Other malignancies in the history of CLL: an international multicenter study conducted by ERIC, the European Research Initiative on CLL, in HARMONY.

Background: Patients with chronic lymphocytic leukemia (CLL) have a higher risk of developing other malignancies (OMs) compared to the general population. However, the impact of CLL-related risk factors and CLL-directed treatment is still unclear and represents the focus of this work. Methods: We conducted a retrospective international multicenter study to assess the incidence of OMs and detect potential risk factors in 19,705 patients with CLL, small lymphocytic lymphoma, or high-count CLL-like monoclonal B-cell lymphocytosis, diagnosed between 2000 and 2016. Data collection took place between October 2020 and March 2022. Findings: In 129,254 years of follow-up after CLL diagnosis, 3513 OMs were diagnosed (27.2 OMs/1000 person-years). The most common hematological OMs were Richter transformation, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Non-melanoma skin (NMSC) and prostate cancers were the most common solid tumors (STs).The only predictor for MDS and AML development was treatment with fludarabine and cyclophosphamide with/without rituximab (FC ± R) (OR = 3.7; 95% CI = 2.79-4.91; p < 0.001). STs were more frequent in males and patients with unmutated immunoglobulin heavy variable genes (OR = 1.77; 95% CI = 1.49-2.11; p < 0.001/OR = 1.89; 95% CI = 1.6-2.24; p < 0.001).CLL-directed treatment was associated with non-melanoma skin and prostate cancers (OR = 1.8; 95% CI = 1.36-2.41; p < 0.001/OR = 2.11; 95% CI = 1.12-3.97; p = 0.021). In contrast, breast cancers were more frequent in untreated patients (OR = 0.17; 95% CI = 0.08-0.33; p < 0.001).Patients with CLL and an OM had inferior overall survival (OS) than those without. AML and MDS conferred the worst OS (p < 0.001). Interpretation: OMs in CLL impact on OS. Treatment for CLL increased the risk for AML/MDS, prostate cancer, and NMSC. FCR was associated with increased risk for AML/MDS. Funding: AbbVie, and EU/EFPIAInnovative Medicines Initiative Joint Undertaking HARMONY grant n° 116026.

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).

Ability of final PET/CT to predict response to first-line treatment in real patients with classical Hodgkin lymphoma.

Up to 25% of patients with classical Hodgkin lymphoma (cHL) and a negative interim PET/CT will progress. Unfortunately, there are few published studies on the predictive value of PET/CT performed after finishing treatment. The objective of our study was to assess the role of the final PET/CT (fPET/CT) in predicting progression in a retrospective series of patients treated in the last 10 years with a homogeneous protocol (ABVD + / - radiotherapy). We reviewed a cohort of 227 patients with newly diagnosed cHL. fPET/CT was performed on 212 patients (93%). In patients with a positive fPET, progression-free survival at 60 months was 17% (94% if fPET was negative, p = 0.000). The positive and negative predictive values for the fPET were 76% and 94%, respectively (Fisher's exact test, p = 0.000). In the subgroup of patients with advanced-stage cHL, progression-free survival at 60 months was 91% with negative fPET and 0% with positive fPET (p = 0.000). However, fPET was negative in 19 of the 29 patients with a positive interim PET/CT (only 2 showed progression). In conclusion, fPET is a useful tool to predict treatment failure in patients with newly diagnosed cHL, especially advanced-stage disease.

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.

Clinical outcome and prognostic factors of patients with Richter syndrome: real-world study of the Spanish Chronic Lymphocytic Leukemia Study Group (GELLC).

Richter syndrome (RS) is an uncommon evolution of chronic lymphocytic leukaemia (CLL) with a dismal prognosis. Clinical-biological features predicting outcome and best therapeutic approach for these patients remain to be established. In this study, 128 patients with RS, including 112 diffuse large B-cell lymphoma (DLBCL)-type RS, 15 Hodgkin lymphoma (HL)-type RS, and one plasmablastic lymphoma, were identified in 11 centres of the Spanish CLL Study Group (GELLC). The median overall survival (OS) was 5·9 months for DLBCL-type RS and 30·8 months for HL-type RS. Eastern Cooperative Oncology Group Performance Status, haemoglobin level, platelet count, serum lactate dehydrogenase and ß2-microglobulin levels, tumour protein p53 (TP53) abnormalities in the CLL clone concomitant to RS, number of prior therapies, and clonal relationship between CLL and RS, were associated with OS in patients with DLBCL-type RS. A platelet count of <100 × 109 /l, prior CLL therapy (0 vs. ≥1), and presence of TP53 alterations maintained an independent prognostic impact in the multivariate analysis. Patients without any of these factors had a better clinical outcome, with a median OS of 75·3 months, while patients with one or two or more of these factors presented a median OS of 25·5 and 3 months, respectively. Although OS of patients with RS is generally poor, a proportion of patients achieved prolonged survival. Treatment of RS remains a medical need, and further therapeutic approaches with novel therapies are warranted.

Response to erythropoietic-stimulating agents in patients with chronic myelomonocytic leukemia.

BACKGROUND: The efficacy of erythropoietic-stimulating agents (ESA) in chronic myelomonocytic leukemia (CMML) is unknown. Our objective was to analyze erythroid response (ER) and overall survival (OS) in a series of 94 patients with CMML treated with ESA. METHODS: We analyzed a series of 94 patients with CMML treated with ESA included in the Spanish and Düsseldorf-MDS registries. FINDINGS: ER was observed in 64% of patients and red blood cell (RBC) transfusion independence in 31%. The median duration of ER was 7 months (range, 0-88). CPSS and EPO level were significantly associated with ER in multivariate analysis (P = 0.003). Considering only patients with CPSS low- or intermediate-1-risk group, the absence of RBC transfusion dependence and erythropoietin (EPO) level predicted ER (P = 0.003 and P = 0.008, respectively). In multivariate analysis, only the EPO level retained its prognostic value (P = 0.029). Achievement of ER correlated with a better survival since ER evaluation (P = 0.016). INTERPRETATION: The CPSS and EPO levels are adequate tools to select CMML patients with symptomatic anemia who may benefit from treatment with ESA. A significant ER to ESA is expected in anemic patients with low/intermediate-1 CMML risk by the CPSS and a low endogenous serum EPO level.

Effectiveness and safety of different azacitidine dosage regimens in patients with myelodysplastic syndromes or acute myeloid leukemia.

We investigated the effectiveness and tolerability of azacitidine in patients with World Health Organization-defined myelodysplastic syndromes, or acute myeloid leukemia with 20-30% bone marrow blasts. Patients were treated with azacitidine, with one of three dosage regimens: for 5 days (AZA 5); 7 days including a 2-day break (AZA 5-2-2); or 7 days (AZA 7); all 28-day cycles. Overall response rates were 39.4%, 67.9%, and 51.3%, respectively, and median overall survival (OS) durations were 13.2, 19.1, and 14.9 months. Neutropenia was the most common grade 3-4 adverse event. These results suggest better effectiveness-tolerability profiles for 7-day schedules.

Clinical experience of bendamustine treatment for non-Hodgkin lymphoma and chronic lymphocytic leukemia in Spain.

Bendamustine is a alkylating agent with a purine-like benzamidazole ring currently approved in Europe for indolent non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL) and multiple myeloma. Our aim was to analyze retrospectively the efficacy and toxicity of bendamustine in NHL and CLL in Spain in the bendamustine Compassionate Use Program. Patients with relapsed/refractory NHL or CLL were eligible. Any regimen containing bendamustine was eligible. 109 patients were included from 22 institutions. Forty-nine patients had indolent NHL, 18 aggressive NHL and 42 CLL, being 44 patients (40%) refractory to previous treatment. 63% of patients had adverse events grade 3-4, mainly hematological. Overall response rate (ORR) was 66%, complete responses 30%. ORR observed in refractory patients was 45%. The median progression-free survival (PFS) was 13 months. Outcome was influenced by histology, number of previous treatments, resistance to previous chemotherapy and type of response achieved with bendamustine. Alone or in combination, bendamustine shows a meaningful clinical antitumor activity in patients with relapsed or refractory NHL or CLL, with an acceptable toxicity profile.