Ixazomib, daratumumab and low-dose dexamethasone in intermediate-fit patients with newly diagnosed multiple myeloma:an open-label phase 2 trial

Background: The outcome of non-transplant eligible newly diagnosed multiple myeloma (NDMM) patients is heterogeneous, partly depending on frailty level. The aim of this study was to prospectively investigate the efficacy and safety of Ixazomib-Daratumumab-low-dose dexamethasone (Ixa-Dara-dex) in NDMM intermediate-fit patients. Methods: In this phase II multicenter HOVON-143 study, IMWG Frailty index based intermediate-fit patients, were treated with 9 induction cycles of Ixa-Dara-dex, followed by maintenance with ID for a maximum of 2 years. The primary endpoint was overall response rate on induction treatment. Patients were included from October 2017 until May 2019. Trial Registration Number: NTR6297. Findings: Sixty-five patients were included. Induction therapy resulted in an overall response rate of 71%. Early mortality was 1.5%. At a median follow-up of 41.0 months, median progression-free survival (PFS) was 18.2 months and 3-year overall survival 83%. Discontinuation of therapy occurred in 77% of patients, 49% due to progression, 9% due to toxicity, 8% due to incompliance, 3% due to sudden death and 8% due to other reasons. Dose modifications of ixazomib were required frequently (37% and 53% of patients during induction and maintenance, respectively), mainly due to, often low grade, polyneuropathy. During maintenance 23% of patients received daratumumab alone. Global quality of life (QoL) improved significantly and was clinically relevant, which persisted during maintenance treatment. Interpretation: Ixazomib-Daratumumab-low-dose dexamethasone as first line treatment in intermediate-fit NDMM patients is safe and improves global QoL. However, efficacy was limited, partly explained by ixazomib-induced toxicity, hampering long term tolerability of this 3-drug regimen. This highlights the need for more efficacious and tolerable regimens improving the outcome in vulnerable intermediate-fit patients. Funding: Janssen Pharmaceuticals, Takeda Pharmaceutical Company Limited.</p

COVID-19 severity and mortality in patients with CLL: an update of the international ERIC and Campus CLL study

Patients with chronic lymphocytic leukemia (CLL) may be more susceptible to Coronavirus disease 2019 (COVID-19) due to age, disease, and treatment-related immunosuppression. We aimed to assess risk factors of outcome and elucidate the impact of CLL-directed treatments on the course of COVID-19. We conducted a retrospective, international study, collectively including 941 patients with CLL and confirmed COVID-19. Data from the beginning of the pandemic until March 16, 2021, were collected from 91 centers. The risk factors of case fatality rate (CFR), disease severity, and overall survival (OS) were investigated. OS analysis was restricted to patients with severe COVID-19 (definition: hospitalization with need of oxygen or admission into an intensive care unit). CFR in patients with severe COVID-19 was 38.4%. OS was inferior for patients in all treatment categories compared to untreated (p < 0.001). Untreated patients had a lower risk of death (HR = 0.54, 95% CI:0.41–0.72). The risk of death was higher for older patients and those suffering from cardiac failure (HR = 1.03, 95% CI:1.02–1.04; HR = 1.79, 95% CI:1.04–3.07, respectively). Age, CLL-directed treatment, and cardiac failure were significant risk factors of OS. Untreated patients had a better chance of survival than those on treatment or recently treated

The evolving landscape of COVID‐19 and post‐COVID condition in patients with chronic lymphocytic leukemia: A study by ERIC, the European research initiative on CLL

In this retrospective international multicenter study, we describe the clinical characteristics and outcomes of patients with chronic lymphocytic leukemia (CLL) and related disorders (small lymphocytic lymphoma and high-count monoclonal B lymphocytosis) infected by SARS-CoV-2, including the development of post-COVID condition. Data from 1540 patients with CLL infected by SARS-CoV-2 from January 2020 to May 2022 were included in the analysis and assigned to four phases based on cases disposition and SARS-CoV-2 variants emergence. Post-COVID condition was defined according to the WHO criteria. Patients infected during the most recent phases of the pandemic, though carrying a higher comorbidity burden, were less often hospitalized, rarely needed intensive care unit admission, or died compared to patients infected during the initial phases. The 4-month overall survival (OS) improved through the phases, from 68% to 83%, p = .0015. Age, comorbidity, CLL-directed treatment, but not vaccination status, emerged as risk factors for mortality. Among survivors, 6.65% patients had a reinfection, usually milder than the initial one, and 16.5% developed post-COVID condition. The latter was characterized by fatigue, dyspnea, lasting cough, and impaired concentration. Infection severity was the only risk factor for developing post-COVID. The median time to resolution of the post-COVID condition was 4.7 months. OS in patients with CLL improved during the different phases of the pandemic, likely due to the improvement of prophylactic and therapeutic measures against SARS-CoV-2 as well as the emergence of milder variants. However, mortality remained relevant and a significant number of patients developed post-COVID conditions, warranting further investigations

Metastatic breast cancer: different aspects in real-world treatment and outcome

The introduction of several new medicines has improved the prognosis of patients with metastatic breast cancer over recent years. However, these new medicines contribute to rising costs of oncology care. In addition, drug treatments may have side effects and, therefore, adversely affect quality of life. This thesis demonstrates that in daily practice, the quality of life of patients with metastatic breast cancer is determined by age and the presence of comorbidity rather than the duration of metastatic disease and the number of therapies given. It is also shown that the implementation of new medicines in daily practice differs from the implementation described in the guideline. Therefore, it is important that research is conducted into efficient use of oncology medicines in daily practice

Functional status decline in older patients with breast and colorectal cancer after cancer treatment: A prospective cohort study

OBJECTIVES: The aim of the present study was to disentangle the impact of age and that of cancer diagnosis and treatment on functional status (FS) decline in older patients with cancer. MATERIALS AND METHODS: Patients with breast and colorectal cancer aged 50-69years and aged ≥70years who had undergone surgery, and older patients without cancer aged ≥70years were included. FS was assessed at baseline and after 12months follow-up, using the Katz index for activities of daily living (ADL) and the Lawton scale for instrumental activities of daily living (IADL). FS decline was defined as ≥1 point decrease on the ADL or IADL scale from baseline to 12months follow-up. RESULTS: In total, 179 older patients with cancer (≥ 70years), 341 younger patients with cancer (50-69years) and 317 older patients without cancer (≥ 70years) were included. FS decline was found in 43.6%, 24.6% and 28.1% of the groups, respectively. FS decline was significantly worse in older compared to younger patients with cancer receiving no chemotherapy (44.5% versus 17.6%, p<0.001), but not for those who did receive chemotherapy (39.4% versus 30.8%, p=0.33). Among the patients with cancer, FS decline was significantly associated with older age (OR 2.63), female sex (OR 3.72), colorectal cancer (OR 2.81), polypharmacy (OR 2.10) and, inversely, with baseline ADL dependency (OR 0.44). CONCLUSION: Cancer treatment, and older age are important predictors of FS decline. The relation of baseline ADL dependency and chemotherapy with FS decline suggest that the fittest of the older patients with cancer were selected for chemotherapy.publisher: Elsevier articletitle: Functional status decline in older patients with breast and colorectal cancer after cancer treatment: A prospective cohort study journaltitle: Journal of Geriatric Oncology articlelink: http://dx.doi.org/10.1016/j.jgo.2017.01.003 content_type: article copyright: © 2017 The Authors. Published by Elsevier Ltd.status: publishe

An unexpected, invasive disease of the mastoid bone and external auditory canal

A 65-year-old male patient with a history of Myelodysplastic Syndrome (MDS) and Systemic Mastocytosis (SM) presented with an invasive disease of the external auditory canal (EAC) and a parotid gland abscess. Abscess drainage and treatment for a malignant otitis externa (MOE) was started, which did not lead to clinical improvement. Computed Tomography (CT) of the petrous bone as well as a Positron Emission Tomography/Computed Tomography with 2-[fluorine-18]-fluoro-2-deoxy-D-glucose (FDG-PET-CT) showed bony erosion of the EAC with a symmetrical FDG distribution at the level of both EACs. Histopathological biopsies of the EAC revealed a rarely encountered localization of systemic mastocytosis (SM). Especially patients with a hematological disorder such as a MDS are at risk to develop SM. In case of a fulminant infectious disease of the EAC in these patients, a localization of SM should be considered as well. This is the first report on SM with a localization in the EAC

Gene expression responses reflecting 5-FU-induced toxicity: Comparison between patient colon tissue and 3D human colon organoids

Capecitabine is a chemotherapeutic drug that is widely used as a monotherapy option in advanced cancer patients. After administration, it is converted into its active metabolite 5-fluorouracil (5-FU), a cytotoxic compound that may also induce adverse side effects in the gastrointestinal (GI) tract. Although these side effects can interfere with the continuation of the chemotherapy, diagnostic tools to detect early onset and prevention strategies are not available. In this explorative case study, we aim to identify differentially expressed genes (DEGs) that provide insight into the molecular mechanisms of toxicity induced by 5-FU in healthy colon tissue of breast cancer patients receiving capecitabine. Gene expression responses observed in patients were compared with those established in an in vitro model of healthy colon organoids. Colon biopsies from two patients with advanced breast cancer were collected before and after the treatment with capecitabine and used for RNA sequencing to determine transcriptomic responses. Differential expression analysis resulted in 31 affected genes, showing that the most affected pathways were transport of small molecules, cellular responses to stress, folate metabolism, NF-kB signalling pathway and immune system responses. The most biologically relevant genes were haemoglobin subunits encoding genes, involved in several processes; ATP12A, SLC26A3 and AQP8, involved in the transport of ions and water; TRIM31, a regulator of NF-kB signalling pathway; MST1P2 and MST1L, stimulators of macrophages. Comparison of human in vitro and in vivo responses showed that the gene expression of TRIM31 was similarly altered in the colon organoids exposed to 5-FU. Therefore, this gene constitutes a potential biomarker of colon toxicity that might be used in future in vitro drug safety design and screening

Regulation of Bcl-XL by non-canonical NF-κB in the context of CD40-induced drug resistance in CLL

In chronic lymphocytic leukemia (CLL), the lymph node (LN) microenvironment delivers critical survival signals by inducing the expression of anti-apoptotic Bcl-2 members Bcl-XL, Bfl-1, and Mcl-1, resulting in apoptosis blockade. We determined previously that resistance against various drugs, among which is the clinically applied BH3 mimetic venetoclax, is dominated by upregulation of the anti-apoptotic regulator Bcl-XL. Direct clinical targeting of Bcl-XL by, e.g., Navitoclax is however not desirable due to induction of thrombocytopenia. Since the actual regulation of Bcl-XL in CLL in the context of the LN microenvironment is not well elucidated, we investigated various candidate LN signals to drive Bcl-XL expression. We found a dominance for NF-κB signaling upon CD40 stimulation, which results in activation of both the canonical and non-canonical NF-κB signaling pathways. We demonstrate that expression of Bcl-XL is first induced by the canonical NF-κB pathway, and subsequently boosted and continued via non-canonical NF-κB signaling through stabilization of NIK. NF-κB subunits p65 and p52 can both bind to the Bcl-XL promoter and activate transcription upon CD40 stimulation. Moreover, canonical NF-κB signaling was correlated with Bfl-1 expression, whereas Mcl-1 in contrast, was not transcriptionally regulated by NF-κB. Finally, we applied a novel compound targeting NIK to selectively inhibit the non-canonical NF-κB pathway and showed that venetoclax-resistant CLL cells were sensitized to venetoclax. In conclusion, protective signals from the CLL microenvironment can be tipped towards apoptosis sensitivity by interfering with non-canonical NF-κB signaling