Predictors of Survival, Treatment Modalities, and Clinical Outcomes of Diffuse Large B-Cell Lymphoma in Patients Older Than 70 Years Still an Unmet Medical Need in 2024 Based on Real-World Evidence.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) especially affects the older population. Old (≥60 years) and very old age (≥80 years) DLBCL patients often present high-risk molecular alterations, lower tolerability to conventional immunochemotherapy, and poor clinical outcomes. In this scenario, attenuated therapeutic strategies, such as the R-MiniCHOP and R-MiniCHOP of the elderly regimens, have emerged for this particularly fragile population. However, the responses, clinical outcomes, and toxicities of these regimens currently remain poorly understood, mainly because these individuals are not usually included in controlled clinical trials. METHODS: This retrospective, observational, and single-center real-world study included 185 DLBCL, NOS patients older than 70 years treated at the largest oncology center in Latin America from 2009 to 2020. We aimed to assess the outcomes, determine survival predictors, and compare responses and toxicities between three different primary therapeutic strategies, including the conventional R-CHOP regimen and the attenuated R-MiniCHOP and R-MiniCHOP of the elderly protocols. RESULTS: The median age at diagnosis was 75 years (70-97 years), and 58.9% were female. Comorbidities were prevalent, including 19.5% with immobility, 28.1% with malnutrition, and 24.8% with polypharmacy. Advanced clinical stage was observed in 72.4%, 48.6% had bulky disease ≥7 cm, 63.2% had B-symptoms, and 67.0% presented intermediate-high/high-risk IPI. With a median follow-up of 6.3 years, the estimated 5-year OS and PFS were 50.2% and 44.6%, respectively. The R-MiniCHOP of the elderly regimen had a lower ORR (p = 0.040); however, patients in this group had higher rates of unfavorable clinical and laboratory findings, including hypoalbuminemia (p = 0.001), IPI ≥ 3 (p = 0.013), and NCCN-IPI ≥ 3 (p = 0.002). Although associated with higher rates of severe neutropenia (p = 0.003), the R-CHOP regimen promoted increased OS (p = 0.003) and PFS (p = 0.005) in comparison to the attenuated protocols. Additionally, age ≥ 75 years, high levels of LDH, B-symptoms, advanced clinical stage (III/IV), neutrophilia, and low lymphocyte/monocyte ratio were identified as poor prognostic factors in this cohort. CONCLUSIONS: In this large and real-life Latin American cohort, we demonstrated that patients with DLBCL, NOS older than 70 years still do not have satisfactory clinical outcomes in 2024, with half of cases not reaching 5 years of life expectancy after diagnosis. Although the conventional R-CHOP offers response and survival advantages over attenuated regimens, its myelotoxicity is not negligible. Therefore, the outcomes reported and the prognostic factors here identified may assist clinicians in the appropriate selection of therapeutic strategies adapted to the risk for old and very old DLBCL patients.

The role of whole-brain radiotherapy (WBRT) in primary central nervous system lymphoma: is it an alternative to ASCT for consolidation following HD-methotrexate based induction in low-income settings?

BACKGROUND: Primary central nervous system lymphoma (PCNSL) is a rare and aggressive malignancy. Although potentially curable, its prognosis remains dismal. Its treatment is based on high-doses of methotrexate (HD-MTX) and rituximab, followed by consolidation therapy with whole-brain radiotherapy (WBRT) or autologous stem cell transplantation (ASCT). Currently, there is no consensus about the best consolidation strategy, but better outcomes with ASCT are obtained with conditioning regimens based on thiotepa, a high-cost drug with restricted use in resource-constrained settings. Latin American data on clinical outcomes, prognostic factors, and therapeutic management in PCNSL are virtually unknown. METHODS: This is a retrospective, observational, and single-center study involving 47-Brazilian patients with PCNSL. We aim to assess outcomes, determine predictors of survival, and compare responses, as well as toxicities in patients consolidated with chemotherapy alone versus chemotherapy plus WBRT. RESULTS: The median age at diagnosis was 59 years (24-88 years), and 53.1% were male. LDH ≥ UVN occurred in 44.7%, ECOG ≥ 2 in 67.6%, and 34.1% had multifocal disease. Hemiparesis was the main clinical presentation, observed in 55.3%, 51.0% had intermediate-/high-risk IELSG prognostic score, and 57.6% had an ABC-like phenotype by IHC. With a median follow-up of 24.4 months, estimated 5-year OS and PFS were 45.5% and 36.4%, respectively. Among 40 patients treated with HD-MTX-based induction, estimated 2-year OS was 85.8% for those consolidated with WBRT plus HIDAC versus only 41.5% for those consolidated with HIDAC alone (p < 0.001). Hematologic and non-hematologic toxicities were not significant, and severe cognitive impairment occurred in only 6.3% (3/47) of cases, all of them treated with WBRT. Age < 60 years, Hb ≥ 120 g/L and WBRT consolidation were associated with increased OS, however, LDH ≥ UVN, hypoalbuminemia, ECOG ≥ 2, Karnofsky PS < 70 and intermediate-/high-risk Barcelona score were associated with decreased OS. CONCLUSION: Combined consolidation therapy (CCT) based on WBRT plus HIDAC was associated with increased OS in PCNSL compared to isolated consolidation therapy (ICT) based on HIDAC alone. Here, severe late neurotoxicity was uncommon with this approach. These data suggest that WBRT may be an effective and safe alternative to ASCT for consolidation therapy in PCNSL, particularly in resource-constrained settings, where access to thiotepa for pre-ASCT conditioning is not universal.

Emerging targets for combination therapy in melanomas.

Cutaneous melanomas are often difficult to treat when diagnosed in advanced stages. Melanoma cells adapt to survive in extreme environmental conditions and are among the tumors with larger genomic instability. Here we discuss some intrinsic and extrinsic mechanisms of resistance of melanoma cells to both conventional and target therapies, such as autophagy, adaptation to endoplasmic reticulum stress, metabolic reprogramming, mechanisms of tumor repopulation and the role of extracellular vesicles in this later phenomenon. These biological processes are potentially targetable and thus provide a platform for research and discovery of new drugs for combination therapy to manage melanoma patient treatment.