Management of front line chronic lymphocytic leukemia

Kutsch, Nadine; Fink, Anna Maria; Fischer, Kirsten

doi:10.1002/ajh.26677

Cited by 3 publications

(3 citation statements)

References 81 publications

(186 reference statements)

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“…However, it's worth noting that the treatments caused the mortality of 3 out of 9 mice in the ibrutinib group and 4 out of 9 in the venetoclax group by day 18, reflecting side effects seen in some B-CLL patients [51]. In one case, a mouse treated with venetoclax had to be sacrificed due to severe lymphocyte loss.…”

Section: Discussionmentioning

confidence: 99%

Mice Overexpressing Wild Type RRAS2: A Novel Preclinical Model for Testing Anti-Chronic Lymphocytic Leukemia Therapies

Alarcón,

Hortal,

Villanueva

et al. 2023

Preprint

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B-cell chronic lymphocytic leukemia (B-CLL) is the most common type of leukemia in the Western world. Mutations in different genes, such as TP53 and ATM, and deletions in specific chromosomal regions, including 11q or 17p, have been associated with a worse prognosis for the disease. Recent research from our group has demonstrated that, contrary to the usual cancer development process through missense mutations, B-CLL is driven by the overexpression of the small GTPase RRAS2 in its wild-type form, without activating mutations. While some mouse models of this disease have been developed to date and are commonly used in B-CLL research, they come with various disadvantages, such as a long waiting period until the leukemia fully develops, the need for cell engraftment, or, in some cases, a failure to replicate the alterations found in human patients. We have recently introduced Rosa26-RRAS2fl/flxmb1-Cre as a new mouse model of B-CLL with full disease penetrance. In this work, we have validated this mouse model as a novel tool for the development of new therapies for B-CLL by testing two of the most widely applied targeted agents: ibrutinib and venetoclax. This also paves the way for the development of new targeted agents against R-RAS2 itself, an approach that has not yet been explored in clinical practice.

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Section: Discussionmentioning

confidence: 99%

Mice Overexpressing Wild Type RRAS2: A Novel Preclinical Model for Testing Anti-Chronic Lymphocytic Leukemia Therapies

Alarcón,

Hortal,

Villanueva

et al. 2023

Preprint

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show abstract

“…This reflects that the venetoclax treatment is not selective for the leukemic cells. Severe side effects are also described in humans, where venetoclax can cause tumor lysis syndrome and secondary infections [52], as well as neutropenia, anemia or thrombocytopenia [53]. All this clearly calls for the development of new therapeutic regimens that maximize efficacy while minimizing their side effects.…”

Section: Discussionmentioning

confidence: 99%

Mice Overexpressing Wild-Type RRAS2 Are a Novel Model for Preclinical Testing of Anti-Chronic Lymphocytic Leukemia Therapies

Hortal,

Villanueva,

Arellano

et al. 2023

Cancers

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B-cell chronic lymphocytic leukemia (B-CLL) is the most common type of leukemia in the Western world. Mutation in different genes, such as TP53 and ATM, and deletions at specific chromosomic regions, among which are 11q or 17p, have been described to be associated to worse disease prognosis. Recent research from our group has demonstrated that, contrary to what is the usual cancer development process through missense mutations, B-CLL is driven by the overexpression of the small GTPase RRAS2 in its wild-type form without activating mutations. Some mouse models of this disease have been developed to date and are commonly used in B-CLL research, but they present different disadvantages such as the long waiting period until the leukemia fully develops, the need to do cell engraftment or, in some cases, the fact that the model does not recapitulate the alterations found in human patients. We have recently described Rosa26-RRAS2fl/flxmb1-Cre as a new mouse model of B-CLL with a full penetrance of the disease. In this work, we have validated this mouse model as a novel tool for the development of new therapies for B-CLL, by testing two of the most broadly applied targeted agents: ibrutinib and venetoclax. This also opens the door to new targeted agents against R-RAS2 itself, an approach not yet explored in the clinic.

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“…Venetoclax (ABT-199, BCL2 inhibitor), the best known and trialled BH-3 mimetic, is a small-molecule proapoptotic drug with significant clinical activity, that is considered practice-changing for several adult cancers. Venetoclax, in combination with other drugs, became a standard of care in certain situations in chronic lymphocytic leukaemia (CLL), is increasingly used in multiple myeloma, acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS), and has been experimentally administered in other malignancies including ALL [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 ]. Although in AML, venetoclax is indicated especially in unfit or elderly adults who would likely not tolerate high-dose chemotherapy, it is frequently used in the relapse or salvage setting, and in the future may be a component of first line therapies [ 3 , 7 , 9 , 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

Venetoclax Use in Paediatric Haemato-Oncology Centres in Poland: A 2022 Survey

et al. 2023

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Venetoclax, the best established BH3 mimetic, is a practice-changing proapoptotic drug to treat blood cancers in adults. In paediatrics, the data are less but exciting results were recently presented in relapsed or refractory leukaemias demonstrating significant clinical activity. Importantly, the interventions could be potentially molecularly guided as vulnerabilities to BH3 mimetics were reported. Currently, venetoclax is not incorporated into paediatric treatment schedules in Poland but it has been already used in patients that failed conventional therapy in Polish paediatric haemato-oncology departments. The aim of the study was to gather clinical data and correlates of all paediatric patients treated thus far with venetoclax in Poland. We set out to gather this data to help choose the right clinical context for the drug and stimulate further research. The questionnaire regarding the use of venetoclax was sent to all 18 Polish paediatric haemato-oncology centres. The data of November 2022 were gathered and analysed for the diagnoses, triggers for the intervention, treatment schedules, outcomes and molecular associations. We received response from 11 centres, 5 of which administered venetoclax to their patients. Clinical benefit, in most cases consistent with haematologic complete remission (CR), was reported in five patients out of ten, whereas five patients did not show clinical benefit from the intervention. Importantly, patients with CR included subtypes expected to show venetoclax vulnerability, such as poor-prognosis ALL with TCF::HLF fusion. We believe that BH3 mimetics have clinical activity in children and should be available to paediatric haemato-oncology practitioners in well-selected applications.

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Management of front line chronic lymphocytic leukemia

Cited by 3 publications

References 81 publications

Mice Overexpressing Wild Type RRAS2: A Novel Preclinical Model for Testing Anti-Chronic Lymphocytic Leukemia Therapies

Mice Overexpressing Wild Type RRAS2: A Novel Preclinical Model for Testing Anti-Chronic Lymphocytic Leukemia Therapies

Mice Overexpressing Wild-Type RRAS2 Are a Novel Model for Preclinical Testing of Anti-Chronic Lymphocytic Leukemia Therapies

Venetoclax Use in Paediatric Haemato-Oncology Centres in Poland: A 2022 Survey

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