Trasplante alogénico de progenitores hematopoyéticos en adultos con leucemia linfoblástica aguda

Los avances terapéuticos en la leucemia linfoblástica aguda (LLA) han sido notables en los últimos años con la incorporación de esquemas de quimioterapia más intensivos, los inhibidores de tirosina quinasa y los grandes avances en el campo del trasplante alogénico de progenitores hematopoyéticos (TPH). El objetivo del estudio ha sido analizar los resultados del TPH en una amplia serie de pacientes adultos con LLA y proponer ideas de mejora. Para ello, un primer estudio ha evaluado exhaustivamente el tipo de donante, fuentes de progenitores hematopoyéticos e intensidad del acondicionamiento en una serie retrospectiva de 211 pacientes con LLA del Hospital Universitario y Politécnico La Fe (HUP La Fe). Un segundo estudio comparativo multicéntrico retrospectivo con 203 pacientes adultos con LLA ha comparado el acondicionamiento mieloablativo con y sin irradiación corporal total (ICT) como parte del acondicionamiento. El estudio de la serie del HUP La Fe puso de manifiesto que el TSCU se asoció con un retraso significativo en el injerto mieloide y plaquetar, una mayor MSR y una menor SLE que el resto de modalidades de trasplante en los pacientes con LLA. Otras características que mostraron un impacto en los resultados de los trasplantes fueron una menor tasa de EICR grado III-IV cuando el donante y el receptor fueron serológicamente negativos al CMV o se trasplantaron más recientemente. En cambio, se observó una mayor incidencia de EICR crónica y crónica extensa en los TPH de hermano HLA-idéntico, los pacientes de mayor edad y las LLA-B Ph+. De interés también resaltar la mayor MSR asociada al uso de acondicionamientos con ciclofosfamida, comparado con fludarabina, y la mayor incidencia de recaídas en los pacientes con LLA-B Ph- y especialmente con LLA-T, en los trasplantados en fases más avanzadas de la enfermedad y con ERM positiva en el momento del trasplante. La reciente introducción de esquemas de profilaxis de la EICR basados en el uso de CY-PT tanto para trasplantes haploidénticos como de donantes HLA-idénticos ha repercutido globalmente en una mejora de la SLE y la SG. En el estudio multicéntrico, los resultados mostraron una menor tasa de recaídas en la cohorte con ICT en el acondicionamiento, pero el análisis multivariante sólo pudo demostrar el valor pronóstico independiente de esta variable en la recaída extramedular. Para el conjunto de las recaídas, sólo el subtipo de LLA (LLA-T la de mayor riesgo y LLA-B Ph+ la de menor riesgo) y el estatus de la ERM fueron las variables seleccionadas en el análisis multivariante. En cambio, el acondicionamiento con ICT, junto con la mayor edad y las fases avanzadas de la LLA fueron las variables que se asociaron en el análisis multivariante a una mayor tasa de MSR. No obstante, esto no se tradujo en un impacto significativo del tipo de acondicionamiento en la supervivencia según se incluyese o no ICT. Tampoco se observó ningún incremento significativo de eventos tardíos postrasplante potencialmente asociados a la ICT

Proposed global prognostic score for systemic mastocytosis: a retrospective prognostic modelling study

[Background]: Several risk stratification models have been proposed in recent years for systemic mastocytosis but have not been directly compared. Here we designed and validated a risk stratification model for progression-free survival (PFS) and overall survival (OS) in systemic mastocytosis on the basis of all currently available prognostic factors, and compared its predictive capacity for patient outcome with that of other risk scores.[Methods]: We did a retrospective prognostic modelling study based on patients diagnosed with systemic mastocytosis between March 1, 1983, and Oct 11, 2019. In a discovery cohort of 422 patients from centres of the Spanish Network on Mastocytosis (REMA), we evaluated previously identified, independent prognostic features for prognostic effect on PFS and OS by multivariable analysis, and designed a global prognostic score for mastocytosis (GPSM) aimed at predicting PFS (GPSM-PFS) and OS (GPSM-OS) by including only those variables that showed independent prognostic value (p<0·05). The GPSM scores were validated in an independent cohort of 853 patients from centres in Europe and the USA, and compared with pre-existing risk models in the total patient series (n=1275), with use of Harrells' concordance index (C-index) as a readout of the ability of each model to risk-stratify patients according to survival outcomes.[Findings]: Our GPSM-PFS and GPSM-OS models were based on unique combinations of independent prognostic factors for PFS (platelet count ≤100 × 109 cells per L, serum β2-microglobulin ≥2·5 μg/mL, and serum baseline tryptase ≥125 μg/L) and OS (haemoglobin ≤110 g/L, serum alkaline phosphatase ≥140 IU/L, and at least one mutation in SRSF2, ASXL1, RUNX1, or DNMT3A). The models showed clear discrimination between low-risk and high-risk patients in terms of worse PFS and OS prognoses in the discovery and validation cohorts, and further discrimination of intermediate-risk patients. The GPSM-PFS score was an accurate predictor of PFS in systemic mastocytosis (C-index 0·90 [95% CI 0·87–0·93], vs values ranging from 0·85 to 0·88 for pre-existing models), particularly in non-advanced systemic mastocytosis (C-index 0·85 [0·76–0·92], within the range for pre-existing models of 0·80 to 0·93). Additionally, the GPSM-OS score was able to accurately predict OS in the entire cohort (C-index 0·92 [0·89–0·94], vs 0·67 to 0·90 for pre-existing models), and showed some capacity to predict OS in advanced systemic mastocytosis (C-index 0·72 [0·66–0·78], vs 0·64 to 0·73 for pre-existing models).[Interpretation]: All evaluated risk classifications predicted survival outcomes in systemic mastocytosis. The REMA-PFS and GPSM-PFS models for PFS, and the International Prognostic Scoring System for advanced systemic mastocytosis and GPSM-OS model for OS emerged as the most accurate models, indicating that robust prognostication might be prospectively achieved on the basis of biomarkers that are accessible in diagnostic laboratories worldwide.Carlos III Health Institute, European Regional Development Fund, Spanish Association of Mastocytosis and Related Diseases, Rare Diseases Strategy of the Spanish National Health System, Junta of Castile and León, Charles and Ann Johnson Foundation, Stanford Cancer Institute Innovation Fund, Austrian Science Fund

Proposed global prognostic score for systemic mastocytosis: a retrospective prognostic modelling study

[Background]: Several risk stratification models have been proposed in recent years for systemic mastocytosis but have not been directly compared. Here we designed and validated a risk stratification model for progression-free survival (PFS) and overall survival (OS) in systemic mastocytosis on the basis of all currently available prognostic factors, and compared its predictive capacity for patient outcome with that of other risk scores.[Methods]: We did a retrospective prognostic modelling study based on patients diagnosed with systemic mastocytosis between March 1, 1983, and Oct 11, 2019. In a discovery cohort of 422 patients from centres of the Spanish Network on Mastocytosis (REMA), we evaluated previously identified, independent prognostic features for prognostic effect on PFS and OS by multivariable analysis, and designed a global prognostic score for mastocytosis (GPSM) aimed at predicting PFS (GPSM-PFS) and OS (GPSM-OS) by including only those variables that showed independent prognostic value (p<0·05). The GPSM scores were validated in an independent cohort of 853 patients from centres in Europe and the USA, and compared with pre-existing risk models in the total patient series (n=1275), with use of Harrells' concordance index (C-index) as a readout of the ability of each model to risk-stratify patients according to survival outcomes.[Findings]: Our GPSM-PFS and GPSM-OS models were based on unique combinations of independent prognostic factors for PFS (platelet count ≤100 × 109 cells per L, serum β2-microglobulin ≥2·5 μg/mL, and serum baseline tryptase ≥125 μg/L) and OS (haemoglobin ≤110 g/L, serum alkaline phosphatase ≥140 IU/L, and at least one mutation in SRSF2, ASXL1, RUNX1, or DNMT3A). The models showed clear discrimination between low-risk and high-risk patients in terms of worse PFS and OS prognoses in the discovery and validation cohorts, and further discrimination of intermediate-risk patients. The GPSM-PFS score was an accurate predictor of PFS in systemic mastocytosis (C-index 0·90 [95% CI 0·87–0·93], vs values ranging from 0·85 to 0·88 for pre-existing models), particularly in non-advanced systemic mastocytosis (C-index 0·85 [0·76–0·92], within the range for pre-existing models of 0·80 to 0·93). Additionally, the GPSM-OS score was able to accurately predict OS in the entire cohort (C-index 0·92 [0·89–0·94], vs 0·67 to 0·90 for pre-existing models), and showed some capacity to predict OS in advanced systemic mastocytosis (C-index 0·72 [0·66–0·78], vs 0·64 to 0·73 for pre-existing models).[Interpretation]: All evaluated risk classifications predicted survival outcomes in systemic mastocytosis. The REMA-PFS and GPSM-PFS models for PFS, and the International Prognostic Scoring System for advanced systemic mastocytosis and GPSM-OS model for OS emerged as the most accurate models, indicating that robust prognostication might be prospectively achieved on the basis of biomarkers that are accessible in diagnostic laboratories worldwide.Carlos III Health Institute, European Regional Development Fund, Spanish Association of Mastocytosis and Related Diseases, Rare Diseases Strategy of the Spanish National Health System, Junta of Castile and León, Charles and Ann Johnson Foundation, Stanford Cancer Institute Innovation Fund, Austrian Science Fund

CNL and aCML should be considered as single entity based on molecular profiles and outcomes

Chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML) are rare myeloid disorders that are challenging with regard to diagnosis and clinical management. To study the similarities and differences of these disorders we undertook a multi-center international study of one of the largest case series (CNL, n=24; aCML, n=37 cases, respectively), focusing on the clinical and mutational profiles (n=53 with molecular data) of these diseases. We found no differences in clinical presentation or outcomes between both entities. As previously described, both CNL and aCML share a complex mutational profile with mutations in genes involved in epigenetic regulation, splicing and signaling pathways. Apart from CSF3R, only EZH2 and TET2 were differentially mutated between them. The molecular profiles support the notion of CNL and aCML being a continuum of the same disease that may fit best within the myelodysplastic/myeloproliferative neoplasms (MDS/MPN). We identified four high-risk mutated genes, specifically CEBPA (β=2.26, HR=9.54, p=0.003), EZH2 (β=1.12, HR=3.062, p=0.009), NRAS (β=1.29, HR=3.63, p=0.048) and U2AF1 (β=1.75, HR=5.74, p=0.013) by multivariate analysis. Our findings underscore the relevance of molecular-risk classification in CNL/aCML as well as the importance of CSF3R mutations in these diseases.</p

Toxicity of Asciminib in Real Clinical Practice: Analysis of Side Effects and Cross-Toxicity with Tyrosine Kinase Inhibitors

Simple Summary After the recent irruption of asciminib into the therapeutic arsenal for chronic myeloid leukemia, real-life data remain scarce to determine which patients may benefit most from this drug. Data on the efficacy of the drug in real-world setting have been reported, but a detailed analysis of the toxicity profile and the influence of prior intolerance to classical tyrosine kinase inhibitors (TKIs) has not been performed. The aim of the present analysis is to study in detail the toxicity profile of asciminib as well as to describe the risk of cross-toxicity with classical TKIs. These results may help to select the patient profile with the best chance of therapeutic success with asciminib monotherapy. (1) Background: Despite the prognostic improvements achieved with tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML), a minority of patients still fail TKIs. The recent introduction of asciminib may be a promising option in intolerant patients, as it is a first-in-class inhibitor with a more selective mechanism of action different from the ATP-competitive inhibition that occurs with TKIs. Therefore, our goal was to analyze toxicities shown with asciminib as well as to study cross-toxicity with previous TKIs. (2) Methods: An observational, multicenter, retrospective study was performed with data from 77 patients with CML with therapeutic failure to second-generation TKIs who received asciminib through a managed-access program (MAP) (3) Results: With a median follow-up of 13.7 months, 22 patients (28.5%) discontinued treatment: 32% (7/22) due to intolerance and 45% (10/22) due to resistance. Fifty-five percent of the patients reported adverse effects (AEs) with asciminib and eighteen percent grade 3-4. Most frequent AEs were: fatigue (18%), thrombocytopenia (17%), anemia (12%), and arthralgias (12%). None of the patients experienced cardiovascular events or occlusive arterial disease. Further, 26%, 25%, and 9% of patients required dose adjustment, temporary suspension, or definitive discontinuation of treatment, respectively. Toxicities under asciminib seemed lower than with prior TKIs for anemia, cardiovascular events, pleural/pericardial effusion, diarrhea, and edema. Cross-toxicity risk was statistically significant for thrombocytopenia, anemia, neutropenia, fatigue, vomiting, and pancreatitis. (4) Conclusion: Asciminib is a molecule with a good safety profile and with a low rate of AEs. However, despite its new mechanism of action, asciminib presents a risk of cross-toxicity with classical TKIs for some AEs

Toxicity of Asciminib in Real Clinical Practice: Analysis of Side Effects and Cross-Toxicity with Tyrosine Kinase Inhibitors

(1) Background: Despite the prognostic improvements achieved with tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML), a minority of patients still fail TKIs. The recent introduction of asciminib may be a promising option in intolerant patients, as it is a first-in-class inhibitor with a more selective mechanism of action different from the ATP-competitive inhibition that occurs with TKIs. Therefore, our goal was to analyze toxicities shown with asciminib as well as to study cross-toxicity with previous TKIs. (2) Methods: An observational, multicenter, retrospective study was performed with data from 77 patients with CML with therapeutic failure to second-generation TKIs who received asciminib through a managed-access program (MAP) (3) Results: With a median follow-up of 13.7 months, 22 patients (28.5%) discontinued treatment: 32% (7/22) due to intolerance and 45% (10/22) due to resistance. Fifty-five percent of the patients reported adverse effects (AEs) with asciminib and eighteen percent grade 3&ndash;4. Most frequent AEs were: fatigue (18%), thrombocytopenia (17%), anemia (12%), and arthralgias (12%). None of the patients experienced cardiovascular events or occlusive arterial disease. Further, 26%, 25%, and 9% of patients required dose adjustment, temporary suspension, or definitive discontinuation of treatment, respectively. Toxicities under asciminib seemed lower than with prior TKIs for anemia, cardiovascular events, pleural/pericardial effusion, diarrhea, and edema. Cross-toxicity risk was statistically significant for thrombocytopenia, anemia, neutropenia, fatigue, vomiting, and pancreatitis. (4) Conclusion: Asciminib is a molecule with a good safety profile and with a low rate of AEs. However, despite its new mechanism of action, asciminib presents a risk of cross-toxicity with classical TKIs for some AEs