Venetoclax with high‐dose methotrexate and rituximab seem effective and well‐tolerated in the treatment of central nervous system involvement of chronic lymphocytic leukemia: A case report

Beziat, Guillaume; Gauthier, Martin; Protin, Caroline; Obéric, Lucie; Lerebours, Fleur; Carlier, Jasmine; Ysebaert, Loïc

doi:10.1002/ccr3.2580

Cited by 9 publications

(7 citation statements)

References 12 publications

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“…The HER2-FASN lipogenic axis therefore delineates a subgroup of patients that might benefit from therapeutic regimens containing FASNis and BCL-2 BH3 mimetics. The recent discovery that brain metastases in HER2 + breast cancer patients rely on FASN [82,83] illuminates the important translational impact of combining blood-brain-barrier penetrable versions of FASNis and BCL-2 BH3 mimetics such as venetoclax, which has already shown a potential efficacy in the treatment of malignancies with central nervous system involvement [84][85][86].…”

Section: Discussionmentioning

confidence: 99%

Fatty acid synthase (FASN) regulates the mitochondrial priming of cancer cells

et al. 2021

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Inhibitors of the lipogenic enzyme fatty acid synthase (FASN) have attracted much attention in the last decade as potential targeted cancer therapies. However, little is known about the molecular determinants of cancer cell sensitivity to FASN inhibitors (FASNis), which is a major roadblock to their therapeutic application. Here, we find that pharmacological starvation of endogenously produced FAs is a previously unrecognized metabolic stress that heightens mitochondrial apoptotic priming and favors cell death induction by BH3 mimetic inhibitors. Evaluation of the death decision circuits controlled by the BCL-2 family of proteins revealed that FASN inhibition is accompanied by the upregulation of the pro-death BH3-only proteins BIM, PUMA, and NOXA. Cell death triggered by FASN inhibition, which causally involves a palmitate/NADPH-related redox imbalance, is markedly diminished by concurrent loss of BIM or PUMA, suggesting that FASN activity controls cancer cell survival by fine-tuning the BH3 only proteins-dependent mitochondrial threshold for apoptosis. FASN inhibition results in a heightened mitochondrial apoptosis priming, shifting cells toward a primed-for-death state “addicted” to the anti-apoptotic protein BCL-2. Accordingly, co-administration of a FASNi synergistically augments the apoptosis-inducing activity of the dual BCL-XL/BCL-2 inhibitor ABT-263 (navitoclax) and the BCL-2 specific BH3-mimetic ABT-199 (venetoclax). FASN inhibition, however, fails to sensitize breast cancer cells to MCL-1- and BCL-XL-selective inhibitors such as S63845 and A1331852. A human breast cancer xenograft model evidenced that oral administration of the only clinically available FASNi drastically sensitizes FASN-addicted breast tumors to ineffective single-agents navitoclax and venetoclax in vivo. In summary, a novel FASN-driven facet of the mitochondrial priming mechanistically links the redox-buffering mechanism of FASN activity to the intrinsic apoptotic threshold in breast cancer cells. Combining next-generation FASNis with BCL-2-specific BH3 mimetics that directly activate the apoptotic machinery might generate more potent and longer-lasting antitumor responses in a clinical setting.

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Section: Discussionmentioning

confidence: 99%

Fatty acid synthase (FASN) regulates the mitochondrial priming of cancer cells

et al. 2021

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“…In addition, there have been two reports showing the effectiveness of venetoclax against CNS lesions ( Table 2 ). 17 , 18 One of those was a case where venetoclax was effective after Ibr resistance, and thus it may be beneficial to test venetoclax against CNS involvement in CLL.…”

Section: Discussionmentioning

confidence: 99%

Refractory Chronic Lymphocytic Leukemia with Central Nervous System Involvement: A Case Report with Literature Review

Nakanishi

Ito

Fujita

et al. 2020

JBM

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There have been few reports on central nervous system (CNS) involvement in chronic lymphocytic leukemia (CLL). This is an extremely rare disease with poor prognosis, owing to resistance to various treatments. We describe a 33-year-old man with intractable CLL with CNS involvement. He was diagnosed with CLL, with diplopia as the first manifestation. Magnetic resonance imaging revealed a contrast-enhancing tumor in the right temporal lobe, which was diagnosed as CNS involvement in CLL on brain biopsy. High-dose methotrexate therapy was ineffective for this lesion, which was also resistant to subsequent whole-brain irradiation, treatment with fludarabine–cyclophosphamide–rituximab chemoimmunotherapy, and ibrutinib administration. Because no standard protocol exists for CLL with CNS involvement, it is important to accumulate case data to verify the choice of new drugs for administration at an early stage. Therefore, we also conducted a literature review of 50 case reports of CNS lesions in the last 10 years to consider the pathophysiology, diagnosis, and treatment of CNS involvement in CLL. The possibility of new therapeutic agents, eg, ibrutinib and venetoclax, or a combination of these agents and methotrexate, can be envisioned as a treatment strategy for CLL with CNS involvement.

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“…Similar observations were reported in case reports in patients with AML and CLL. Reda et al and Beziat et al in patients with CLL [13,14,17]. Reda et al was first to report venetoclax concentrations close to the IC50 of CLL cells in the CSF of a CLL patient (1.…”

Section: Discussionmentioning

confidence: 99%

“…5 -2.8 ng/ml) receiving 400 mg of venetoclax [13]. Moreover, Beziat et al demonstrated that administering venetoclax in combination with systemic chemotherapy was tolerated and resulted in well-controlled CNS manifestations in another CLL patient with minimal side effects [17]. In fact, neurologic improvements were maintained under continuous venetoclax exposure, six months after the last methotrexate infusion, with absence of new symptoms [17].…”

Section: Discussionmentioning

confidence: 99%

Venetoclax Penetrates the Blood Brain Barrier: A Pharmacokinetic Analysis in Pediatric Leukemia Patients

Badawi¹,

Menon²,

Place³

et al. 2023

J. Cancer

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Infiltration of malignant cells into the central nervous system in hematological malignancies correlates with poor clinical outcomes. Investigations into the penetration of venetoclax into the central nervous system have been limited. We report venetoclax pharmacokinetics in plasma and cerebrospinal fluid samples from a Phase 1 study in pediatric patients with relapsed or refractory malignancies that demonstrate venetoclax ability to cross into the central nervous system. Venetoclax was detected in cerebrospinal fluid (CSF) samples, with concentrations ranging from < 0.1 to 26 ng/mL (mean, 3.6 ng/mL) and a plasma:CSF ratio ranging from 44 to 1559 (mean, 385). Plasma:CSF ratios were comparable among patients with AML and ALL and no clear trend was observed in the ratios over the course of treatment. Moreover, improvement in central nervous system (CNS) involvement status was observed in patients who had measurable concentrations of venetoclax in the CSF. CNS resolution was observed for up to six months while on treatment. These findings highlight the potential role of venetoclax and provide the opportunity to further investigate its utility in improving clinical outcomes for patients with CNS complications.

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Venetoclax with high‐dose methotrexate and rituximab seem effective and well‐tolerated in the treatment of central nervous system involvement of chronic lymphocytic leukemia: A case report

Abstract: Venetoclax with high‐dose methotrexate and rituximab seem effective and safe to treat central nervous system involvement of chronic lymphocytic leukemia.

Cited by 9 publications

References 12 publications

Fatty acid synthase (FASN) regulates the mitochondrial priming of cancer cells

Fatty acid synthase (FASN) regulates the mitochondrial priming of cancer cells

Refractory Chronic Lymphocytic Leukemia with Central Nervous System Involvement: A Case Report with Literature Review

Venetoclax Penetrates the Blood Brain Barrier: A Pharmacokinetic Analysis in Pediatric Leukemia Patients

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