Safety and Efficacy of Ibrutinib in Combination With Rituximab and Lenalidomide in Previously Untreated Follicular and Marginal Zone Lymphoma

IRR is highly active as frontline therapy for FL and MZL. Compared to historical results with lenalidomide and rituximab, PFS is similar with higher grade 3-4 toxicity, particularly rash.

source: Cancer

Summary

An Open Label, Phase 2 Study

[Posted 27/Feb/2024]

AUDIENCE: Oncology, Pediatric

KEY FINDINGS: IRR is highly active as frontline therapy for FL and MZL. Compared to historical results with lenalidomide and rituximab, PFS is similar with higher grade 3-4 toxicity, particularly rash.

BACKGROUND: Follicular lymphoma (FL) and marginal zone lymphoma (MZL) are indolent non-Hodgkin lymphomas (iNHL). Median survival for iNHL is approximately 20 years. Because standard treatments are not curative, patients often receive multiple lines of therapy with associated toxicity-rationally designed, combination therapies with curative potential are needed. The immunomodulatory drug lenalidomide was evaluated in combination with rituximab for the frontline treatment of FL in the phase 3 RELEVANCE study. Ibrutinib, an oral Bruton tyrosine kinase inhibitor, is active in NHL and was evaluated in combination with lenalidomide, rituximab, and ibrutinib (IRR) in a phase 1 study.

DETAILS: The authors conducted an open-label, phase 2 clinical trial of IRR for previously untreated FL and MZL. The primary end point was progression-free survival (PFS) at 24 months. This study included 48 participants with previously untreated FL grade 1-3a (N = 38), or MZL (N = 10). Participants received 12, 28-day cycles of lenalidomide (15 mg, days 1-21 cycle 1; 20 mg, cycles 2-12), rituximab (375 mg/m2 weekly in cycle 1; day 1 cycles 2-12), and ibrutinib 560 mg daily. With a median follow-up of 65.3 months, the estimated PFS at 24 months was 78.8% (95% confidence interval [CI], 68.0%-91.4%) and 60-month PFS was 59.7% (95% CI, 46.6%-76.4%). One death occurred unrelated to disease progression. Grade 3-4 adverse events were observed in 64.6%, including 50% with grade 3-4 rash.

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Copyright © John Wiley & Sons, Inc. All rights reserved.

Source: Gordon, M. J., Feng, L., Strati, P., et al. (2024). Safety and Efficacy of Ibrutinib in Combination With Rituximab and Lenalidomide in Previously Untreated Follicular and Marginal Zone Lymphoma: An Open Label, Phase 2 Study. Cancer, . 2024; 130(6): 876-885; Published: March 15, 2024. DOI: 10.1002/cncr.35114.



Rapidly Evolving Pre- and Post-surgical Systemic Treatment of Melanoma

Melanoma therapeutics continues to advance with combination adjuvant approaches now investigating anti-PD1 with lymphocyte activation gene 3 (LAG3), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), and individualized neoantigen therapies. How this progress will be integrated into the management of a unique patient to reduce recurrence, limit toxicity, and avoid over-treatment will dominate clinical research and patient care over the next decade.

source: Am J Clin Dermatol

Summary

[Posted 25/Mar/2024]

AUDIENCE: Dermatology, Family Medicine

KEY FINDINGS: Melanoma therapeutics continues to advance with combination adjuvant approaches now investigating anti-PD1 with lymphocyte activation gene 3 (LAG3), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), and individualized neoantigen therapies. How this progress will be integrated into the management of a unique patient to reduce recurrence, limit toxicity, and avoid over-treatment will dominate clinical research and patient care over the next decade.

BACKGROUND: With the development of effective BRAF-targeted and immune-checkpoint immunotherapies for metastatic melanoma, clinical trials are moving these treatments into earlier adjuvant and perioperative settings. BRAF-targeted therapy is a standard of care in resected stage III-IV melanoma, while anti-programmed death-1 (PD1) immunotherapy is now a standard of care option in resected stage IIB through IV disease.

DETAILS: With both modalities, recurrence-free survival and distant-metastasis-free survival are improved by a relative 35-50%, yet no improvement in overall survival has been demonstrated. Neoadjuvant anti-PD1 therapy improves event-free survival by approximately an absolute 23%, although improvements in overall survival have yet to be demonstrated. Understanding which patients are most likely to recur and which are most likely to benefit from treatment is now the highest priority question in the field. Biomarker analyses, such as gene expression profiling of the primary lesion and circulating DNA, are preliminarily exciting as potential biomarkers, though each has drawbacks. As in the setting of metastatic disease, markers that inform positive outcomes include interferon-γ gene expression, PD-L1, and high tumor mutational burden, while negative predictors of outcome include circulating factors such as lactate dehydrogenase, interleukin-8, and C-reactive protein. Integrating and validating these markers into clinically relevant models is thus a high priority.

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Copyright © Springer Nature. All rights reserved.

Source: Augustin, R. C. and Luke, J. J. (2024). Rapidly Evolving Pre- and Post-surgical Systemic Treatment of Melanoma. American Journal of Clinical Dermatology. Published: March, 2024. DOI: 10.1007/s40257-024-00852-5.



Single-Cell Transcriptomic Analysis Deciphers Heterogenous Cancer Stem-Like Cells in Colorectal Cancer and Their Organ-Specific Metastasis

By using integrative scRNA-seq, spatial transcriptomic analysis and functional assays, authors have uncovered a stem-like cell cluster marked with PTPRO and ASCL2 as the metastatic culprit, whose subpopulations show further different liver or ovary organotropism.

source: Gut

Summary

[Posted 18/Mar/2024]

AUDIENCE: Gastroenterology, Oncology, Internal Medicine

KEY FINDINGS: By using integrative scRNA-seq, spatial transcriptomic analysis and functional assays, authors have uncovered a stem-like cell cluster marked with PTPRO and ASCL2 as the metastatic culprit, whose subpopulations show further different liver or ovary organotropism.

BACKGROUND: Metastasis is the major cause of cancer death. However, what types of heterogenous cancer cells in primary tumour and how they metastasise to the target organs remain largely undiscovered.

DETAILS: Authors performed single-cell RNA sequencing and spatial transcriptomic analysis in primary colorectal cancer (CRC) and metastases in the liver (lCRC) or ovary (oCRC). Authors also conducted immunofluorescence staining and functional experiments to examine the mechanism. Integrative analyses of epithelial cells reveal a stem-like cell cluster with high protein tyrosine phosphatase receptor type O (PTPRO) and achaete scute-like 2 (ASCL2) expression as the metastatic culprit. This cell cluster comprising distinct subpopulations shows distinct liver or ovary metastatic preference. Population 1 (P1) cells with high delta-like ligand 4 (DLL4) and MAF bZIP transcription factor A (MAFA) expression are enriched in primary CRC and oCRC, thus may be associated with ovarian metastasis. P3 cells having a similar expression pattern as cholangiocytes are found mainly in primary CRC and lCRC, presuming to be likely the culprits that specifically metastasise to the liver. Stem-like cells interacted with cancer-associated fibroblasts and endothelial cells via the DLL4-NOTCH signalling pathway to metastasise from primary CRC to the ovary. In the oCRC microenvironment, myofibroblasts provide cancer cells with glutamine and perform a metabolic reprogramming, which may be essential for cancer cells to localise and develop in the ovary.

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Copyright © BMJ Publishing Group Ltd & British Society of Gastroenterology. All rights reserved.

Source: Li, R., Liu, X., Huang, X., et al. (2024). Single-Cell Transcriptomic Analysis Deciphers Heterogenous Cancer Stem-Like Cells in Colorectal Cancer and Their Organ-Specific Metastasis. Gut. 2024; 73(3): 470-484 .Published: March, 2024. DOI: 10.1136/gutjnl-2023-330243.



Increased Risk of Recurrence and Disease-Specific Death Following Delayed Postoperative Radiation for Merkel Cell Carcinoma

Delay of PORT was associated with increased LRR, usually beyond the radiation field. This is consistent with the tendency of MCC to spread quickly via lymphatics. Initiation of PORT within 8 weeks was associated with improved locoregional control and MCC-specific survival.

source: JAAD

Summary

[Posted 19/Feb/2024]

AUDIENCE: Dermatology, Oncology

KEY FINDINGS: Delay of PORT was associated with increased LRR, usually beyond the radiation field. This is consistent with the tendency of MCC to spread quickly via lymphatics. Initiation of PORT within 8 weeks was associated with improved locoregional control and MCC-specific survival.

BACKGROUND: Merkel cell carcinoma (MCC) is often treated with surgery and postoperative radiation therapy (PORT). The optimal time to initiate PORT (Time-to-PORT [ttPORT]) is unknown. Purpose of this study was to assess if delays in ttPORT were associated with inferior outcomes.

DETAILS: Competing risk regression was used to evaluate associations between ttPORT and locoregional recurrence (LRR) for patients with stage I/II MCC in a prospective registry and adjust for covariates. Distant metastasis and death were competing risks. The cohort included 124 patients with median ttPORT of 41 days (range: 8-125 days). Median follow-up was 55 months. 17 (14%) patients experienced a LRR, 14 (82%) of which arose outside the radiation field. LRR at 5 years was increased for ttPORT >8 weeks vs less than or equal to 8 weeks, 28.0% vs 9.2%, P = .006. There was an increase in the cumulative incidence of MCC-specific death with increasing ttPORT (HR = 1.14 per 1-week increase, P = .016).

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Copyright © Elsevier Ltd. All rights reserved.

Source: Alexander, N. A., Schaub, S. K., Goff, P. H., et al. (2024). Increased Risk of Recurrence and Disease-Specific Death Following Delayed Postoperative Radiation for Merkel Cell Carcinoma. Journal of the American Academy of Dermatology. 2024; 90(2): 261-2678. Published: February, 2024. DOI: 10.1016/j.jaad.2023.07.1047.



Severe vs Nonsevere Immune Checkpoint Inhibitor-Induced Myocarditis

In a contemporary analysis of patients with suspected ICI myocarditis, severe ICI myocarditis was associated with increased 1-year cardiovascular mortality, which was lower than previously reported. Patients with nonsevere ICI myocarditis had outcomes similar to negative cases. The optimal management strategies for nonsevere ICI myocarditis need to be re-evaluated.

source: JACC CardioOnco

Summary

Contemporary 1-Year Outcomes

[Posted 17/Jan/2024]

AUDIENCE: Cardiology, Oncology

KEY FINDINGS: In a contemporary analysis of patients with suspected ICI myocarditis, severe ICI myocarditis was associated with increased 1-year cardiovascular mortality, which was lower than previously reported. Patients with nonsevere ICI myocarditis had outcomes similar to negative cases. The optimal management strategies for nonsevere ICI myocarditis need to be re-evaluated.

BACKGROUND: The long-term contemporary outcomes of patients with immune checkpoint inhibitor (ICI) myocarditis, spanning the spectrum of clinical severity, are undetermined. Authors sought to investigate the characteristics and cardiovascular outcomes of patients with severe and nonsevere ICI myocarditis.

DETAILS: This was a retrospective cohort study of patients with suspected ICI myocarditis at Massachusetts General Brigham Health System conducted between 2015 and 2022. Cases were classified as severe, nonsevere, and negative based on the International Cardio-Oncology Society criteria. One-year cardiovascular mortality, all-cause mortality, and cardiovascular readmissions were evaluated. We also evaluated 1-year ICI resumption and left ventricular ejection fraction over a median follow-up of 18 (Q1-Q3: 8-67) weeks. The study included 160 patients: 28 severe, 96 nonsevere, and 36 negative cases. Patients with severe myocarditis had an increased risk of 1-year cardiovascular mortality, particularly in the early post-myocarditis period (29% vs 5%; HR: 6.52; 95% CI: 2.2-19.6; P < 0.001). Patients with nonsevere myocarditis had a cardiovascular mortality rate similar to negative cases (HR: 0.61; 95% CI: 0.14-2.54). One-year all-cause mortality did not differ between severe, nonsevere, and negative cases (P = 0.74). Rates of 1-year cardiovascular readmissions and long-term left ventricular ejection fraction were also similar among the 3 groups. ICI resumption was low, even in negative cases.

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Copyright © American College of Cardiology Foundation. All rights reserved.

Source: Zadok, O. I. B., Levi, A., Divakaran, S., et al. (2023). Severe vs Nonsevere Immune Checkpoint Inhibitor-Induced Myocarditis: Contemporary 1-Year Outcomes. J Am Coll Cardiol CardioOnc. 2023; 5(6): 732–744. Published: December, 2023. DOI: 10.1016/j.jaccao.2023.09.004.



NNMT Enriches for AQP5+ Cancer Stem Cells to Drive Malignant Progression in Early Gastric Cardia Adenocarcinoma

The study extends the understanding of the heterogeneity of EGCA and identifies a functional NNMT+/AQP5+ population that may drive malignant progression in EGCA and could be used for early diagnosis and therapy.

source: Gut

Summary

[Posted 15/Jan/2024]

AUDIENCE: Gastroenterology, Internal Medicine

KEY FINDINGS: The study extends the understanding of the heterogeneity of EGCA and identifies a functional NNMT+/AQP5+ population that may drive malignant progression in EGCA and could be used for early diagnosis and therapy.

BACKGROUND: Early gastric cardia adenocarcinoma (EGCA) is a highly heterogeneous cancer, and the understanding of its classification and malignant progression is limited. This study explored the cellular and molecular heterogeneity in EGCA using single-cell RNA sequencing (scRNA-seq).

DETAILS: scRNA-seq was conducted on 95,551 cells from endoscopic biopsies of low-grade intraepithelial neoplasia, well/moderately/poorly differentiated EGCA and their paired adjacent nonmalignant biopsy samples. Large-scale clinical samples and functional experiments were employed. Integrative analysis of epithelial cells revealed that chief cells, parietal cells and enteroendocrine cells were rarely detected in the malignant epithelial subpopulation, whereas gland and pit mucous cells and AQP5+ stem cells were predominant during malignant progression. Pseudotime and functional enrichment analyses showed that the WNT and NF-κB signalling pathways were activated during the transition. Cluster analysis of heterogeneous malignant cells revealed that NNMT-mediated nicotinamide metabolism was enriched in gastric mucin phenotype cell population, which was associated with tumour initiation and inflammation-induced angiogenesis. Furthermore, the expression level of NNMT was gradually increased during the malignant progression and associated with poor prognosis in cardia adenocarcinoma. Mechanistically, NNMT catalysed the conversion of nicotinamide to 1-methyl nicotinamide via depleting S-adenosyl methionine, which led to a reduction in H3K27 trimethylation (H3K27me3) and then activated the WNT signalling pathway to maintain the stemness of AQP5+ stem cells during EGCA malignant progression.

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Copyright © BMJ Publishing Group Ltd & British Society of Gastroenterology. All rights reserved.

Source: Wang Z., Wang Q., Chen C., et al. (2023). NNMT Enriches for AQP5+ Cancer Stem Cells to Drive Malignant Progression in Early Gastric Cardia Adenocarcinoma. Gut. 2024; 73: 63-77. Published: November, 2023. DOI: 10.1136/gutjnl-2022-328408.



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