Evaluación de estrategias inmunes para el control del mieloma múltiple a largo plazo

[ES] El MM sigue siendo en la actualidad una enfermedad incurable en la mayoría de los pacientes, lo que supone observar recaídas sucesivas tras una primera línea. El objetivo de tratamiento es, por una parte, alcanzar la mejor y más profunda respuesta posible, y mantenerla a largo plazo, para prevenir recaídas y prolongar la supervivencia global. En ese sentido, el sistema inmune tiene un papel clave en el pronóstico del MM, bien porque muchas estrategias se dirigen a potenciarlo o bien porque un sistema inmune lo más sano posible o que se recupere con el tratamiento permitirá un mejor control de la enfermedad. En este estudio, se ha propuesto evaluar el papel del sistema inmune en dos situaciones diferentes: candidatos a ASCT y no candidatos. - Candidatos a ASCT: La administración de altas dosis de quimioterapia y ASCT se considera el estándar de tratamiento en los pacientes con MM que son candidatos a ello. Tras ASCT, diferentes estrategias como la consolidación y el mantenimiento se han intentado estandarizar para profundizar hasta la mejor respuesta posible y mantenerla en el tiempo, con el objetivo de lograr un incremento de la supervivencia. Se considera que la respuesta alcanzada aproximadamente en el día +100 desde el ASCT es la máxima respuesta que se alcanza con dicho procedimiento, por lo que las mejorías en la respuesta que se observan a partir de este momento y bajo consolidación y/o mantenimiento se deben al efecto beneficioso del tratamiento post-ASCT. Sin embargo, algunos estudios sugieren que puede haber pacientes respondedores tardíos que mejoran espontáneamente su respuesta más allá del día +100 post-ASCT, lo cual podría poner en duda la utilidad o necesidad del tratamiento post-ASCT. Por tanto, se considera que el tiempo para evaluar la respuesta es el día +100, pero hipotetizamos que un potencial restablecimiento inmune tras el ASCT, podría inducir respuestas más allá de este momento y, podría interferir en la evaluación de la eficacia de otros tratamientos, como el mantenimiento. - No candidatos a ASCT: En el momento actual, estos pacientes reciben tratamiento hasta la progresión de la enfermedad. Cada vez más se utilizan tratamientos como IMiDs y anti-CD38, en los cuales, la presencia de un sistema inmune preservado puede ser clave para su eficacia. Una de las manifestaciones de la disfunción del sistema inmune es la inmunoparesia (disminución de las inmunoglobulinas policlonales). Nuestra hipótesis es que la utilización de un posible biomarcador del funcionamiento del sistema inmune, como es la inmunoparesia, y, más importante su recuperación durante el tratamiento, podría afectar a la eficacia de estos u otros tratamientos e influir en el pronóstico de estos pacientes. Hipotéticamente, la presencia de inmunoparesia al diagnóstico se relacionaría con peor pronóstico y, al mismo tiempo, la recuperación de la misma durante el tratamiento debería impactar de forma positiva en el pronóstico de los pacientes, como reflejo de una mejor funcionalidad del sistema inmune para el control de la enfermedad. En base a lo anteriormente expuesto, se determinan los siguientes objetivos específicos: - Con respecto a los pacientes candidatos a ASCT • Determinar la tasa de mejoría de respuesta tardía (más allá del día +100) en pacientes con mieloma múltiple que han recibido trasplante autólogo. • Determinar los factores que se puedan relacionar con una mejoría de respuesta tardía post trasplante. • Determinar el impacto pronóstico de la respuesta tardía en supervivencia frente a aquéllos en que no se produce. - Con respecto a los pacientes no candidatos a ASCT • Determinar la frecuencia de inmunoparesia al diagnóstico en los pacientes no candidatos a trasplante autólogo. • Determinar los factores que se asocian con la aparición de inmunoparesia al diagnóstico. • Determinar el impacto pronóstico de la inmunoparesia al diagnóstico en los pacientes con mieloma múltiple no candidatos a trasplante autólogo. • Determinar la tasa de normalización de las inmunoglobulinas policlonales durante el tratamiento o tras la finalización del mismo, en los pacientes con mieloma múltiple no candidatos a trasplante autólogo. • Determinar los factores evolutivos que se relacionan con la normalización de las inmunoglobulinas policlonales. • Determinar el impacto pronóstico de la normalización de las inmunoglobulinas policlonales

Nirmatrelvir/ritonavir in COVID-19 patients with haematological malignancies: a report from the EPICOVIDEHA registry

Background: Nirmatrelvir/ritonavir treatment decreases the hospitalisation rate in immunocompetent patients with COVID-19, but data on efficacy in patients with haematological malignancy are scarce. Here, we describe the outcome of nirmatrelvir/ritonavir treatment in a large cohort of the latter patients. Methods: This is a retrospective cohort study from the multicentre EPICOVIDEHA registry (NCT04733729) on patients with haematological malignancy, who were diagnosed with COVID-19 between January and September 2022. Patients receiving nirmatrelvir/ritonavir were compared to those who did not. A logistic regression was run to determine factors associated with nirmatrelvir/ritonavir administration in our sample. Mortality between treatment groups was assessed with Kaplan–Meier survival plots after matching all the patients with a propensity score. Additionally, a Cox regression was modelled to detect factors associated with mortality in patients receiving nirmatrelvir/ritonavir. Findings: A total of 1859 patients were analysed, 117 (6%) were treated with nirmatrelvir/ritonavir, 1742 (94%) were treated otherwise. Of 117 patients receiving nirmatrelvir/ritonavir, 80% had received ≥1 anti-SARS-CoV-2 vaccine dose before COVID-19 onset, 13% of which received a 2nd vaccine booster. 5% were admitted to ICU. Nirmatrelvir/ritonavir treatment was associated with the presence of extrapulmonary symptoms at COVID-19 onset, for example anosmia, fever, rhinitis, or sinusitis (aOR 2.509, 95%CI 1.448–4.347) and 2nd vaccine booster (aOR 3.624, 95%CI 1.619–8.109). Chronic pulmonary disease (aOR 0.261, 95%CI 0.093–0.732) and obesity (aOR 0.105, 95%CI 0.014–0.776) were not associated with nirmatrelvir/ritonavir use. After propensity score matching, day-30 mortality rate in patients treated with nirmatrelvir/ritonavir was 2%, significantly lower than in patients with SARS-CoV-2 directed treatment other than nirmatrelvir/ritonavir (11%, p = 0.036). No factor was observed explaining the mortality difference in patients after nirmatrelvir/ritonavir administration. Interpretation: Haematological malignancy patients were more likely to receive nirmatrelvir/ritonavir when reporting extrapulmonary symptoms or 2nd vaccine booster at COVID-19 onset, as opposed to chronic pulmonary disease and obesity. The mortality rate in patients treated with nirmatrelvir/ritonavir was lower than in patients with targeted drugs other than nirmatrelvir/ritonavir. Funding: EPICOVIDEHA has received funds from Optics COMMIT (COVID-19 Unmet Medical Needs and Associated Research Extension) COVID-19 RFP program by GILEAD Science, United States (Project 2020-8223)

Age, successive waves, immunization, and mortality in elderly COVID-19 hematological patients: EPICOVIDEHA findings

Elderly patients with hematologic malignancies face the highest risk of severe COVID-19 outcomes. The infection's impact on different age groups remains unstudied in detail.We analyzed elderly patients (age groups: 65-70, 71-75, 76-80, and >80 years old) with hematologic malignancies included in the EPICOVIDEHA registry between January 2020 and July 2022. Univariable and multivariable Cox regression models were conducted to identify factors influencing death in COVID-19 patients with hematological malignancy.The study included data from 3,603 elderly patients (aged 65 or older) with hematological malignancy, with a majority being male (58.1%) and a significant proportion having comorbidities. The patients were divided into four age groups, and the analysis assessed COVID-19 outcomes, vaccination status, and other variables in relation to age and pandemic waves. The 90-day survival rate for patients with COVID-19 was 71.2%, with significant differences between groups. The pandemic waves had varying impacts, with the first wave affecting patients over 80 years old, the second being more severe in 65-70, and the third being the least severe in all age groups. Factors contributing to 90-day mortality included age, comorbidities, lymphopenia, active malignancy, acute leukemia, less than three vaccine doses, severe COVID-19, and using only corticosteroids as treatment.These data underscore the heterogeneity of elderly hematological patients, highlight the different impacts of COVID-19 waves and the pivotal importance of vaccination, and may help in planning future healthcare efforts

Dissecting the role of TP53 alterations in del(11q) chronic lymphocytic leukemia

[EN]Background Several genetic alterations have been identified as driver events in chronic lymphocytic leukemia (CLL) pathogenesis and oncogenic evolution. Concurrent driver alterations usually coexist within the same tumoral clone, but how the cooperation of multiple genomic abnormalities contributes to disease progression remains poorly understood. Specifically, the biological and clinical consequences of concurrent high-risk alterations such as del(11q)/ATM-mutations and del(17p)/TP53-mutations have not been established. Methods We integrated next-generation sequencing (NGS) and clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 techniques to characterize the in vitro and in vivo effects of concurrent monoallelic or biallelic ATM and/or TP53 alterations in CLL prognosis, clonal evolution, and therapy response. Results Targeted sequencing analysis of the co-occurrence of high-risk alterations in 271 CLLs revealed that biallelic inactivation of both ATM and TP53 was mutually exclusive, whereas monoallelic del(11q) and TP53 alterations significantly co-occurred in a subset of CLL patients with a highly adverse clinical outcome. We determined the biological effects of combined del(11q), ATM and/or TP53 mutations in CRISPR/Cas9-edited CLL cell lines. Our results showed that the combination of monoallelic del(11q) and TP53 mutations in CLL cells led to a clonal advantage in vitro and in in vivo clonal competition experiments, whereas CLL cells harboring biallelic ATM and TP53 loss failed to compete in in vivo xenotransplants. Furthermore, we demonstrated that CLL cell lines harboring del(11q) and TP53 mutations show only partial responses to B cell receptor signaling inhibitors, but may potentially benefit from ATR inhibition. Conclusions Our work highlights that combined monoallelic del(11q) and TP53 alterations coordinately contribute to clonal advantage and shorter overall survival in CLL

Chronic lymphocytic leukemia patients with IGH translocations are characterized by a distinct genetic landscape with prognostic implications.

[EN]Chromosome 14q32 rearrangements/translocations involving the immunoglobulin heavy chain (IGH) are rarely detected in chronic lymphocytic leukemia (CLL). The prognostic significance of the IGH translocation is controversial and its mutational profile remains unknown. Here, we present for the first time a comprehensive next-generation sequencing (NGS) analysis of 46 CLL patients with IGH rearrangement (IGHR-CLLs) and we demonstrate that IGHR-CLLs have a distinct mutational profile with recurrent mutations in NOTCH1, IGLL5, POT1, BCL2, FBXW7, ZMYM3, MGA, BRAF and HIST1H1E genes. Interestingly, BCL2 and FBXW7 mutations were significantly associated with this subgroup and almost half of BCL2, IGLL5 and HISTH1E mutations reported were previously identified in non-Hodgkin lymphomas. Notably, IGH/BCL2 rearrangements were associated with a lower mutation frequency and carried BCL2 and IGLL5 mutations, while the other IGHR-CLLs had mutations in genes related to poor prognosis (NOTCH1, SF3B1 and TP53) and shorter time to first treatment (TFT). Moreover, IGHR-CLLs patients showed a shorter TFT than CLL patients carrying 13q-, normal fluorescence in situ hybridization (FISH) and +12 CLL, being this prognosis particularly poor when NOTCH1, SF3B1, TP53, BIRC3 and BRAF were also mutated. The presence of these mutations not only was an independent risk factor within IGHR-CLLs, but also refined the prognosis of low-risk cytogenetic patients (13q-/normal FISH). Hence, our study demonstrates that IGHR-CLLs have a distinct mutational profile from the majority of CLLs and highlights the relevance of incorporating NGS and the status of IGH by FISH analysis to refine the risk-stratification CLL model.Instituto de Salud Carlos III, Grant/Award Numbers: PI15/01471, PI18/01500; Instituto de Salud Carlos III/Fondo Social Europeo 'El Fondo Social Europeo invierte en tu futuro', Grant/Award Numbers: CD19/00222, FI19/00191; European Regional Development Fund; Spanish Fondo de Investigaciones Sanitarias; Ayuda Predoctoral de la Junta de Castilla y León, Grant/Award Number: JCYL-EDU/529/2017; Centro de Investigación Biomédica en Red de Cáncer, Grant/Award Number: CB16/12/00233; Red Temática de Investigación Cooperativa en Cáncer, Grant/Award Number: RD12/0036/0069; Fundación Memoria Don Samuel Solórzano Barruso; Fundación Científica Asociación Española Contra el Cáncer; Fundación Española de Hematología y Hemoterapia/Janssen; Proyectos de Investigación del SACYL, Grant/Award Numbers: GRS1653/A17, 1847/A/18; Consejería de Educación, Junta de Castilla y León, Grant/Award Number: SA271P1

Decoding the historical tale:COVID-19 impact on haematological malignancy patients—EPICOVIDEHA insights from 2020 to 2022

Background: The COVID-19 pandemic heightened risks for individuals with hematological malignancies due to compromised immune systems, leading to more severe outcomes and increased mortality. While interventions like vaccines, targeted antivirals, and monoclonal antibodies have been effective for the general population, their benefits for these patients may not be as pronounced. Methods: The EPICOVIDEHA registry (National Clinical Trials Identifier, NCT04733729) gathers COVID-19 data from hematological malignancy patients since the pandemic's start worldwide. It spans various global locations, allowing comprehensive analysis over the first three years (2020–2022). Findings: The EPICOVIDEHA registry collected data from January 2020 to December 2022, involving 8767 COVID-19 cases in hematological malignancy patients from 152 centers across 41 countries, with 42% being female. Over this period, there was a significant reduction in critical infections and an overall decrease in mortality from 29% to 4%. However, hospitalization, particularly in the ICU, remained associated with higher mortality rates. Factors contributing to increased mortality included age, multiple comorbidities, active malignancy at COVID-19 onset, pulmonary symptoms, and hospitalization. On the positive side, vaccination with one to two doses or three or more doses, as well as encountering COVID-19 in 2022, were associated with improved survival. Interpretation: Patients with hematological malignancies still face elevated risks, despite reductions in critical infections and overall mortality rates over time. Hospitalization, especially in ICUs, remains a significant concern. The study underscores the importance of vaccination and the timing of COVID-19 exposure in 2022 for enhanced survival in this patient group. Ongoing monitoring and targeted interventions are essential to support this vulnerable population, emphasizing the critical role of timely diagnosis and prompt treatment in preventing severe COVID-19 cases. Funding: Not applicable.</p

Correction: Need for ICU and outcome of critically ill patients with COVID-19 and haematological malignancies: results from the EPICOVIDEHA survey (Infection, (2024), 52, 3, (1125-1141), 10.1007/s15010-023-02169-7)

Acknowledgements Members of the EPICOVIDEHA registry: Joseph Meletiadis, Florian Reizine, Jan Novák, Summiya Nizamuddin, Roberta Di Blasi, Alexandra Serris, Pavel Jindra, Sylvain Lamure, François Danion, Maria Chiara Tisi, Mario Virgilio Papa, Nurettin Erben, ľuboš DrgoňA, Nathan C. Bahr, Murtadha Al-Khabori, Ayten Shirinova, Jörg Schubert, Lisset Lorenzo De La Peña, José-Ángel Hernández-Rivas, Elena Busch, Josip Batinić, Giuseppe Sapienza, Mohammad Reza Salehi, Reham Abdelaziz Khedr, Nina Khanna, Baerbel Hoell-Neugebauer, Ana Groh, Eleni Gavriilaki, Rita Fazzi, Rémy Duléry, Roberta Della Pepa, Mario Delia, Nicola Coppola, Maria Calbacho, Darko Antić, Hossein Zarrinfer, Ayel Yahia, Vivien Wai-Man, Ana Torres-TIenza, Alina Daniela Tanasa, Andrés Soto-Silva, Laura Serrano, Enrico Schalk, Ikhwan Rinaldi, Gaëtan Plantefeve, Monica Piedimonte, Maria Enza Mitra, Carolina Miranda-Castillo, Jorge Loureiro-Amigo, Ira Lacej, Martin Kolditz, María-Josefa Jiménez-Lorenzo, Guillemette Fouquet, Omar-Francisco Coronel-Ayala, Mathias Brehon, Panagiotis Tsirigotis, Anastasia Antoniadou, Gina Varricchio, Maria Vehreschild, Agostino Tafuri, José-María Ribera-Santa Susana, Joyce Marques De Almeida, María Fernández-Galán, Avinash Aujayeb, Athanasios Tragiannidis, Malgorzata Mikulska, Sein Win, Elizabeth De Kort, Hans-Beier Ommen, Donald C. Vinh, Hans Martin Orth, Sandra Malak, Przemyslaw Zdziarski, Modar Saleh, Chi Shan Kho, Fabio Guolo, M. Mansour Ceesay, Christopher H. Heath, Sergey Gerasymchuk, Monica Fung, Maximilian Desole, Erik De Cabo, Tania Cushion, Fazle Rabbi Chowdhury, Louis Yi Ann Chai, Fevzi Altuntaş, Charlotte Flasshove. The original article has been updated.</p