RESUMEN
PURPOSE: Surrogate endpoints are commonly used to estimate treatment efficacy in clinical studies of chronic lymphocytic leukemia (CLL). This patient- and trial-level analysis describes the correlation between progression-free survival (PFS) and minimal residual disease (MRD) with overall survival (OS) in first-line trials for CLL. PATIENTS AND METHODS: First, patient-level correlation was confirmed using source data from 12 front-line GCLLSG-trials. Additionally, a joint-frailty copula model was fitted to validate correlation in the setting of targeted therapies.Second, a meta-analysis of first-line phase III trials in CLL from 2008-2024 was performed. Treatment effect correlation was quantified from seven GCLLSG and nine published trials, using hazard ratios for time-to-event and odds ratios for binary endpoints. RESULTS: The GCLLSG analysis set comprised 4237 patients. Patient-level correlation for PFS/OS was strong with Spearman's Rho >0.9. The joint-frailty copula indicated a weak correlation for C/CIT with a tau of 0.52, (95% CI: 0.49 - 0.55) while the correlation was strong for TT (tau = 0.91, 95% CI: 0.89 - 0.93).The meta-analysis set contained a total of 8065 patients including 5198 (64%) patients treated with C/CIT and 2867 (36%) treated with TT. Treatment effect correlation of the hazard ratios (HR) for PFS and OS was R = 0.75 (95% CI: 0.74 - 0.76, R2 = 0.56), while correlation of end-of-treatment MRD with PFS and OS was R = 0.88 (95%CI: -0.87 - 0.89; R2 = 0.78) and 0.71 (95%CI: 0.69 - 0.73; R2 = 0.5), respectively. CONCLUSION: Patient-level correlation was confirmed in the setting of targeted therapies while treatment-effect correlation between PFS and OS remains uncertain. MRD response status showed a high treatment-effect correlation with PFS but not OS, with the caveat of a limited number of randomized trials with available MRD data.
RESUMEN
Venetoclax-obinutuzumab (Ven-Obi) is a standard-of-care for patients with previously untreated chronic lymphocytic leukemia (CLL). In the CLL14 study, patients with previously untreated CLL and coexisting conditions were randomized to 12 cycles of Ven-Obi (n=216) or chlorambucil-obinutuzumab (Clb-Obi, n=216). Progression-free survival (PFS) was the primary endpoint. Key secondary endpoints included time-to-next-treatment (TTNT), rates of undetectable minimal residual disease (uMRD), overall survival (OS) and rates of adverse events. Patient reported outcomes (PROs) of time until definitive deterioration (TUDD) in quality of life (QoL) were analyzed. At a median observation time of 76.4 months, PFS remained superior for Ven-Obi compared to Clb-Obi (median 76.2 vs 36.4 months; HR 0.40[95%CI 0.31-0.52], p<0.0001). Likewise, TTNT was longer after Ven-Obi (6-year-TTNT 65.2% vs 37.1%; HR 0.44, 95%CI 0.33-0.58, p<0.0001). In the Ven-Obi arm, presence of del(17p), unmutated-IGHV and lymph node size ≥5 cm were independent prognostic factors for shorter PFS. Five years after treatment, 17 patients (7.9% of intention-to-treat-population) in the Ven-Obi arm had uMRD (<10-4 in peripheral blood) compared to 4 (1.9%) in the Clb-Obi arm. 6-year-OS rate was 78.7% in the Ven-Obi and 69.2% in the Clb-Obi arm (HR 0.69[95%CI 0.48-1.01], p=0.052). A significantly longer TUDD in global health status/QoL was observed in the Ven-Obi compared to the Clb-Obi arm (median 82.1 vs 65.1 months; HR 0.70[95%CI 0.51-0.97]). Follow-up adjusted SPM incidence rates were 2.3 and 1.4/1000 patient-months in the Ven-Obi and Clb-Obi arm, respectively. The sustained long-term survival, uMRD and QoL benefits support the use of one-year fixed-duration Ven-Obi in CLL. NCT02242942, EudraCT 2014-001810-24.
RESUMEN
Patients with chronic lymphocytic leukemia (CLL) exhibit diverse clinical outcomes. An expanding array of genetic tests is now employed to facilitate the identification of patients with high-risk disease and inform treatment decisions. These tests encompass molecular cytogenetic analysis, focusing on recurrent chromosomal alterations, particularly del(17p). Additionally, sequencing is utilized to identify TP53 mutations and to determine the somatic hypermutation status of the immunoglobulin heavy variable gene. Concurrently, a swift advancement of targeted treatment has led to the implementation of novel strategies for patients with CLL, including kinase and BCL2 inhibitors. This review explores both current and emerging diagnostic tests aimed at identifying high-risk patients who should benefit from targeted therapies. We outline existing treatment paradigms, emphasizing the importance of matching the right treatment to the right patient beyond genetic stratification, considering the crucial balance between safety and efficacy. We also take into consideration the practical and logistical issues when choosing a management strategy for each individual patient. Furthermore, we delve into the mechanisms underlying therapy resistance and stress the relevance of monitoring measurable residual disease to guide treatment decisions. Finally, we underscore the necessity of aggregating real-world data, adopting a global perspective, and ensuring patient engagement. Taken together, we argue that precision medicine is not the mere application of precision diagnostics and accessibility of precision therapies in CLL but encompasses various aspects of the patient journey (e.g., lifestyle exposures and comorbidities) and their preferences toward achieving true personalized medicine for patients with CLL.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Leucemia Linfocítica Crónica de Células B , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/complicaciones , Masculino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Femenino , Anciano , Infecciones/etiología , Infecciones/inducido químicamente , Persona de Mediana EdadAsunto(s)
Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Clorhidrato de Bendamustina , Leucemia Linfocítica Crónica de Células B , Purinas , Quinazolinonas , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Purinas/administración & dosificación , Purinas/uso terapéutico , Purinas/efectos adversos , Quinazolinonas/administración & dosificación , Quinazolinonas/uso terapéutico , Quinazolinonas/efectos adversos , Clorhidrato de Bendamustina/administración & dosificación , Clorhidrato de Bendamustina/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Anciano , Masculino , Femenino , Persona de Mediana EdadRESUMEN
Chromosomal aberrations are a common feature of cancer and can fuel cancer progression and treatment resistance. In chronic lymphocytic leukemia (CLL), the presence of multiple chromosomal aberrations is commonly referred to as "genomic complexity" or "complex karyotype"- (CKT). In the context of chemo- and chemoimmunotherapy, genomic complexity is associated with poor response to treatment and short survival, while some targeted therapies are able to mitigate its adverse prognostic impact. This article reviews currently available data and literature on the role of genomic complexity in CLL. The currently established tools to measure genomic complexity in patients with CLL are summarized and their strengths and weaknesses for routine diagnostics are evaluated. Moreover, possible definitions of CKT as an indicator for genomic complexity are discussed. Finally, data on the impact of CKT on clinical outcomes of patients with CLL are reviewed and the implications for patient stratification are presented.
Asunto(s)
Aberraciones Cromosómicas , Genómica , Leucemia Linfocítica Crónica de Células B , Humanos , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/mortalidad , Leucemia Linfocítica Crónica de Células B/terapia , Pronóstico , Genómica/métodos , Biomarcadores de Tumor/genéticaRESUMEN
ABSTRACT: The phase 2 CLL2-BAAG trial tested the measurable residual disease (MRD)-guided triple combination of acalabrutinib, venetoclax, and obinutuzumab after optional bendamustine debulking in 45 patients with relapsed/refractory chronic lymphocytic leukemia (CLL). MRD was measured by flow cytometry (FCM; undetectable MRD <10-4) in peripheral blood (PB) and circulating tumor DNA (ctDNA) using digital droplet polymerase chain reaction of variable-diversity-joining (VDJ) rearrangements and CLL-related mutations in plasma. The median number of previous treatments was 1 (range, 1-4); 18 patients (40%) had received a Bruton tyrosine kinase inhibitor (BTKi) and/or venetoclax before inclusion, 14 of 44 (31.8%) had TP53 aberrations, and 34 (75.6%) had unmutated immunoglobulin heavy-chain variable region genes. With a median observation time of 36.3 months and all patients off-treatment for a median of 21.9 months, uMRD <10-4 in PB was achieved in 42 of the 45 patients (93.3%) at any time point, including 17 of 18 (94.4%) previously exposed to venetoclax/BTKi and 13 of 14 (92.9%) with TP53 aberrations. The estimated 3-year progression-free and overall survival rates were 85.0% and 93.8%, respectively. Overall, 585 paired FCM/ctDNA samples were analyzed and 18 MRD recurrences (5 with and 13 without clinical progression) occurred after the end of treatment. Twelve samples were first detected by ctDNA, 3 by FCM, and 3 synchronously. In conclusion, time-limited MRD-guided acalabrutinib, venetoclax, and obinutuzumab achieved deep remissions in almost all patients with relapsed/refractory CLL. The addition of ctDNA-based analyses to FCM MRD assessment seems to improve early detection of relapses. This trial was registered at www.clinicaltrials.gov as #NCT03787264.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Benzamidas , Compuestos Bicíclicos Heterocíclicos con Puentes , ADN Tumoral Circulante , Leucemia Linfocítica Crónica de Células B , Neoplasia Residual , Pirazinas , Sulfonamidas , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/mortalidad , Sulfonamidas/administración & dosificación , Sulfonamidas/uso terapéutico , Anciano , Persona de Mediana Edad , Femenino , Masculino , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , ADN Tumoral Circulante/genética , ADN Tumoral Circulante/sangre , Pirazinas/administración & dosificación , Pirazinas/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/uso terapéutico , Benzamidas/administración & dosificación , Benzamidas/uso terapéutico , Adulto , RecurrenciaRESUMEN
ABSTRACT: We evaluated the chronic lymphocytic leukemia International Prognostic Index (CLL-IPI) in patients with CLL treated first line with targeted drugs (n = 991) or chemoimmunotherapy (n = 1256). With a median observation time of 40.5 months, the 3-year progression-free survival (PFS) rates for targeted drug-treated patients varied by CLL-IPI risk group: 96.5% (low), 87.6% (intermediate), 82.4% (high), and 78.7% (very high). Differences between consecutive CLL-IPI risk groups were observed for intermediate vs low and high vs intermediate, but not very high vs high. CLL-IPI factors ß2-microglobulin, immunoglobulin heavy variable (IGHV) status, and TP53 status each retained prognostic value for PFS. The 3-year overall survival (OS) rates by CLL-IPI risk groups were 100%, 96%, 93.9%, and 89.4%, respectively, with no differences between consecutive risk groups. Age, Binet stage, ß2-microglobulin, and TP53 status each retained prognostic value for OS. In chemoimmunotherapy patients (median observation time, 66.9 months), 3-year PFS rates for CLL-IPI risk groups were 78.1%, 51.4%, 40.1%, and 16.5%, respectively; corresponding 3-year OS rates were 97.4%, 93.1%, 81.8%, and 57.3%. In a matched-pair analysis, PFS differences in targeted therapies (n = 812) vs chemoimmunotherapy (n = 812) across all risk groups and OS differences in all but patients at low risk were demonstrated. The CLL-IPI maintains its prognostic value in predicting PFS outcomes with targeted drugs, but its impact in predicting survival appears diminished. Targeted therapies showed enhanced outcomes over chemoimmunotherapy, highlighting their effectiveness across various risk groups. Our findings support ongoing assessment of prognostic tools in CLL treatment evolution. These trials were registered at www.ClinicalTrials.gov as #NCT02345863, #NCT02401503, #NCT02689141, #NCT02445131, #NCT02758665, #NCT02950051, #NCT02242942, #NCT00262782, #NCT00281918, and #NCT01010061.
Asunto(s)
Leucemia Linfocítica Crónica de Células B , Terapia Molecular Dirigida , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/mortalidad , Leucemia Linfocítica Crónica de Células B/diagnóstico , Femenino , Masculino , Anciano , Persona de Mediana Edad , Pronóstico , Anciano de 80 o más Años , Adulto , Microglobulina beta-2 , Tasa de SupervivenciaAsunto(s)
Agammaglobulinemia Tirosina Quinasa , Inhibidores de Proteínas Quinasas , Humanos , Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células B/patología , Leucemia de Células B/tratamiento farmacológico , Leucemia de Células B/patologíaRESUMEN
PURPOSE OF REVIEW: In this review, we provide an overview of different time-limited combination therapies of chronic lymphocytic leukemia (CLL) and summarize the data of pivotal clinical studies. Furthermore, we discuss the relevance of MRD in clinical trials and summarize the challenges that arise in routine clinical care. Finally, we provide an outlook on studies and datasets needed to optimize the use of time-limited treatment strategies and MRD assessments in modern CLL management. RECENT FINDINGS: In recent years, first-line treatment of CLL has undergone a considerable transformation, with targeted substances having largely replaced chemoimmunotherapy (CIT) as a time-limited strategy in the frontline setting. BTK inhibitors were the first class of targeted agents introduced in CLL, which achieved longer progression-free survival (PFS) and in some cases also overall survival (OS) than CIT. However, this required an indefinite drug intake until disease progression, while CIT is generally administered over the course of few months. In contrast to BTK inhibitors, BCL2 inhibitors, another class of targeted agents, can achieve high rates of undetectable minimal residual disease (uMRD) levels and induce deep molecular remissions with the potential to stop treatment while maintaining remissions. Combinations of BCL2 inhibitors with CD20 antibodies or with BTK inhibitors have been explored to establish time-limited treatment strategies with targeted agents. In this context, one of the strongest predictors of long-term outcomes is MRD status at the end of treatment, which has been shown to correlate closely with PFS and OS in most cases.
Asunto(s)
Antineoplásicos , Leucemia Linfocítica Crónica de Células B , Humanos , Leucemia Linfocítica Crónica de Células B/terapia , Neoplasia Residual/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antineoplásicos/uso terapéutico , Proteínas Proto-Oncogénicas c-bcl-2RESUMEN
BACKGROUND: The level of minimal residual disease (MRD), often binarized into detectable or undetectable MRD according to certain thresholds, is strongly associated with long-term outcomes after chemo- and chemoimmunotherapy. SUMMARY: Driven by our improved understanding of the biology of chronic lymphocytic leukemia (CLL), the recent decade has shown a shift from chemotherapy-based regimens to regimens based on targeted agents that exploit distinct biological vulnerabilities of CLL. These targeted agents can be broadly classified into inhibitors of Bruton tyrosine kinase (BTK) and BCL2 as well as CD20-directed antibodies. Depending on which agent and which combination of agents is used, the levels or status of MRD can have varying clinical relevance. This has implications on the prognosis after therapy as well as on possible strategies to guide treatment duration and intensity. KEY MESSAGES: This review summarizes the main discoveries related to MRD in the context of targeted therapies. Furthermore, it provides an overview on current hurdles and caveats related to the implementation of MRD in regular clinical care and summarize open research questions that need to be addressed with future clinical studies.
Asunto(s)
Antineoplásicos , Leucemia Linfocítica Crónica de Células B , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Neoplasia Residual , Antineoplásicos/uso terapéutico , Pronóstico , Inmunoterapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
In patients with chronic lymphocytic leukemia, Richter transformation (RT) reflects the development of an aggressive lymphoma that is associated with poor response to chemotherapy and short survival. We initiated an international, investigator-initiated, prospective, open-label phase 2 study in which patients with RT received a combination of the PD-1 inhibitor tislelizumab plus the BTK inhibitor zanubrutinib for 12 cycles. Patients responding to treatment underwent maintenance treatment with both agents. The primary end point was overall response rate after six cycles. Of 59 enrolled patients, 48 patients received at least two cycles of treatment and comprised the analysis population according to the study protocol. The median observation time was 13.9 months, the median age was 67 (range 45-82) years. Ten patients (20.8%) had received previous RT-directed therapy. In total, 28 out of 48 patients responded to induction therapy with an overall response rate of 58.3% (95% confidence interval (CI) 43.2-72.4), including 9 (18.8%) complete reponse and 19 (39.6%) partial response, meeting the study's primary end point by rejecting the predefined null hypothesis of 40% (P = 0.008). Secondary end points included duration of response, progression-free survival and overall survival. The median duration of response was not reached, the median progression-free survival was 10.0 months (95% CI 3.8-16.3). Median overall survival was not reached with a 12-month overall survival rate of 74.7% (95% CI 58.4-91.0). The most common adverse events were infections (18.0%), gastrointestinal disorders (13.0%) and hematological toxicities (11.4%). These data suggest that combined checkpoint and BTK inhibition by tislelizumab plus zanubrutinib is an effective and well-tolerated treatment strategy for patients with RT. ClinicalTrials.gov Identifier: NCT04271956 .
Asunto(s)
Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Leucemia Linfocítica Crónica de Células B , Piperidinas , Pirazoles , Pirimidinas , Humanos , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Estudios Prospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológicoRESUMEN
Acquired mutations in BTK, PLCG2, and BCL2 are associated with resistance to continuous targeted agent therapy in chronic lymphocytic leukemia (CLL). Here, we discuss new evidence that limiting the duration of CLL therapy may prevent the evolution of such resistance mutations, potentially facilitating effective retreatment strategies. See related article by Jain et al., p. 498.
Asunto(s)
Antineoplásicos , Leucemia Linfocítica Crónica de Células B , Humanos , Agammaglobulinemia Tirosina Quinasa/genética , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/genética , Resistencia a Antineoplásicos/genética , Mutación , Antineoplásicos/farmacología , Antineoplásicos/uso terapéuticoRESUMEN
Venetoclax is a standard treatment for patients with CLL following covalent BTK inhibitor (cBTKi) therapy, despite relatively limited prospective data in this setting. Pirtobrutinib is a highly selective, non-covalent (reversible) BTKi that was designed to overcome the pharmacologic limitations of cBTKi and re-establish BTK inhibition. An unanchored matching-adjusted indirect comparison (MAIC) was conducted to estimate the treatment effect of pirtobrutinib versus venetoclax monotherapy in patients with cBTKi pre-treated CLL. Data from patients with CLL who were venetoclax-naïve and pre-treated with cBTKi received pirtobrutinib (n=146) in the phase 1/2 BRUIN study were compared with the only identified trial of patients with CLL receiving venetoclax after a cBTKi (n=91), as administered as monotherapy until progression. Outcomes included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and treatment-emergent adverse events (TEAEs). Both unweighted and weighted analyses were conducted. PFS and OS of pirtobrutinib and venetoclax were comparable in both unweighted and weighted analyses (weighted hazard ratios for PFS: 1.01, 95% CI: 0.58-1.73, p=0.98 and OS: 0.64, 95% CI: 0.25-1.67, p=0.34). ORR was significantly higher for pirtobrutinib (80.2% vs 64.8%, p=0.01). Grade ≥3 TEAEs were lower in weighted analyses for pirtobrutinib vs venetoclax (all p.
RESUMEN
The final analysis of the open-label, multicenter phase 2 CLL2-GIVe trial shows response and tolerability of the triple combination of obinutuzumab, ibrutinib, and venetoclax (GIVe regimen) in 41 previously untreated patients with high-risk chronic lymphocytic leukemia (CLL) with del(17p) and/or TP53 mutation. Induction consisted of 6 cycles of GIVe; venetoclax and ibrutinib were continued up to cycle 12 as consolidation. Ibrutinib was given until cycle 15 or up to cycle 36 in patients not achieving a complete response and with detectable minimal residual disease. The primary end point was the complete remission rate at cycle 15, which was achieved at 58.5% (95% CI, 42.1-73.7; P < .001). The last patient reached the end of the study in January 2022. After a median observation time of 38.4 months (range, 3.7-44.9), the 36-month progression-free survival was 79.9%, and the 36-month overall survival was 92.6%. Only 6 patients continued ibrutinib maintenance. Adverse events of concern were neutropenia (48.8%, grade ≥3) and infections (19.5%, grade ≥3). Cardiovascular toxicity grade 3 occurred as atrial fibrillation at a rate of 2.4% between cycles 1 and 12, as well as hypertension (4.9%) between cycles 1 and 6. The incidence of adverse events of any grade and grade ≥3 was highest during induction and decreased over time. Progressive disease was observed in 7 patients between cycles 27 and 42. In conclusion, the CLL2-GIVe regimen is a promising fixed-duration, first-line treatment for patients with high-risk CLL with a manageable safety profile.
Asunto(s)
Leucemia Linfocítica Crónica de Células B , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/genética , Anticuerpos Monoclonales Humanizados/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
Data on long-term outcomes and biological drivers associated with depth of remission after BCL2 inhibition by venetoclax in the treatment of chronic lymphocytic leukemia (CLL) are limited. In this open-label parallel-group phase-3 study, 432 patients with previously untreated CLL were randomized (1:1) to receive either 1-year venetoclax-obinutuzumab (Ven-Obi, 216 patients) or chlorambucil-Obi (Clb-Obi, 216 patients) therapy (NCT02242942). The primary endpoint was investigator-assessed progression-free survival (PFS); secondary endpoints included minimal residual disease (MRD) and overall survival. RNA sequencing of CD19-enriched blood was conducted for exploratory post-hoc analyses. After a median follow-up of 65.4 months, PFS is significantly superior for Ven-Obi compared to Clb-Obi (Hazard ratio [HR] 0.35 [95% CI 0.26-0.46], p < 0.0001). At 5 years after randomization, the estimated PFS rate is 62.6% after Ven-Obi and 27.0% after Clb-Obi. In both arms, MRD status at the end of therapy is associated with longer PFS. MRD + ( ≥ 10-4) status is associated with increased expression of multi-drug resistance gene ABCB1 (MDR1), whereas MRD6 (< 10-6) is associated with BCL2L11 (BIM) expression. Inflammatory response pathways are enriched in MRD+ patient solely in the Ven-Obi arm. These data indicate sustained long-term efficacy of fixed-duration Ven-Obi in patients with previously untreated CLL. The distinct transcriptomic profile of MRD+ status suggests possible biological vulnerabilities.
Asunto(s)
Leucemia Linfocítica Crónica de Células B , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/genética , Transcriptoma , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Clorambucilo/uso terapéutico , Clorambucilo/efectos adversos , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéuticoRESUMEN
Cancer-associated cachexia (CAC) is a major contributor to morbidity and mortality in individuals with non-small cell lung cancer. Key features of CAC include alterations in body composition and body weight. Here, we explore the association between body composition and body weight with survival and delineate potential biological processes and mediators that contribute to the development of CAC. Computed tomography-based body composition analysis of 651 individuals in the TRACERx (TRAcking non-small cell lung Cancer Evolution through therapy (Rx)) study suggested that individuals in the bottom 20th percentile of the distribution of skeletal muscle or adipose tissue area at the time of lung cancer diagnosis, had significantly shorter lung cancer-specific survival and overall survival. This finding was validated in 420 individuals in the independent Boston Lung Cancer Study. Individuals classified as having developed CAC according to one or more features at relapse encompassing loss of adipose or muscle tissue, or body mass index-adjusted weight loss were found to have distinct tumor genomic and transcriptomic profiles compared with individuals who did not develop such features. Primary non-small cell lung cancers from individuals who developed CAC were characterized by enrichment of inflammatory signaling and epithelial-mesenchymal transitional pathways, and differentially expressed genes upregulated in these tumors included cancer-testis antigen MAGEA6 and matrix metalloproteinases, such as ADAMTS3. In an exploratory proteomic analysis of circulating putative mediators of cachexia performed in a subset of 110 individuals from TRACERx, a significant association between circulating GDF15 and loss of body weight, skeletal muscle and adipose tissue was identified at relapse, supporting the potential therapeutic relevance of targeting GDF15 in the management of CAC.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Masculino , Humanos , Caquexia/complicaciones , Neoplasias Pulmonares/patología , Carcinoma de Pulmón de Células no Pequeñas/patología , Proteómica , Recurrencia Local de Neoplasia/patología , Composición Corporal , Peso Corporal , Músculo Esquelético/metabolismo , Antígenos de Neoplasias/metabolismo , Proteínas de NeoplasiasRESUMEN
Patients aged 80 years and older make up a fifth of patients with CLL but are underrepresented in clinical trials. We analyzed the outcomes of these patients treated with targeted agents in the front-line setting in six trials of the German CLL Study Group. Targeted agents included venetoclax, ibrutinib, and idelalisib, mainly used in combination with anti-CD20 antibodies. Among 716 patients, 33 matched the selection criteria (5%). Of those, the majority had relevant comorbidity, organ dysfunctions, and/or high-/very high-risk disease. The overall response rate was 73%. The median progression-free survival was 49.2 months compared with those not reached in younger patients. There were 11 documented deaths of which two were deemed related to therapy. Additional results including 40 patients treated with BTK-inhibitors from the GCLLSG registry suggest that treatment with targeted agents is feasible and effective. Dedicated studies are warranted for this particular subgroup of patients.