotherapy combination provides a very high rate of cures. However, although narrow, there is room for improvement by reducing each of the different causes of treatment failure. Given the heterogeneity of the causes of failure, we hypothesize that an analysis of these causes and the identification of prognostic variables associated to the patient, leukemia, or to the treatment itself, could be useful to implement therapeutic measures to improve the clinical outcomes. Thus, the identification of prognostic variables could help to design risk-tadapted strategies. A detailed analysis of the short and long term complications and outcomes in different therapeutic phases, should help to refine the management of these complications and optimise future protocols, in order to offer a lower toxicity while maintaining a high antileukemic efficacy. This study includes the results of 3 manuscripts published in 2 high impact journals specialized in hematology. They all share a common feature; the analysis of a large series of patients treated with two consecutive protocols of the Spanish cooperative group PETHEMA for the treatment of APL (LPA96 and LPA99 trials). The first manuscript assessed the long-term results of the LPA99 trial, using a risk-adapted chemotherapy schedule based on the relapse score developed jointly in 2000 by the PETHEMA and GIMEMA groups. This analysis provided robust results, showing the positive impact of the intensification of the dosage of anthracyclines and ATRA in those patients with intermediate and high risk of relapse. This was the basis for the subsequent APL trials of the PETHEMA group. The second manuscript aimed to analyse a life-threatening complication of induction therapy in APL: the differentiation syndrome. This study identified the risk factors for the development of this syndrome, in order to adapt the prophylaxis and management according to the risk of developing severe forms. Thanks to this work, the prevention of differentiation syndrome was implemented using a risk-adapted startegy in the following PETHEMA trials. The third manuscript examined the prognostic impact of a molecular marker in APL, the FLT3 mutations. There was controversy about the independent prognostic value of FLT3 and its potential use to design risk-adapted therapeutic strategies. Our study permitted to establish the clinical and biological characteristics associated with the presence of FLT3, and recommended not to make changes in the therapeutic algorithms based on the presence of these mutations. This set of studies has allowed a deep understanding and a step forward in the management of APL in successive phases of treatment. However, the findings reported here will have to be validated in different therapeutic contexts

Tratamiento adaptado al riesgo de la leucemia promielocítica aguda con ATRA y quimioterapia

El tratamiento actual de la leucemia promielocítica aguda (LPA) con la combinación de ácido trans-retinóico (ATRA) y quimioterapia proporciona una tasa muy elevada de curaciones. No obstante, aunque estrecho, hay un margen de mejora mediante la reducción de cada una de las diferentes causas de fracaso terapéutico. Dada la heterogeneidad de estas causas de fracaso, planteamos la hipótesis de que un análisis de dichas causas y la identificación de las variables ligadas al paciente, a su enfermedad y al propio tratamiento, podrían ser de ayuda en la implementación de las medidas apropiadas para mejorar dichos resultados. Así, la identificación de diferentes variables pronósticas podría ayudar a diseñar esquemas de tratamiento adaptado al riesgo. El análisis pormenorizado, a corto y a largo plazo, de las diferentes complicaciones y de los resultados de los esquemas quimioterápicos en sus diferentes fases, deberían ayudar a refinar el manejo de las complicaciones y optimizar los futuros protocolos con el fin de ofrecer una menor toxicidad, pero al mismo tiempo manteniendo una elevada eficacia antileucémica. Esta Tesis recoge los resultados de 3 estudios publicados en 2 revistas internacionales de alto impacto especializadas en hematología. Todos ellos comparten un nexo común; el análisis de una serie de pacientes tratados con dos protocolos consecutivos del grupo cooperativo Español PETHEMA (LPA96 y LPA99) para el tratamiento de la LPA. El primer estudio evalúa los resultados a largo plazo del protocolo LPA99, con consolidaciones adaptadas al riesgo de recaída según el índice pronóstico desarrollado conjuntamente en el año 2000 por los grupos PETHEMA y GIMEMA. Este trabajo ofreció unos resultados robustos sobre el impacto positivo de las modificaciones realizadas en la intensidad de la dosificación de las antraciclinas y del ATRA en aquellos pacientes con riesgo intermedio y alto de recaída. Éste sirvió de base para los siguientes protocolos de tratamiento de la LPA del grupo PETHEMA. El segundo estudio se centró en el análisis detallado de una complicación propia del tratamiento de inducción: el síndrome de diferenciación. Este estudio se planteó identificar los factores de riesgo para el desarrollo de este síndrome, con el fin de adaptar la profilaxis y el manejo del mismo según el riesgo de presentar formas graves del mismo. Gracias a este trabajo, la prevención del síndrome de diferenciación se implementó de forma adaptada al riesgo en los siguientes protocolos PETHEMA. El tercer trabajo analizó el impacto pronóstico de un marcador molecular presente en la LPA, las mutaciones de FLT3. Existiendo controversia sobre el valor pronóstico independiente de FLT3, y por tanto de su posible incorporación a estrategias terapéuticas adaptadas al riesgo, desde el grupo PETHEMA se realizó este estudio de marcado carácter traslacional. Los resultados ayudaron a establecer la incidencia y las características clínicas y biológicas asociadas a la presencia de FLT3, y sirvieron para tomar la decisión de no realizar modificaciones en los algoritmos terapéuticos basados en la presencia de ese marcador. Este conjunto de estudios ha permitido un conocimiento profundo y un avance en el manejo de la LPA en sus sucesivas fases de tratamiento. Sin embargo, los hallazgos reportados aquí tendrán que ser validados en diferentes contextos terapéuticos.Current treatment of acute promyelocytic leukemia (APL) with all trans-retinoic acid (ATRA) and chemotherapy combination provides a very high rate of cures. However, although narrow, there is room for improvement by reducing each of the different causes of treatment failure. Given the heterogeneity of the causes of failure, we hypothesize that an analysis of these causes and the identification of prognostic variables associated to the patient, leukemia, or to the treatment itself, could be useful to implement therapeutic measures to improve the clinical outcomes. Thus, the identification of prognostic variables could help to design risk-tadapted strategies. A detailed analysis of the short and long term complications and outcomes in different therapeutic phases, should help to refine the management of these complications and optimise future protocols, in order to offer a lower toxicity while maintaining a high antileukemic efficacy. This study includes the results of 3 manuscripts published in 2 high impact journals specialized in hematology. They all share a common feature; the analysis of a large series of patients treated with two consecutive protocols of the Spanish cooperative group PETHEMA for the treatment of APL (LPA96 and LPA99 trials). The first manuscript assessed the long-term results of the LPA99 trial, using a risk-adapted chemotherapy schedule based on the relapse score developed jointly in 2000 by the PETHEMA and GIMEMA groups. This analysis provided robust results, showing the positive impact of the intensification of the dosage of anthracyclines and ATRA in those patients with intermediate and high risk of relapse. This was the basis for the subsequent APL trials of the PETHEMA group. The second manuscript aimed to analyse a life-threatening complication of induction therapy in APL: the differentiation syndrome. This study identified the risk factors for the development of this syndrome, in order to adapt the prophylaxis and management according to the risk of developing severe forms. Thanks to this work, the prevention of differentiation syndrome was implemented using a risk-adapted startegy in the following PETHEMA trials. The third manuscript examined the prognostic impact of a molecular marker in APL, the FLT3 mutations. There was controversy about the independent prognostic value of FLT3 and its potential use to design risk-adapted therapeutic strategies. Our study permitted to establish the clinical and biological characteristics associated with the presence of FLT3, and recommended not to make changes in the therapeutic algorithms based on the presence of these mutations. This set of studies has allowed a deep understanding and a step forward in the management of APL in successive phases of treatment. However, the findings reported here will have to be validated in different therapeutic contexts

Tratamiento adaptado al riesgo de la leucemia promielocítica aguda con ATRA y quimioterapia

El tratamiento actual de la leucemia promielocítica aguda (LPA) con la combinación de ácido trans-retinóico (ATRA) y quimioterapia proporciona una tasa muy elevada de curaciones. No obstante, aunque estrecho, hay un margen de mejora mediante la reducción de cada una de las diferentes causas de fracaso terapéutico. Dada la heterogeneidad de estas causas de fracaso, planteamos la hipótesis de que un análisis de dichas causas y la identificación de las variables ligadas al paciente, a su enfermedad y al propio tratamiento, podrían ser de ayuda en la implementación de las medidas apropiadas para mejorar dichos resultados. Así, la identificación de diferentes variables pronósticas podría ayudar a diseñar esquemas de tratamiento adaptado al riesgo. El análisis pormenorizado, a corto y a largo plazo, de las diferentes complicaciones y de los resultados de los esquemas quimioterápicos en sus diferentes fases, deberían ayudar a refinar el manejo de las complicaciones y optimizar los futuros protocolos con el fin de ofrecer una menor toxicidad, pero al mismo tiempo manteniendo una elevada eficacia antileucémica. Esta Tesis recoge los resultados de 3 estudios publicados en 2 revistas internacionales de alto impacto especializadas en hematología. Todos ellos comparten un nexo común; el análisis de una serie de pacientes tratados con dos protocolos consecutivos del grupo cooperativo Español PETHEMA (LPA96 y LPA99) para el tratamiento de la LPA. El primer estudio evalúa los resultados a largo plazo del protocolo LPA99, con consolidaciones adaptadas al riesgo de recaída según el índice pronóstico desarrollado conjuntamente en el año 2000 por los grupos PETHEMA y GIMEMA. Este trabajo ofreció unos resultados robustos sobre el impacto positivo de las modificaciones realizadas en la intensidad de la dosificación de las antraciclinas y del ATRA en aquellos pacientes con riesgo intermedio y alto de recaída. Éste sirvió de base para los siguientes protocolos de tratamiento de la LPA del grupo PETHEMA. El segundo estudio se centró en el análisis detallado de una complicación propia del tratamiento de inducción: el síndrome de diferenciación. Este estudio se planteó identificar los factores de riesgo para el desarrollo de este síndrome, con el fin de adaptar la profilaxis y el manejo del mismo según el riesgo de presentar formas graves del mismo. Gracias a este trabajo, la prevención del síndrome de diferenciación se implementó de forma adaptada al riesgo en los siguientes protocolos PETHEMA. El tercer trabajo analizó el impacto pronóstico de un marcador molecular presente en la LPA, las mutaciones de FLT3. Existiendo controversia sobre el valor pronóstico independiente de FLT3, y por tanto de su posible incorporación a estrategias terapéuticas adaptadas al riesgo, desde el grupo PETHEMA se realizó este estudio de marcado carácter traslacional. Los resultados ayudaron a establecer la incidencia y las características clínicas y biológicas asociadas a la presencia de FLT3, y sirvieron para tomar la decisión de no realizar modificaciones en los algoritmos terapéuticos basados en la presencia de ese marcador. Este conjunto de estudios ha permitido un conocimiento profundo y un avance en el manejo de la LPA en sus sucesivas fases de tratamiento. Sin embargo, los hallazgos reportados aquí tendrán que ser validados en diferentes contextos terapéuticos.Current treatment of acute promyelocytic leukemia (APL) with all trans-retinoic acid (ATRA) and chemotherapy combination provides a very high rate of cures. However, although narrow, there is room for improvement by reducing each of the different causes of treatment failure. Given the heterogeneity of the causes of failure, we hypothesize that an analysis of these causes and the identification of prognostic variables associated to the patient, leukemia, or to the treatment itself, could be useful to implement therapeutic measures to improve the clinical outcomes. Thus, the identification of prognostic variables could help to design risk-tadapted strategies. A detailed analysis of the short and long term complications and outcomes in different therapeutic phases, should help to refine the management of these complications and optimise future protocols, in order to offer a lower toxicity while maintaining a high antileukemic efficacy. This study includes the results of 3 manuscripts published in 2 high impact journals specialized in hematology. They all share a common feature; the analysis of a large series of patients treated with two consecutive protocols of the Spanish cooperative group PETHEMA for the treatment of APL (LPA96 and LPA99 trials). The first manuscript assessed the long-term results of the LPA99 trial, using a risk-adapted chemotherapy schedule based on the relapse score developed jointly in 2000 by the PETHEMA and GIMEMA groups. This analysis provided robust results, showing the positive impact of the intensification of the dosage of anthracyclines and ATRA in those patients with intermediate and high risk of relapse. This was the basis for the subsequent APL trials of the PETHEMA group. The second manuscript aimed to analyse a life-threatening complication of induction therapy in APL: the differentiation syndrome. This study identified the risk factors for the development of this syndrome, in order to adapt the prophylaxis and management according to the risk of developing severe forms. Thanks to this work, the prevention of differentiation syndrome was implemented using a risk-adapted startegy in the following PETHEMA trials. The third manuscript examined the prognostic impact of a molecular marker in APL, the FLT3 mutations. There was controversy about the independent prognostic value of FLT3 and its potential use to design risk-adapted therapeutic strategies. Our study permitted to establish the clinical and biological characteristics associated with the presence of FLT3, and recommended not to make changes in the therapeutic algorithms based on the presence of these mutations. This set of studies has allowed a deep understanding and a step forward in the management of APL in successive phases of treatment. However, the findings reported here will have to be validated in different therapeutic contexts

Clinical outcomes after CPX-351 in patients with high-risk acute myeloid leukemia: A comparison with a matched cohort from the Spanish PETHEMA registry

Background CPX-351 is approved for the treatment of therapy related acute myeloid leukemia (t-AML) and AML with myelodysplastic related changes (MRC-AML). The benefits of this treatment over standard chemotherapy has not been addressed in well matched cohorts of real-life patients. Methods Retrospective analysis of AML patients treated with CPX-351 as per routine practice. A propensity score matching (PSM) was used to compare their main outcomes with those observed in a matched cohort among 765 historical patients receiving intensive chemotherapy (IC), all of them reported to the PETHEMA epidemiologic registry. Results Median age of 79 patients treated with CPX-351 was 67 years old (interquartile range 62–71), 53 were MRC-AML. The complete remission (CR) rate or CR without recovery (CRi) after 1 or 2 cycles of CPX-351 was 52%, 60-days mortality 18%, measurable residual disease <0.1% in 54% (12 out of 22) of them. Stem cell transplant (SCT) was performed in 27 patients (34%), median OS was 10.3 months, and 3-year relapse incidence was 50%. Using PSM, we obtained two comparable cohorts treated with CPX-351 (n = 52) or IC (n = 99), without significant differences in CR/CRi (60% vs. 54%) and median OS (10.3 months vs. 9.1 months), although more patients were bridged to SCT in the CPX-351 group (35% vs. 12%). The results were confirmed when only 3 + 7 patients were included in the historical cohort. In multivariable analyses, SCT was associated with better OS (HR 0.33 95% CI: 0.18–0.59), p < 0.001. Conclusion Larger post-authorization studies may provide evidence of the clinical benefits of CPX-351 for AML in the real-life setting.Jazz Pharmaceuticals4.711 Q2 JCR 20211.188 Q1 SJR 2022No data IDR 2021UE