Venetoclax-based therapy is a standard-of-care option in first-line and relapsed/refractory chronic lymphocytic leukemia (CLL). Patient management following venetoclax discontinuation remains ...nonstandard and poorly understood.
To address this, we conducted a large international study to identify a cohort of 326 patients who discontinued venetoclax and have been subsequently treated. Coprimary endpoints were overall response rate (ORR) and progression-free survival for the post-venetoclax treatments stratified by treatment type Bruton's tyrosine kinase inhibitor (BTKi), PI3K inhibitor (PI3Ki), and cellular therapies.
We identified patients with CLL who discontinued venetoclax in the first-line (4%) and relapsed/refractory settings (96%). Patients received a median of three therapies prior to venetoclax; 40% were BTKi naïve (
= 130), and 81% were idelalisib naïve (
= 263). ORR to BTKi was 84% (
= 44) in BTKi-naïve patients versus 54% (
= 30) in BTKi-exposed patients. We demonstrate therapy selection following venetoclax requires prior novel agent exposure consideration and discontinuation reasons.
For BTKi-naïve patients, selection of covalently binding BTKis results in high ORR and durable remissions. For BTKi-exposed patients, covalent BTK inhibition is not effective in the setting of BTKi resistance. PI3Kis following venetoclax do not appear to result in durable remissions. We conclude that BTKi in naïve or previously responsive patients and cellular therapies following venetoclax may be the most effective strategies.
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•Blinatumomab + TKI led to eradication of MRD in most patients with Ph + ALL.•Durable molecular responses seen, including in patients relapsed post-allograft.•Incidence and severity of neurologic ...toxicity was less than seen in other studies.•Incidence of CRS was higher than in previous reports, but severity was mild.
Incorporation of ABL-targeted oral tyrosine kinase inhibitors (TKIs) into frontline therapeutic regimens has improved outcomes for adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL). However, patients with persistent minimal residual disease (MRD) exhibit increased risk of relapse. Combining consolidative chemotherapy with TKIs may increase rates of infectious complications, organ toxicity, hospitalization, and non-relapse mortality. Blinatumomab has demonstrated single-agent activity in patients with relapsed B-ALL or persistent MRD, including Ph + B-ALL. We have used blinatumomab concomitantly with commercially available TKIs as consolidative therapy to spare toxicities of conventional chemotherapy. We evaluated 11 adults with previously treated Ph + B-ALL who received blinatumomab concurrent with TKI (ponatinib, n = 5; dasatinib, n = 4; nilotinib, n = 1; imatinib, n = 1) to eradicate MRD or sustain MRD-negativity. Eight of 9 patients with MRD achieved BCR-ABL1 negativity (complete molecular response, CMR) after a median of one cycle; 2/2 patients without measurable disease durably maintained CMR. Cytokine release syndrome (all grade 1–2) was observed in 3/11 patients; one patient experienced transient grade 1 neurologic toxicity. Transient grade 2 transaminitis was observed in 6/11 patients, including 4/5 recipients of blinatumomab + ponatinib. This small series suggests blinatumomab + TKI is a safe and effective consolidation strategy for patients with Ph + ALL to achieve or maintain CMR.
Azacitidine + venetoclax, decitabine + venetoclax, and low-dose cytarabine + venetoclax are now standard treatments for newly diagnosed older or unfit patients with acute myeloid leukemia (AML). ...Although these combinations are also commonly used in relapsed or refractory AML (RR-AML), clinical and molecular predictors of response and survival in RR-AML are incompletely understood. We retrospectively analyzed clinical and molecular characteristics and outcomes for 86 patients with RR-AML who were treated with venetoclax combinations. The complete remission (CR) or CR with incomplete hematologic recovery (CRi) rate was 24%, and the overall response rate was 31% with the inclusion of a morphologic leukemia-free state. Azacitidine + venetoclax resulted in higher response rates compared with low-dose cytarabine + venetoclax (49% vs 15%; P = .008). Median overall survival (OS) was 6.1 months, but it was significantly longer with azacitidine + venetoclax compared with low-dose cytarabine + venetoclax (25 vs 3.9 months; P = .003). This survival advantage of azacitidine + venetoclax over low-dose cytarabine + venetoclax persisted when patients were censored for subsequent allogeneic stem cell transplantation (8.1 vs 3.9 months; P = .035). Mutations in NPM1 were associated with higher response rates, whereas adverse cytogenetics and mutations in TP53, KRAS/NRAS, and SF3B1 were associated with worse OS. Relapse was driven by diverse mechanisms, including acquisition of novel mutations and an increase in cytogenetic complexity. Venetoclax combination therapy is effective in many patients with RR-AML, and pretreatment molecular characteristics may predict outcomes. Trials that evaluate novel agents in combination with venetoclax therapy in patients with RR-AML that have adverse risk genomic features are warranted.
•In patients with RR-AML, venetoclax combination therapy resulted in responses in 31% of patients and a median OS of 6.1 months.•NPM1 mutations predicted higher response rates; adverse cytogenetics and mutations in TP53, KRAS/NRAS, and SF3B1 predicted worse OS.
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Objective: To review the pharmacology, efficacy, and safety of venetoclax for treatment of lymphoid malignancies. Data Sources: A literature search was performed of PubMed and MEDLINE databases (2005 ...to September 2016), abstracts from the American Society of Hematology and the American Society of Clinical Oncology, and ongoing studies from clinicaltrials.gov. Searches were performed utilizing the following key terms: venetoclax, ABT-199, GDC-199, obatoclax, GX15-070, BCL-2 inhibitor, navitoclax, ABT-263, and Venclexta. Study Selection/Data Extraction: Studies of pharmacology, pharmacokinetics, pharmacodynamics, clinical efficacy, and safety of venetoclax in lymphoid malignancies were identified. Data Synthesis: Recently, treatment of B-cell lymphoproliferative disorders has shifted from conventional cytotoxic chemotherapy to novel small-molecule inhibitors. The advent of recently Food and Drug Administration–approved oral agents ibrutinib and idelalisib has shifted the paradigm of chronic lymphocytic leukemia (CLL) treatment; however, complete remission is uncommon, and the outcome for patients progressing on these treatments remains poor. Attention has been focused on a novel target, the B-cell lymphoma-2 protein (BCL-2), which serves an essential role in regulation of apoptosis. Venetoclax has demonstrated efficacy in multiple subtypes of lymphoid malignancies, including patients with relapsed/refractory CLL harboring deletion 17p, with an overall response rate of nearly 80%. Venetoclax is generally well tolerated, with the significant adverse effect being tumor lysis syndrome, for which there are formal management recommendations. Conclusion: Venetoclax has demonstrated promising results in relapsed/refractory lymphoid malignancies, with an acceptable adverse effect profile. As the role of BCL-2 inhibition in various malignancies becomes further elucidated, venetoclax may offer benefit to a myriad other patient populations.
Objective: To review the literature for the treatment of classical and variant hairy cell leukemia (HCL, HCLv), evaluating efficacy, safety, and supportive care involved in the use of purine ...analogues (PAs), interferon, BRAF inhibitors, monoclonal antibodies, Bruton’s tyrosine kinase inhibitors, and new immunotoxin, moxetumomab pasudotox-tdfk (MPT). An electronic literature search of PubMed (January 1958 to January 2019) was conducted in PubMed using the MESH terms hairy cell leukemia, hairy cell leukemia variant, cladribine, pentostatin, rituximab, interferon, vemurafenib, moxetumomab pasudotox. Study Selection and Data Extraction: Studies written in the English language were considered for this article. The significance of each article was determined by authors independently. Data Synthesis: HCL and HCLv are rare B-cell lymphoproliferative disorders, each with distinct biologies. Symptoms are characterized by pancytopenia and splenomegaly. Initial treatments for HCL were suboptimal, leading to minimal and transient remissions. PAs significantly improved outcomes, inducing remission in most patients. However, those with purine-resistant disease were left with a dearth of options, leading to implementation of vemurafenib for BRAF V600 mutated disease and chemoimmunotherapy with rituximab. Despite these advances, some HCL and a majority of HCLv patients experience relapse. Newer targeted agents offer promise for relapsed and refractory patients, including the recently approved MPT. Relevance to Patient Care and Clinical Practice: This review provides a comprehensive update on the pharmacological management of HCL and HCLv for clinicians who encounter patients with this rare disease. Conclusion: HCL and HCLv are uncommon lymphoid neoplasms that lead to a characteristic constellation of symptoms. The emergence of PAs and novel targeted agents have improved the likelihood and durability of responses for these patients.
The role of allogeneic hematopoietic cell transplant (allo-HCT) as consolidation after initial venetoclax therapy and the efficacy of venetoclax salvage therapy for relapse after allo-HCT in patients ...with acute myeloid leukemia (AML) are unclear. We conducted a retrospective study of patients with AML or myelodysplastic syndrome (MDS) who received venetoclax either before or after allo-HCT at Memorial Sloan Kettering Cancer Center and Yale University from 11 August 2016 to 16 November 2020. Among 39 heavily pretreated patients who received venetoclax before allo-HCT, median OS from allo-HCT was not reached after a median follow up of 12.5 months resulting in a 12-month OS estimate of 79.0%. In 37 patients who had received venetoclax-based combinations as salvage therapy after allo-HCT, the overall response rate was 32% with a median OS of 4.7 months (12-month OS estimate: 43.4%). Four patients underwent a second allo-HCT following venetoclax-based salvage therapy suggesting it as a potential salvage treatment option.
The advent of novel targeted therapies, including B-cell receptor (BCR) pathway and B-cell lymphoma 2 (BCL2) inhibitors, has substantially changed the treatment paradigm for chronic lymphocytic ...leukemia (CLL). Although targeted therapies have improved outcomes compared to traditional chemoimmunotherapy in the front-line and relapsed or refractory settings, they are associated with resistance mutations and suboptimal outcomes in certain high-risk patients. Additionally, targeted therapies are associated with drug interactions and unique adverse effect profiles which can be challenging for patients and clinicians to manage. Ongoing studies continue to address questions regarding optimal sequencing of therapies, the role of treatment combinations, and the efficacy of next-generation novel agents. This review provides a comprehensive overview regarding the clinical management of targeted therapies for CLL and applies current literature to clinical practice.
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