Identification of recurrent genomic alterations in the apoptotic machinery in chronic lymphocytic leukemia patients treated with venetoclax monotherapy.
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ABSTRACT:
SUBMITTER: Popovic R
PROVIDER: S-EPMC10015991 | biostudies-literature | 2022 Feb
REPOSITORIES: biostudies-literature
Publications
Identification of recurrent genomic alterations in the apoptotic machinery in chronic lymphocytic leukemia patients treated with venetoclax monotherapy.
Popovic Relja R Dunbar Fengjiao F Lu Charles C Robinson Kenneth K Quarless Danjuma D Warder Scott E SE Mukherjee Nabanita N Pesko John J Souers Andrew J AJ Waring Jeffrey F JF Davids Matthew S MS Tausch Eugen E Stilgenbauer Stephan S Ross Jeremy A JA Leverson Joel D JD Kim Su Young SY Chyla Brenda J BJ
American journal of hematology 20211124 2
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Project description:To identify genomic alterations in chronic lymphocytic leukemia (CLL), we performed single-nucleotide polymorphism (SNP)-array analysis on 353 samples from previously untreated patients entered on the CLL8 treatment trial. Based on paired-sample analysis (n=147), a mean of 1.8 copy number alterations (CNAs) per case were identified; about 60% of cases carried no CNAs other than those detected by routine fluorescence in-situ hybridization analysis. Copy-neutral loss-of- heterozygosity was detected in 6% of cases, and most frequently found on 13q, 17p and 11q. Minimal deleted regions (MDRs) were refined on 13q14 (deleted in 61% of cases) to the DLEU1 and DLEU2 genes, on 11q22.3 (27%) to ATM, on 2p (gained in 7% of cases) to a 1.9 Mb fragment containing 9 genes, and on 8q24 (5%) to a segment 486 Kb proximal of the MYC locus. 13q deletions exhibited proximal and distal breakpoint cluster regions. Among the most common novel lesions were deletions at 15q15.1 (4%), with the smallest deletion (70.5 Kb) found in the MGA locus; sequence analysis of MGA in 59 samples revealed a truncating mutation in one case lacking a 15q deletion. MNT at 17p13.3, which in addition to MGA and MYC encodes for the network of MAX-interacting proteins, was also found recurrently deleted.
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Project description:The identification of targetable vulnerabilities in the context of therapeutic resistance is a key challenge in cancer treatment. We detected pervasive aberrant splicing as a characteristic feature of chronic lymphocytic leukemia (CLL), irrespective of splicing factor mutation status, which was associated with sensitivity to the spliceosome modulator, E7107. Splicing modulation affected CLL survival pathways, including members of the B cell lymphoma-2 (BCL2) family of proteins, remodeling antiapoptotic dependencies of human and murine CLL cells. E7107 treatment decreased myeloid cell leukemia-1 (MCL1) dependence and increased BCL2 dependence, sensitizing primary human CLL cells and venetoclax-resistant CLL-like cells from an Eμ-TCL1-based adoptive transfer murine model to treatment with the BCL2 inhibitor venetoclax. Our data provide preclinical rationale to support the combination of venetoclax with splicing modulators to reprogram apoptotic dependencies in CLL for treating venetoclax-resistant CLL cases.
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Project description:Venetoclax is a potent oral, highly selective small-molecule inhibitor of the antiapoptotic B-cell lymphoma 2 protein approved for chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma in treatment-naive patients (in combination with obinutuzumab) or for patients with relapsed/refractory CLL (in combination with rituximab). Venetoclax, in combination with azacitidine, decitabine, or low-dose cytarabine, is also approved in the United States for the treatment of newly diagnosed acute myeloid leukemia (AML) in adults who are ≥ 75 years or have comorbidities that preclude use of intensive induction chemotherapy. Clinical studies of patients with CLL or AML report both hematologic (e.g., neutropenia) and nonhematologic (e.g., gastrointestinal disorders and tumor lysis syndrome) adverse events associated with administration of venetoclax. It is therefore essential to provide information on the appropriate management of venetoclax-associated side effects. This article discusses the efficacy and safety of venetoclax administration and presents strategies specifically for the management of neutropenia and certain nonhematologic adverse events in patients receiving venetoclax for the treatment of AML and CLL.
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Project description:To identify genomic alterations in chronic lymphocytic leukemia (CLL), we performed single-nucleotide polymorphism (SNP)-array analysis on 353 samples from previously untreated patients entered on the CLL8 treatment trial. Based on paired-sample analysis (n=147), a mean of 1.8 copy number alterations (CNAs) per case were identified; about 60% of cases carried no CNAs other than those detected by routine fluorescence in-situ hybridization analysis. Copy-neutral loss-of- heterozygosity was detected in 6% of cases, and most frequently found on 13q, 17p and 11q. Minimal deleted regions (MDRs) were refined on 13q14 (deleted in 61% of cases) to the DLEU1 and DLEU2 genes, on 11q22.3 (27%) to ATM, on 2p (gained in 7% of cases) to a 1.9 Mb fragment containing 9 genes, and on 8q24 (5%) to a segment 486 Kb proximal of the MYC locus. 13q deletions exhibited proximal and distal breakpoint cluster regions. Among the most common novel lesions were deletions at 15q15.1 (4%), with the smallest deletion (70.5 Kb) found in the MGA locus; sequence analysis of MGA in 59 samples revealed a truncating mutation in one case lacking a 15q deletion. MNT at 17p13.3, which in addition to MGA and MYC encodes for the network of MAX-interacting proteins, was also found recurrently deleted. Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from cryopreserved diagnostic peripheral blood samples. Copy number analysis of Affymetrix® performed for 353 CLL samples. There are also 147 samples from mononuclear cells negative for CD19, which were used as references for copy number inference.
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Project description:AbstractVenetoclax is a B-cell lymphoma 2 inhibitor used in chronic lymphocytic leukemia (CLL), which can cause tumor lysis syndrome (TLS). We aimed to determine the incidence of, and risk factors for, TLS among patients with CLL/small lymphocytic lymphoma who received treatment with venetoclax at our institution from 1 January 2016 to 31 December 2020. We included 616 venetoclax escalations among 136 patients with CLL. Overall, 74 patients (54%) underwent escalation exclusively outpatient, 35 (26%) had at least 1 planned hospitalization, and 27 (20%) were escalated exclusively inpatient. During venetoclax initiation, 86% of patients received allopurinol, 71% intravenous hydration, 18% phosphate binders, and 10% prophylactic rasburicase. Among the entire cohort, 7 patients (5.1%) developed laboratory TLS by modified Cairo Bishop criteria and none developed clinical TLS. Incidence of laboratory TLS was 15% for those escalated exclusively inpatient, 2.9% for those with any prophylactic hospitalization, and 2.7% for those escalated exclusively outpatient. Those who developed TLS were more likely to have higher TLS risk, and no additional risk factors were identified. In this single institution retrospective cohort study, laboratory TLS was observed, although clinical TLS was not. Prophylactic measures, including use of IV hydration, may have contributed to low rates of observed TLS in the outpatient setting.
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