Everolimus in Diffuse Large B-Cell Lymphomas

Merli, Michele; Ferrario, Andrea; Maffioli, Margherita; Arcaini, Luca; Passamonti, Francesco

doi:10.2217/fon.14.264

Cited by 21 publications

(15 citation statements)

References 42 publications

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“…The interest on sirolimus is related to the fact that sirolimus is a well-known agent, used for many years for other indications [64][65][66][67][68][69][70][71][72][73][74][75][76][77] (see Supplementary Table S10). For instance, sirolimus or sirolimus-related compounds have been employed for treatment of kidney transplantation [64,65], cardiac [66] and liver [67] transplantation, lupus erythematosus (SLE) [68], autoimmune cytopenias [69], lymphangioleiomyomatosis (LAM) [70], tuberous sclerosis complex [71], recurrent meningioma [72], pancreatic neuroendocrine tumors (NET) [73], advanced differentiated thyroid cancers [74], advanced breast cancer [75], Bcell lymphomas [76], metastatic renal cell carcinoma [77].…”

Section: Discussionmentioning

confidence: 99%

Expression of γ-globin genes in β-thalassemia patients treated with sirolimus: results from a pilot clinical trial (Sirthalaclin)

Zuccato

Cosenza

Zurlo

et al. 2021

Preprint

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Introduction: The β-thalassemias are due to autosomal mutations of the β-globin gene, inducing absence or low-level synthesis of β-globin in erythroid cells. It is widely accepted that high production of fetal hemoglobin (HbF) is beneficial for β-thalassemia patients. Sirolimus, also known as rapamycin, is a lipophilic macrolide isolated from a strain of Streptomyces hygroscopicus found to be a strong HbF inducer in vitro and in vivo. In this study, we report biochemical, molecular and clinical results of the sirolimus-based NCT03877809 clinical trial (A Personalized Medicine Approach for β-thalassemia Transfusion Dependent Patients: Testing sirolimus in a First Pilot Clinical Trial: Sirthalaclin). Methods: Accumulation of γ-globin mRNA was analyzed by reverse-transcription-quantitative PCR and the hemoglobin pattern by HPLC. The immunophenotype was analyzed by FACS using antibodies against CD3, CD4, CD8, CD14, CD19, CD25. Results: The results were obtained in 8 patients with β+/β+ and β+/β0 genotypes, treated with a starting dosage of 1 mg/day sirolimus for 24-48 weeks. The first finding of the study was that expression of γ-globin mRNA was increased in blood and erythroid precursor cells isolated from β-thalassemia patients treated with low-dose sirolimus. A second important conclusion of our trial was that sirolimus influences erythropoiesis and reduces biochemical markers associated to ineffective erythropoiesis (I.E.) (excess of free α-globin chains, bilirubin, soluble transferrin receptor and ferritin). In most (7/8) of the patients a decrease of the transfusion index was observed. The drug was well tolerated with minor effects on immunophenotype, the only side effect being frequently occurring stomatitis. Conclusions: The data obtained indicate that sirolimus given at low doses modifies hematopoiesis and induces increased expression of γ-globin genes in a sub-set of β-thalassemia patients. Further clinical trials are warranted, considering the possibility to test the drug in patients with less severe forms of the disease and exploring combination therapies.

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Section: Discussionmentioning

confidence: 99%

Expression of γ-globin genes in β-thalassemia patients treated with sirolimus: results from a pilot clinical trial (Sirthalaclin)

Zuccato

Cosenza

Zurlo

et al. 2021

Preprint

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“…Meanwhile, Everolimus combined with rituximab hassled to stronger cell lethality. The objective response rate was 38%, the complete response rate was 13%, and there was no increase in toxicity [ 286 ].…”

Section: Targeted Therapymentioning

confidence: 99%

Altered pathways and targeted therapy in double hit lymphoma

Zhuang

Che

et al. 2022

J Hematol Oncol

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High-grade B-cell lymphoma with translocations involving MYC and BCL2 or BCL6, usually referred to as double hit lymphoma (DHL), is an aggressive hematological malignance with distinct genetic features and poor clinical prognosis. Current standard chemoimmunotherapy fails to confer satisfying outcomes and few targeted therapeutics are available for the treatment against DHL. Recently, the delineating of the genetic landscape in tumors has provided insight into both biology and targeted therapies. Therefore, it is essential to understand the altered signaling pathways of DHL to develop treatment strategies with better clinical benefits. Herein, we summarized the genetic alterations in the two DHL subtypes (DHL-BCL2 and DHL-BCL6). We further elucidate their implications on cellular processes, including anti-apoptosis, epigenetic regulations, B-cell receptor signaling, and immune escape. Ongoing and potential therapeutic strategies and targeted drugs steered by these alterations were reviewed accordingly. Based on these findings, we also discuss the therapeutic vulnerabilities that coincide with these genetic changes. We believe that the understanding of the DHL studies will provide insight into this disease and capacitate the finding of more effective treatment strategies.

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“…Up to now, the most promising agents are inhibitors of mTor and PI3K, for example, everolimus and idelalisib. Both of them were already more or less successfully used for the treatment of various types of lymphoma [36][37][38] and several trials are ongoing or were only recently completed (e.g., NCT00967044, NCT00671112, NCT01306643, NCT01088048).…”

Section: Immunomodulatory Agentsmentioning

confidence: 99%

Changing treatment paradigms in lymphoma: new targets and new drugs

Mian

Chiappella²

2015

memo

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The knowledge about biological mechanisms contributing to lymphomagenesis represents the basis for targeted therapies in lymphoproliferative disorders. Herein, we provide a short overview about the novel drugs targeting B-cell non-Hodgkin lymphomas, with a focus on diffuse large B-cell lymphomas. Due to the plethora of new drugs, we present some of the most important new drug developments in lymphoma treatment, namely humanized monoclonal antibodies, monoclonal antibody conjugates, immunomodulatory agents, and tyrosine kinase inhibitors. The use of these agents alone or in combination with chemotherapy showed promising results with a good safety profile in a setting of relapsed/refractory lymphomas. Since many of them demonstrated to be highly active, several clinical trials evaluating their efficacy in first-line treatment are ongoing.

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Everolimus in Diffuse Large B-Cell Lymphomas

Cited by 21 publications

References 42 publications

Expression of γ-globin genes in β-thalassemia patients treated with sirolimus: results from a pilot clinical trial (Sirthalaclin)

Expression of γ-globin genes in β-thalassemia patients treated with sirolimus: results from a pilot clinical trial (Sirthalaclin)

Altered pathways and targeted therapy in double hit lymphoma

Changing treatment paradigms in lymphoma: new targets and new drugs

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