Ibrutinib and R-GemOx in patients with relapsed or refractory diffuse large B-cell lymphoma of non-GCB type: Phase II clinical trial of the Spanish GELTAMO group.

PURPOSE: This phase II clinical trial evaluated the combination of Ibrutinib with rituximab, gemcitabine and oxaliplatin (R-GemOx) in patients with non-germinal centre B-cell-like (non-GCB) diffuse large B-cell lymphoma (DLBCL). PATIENTS AND METHODS: The IBDCL trial (NCT02692248) included patients with histological diagnosis of non-GCB DLBCL with relapsed or refractory disease and non-candidates for stem cell transplantation. Patients received an induction treatment consisting of 6 or 8 cycles of R-GemOx at standard doses every 2 weeks, in combination with ibrutinib (560 mg daily), followed by a maintenance treatment with ibrutinib for a maximum of 2 years. The primary objective was to evaluate the overall response rate (ORR) after 4 cycles. RESULTS: Sixty-four patients were included, 72% of them refractory to the last regimen. The ORR and CR rate after the 4th cycle were 53% (95% confidence interval [CI], 41-65) and 34% (95% CI, 24-46), respectively. Twenty-four (37%) patients started maintenance and 7 (11%) completed the planned 2 years. After a median follow-up of 29.7 months (range: 0.4-48.6), the estimated 2-year PFS and OS were 18% (95% CI, 8 - 28) and 26% (95% CI, 14 - 37), respectively. The most common grade ≥3 treatment-related adverse events (TRAEs) were thrombocytopenia (44%), neutropenia (30%) and anemia (14%). Grade ≥3 infectious and cardiovascular TRAEs were reported in 6 (9%) and 1 (2%) patient, respectively. CONCLUSIONS: Ibrutinib in combination with R-GemOx, followed by ibrutinib maintenance, demonstrated encouraging antitumor activity with durable responses and a manageable toxicity in patients with non-GCB DLBCL.

Hepatotoxicity as dose-limiting toxicity of the combination of bosutinib and atezolizumab in patients with chronic myeloid leukemia. Results of the ZEROLMC study.

In the field of chronic myeloid leukemia (CML), new strategies are needed to increase the rate of successful treatment discontinuations, a crucial goal in this disease. Anti-PD-L1 checkpoint inhibitors are a promising therapeutic approach in CML after the demonstration of an increase of these inhibitory molecules in patients with CML. A phase Ib/II (NCT04793399, registration date March 11, 2021) open-label exploratory trial has been conducted to evaluate the safety of atezolizumab, a humanized anti-PD-L1 antibody, in combination with bosutinib in patients with newly diagnosed chronic phase CML. A total of 36 patients were planned to be enrolled, but the study had to be prematurely terminated due to safety concerns. Nine patients were included in the study, and only 8 went on to receive the combination with atezolizumab. There were a total of 44 adverse events (AEs) during the study period. The most frequent were gastrointestinal (50%), mostly mild (86% grade 1-2). The most serious AEs were hepatic. There were 17 hepatic AEs in 5 patients. Of the hepatic AEs 5 were during the bosutinib monotherapy phase and 12 during the combination phase (AST increase x4, ALT increase x4, blood bilirubin increase x1, alkaline phosphatase elevation x2, GGT increase x2), most of them grade 3-4. There were 2 patients who presented a dose-limiting toxicity; a grade 3 elevation of transaminases, that led to premature termination of the study. The combination of atezolizumab with bosutinib presents hepatotoxicity as a dose-limiting effect and therefore we do not recommend to explore this combination in future studies.

Obinutuzumab plus bendamustine for relapsed/refractory chronic lymphocytic leukemia and predictive and prognostic impact of genetic alterations: the phase II GABRIELL study.

GABRIELL was a phase II single-arm study to evaluate the efficacy and safety of obinutuzumab plus bendamustine for relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Seventy-two patients with active disease received treatment for up to six 28-day cycles. Overall response rate was 78.6% with a median progression-free survival (PFS) of 26 months, and overall survival (OS) not reached at the end of follow-up (36 months). Undetectable measurable residual disease (≤0.01%; 36.4% in bone marrow and 53.4% in peripheral blood) correlated with a significantly longer PFS and OS (vs. >0.01). Common grade ≥3 adverse events (76.4%) were neutropenia (58.3%), thrombocytopenia (26.4%) and febrile neutropenia (11.1%). TP53 disruption was the only independent predictive factor for response (Hazard ratio; HR: 0.228). Unmutated immunoglobulin heavy chain variable region (HR: 16.061) was a negative prognostic factor for PFS. In conclusion, the combination of obinutuzumab plus bendamustine is an active and generally adequately-tolerated treatment for R/R CLL.

BTLA dysregulation correlates with poor outcome and diminished T cell-mediated antitumor responses in chronic lymphocytic leukemia.

Patients with chronic lymphocytic leukemia (CLL) progressively develop marked immunosuppression, dampening innate and adaptive-driven antitumor responses. However, the underlying mechanisms promoting immune exhaustion are largely unknown. Herein, we provide new insights into the role of BTLA/HVEM axis promoting defects in T cell-mediated responses against leukemic cells. Increased expression of BTLA, an inhibitory immune checkpoint, was detected on the surface of CD4 + and CD8 + T lymphocytes in patients with CLL. Moreover, high levels of BTLA on CD4 + T cells correlated with diminished time to treatment. Signaling through BTLA activation led to decreased IL-2 and IFN-γ production ex vivo, whereas BTLA/HVEM binding disruption enhanced IFN-γ + CD8 + T lymphocytes. Accordingly, BTLA blockade in combination with bispecific anti-CD3/anti-CD19 antibody promoted CD8 + T cell-mediated anti-leukemic responses. Finally, treatment with an anti-BLTA blocking monoclonal antibody alone or in combination with ibrutinib-induced leukemic cell depletion in vitro. Altogether, our data reveal that BTLA dysregulation has a prognostic role and is limiting T cell-driven antitumor responses, thus providing new insights about immune exhaustion in patients with CLL.

Machine Learning Improves Risk Stratification in Myelofibrosis: An Analysis of the Spanish Registry of Myelofibrosis.

Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) with heterogeneous clinical course. Allogeneic hematopoietic cell transplantation remains the only curative therapy, but its morbidity and mortality require careful candidate selection. Therefore, accurate disease risk prognostication is critical for treatment decision-making. We obtained registry data from patients diagnosed with MF in 60 Spanish institutions (N = 1386). These were randomly divided into a training set (80%) and a test set (20%). A machine learning (ML) technique (random forest) was used to model overall survival (OS) and leukemia-free survival (LFS) in the training set, and the results were validated in the test set. We derived the AIPSS-MF (Artificial Intelligence Prognostic Scoring System for Myelofibrosis) model, which was based on 8 clinical variables at diagnosis and achieved high accuracy in predicting OS (training set c-index, 0.750; test set c-index, 0.744) and LFS (training set c-index, 0.697; test set c-index, 0.703). No improvement was obtained with the inclusion of MPN driver mutations in the model. We were unable to adequately assess the potential benefit of including adverse cytogenetics or high-risk mutations due to the lack of these data in many patients. AIPSS-MF was superior to the IPSS regardless of MF subtype and age range and outperformed the MYSEC-PM in patients with secondary MF. In conclusion, we have developed a prediction model based exclusively on clinical variables that provides individualized prognostic estimates in patients with primary and secondary MF. The use of AIPSS-MF in combination with predictive models that incorporate genetic information may improve disease risk stratification.

Geriatric assessment in hematology scale predicts treatment tolerability in older patients diagnosed with hematological malignancies: The RETROGAH study.

INTRODUCTION: The GAH (Geriatric Assessment in Hematology) scale is a psychometrically valid tool aimed at identifying older patients with hematological malignancies at higher risk of treatment-related toxicity. Our objective in this study was to determine the weights for each dimension of the GAH scale and the cut-off point to reliably predict treatment tolerability in this population, estimated by a weighted receiver operating characteristic (ROC) analysis and quantified by the area under the curve (AUC). MATERIAL AND METHODS: The RETROGAH was a retrospective cohort study including 126 patients who had previously participated in the GAH study. Patients were ≥ 65 years old with newly diagnosed myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML), multiple myeloma (MM), or chronic lymphoid leukemia (CLL) and treated with standard front-line therapy within three months after having completed the GAH scale. RESULTS: The optimal cut-off value of the GAH total score to discriminate patients at higher risk of treatment toxicity was 42, with 68.5% sensitivity and 55.8% specificity. Using this value, 66.1% of patients evaluated were found to develop some type of toxicity. The AUC was 0.6259 (95% CI: 0.512-0.739; p = 0.035). DISCUSSION: The GAH scale not only would enable clinicians to individualize therapy based on individual risk of toxicity but also discriminate patients that will benefit most from intensive treatments from those requiring an adapted approach. While futures studies in clinical practice may improve the model and overcome its limitations, the GAH scale should not be used alone when making treatment decisions.

Predictors of thrombosis and bleeding in 1613 myelofibrosis patients from the Spanish Registry of Myelofibrosis.

Available data have proved insufficient to develop consensus recommendations on the prevention of thrombosis and bleeding in myelofibrosis (MF). We evaluated the incidence and risk factors of vascular complications in 1613 patients from the Spanish Myelofibrosis Registry. Over a total of 6981 patient-years at risk, 6.4% of the study population had at least one thrombotic event after MF diagnosis, amounting to an incidence rate of 1.65 per 100 patient-years. Prior history of thrombosis, the JAK2 mutation, and the intermediate-2/high-risk International Prognostic Scoring System (IPSS) categories conferred an increased thrombotic risk after adjustment for the risk-modifying effect of anti-thrombotic and cytoreductive treatments. History of thrombosis and the JAK2 mutation allowed us to pinpoint a group of patients at higher risk of early thrombosis. No decreased incidence of thrombosis was observed while patients were on anti-thrombotic or cytoreductive treatment. An increased risk of venous thrombosis was found during treatment with immunomodulatory agents. A total of 5.3% of patients had at least one episode of major bleeding, resulting in an incidence rate of 1.5 events per 100 patient-years. Patients in the intermediate-2/high-risk IPSS categories treated with anti-coagulants had an almost sevenfold increased risk of major bleeding. These findings should prove useful for guiding decision-making in clinical practice.

Cost-minimisation analysis of chronic lymphocytic leukemia in Spain in the era of oral targeted therapies.

OBJECTIVE: Chronic lymphocytic leukaemia places a considerable economic burden on the Spanish National Health System. This study estimated the direct costs of chronic lymphocytic leukaemia oral targeted therapies from 2011 to 2025, inclusive, in a scenario with fixed  treatment oral targeted therapies and in a scenario without them. Method: The clinical course of adult chronic lymphocytic leukaemia patients  was represented by a Markov model with four health states: watchful waiting,  first-line treatment, relapse, and death. The treatment pattern was defined  according to patient type by disease status or situation, age, presence or  absence of deletion in the short arm of chromosome 17, immunoglobulin heavy  chain mutation status, and year of treatment. The treatment algorithm  was simulated from 2011 to 2025, and included therapies funded by the  Spanish National Health System and their use in routine clinical practice,  validated by leading experts. A single treatment option was assumed for each  type of patient and time period (the most widely option used at each time  point). Direct costs were included: pharmacological, administration, tests  performed, routine visits, hospitalizations, and adverse events. Results: From 2011 to 2025, there would be a mean annual chronic  ymphocytic leukaemia prevalence of 16,436 patients in the scenario without  fixed treatment oral targeted therapies and 16,413 in the scenario  with  in the scenario without fixed treatment oral targeted therapies would be €4,676.7 million and in the scenario with fixed treatment oral targeted therapies they would be €4,111.8 million. Thus, the introduction of fixed treatment oral targeted therapies would entail a saving of €564.9 million (12.1% of the total cost of care of chronic lymphocytic leukaemia patients during the period assessed). In this period, the total cost per patient would decrease from €266,019 in the scenario without fixed treatment oral targeted therapies to €236,852 in the scenario with fixed treatment oral targeted therapies, representing a saving of €29,167 per patient. CONCLUSIONS: This study estimates that, between 2011 and 2025, the introduction of fixed treatment oral targeted therapies for the treatment of chronic lymphocytic leukaemia would entail €564.9 million cost savings for  the Spanish National Health System (12.1% of the total cost of care of chronic  lymphocytic leukaemia patients during the period assessed).

OBJETIVO: La leucemia linfocítica crónica supone una carga económica considerable para el Sistema Nacional de Salud español. Este  estudio estimó los costes directos de las terapias orales dirigidas para leucemia linfocítica crónica desde 2011 a 2025, inclusive, en un escenario con terapias orales de duración fija y en un escenario sin ellas.Método: Se representó el curso clínico de pacientes adultos con leucemia linfocítica crónica mediante un modelo de Markov con cuatro estados de salud: vigilancia activa, tratamiento de primera línea, recaída y  muerte. Patrón de tratamiento definido por tipo de paciente: estado o situación  de la enfermedad, edad, presencia o no de deleción en el brazo corto  del cromosoma 17, estado mutacional de la cadena pesada de  inmunoglobulinas y año de tratamiento. Algoritmo de tratamiento simulado  desde 2011 a 2025, incluyendo terapias financiadas por el Sistema Nacional de Salud español y su uso en práctica clínica habitual, validado por expertos de  referencia. Se asumió una opción de tratamiento por tipo de  paciente y periodo de tiempo (la más ampliamente utilizada en cada  momento). Se incluyeron costes directos: farmacológicos, administración,  pruebas realizadas, visitas rutinarias, hospitalizaciones y acontecimientos  adversos. RESULTADOS: Se estimó una prevalencia media anual de leucemia linfocítica crónica desde 2011 a 2025 de 16.436 pacientes en el escenario sin  terapias orales de duración fija y 16.413 en el escenario con terapias  orales de  duración fija. Los costes totales desde 2011 a 2025 en el escenario sin  terapias orales de duración fija ascendieron a 4.676,7 millones de € y a  4.111,8 millones de € en el escenario con terapias orales de duración fija. Así,  la introducción de las terapias orales de duración fija supondría un ahorro de  564,9 millones de € (12,1% del total del coste de atención de los pacientes con  leucemia linfocítica crónica durante el periodo evaluado). El coste total por  paciente en este periodo de tiempo pasaba de 266.019 € en el escenario  sin terapias orales de duración fija a 236.852 € en el escenario con terapias  rales de duración fija, suponiendo un ahorro de 29.167 € por paciente. CONCLUSIONES: Este estudio estima que la introducción de las terapias orales  de duración fija para el tratamiento de la leucemia linfocítica crónica entre  2011 y 2025 supone un ahorro para el Sistema Nacional de Salud español de  564,9 millones de € (12,1% del total del coste de atención de los pacientes con  leucemia linfocítica crónica durante el periodo evaluado).

Análisis de minimización de costes de la leucemia linfocítica crónica en España en la era de las terapias orales dirigidas / Cost-minimisation analysis of chronic lymphocytic leukemia in Spain in the era of oral targeted therapies

Objetivo: La leucemia linfocítica crónica supone una carga económica considerable para el Sistema Nacional de Salud español. Este estudioestimó los costes directos de las terapias orales dirigidas para leucemia linfocítica crónica desde 2011 a 2025, inclusive, en un escenario conterapias orales de duración fija y en un escenario sin ellas.Método: Se representó el curso clínico de pacientes adultos con leucemia linfocítica crónica mediante un modelo de Markov con cuatro estados de salud: vigilancia activa, tratamiento de primera línea, recaída y muerte. Patrón de tratamiento definido por tipo de paciente: estado o situación dela enfermedad, edad, presencia o no de deleción en el brazo corto del cromosoma 17, estado mutacional de la cadena pesada de inmunoglobulinasy año de tratamiento. Algoritmo de tratamiento simulado desde 2011a 2025, incluyendo terapias financiadas por el Sistema Nacional deSalud español y su uso en práctica clínica habitual, validado por expertosde referencia. Se asumió una opción de tratamiento por tipo de pacientey periodo de tiempo (la más ampliamente utilizada en cada momento).Se incluyeron costes directos: farmacológicos, administración, pruebasrealizadas, visitas rutinarias, hospitalizaciones y acontecimientos adversos.Resultados: Se estimó una prevalencia media anual de leucemia linfocíticacrónica desde 2011 a 2025 de 16.436 pacientes en el escenariosin terapias orales de duración fija y 16.413 en el escenario con terapias orales de duración fija. Los costes totales desde 2011 a 2025 en el escenariosin terapias orales de duración fija ascendieron a 4.676,7 millonesde € y a 4.111,8 millones de € en el escenario con terapias orales deduración fija. Así, la introducción de las terapias orales de duración fijasupondría un ahorro de 564,9 millones de € (12,1% del total del costede atención de los pacientes con leucemia linfocítica crónica durante elperiodo evaluado).

Objective: Chronic lymphocytic leukaemia places a considerable economicburden on the Spanish National Health System. This study estimatedthe direct costs of chronic lymphocytic leukaemia oral targetedtherapies from 2011 to 2025, inclusive, in a scenario with fixed treatmentoral targeted therapies and in a scenario without them.Method: The clinical course of adult chronic lymphocytic leukaemiapatients was represented by a Markov model with four health states: watchfulwaiting, first-line treatment, relapse, and death. The treatment patternwas defined according to patient type by disease status or situation, age,presence or absence of deletion in the short arm of chromosome 17,immunoglobulin heavy chain mutation status, and year of treatment. Thetreatment algorithm was simulated from 2011 to 2025, and includedtherapiesfunded by the Spanish National Health System and their use inroutine clinical practice, validated by leading experts. A single treatmentoption was assumed for each type of patient and time period (the mostwidely option used at each time point). Direct costs were included: pharmacological,administration, tests performed, routine visits, hospitalizations,and adverse events.Results: From 2011 to 2025, there would be a mean annual chronic lymphocyticleukaemia prevalence of 16,436 patients in the scenario withoutfixed treatment oral targeted therapies and 16,413 in the scenario with fixed treatment oral targeted therapies. In the same period, the total costsin the scenario without fixed treatment oral targeted therapies would be€4,676.7 million and in the scenario with fixed treatment oral targetedtherapies they would be €4,111.8 million. Thus, the introduction of fixedtreatment oral targeted therapies would entail a saving of €564.9 million(12.1% of the total cost of care of chronic lymphocytic leukaemia patientsduring the period assessed).

Real-World Characteristics and Outcome of Patients Treated With Single-Agent Ibrutinib for Chronic Lymphocytic Leukemia in Spain (IBRORS-LLC Study).

BACKGROUND: Ibrutinib demonstrated remarkable efficacy and favorable tolerability in patients with untreated or relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL), including those with high-risk genetic alterations. The IBRORS-CLL study assessed the characteristics, clinical management and outcome of CLL patients receiving ibrutinib in routine clinical practice in Spain. PATIENTS: Observational, retrospective, multicenter study in CLL patients who started single-agent ibrutinib as first-line treatment or at first or second relapse between January 2016 and January 2019. RESULTS: A total of 269 patients were included (median age: 70.9 years; cardiovascular comorbidity: 55.4%, including hypertension [47.6%] and atrial fibrillation [AF] [7.1%]). Overall, 96.7% and 69% of patients underwent molecular testing for del(17p)/TP53 mutation and IGHV mutation status. High-risk genetic features included unmutated IGHV (79%) and del(17p)/TP53 mutation (first-line: 66.3%; second-line: 23.1%). Overall, 84 (31.2%) patients received ibrutinib as first-line treatment, and it was used as second- and third-line therapy in 121 (45.0%) and 64 (23.8%) patients. The median progression-free survival and overall survival were not reached irrespective of del(17p)/TP53, or unmutated IGHV. Common grade ≥3 adverse events were infections (12.2%) and bleeding (3%). Grade ≥3 AF occurred in 1.5% of patients. CONCLUSION: This real-world study shows that single-agent ibrutinib is an effective therapy for CLL, regardless of age and high-risk molecular features, consistent with clinical trials. Additionally, single-agent ibrutinib was well tolerated, with a low rate of cardiovascular events. This study also emphasized a high molecular testing rate of del(17p)/TP53 mutation and IGHV mutation status in clinical practice according to guideline recommendations.

BTLA/HVEM Axis Induces NK Cell Immunosuppression and Poor Outcome in Chronic Lymphocytic Leukemia.

Chronic lymphocytic leukemia (CLL) is characterized by progressive immunosuppression and diminished cancer immunosurveillance. Immune checkpoint blockade (ICB)-based therapies, a major breakthrough against cancer, have emerged as a powerful tool to reinvigorate antitumor responses. Herein, we analyzed the role of the novel inhibitory checkpoint BTLA and its ligand, HVEM, in the regulation of leukemic and natural killer (NK) cells in CLL. Flow cytometry analyses showed that BTLA expression is upregulated on leukemic cells and NK cells from patients with CLL, whereas HVEM is downregulated only in leukemic cells, especially in patients with advanced Rai-Binet stage. In silico analysis revealed that increased HVEM, but not BTLA, mRNA expression in leukemic cells correlated with diminished overall survival. Further, soluble BTLA (sBTLA) was found to be increased in the sera of patients with CLL and highly correlated with poor prognostic markers and shorter time to treatment. BTLA blockade with an anti-BTLA monoclonal antibody depleted leukemic cells and boosted NK cell-mediated responses ex vivo by increasing their IFN-γ production, cytotoxic capability, and antibody-dependent cytotoxicity (ADCC). In agreement with an inhibitory role of BTLA in NK cells, surface BTLA expression on NK cells was associated with poor outcome in patients with CLL. Overall, this study is the first to bring to light a role of BTLA/HVEM in the suppression of NK cell-mediated immune responses in CLL and its impact on patient's prognosis, suggesting that BTLA/HVEM axis may be a potential therapeutic target in this disease.

LAG-3 Blockade with Relatlimab (BMS-986016) Restores Anti-Leukemic Responses in Chronic Lymphocytic Leukemia.

The inclusion of monoclonal antibodies targeting immune checkpoints such PD-1/PD-L1 or CTLA-4 has revolutionized the landscape of anti-cancer therapy. However, PD-1 and CTLA-4 blockade failed to achieve clinical benefit in CLL, thus attention has been focused on emerging checkpoints in this malignancy. LAG-3 is an immune checkpoint receptor that negatively regulates T cell-mediated responses by inducing an hyporesponsive state, thus promoting tumor escape. Patients with chronic lymphocytic leukemia (CLL) develop a profound immune suppression that leads to lessened immunosurveillance and increased risk of developing a secondary neoplasia. In the study herein, we report the profound dysregulation of LAG-3 on leukemic cells in CLL. Likewise, natural killer (NK) and T cells showed increased LAG-3 expression, hence suggesting a role for this checkpoint in CLL-associated immunosuppression. High LAG-3 expression, as well as high levels of soluble LAG-3 (sLAG-3), correlated with adverse cytogenetics and poor outcome in patients with CLL, highlighting the clinical relevance of this immune checkpoint. Treatment of peripheral blood mononuclear cells (PBMCs) from patients with CLL with relatlimab, a new anti-LAG-3 blocking antibody currently evaluated in numerous clinical trials, depleted leukemic cells and restored NK cell- and T cell-mediated responses. Moreover, combination of LAG-3 with the immunomodulatory drug (IMiD) lenalidomide significantly increased IL-2 production by T cells and antibody-dependent cytotoxicity (ADCC) mediated by NK cells. Altogether, these data provide new insights into the potential anti-leukemic effects of relatlimab, currently in clinical trials in CLL, and provides the rationale to further investigate its combination with IMiDs for the management of hematological malignancies.

Treatment patterns and outcomes in real-world transplant-ineligible patients newly diagnosed with multiple myeloma.

Despite the significant proportion of older patients with newly diagnosed multiple myeloma (MM), most clinical trials driving therapeutic decisions in routine practice include younger and presumably healthier patients than those in the real world. Furthermore, longitudinal studies suggest that elderly, transplant-ineligible patients with MM are not benefitting enough from new anti-MM agents. We retrospectively analyzed the profile of and treatment patterns and outcomes in 675 transplant-ineligible patients with MM who started frontline therapy in routine practice. The mean (SD) age was 75.6 (6.7) years; 152 (47.4%) had Eastern Cooperative Oncology Group performance status (ECOG PS) 2-4, and 73 (25.1%) had high cytogenetic risk. The most frequent frontline therapy was non-VMP bortezomib-based regimens (n=207; 30.7%), which were more frequent among patients with ECOG PS 0/1 and higher risk (e.g., international staging system (ISS) stage III, severely impaired glomerular filtrate rate (GFR), high lactate dehydrogenase (LDH), and high-risk cytogenetics); 185 patients (27.4%) started an attenuated (lite) VMP regimen, and 159 (23.6%) a VMP (VISTA) regimen. Median progression-free survival and overall survival (OS) were 15.3 months (95%CI 14.0-16.9) and 33.5 months (95%CI 29.1-37.2), respectively; 405 patients (78.2%) achieved partial response or better. Age, ECOG PS, ISS stage, serum LDH, GFR, cytogenetic risk, and treatment regimen significantly influenced OS. In this study, a remarkable proportion of transplant-ineligible patients with MM were older, frontline regimens were highly heterogeneous, and patients at higher risk often received less efficacious combinations. These findings suggest that clinicians have limited objective criteria for therapeutic decisions for this patient group.

Driver Mutations and Single Copy Number Abnormalities Identify Binet Stage A Patients with Chronic Lymphocytic Leukemia with Aggressive Progression.

The correlation between progression and the genetic characteristics of Binet stage A patients with chronic lymphocytic leukemia (CLL) detected by whole exome sequencing (WES) was analyzed in 55 patients. The median follow-up for the patients was 102 months. During the follow-up, 24 patients (43%) progressed. Univariate Cox analysis showed that the presence of driver mutations, the accumulation of two or more mutations, the presence of adverse mutations, immunoglobulin heavy chain genes (IGHV) mutation status and unfavorable single copy number abnormalities (SCNAs) were associated with a higher risk of progression. Particularly, the occurrence of an adverse mutation and unfavorable SCNAs increased the risk of progression nine-fold and five-fold, respectively. Nevertheless, only the occurrence of adverse mutations retained statistical significance in the multivariate analysis. All patients carrying an unfavorable mutation progressed with a median progression-free survival (PFS) of 29 months. The accumulation of two or more mutations also increased the risk of progression with a median PFS of 29 months. The median PFS of patients with unfavorable SCNAs was 38 months. Combining mutations and SCNAs, patients may be stratified into three groups with different prognostic outcomes: adverse (17% probability of five-year PFS), protective (86% probability of five-year PFS) and neither (62% probability of five-year PFS, p < 0.001). Overall, the analysis of the mutational status of patients with CLL at an early stage of the disease may allow the identification of patients with a high risk of progression. The feasibility of an early therapeutic intervention in these particular patients requires further investigation.

Características clínico-biológicas de los pacientes con mielofibrosis: un análisis de 1.000 casos del Registro Español de Mielofibrosis / Clinico-biological characteristics of patients with myelofibrosis: an analysis of 1.000 cases from the Spanish Registry of Myelofibrosis

ANTECEDENTES Y OBJETIVO: La mielofibrosis es una neoplasia mieloproliferativa crónica infrecuente. Nuestro objetivo fue describir las características clínico-biológicas, el tratamiento y el curso evolutivo de los pacientes con mielofibrosis en España. MATERIAL Y MÉTODOS: Se analizaron 1.000 pacientes del Registro Español de Mielofibrosis diagnosticados de mielofibrosis primaria (n=641) o secundaria (n=359). RESULTADOS: La mediana de edad era de 68 años. La frecuencia de sintomatología constitucional, anemia moderada o severa (Hb<10g/dl) y esplenomegalia sintomática fue del 35, 36 y 17%, respectivamente. La incidencia de trombosis y hemorragia fue de 1,96 y 1,6 eventos por 100 años-paciente, respectivamente. La incidencia acumulada de leucemia fue del 15% a los 10 años. Para la anemia se emplearon principalmente agentes eritropoyéticos y danazol. A partir del 2010 se observó un incremento significativo del uso de ruxolitinib. Un 7,5% de los pacientes fue trasplantado. El 42% de los enfermos falleció, debido principalmente al deterioro clínico provocado por la mielofibrosis y a la transformación leucémica. La supervivencia mediana de la serie fue de 5,7 años. El IPSS identificó 4 grupos de riesgo: la supervivencia mediana no se alcanzó en el de bajo riesgo, mientras que fue de 8,8 años, 5,3 años y 2,8 años en los de riesgo intermedio-1, intermedio-2 y alto, respectivamente. CONCLUSIONES: la mielofibrosis es una enfermedad invalidante que afecta sobre todo a personas de edad avanzada y cuyo tratamiento es fundamentalmente sintomático. A pesar de su heterogeneidad clínica se dispone de modelos pronósticos útiles para la selección de candidatos a trasplante

Background and objective Myelofibrosis: is an infrequent chronic myeloproliferative neoplasm. We aimed to describe the clinico-biological characteristics, treatment, and evolutive course of myelofibrosis patients in Spain. MATERIAL AND METHODS: A total of 1,000 patients from the Spanish Registry of Myelofibrosis diagnosed with primary (n=641) or secondary (n=359) myelofibrosis were analysed. RESULTS: Median age was 68 years. The frequency of constitutional symptoms, moderate to severe anaemia (Hb<10g/dL), and symptomatic splenomegaly was 35%, 36%, and 17%, respectively. The rate of thrombosis and haemorrhage was 1.96 and 1.6 events per 100 patient-years, respectively. The cumulative incidence of leukaemia at 10 years was 15%. The most frequent therapies for the anaemia were the erythropoiesis stimulating agents and danazol. From 2010, a progressive increase in the use of ruxolitinib was noticed. A total of 7.5% of patients were transplanted. During the observation period, 42% of patients died mainly due to the clinical deterioration caused by myelofibrosis or leukaemic transformation. The median survival of the series was 5.7 years. Four different risk categories were identified by the IPSS: median survival was not reached in the low risk group and was 8.8 years, 5.3 years, and 2.8 years in the intermediate-1, intermediate-2, and high-risk groups, respectively. CONCLUSIONS: Myelofibrosis is a disabling condition mainly affecting elderly people. Its treatment is mostly driven by symptom control. Despite its clinical heterogeneity, several prognostic models are useful to select candidates for transplantation

Early Prediction of Subsequent Molecular Response to Nilotinib in Patients with Chronic Myeloid Leukemia: Comparison of the Quantification of BCR-ABL1 Ratios Using ABL1 or GUSB Control Genes.

Molecular monitoring of BCR-ABL1 transcripts is a critical prognostic indicator of treatment response in chronic myeloid leukemia (CML). Quantification of BCR-ABL1 transcripts using ABL1 or GUSB as control genes on the early molecular response (MR) to frontline nilotinib was studied using data from 60 patients with chronic-phase CML from the Evaluating Nilotinib Efficacy and Safety in Clinical Trials as First-Line Treatment (ENEST1st) substudy. Effects of BCR-ABL1/ABL1 and BCR-ABL1/GUSB ratios at early time points as independent variables on subsequent MR were determined by logistic regression analyses and predictive cut-off values determined by receiver operating curve analyses. From day 45, concordance was found for both control genes' early transcript kinetics and ability to predict subsequent deep MR at 18 months. From baseline to 3 months, transcripts descended linearly with both control genes. Use of ABL1 allowed for an earlier prediction (2 months) of subsequent MR than with GUSB (3 months), with cut-off values of 1.5% and 0.19%, respectively. The dynamic determination of BCR-ABL1 transcripts using either internal control gene is valid and predictive of subsequent MR. The use of GUSB to predict an earlier and more accurate response than ABL1 is not supported in the results. Accurate early indicators of MR are essential to identify patients likely to have inferior outcomes who may benefit from treatment with an alternative tyrosine kinase inhibitor.

Mechanisms of Apoptosis Resistance to NK Cell-Mediated Cytotoxicity in Cancer.

Natural killer (NK) cells are major contributors to immunosurveillance and control of tumor development by inducing apoptosis of malignant cells. Among the main mechanisms involved in NK cell-mediated cytotoxicity, the death receptor pathway and the release of granules containing perforin/granzymes stand out due to their efficacy in eliminating tumor cells. However, accumulated evidence suggest a profound immune suppression in the context of tumor progression affecting effector cells, such as NK cells, leading to decreased cytotoxicity. This diminished capability, together with the development of resistance to apoptosis by cancer cells, favor the loss of immunogenicity and promote immunosuppression, thus partially inducing NK cell-mediated killing resistance. Altered expression patterns of pro- and anti-apoptotic proteins along with genetic background comprise the main mechanisms of resistance to NK cell-related apoptosis. Herein, we summarize the main effector cytotoxic mechanisms against tumor cells, as well as the major resistance strategies acquired by tumor cells that hamper the extrinsic and intrinsic apoptotic pathways related to NK cell-mediated killing.

Treatment with daratumumab in patients with relapsed/refractory AL amyloidosis: a multicentric retrospective study and review of the literature.

Management of patients with relapsed or refractory (R/R) AL amyloidosis is complex. Some initial reports have shown positive results with daratumumab in heavily pre-treated AL amyloidosis patients. In this retrospective multicentric study, 38 patients (mean age 64 ± 9 years) with R/R AL amyloidosis treated with daratumumab were included. Cardiac and renal involvement was present in 76 and 74% of patients, and 42% had ≥3 organs involved. Median number of previous lines of therapy was 2 (range 1-8). Overall hematological response was 72%, including 28% complete responses. The median time to first hematological response was 2 weeks. A high-quality response (≥very good partial response) was obtained in 65% of patients who had never achieved such depth of response previously. Hematological responses were more frequent among patients receiving daratumumab as second-line therapy compared to subsequent therapies (92 vs. 61%). Cardiac and renal organ response rates were 37 and 59%. At 12 months, overall and progression-free survival were 59% (95%CI: 0.36-0.77) and 52% (95%CI: 0.29-0.70), respectively. Daratumumab is a safe and effective drug in the treatment of R/R AL amyloidosis and should be considered early in the course of the disease.