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ABSTRACT: Targeted protein degradation (TPD) is a revolutionary approach to targeted therapy in hematological malignancies that potentially circumvents many constraints of existing small-molecule inhibitors. Heterobifunctional proteolysis-targeting chimeras (PROTACs) are the leading TPD drug class, with numerous agents now in clinical trials for a range of blood cancers. PROTACs harness the cell-intrinsic protein recycling infrastructure, the ubiquitin-proteasome system, to completely degrade target proteins. Distinct from targeted small-molecule inhibitor therapies, PROTACs can eliminate critical but conventionally "undruggable" targets, overcome resistance mechanisms to small-molecule therapies, and can improve tissue specificity and off-target toxicity. Orally bioavailable, PROTACs are not dependent on the occupancy-driven pharmacology inherent to inhibitory therapeutics, facilitating substoichiometric dosing that does not require an active or allosteric target binding site. Preliminary clinical data demonstrate promising therapeutic activity in heavily pretreated populations and novel technology platforms are poised to exploit a myriad of permutations of PROTAC molecular design to enhance efficacy and targeting specificity. As the field rapidly progresses and various non-PROTAC TPD drug candidates emerge, this review explores the scientific and preclinical foundations of PROTACs and presents them within common clinical contexts. Additionally, we examine the latest findings from ongoing active PROTAC clinical trials.
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Neoplasias Hematológicas , Humanos , Neoplasias Hematológicas/tratamento farmacológico , Proteólise , Sítio Alostérico , Citoplasma , Sistemas de Liberação de Medicamentos , Complexo de Endopeptidases do Proteassoma , Ubiquitina-Proteína LigasesRESUMO
In the phase-2 clinical trial (AIM) of venetoclax-ibrutinib, 24 patients with mantle cell lymphoma (MCL; 23 with relapsed/refractory [R/R] disease) received ibrutinib 560mg and venetoclax 400mg both once daily. High complete remission (CR) and measurable residual disease negative (MRD-negative) CR rates were previously reported. With median survivor follow-up now exceeding 7 years, we report long-term results. Treatment was initially continuous, with elective treatment interruption (ETI) allowed after protocol amendment for patients in MRD-negative CR. For R/R MCL, the estimated 7-year progression-free survival (PFS) was 30% [95%CI: 14-49] (median 28 months [95%CI: 13-82]) and overall survival was 43% [95%CI: 23-62] (median 32 months [95%CI: 15-NE]). Eight patients in MRD-negative CR entered ETI for a median of 58 months (95%CI, 37-79), with four experiencing disease recurrence. Two of 3 re-attained CR on retreatment. Time-to-treatment-failure (TTF), which excluded progression in ETI for those reattaining response, was 39% overall and 68% at 7-years for responders. Beyond 56 weeks ï³Grade 3 and serious adverse events were uncommon. Newly emergent or increasing cardiovascular toxicity were not observed beyond 56 weeks. We demonstrate long-term durable responses and acceptable toxicity profile of venetoclax-ibrutinib in R/R MCL and show feasibility of treatment interruption while maintaining ongoing disease control. (NCT02471391).
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Chronic lymphocytic leukemia (CLL) progression during Bruton tyrosine kinase (BTK) inhibitor treatment is typically characterized by emergent B-cell receptor pathway mutations. Using peripheral blood samples from relapsed/refractory CLL patients in ELEVATE-RR (NCT02477696) (median 2 prior therapies), we report clonal evolution data for patients progressing on acalabrutinib or ibrutinib (median follow-up 41 months). Paired (baseline and progression) samples were available for 47 (excluding 1 Richter) acalabrutinib-treated and 30 (excluding 6 Richter) ibrutinib-treated patients. At progression, emergent BTK mutations were observed in 31 (66%) acalabrutinib-treated and 11 (37%) ibrutinib-treated patients (median variant allele fraction [VAF]: 16.1% vs 15.6%). BTK C481S mutations were most common in both groups; T474I (n = 9; 8 co-occurring with C481) and the novel E41V mutation within the pleckstrin homology domain of BTK (n = 1) occurred with acalabrutinib, while neither mutation occurred with ibrutinib. L528W and A428D co-mutations presented in one ibrutinib-treated patient. Pre-existing TP53 mutations were present in 25 (53.2%) acalabrutinib-treated and 16 (53.3%) ibrutinib-treated patients at screening. Emergent TP53 mutations occurred with acalabrutinib and ibrutinib (13% vs 7%; median VAF: 6.0% vs 37.3%, respectively). Six acalabrutinib-treated patients and one ibrutinib-treated patient had emergent TP53/BTK co-mutations. Emergent PLCG2 mutations occurred in 3 (6%) acalabrutinib-treated and 6 (20%) ibrutinib-treated patients. One acalabrutinib-treated patient and 4 ibrutinib-treated patients had emergent BTK/PLCG2 co-mutations. While common BTK C481 mutations were observed with both treatments, patterns of mutation and co-mutation frequency, mutation VAF, and uncommon BTK variants varied with acalabrutinib (T474I and E41V) and ibrutinib (L528W, A428D) in this patient population.
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This analysis investigated the incidence of sudden deaths (SDs) and non-fatal and fatal ventricular arrhythmias (VAs) in five acalabrutinib clinical trials. In total, 1299 patients received acalabrutinib (exposure, 4568.4 patient-years). Sixteen (1.2%) patients experienced SD or VA (event rate, 0.350/100 patient-years). Non-fatal VAs occurred in 11 (0.8%) patients, nine (0.7%) of whom had premature ventricular contractions only. SD and fatal VAs occurred in five (0.4%) patients (event rate, 0.109/100 patient-years; median time to event: 46.2 months). SDs and VAs with acalabrutinib occurred at low rates, and there are insufficient data to point to an increased risk of SD or VA with acalabrutinib.
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Benzamidas , Pirazinas , Ensaios Clínicos Controlados Aleatórios como Assunto , Humanos , Benzamidas/efeitos adversos , Benzamidas/uso terapêutico , Pirazinas/efeitos adversos , Pirazinas/uso terapêutico , Pirazinas/administração & dosagem , Masculino , Feminino , Arritmias Cardíacas/induzido quimicamente , Arritmias Cardíacas/mortalidade , Estudos Prospectivos , Pessoa de Meia-Idade , Idoso , Morte Súbita/etiologia , Morte Súbita/epidemiologia , Morte Súbita Cardíaca/etiologia , Morte Súbita Cardíaca/epidemiologia , Adulto , IncidênciaRESUMO
Primary gastric diffuse large B-cell lymphoma (PG-DLBCL) accounts for the majority of extra-nodal DLBCL. Even so, literature is lacking on early, localised presentations. We studied a cohort of patients with stage I disease, diagnosed between 2006 and 2018, from six centres between Australia, Canada and Denmark. Our goal was to characterise outcomes, review treatment and investigate the role of interim positron emission tomography (iPET). Thirty-seven eligible patients were identified. The median duration of follow-up was 42.2 months. All received chemoimmunotherapy with 91.9% (n = 34) given rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP). 35.1% (n = 13) underwent consolidative radiotherapy. Eighteen patients were H. pylori positive and 11 had the documentation of H. pylori eradication therapy. The 4-year progression-free survival and overall survival of R-CHOP was 88% (95% CI: 71-95) and 91% (95% CI: 75-97) respectively. All patients who achieved a partial metabolic response or complete metabolic response on iPET went on to achieve complete response at the end of treatment. R-CHOP-based therapy with iPET assessment appears to offer favourable outcomes, with radiotherapy and H. pylori eradication therapy implemented on a case-by-case basis.
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Protocolos de Quimioterapia Combinada Antineoplásica , Linfoma Difuso de Grandes Células B , Neoplasias Gástricas , Humanos , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/terapia , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Estudos Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Gástricas/terapia , Neoplasias Gástricas/patologia , Adulto , Idoso de 80 Anos ou mais , Rituximab/uso terapêutico , Rituximab/administração & dosagem , Vincristina/uso terapêutico , Vincristina/administração & dosagem , Prednisona/uso terapêutico , Prednisona/administração & dosagem , Ciclofosfamida/uso terapêutico , Ciclofosfamida/administração & dosagem , Doxorrubicina/uso terapêutico , Doxorrubicina/administração & dosagem , Infecções por Helicobacter/complicações , Infecções por Helicobacter/tratamento farmacológico , Helicobacter pylori , Tomografia por Emissão de Pósitrons , Linfoma não HodgkinRESUMO
The Phase 2 portion of this study evaluated safety and efficacy of polatuzumab vedotin 1.8 mg/kg and venetoclax 800 mg, plus fixed-dose obinutuzumab 1000 mg or rituximab 375 mg/m2 in patients with relapsed/refractory (R/R) follicular lymphoma (FL) or diffuse large B-cell lymphoma (DLBCL), respectively. Patients with complete response (CR) or partial response (PR)/stable disease (FL) or CR/PR (DLBCL) at end of induction (EOI; six 21-day cycles) received post-induction therapy with venetoclax and obinutuzumab or rituximab, respectively. Primary endpoint was CR rate at EOI. Safety-evaluable populations included 74 patients (FL cohort; median age 64 years; progression of disease within 24 months on first-line treatment, 25.7%; FL International Prognostic Index 3-5, 54.1%; ≥2 previous therapies, 74.3%) and 57 patients (DLBCL cohort; median age 65 years; International Prognostic Index 3-5, 54.4%; ≥2 previous therapies, 77.2%). The most common non-hematologic adverse events (mostly Grades 1-2) in the FL and DLBCL cohorts were diarrhea (55.4% and 47.4%, respectively) and nausea (47.3% and 36.8%); neutropenia was the most common Grades 3-4 toxicity (39.2% and 52.6%). Efficacy-evaluable populations included patients treated at the recommended Phase 2 dose (FL, n = 49; DLBCL, n = 48). CR rates at EOI were 59.2% (FL) and 31.3% (DLBCL); median progression-free survival was 22.8 months (95% confidence interval [CI], 14.5-not evaluable) and 4.6 months (95% CI, 3.6-8.1), respectively. Polatuzumab vedotin plus venetoclax and obinutuzumab/rituximab had acceptable safety in patients with R/R FL or DLBCL, with promising response rates in R/R FL, including high-risk patients.
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Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Compostos Bicíclicos Heterocíclicos com Pontes , Linfoma Difuso de Grandes Células B , Rituximab , Sulfonamidas , Humanos , Pessoa de Meia-Idade , Idoso , Masculino , Sulfonamidas/administração & dosagem , Sulfonamidas/uso terapêutico , Sulfonamidas/efeitos adversos , Feminino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Adulto , Idoso de 80 Anos ou mais , Rituximab/administração & dosagem , Rituximab/uso terapêutico , Rituximab/efeitos adversos , Linfoma Folicular/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Recidiva , ImunoconjugadosRESUMO
Chronic lymphocytic leukemia (CLL) predominantly affects older adults, characterized by a relapsing and remitting pattern with sequential treatments available for many patients. Identification of progressive/relapsed CLL should prompt close monitoring and early discussion about the next therapies when treatment indications are present. The intervening period represents an opportunity to optimize patient health, including establishing adequate vaccination and surveillance for second primary malignancies, and treating non-CLL-related comorbidities which may impact well-being and CLL therapy. We now see patients with relapsed/refractory (RR) CLL in the clinic who have been previously treated with chemoimmunotherapy (CIT) and/or one or more novel therapies. Continuous covalent inhibitors of Bruton's tyrosine kinase (cBTKi) and fixed-duration venetoclax (Ven)-anti-CD20 monoclonal antibody (mAb) are preferred over CIT given the survival advantages associated with these therapies, although have never been evaluated head-to-head. While both classes are effective for RR CLL, potential side effects and the logistics of administration differ. Few randomized data demonstrate the sequential use of cBTKi and fixed-duration Ven-anti-CD20 mAb; however, they may be used in either sequence. Newer non-covalent BTKi, active against BTK C481 resistance mutations emerging with continuous cBTKi exposure, and novel approaches such as BTK degraders, bispecific antibodies, and chimeric antigen receptor T-cell therapies demonstrate impressive efficacy. In this review of RR CLL we explore relevant investigations, consideration of broader CLL- and non-CLL-related health needs, and evidence for efficacy and safety of B-cell receptor inhibitors and Ven, including available data to support drug sequencing or switching. We describe novel approaches to RR CLL, including rechallenging with fixed-duration therapies, allogeneic stem cell transplant indications in the novel therapy era, and highlight early data supporting the use of T-cell directing therapies and novel drug targets.
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Antineoplásicos , Leucemia Linfocítica Crônica de Células B , Linfoma de Células B , Humanos , Idoso , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/etiologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma de Células B/tratamento farmacológico , Antineoplásicos/uso terapêutico , Tirosina Quinase da Agamaglobulinemia , Anticorpos Monoclonais/uso terapêuticoRESUMO
The clinical application of Pharmacogenomics (PGx) has improved patient safety. However, comprehensive PGx testing has not been widely adopted in clinical practice, and significant opportunities exist to further optimize PGx in cancer care. This systematic review and meta-analysis aim to evaluate the safety outcomes of reported PGx-guided strategies (Analysis 1) and identify well-studied emerging pharmacogenomic variants that predict severe toxicity and symptom burden (Analysis 2) in patients with cancer. We searched MEDLINE, EMBASE, CENTRAL, clinicaltrials.gov, and International Clinical Trials Registry Platform from inception to January 2023 for clinical trials or comparative studies evaluating PGx strategies or unconfirmed pharmacogenomic variants. The primary outcomes were severe adverse events (SAE; ≥ grade 3) or symptom burden with pain and vomiting as defined by trial protocols and assessed by trial investigators. We calculated pooled overall relative risk (RR) and 95% confidence interval (95%CI) using random effects models. PROSPERO, registration number CRD42023421277. Of 6811 records screened, six studies were included for Analysis 1, 55 studies for Analysis 2. Meta-analysis 1 (five trials, 1892 participants) showed a lower absolute incidence of SAEs with PGx-guided strategies compared to usual therapy, 16.1% versus 34.0% (RR = 0.72, 95%CI 0.57-0.91, p = 0.006, I2 = 34%). Meta-analyses 2 identified nine medicine(class)-variant pairs of interest across the TYMS, ABCB1, UGT1A1, HLA-DRB1, and OPRM1 genes. Application of PGx significantly reduced rates of SAEs in patients with cancer. Emergent medicine-variant pairs herald further research into the expansion and optimization of PGx to improve systemic anti-cancer and supportive care medicine safety and efficacy.
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Neoplasias , Farmacogenética , Adulto , Humanos , Antineoplásicos/efeitos adversos , Antineoplásicos/administração & dosagem , Mutação em Linhagem Germinativa , Neoplasias/tratamento farmacológico , Neoplasias/genética , Testes Farmacogenômicos , Variantes Farmacogenômicos , Carga de SintomasRESUMO
Venetoclax, a highly selective, oral B-cell lymphoma 2 inhibitor, provides a robust targeted-therapy option for the treatment of chronic lymphocytic leukemia (CLL), including patients with high-risk del(17p)/mutated-TP53 and immunoglobulin heavy variable region unmutated CLL and those refractory to chemoimmunotherapy across all age groups. Due to the potent pro-apoptotic effect of venetoclax, treatment initiation carries a risk of tumor lysis syndrome (TLS). Prompt and appropriate management is needed to limit clinical TLS, which may entail serious adverse events and death. Venetoclax ramp-up involves gradual, stepwise increases in daily venetoclax dosing from 20 mg to 400 mg (target dose) over 5 weeks; adherence to on-label scheduling provides a tumor debulking phase, reducing the risk of TLS. The key components of safe venetoclax therapy involve assessment (radiographic evaluation and baseline blood chemistry), preparation (adequate hydration), and initiation (blood chemistry monitoring). In addition to summarizing the evidence for venetoclax's efficacy and safety, this review uses hypothetical patient scenarios based on risk level for TLS (high, medium, low) to share the authors' clinical experience with venetoclax initiation and present global approaches utilized in various treatment settings. These hypothetical scenarios highlight the importance of a multidisciplinary approach and shared decision-making, outlining best practices for venetoclax initiation and overall optimal treatment strategies in patients with CLL.
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ABSTRACT: Chromosome 17p deletion (del[17p]) is associated with poor prognosis in patients with chronic lymphocytic leukemia (CLL). Venetoclax is approved for treatment of previously untreated and relapsed/refractory (R/R) CLL, including patients with del(17p), based on the open-label, multicenter, phase 2 M13-982 trial (NCT01889186). Here, we detail the 6-year follow-up analysis for M13-982. A total of 158 patients with previously untreated (n = 5) or R/R (n = 153) del(17p) CLL received 400 mg venetoclax daily after initial ramp-up until progressive disease. After a median follow-up of 70 months, the best objective response rate (ORR) was 77% (21% complete remission [CR] and 49% partial remission [PR]), with a median duration of response (DOR) of 39.3 months (95% confidence interval [CI], 31.1-50.5). The median progression-free survival (PFS) was 28.2 months (95% CI, 23.4-37.6), and median overall survival (OS) was 62.5 months (95% CI, 51.7-not reached), with 16% of patients remaining on treatment after 6 years. Multivariable analysis did not identify statistically significant correlation between patient subgroups defined by clinical or laboratory variables and ORR or PFS. The most common grade ≥3 adverse events were neutropenia (42%), infections (33%), anemia (16%), and thrombocytopenia (16%). Post hoc comparative analyses of PFS and OS from treatment initiation, from a 24-month landmark, and by minimal residual disease status were performed between patients with del(17p) in the M13-982 and MURANO studies in the interest of understanding these data in another context. These long-term data show the continued benefits of venetoclax in patients with del(17p) CLL. The trial was registered at www.clinicaltrials.gov as #NCT01889186.
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Leucemia Linfocítica Crônica de Células B , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/genética , Seguimentos , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Sulfonamidas/efeitos adversos , Recidiva , Deleção CromossômicaRESUMO
BACKGROUND: Richter transformation usually presents as an aggressive diffuse large B-cell lymphoma, occurs in up to 10% of patients with chronic lymphocytic leukaemia, has no approved therapies, and is associated with a poor prognosis. Pirtobrutinib has shown promising efficacy and tolerability in patients with relapsed or refractory B-cell malignancies, including those who progress on covalent Bruton tyrosine kinase (BTK) inhibitors. This study aims to report the safety and activity of pirtobrutinib monotherapy in a subgroup of patients with Richter transformation from the multicentre, open-label, phase 1/2 BRUIN study. METHODS: This analysis included adult patients (aged ≥18 years) with histologically confirmed Richter transformation, an Eastern Cooperative Oncology Group performance status score of 0-2, and no limit of previous therapies, with patients receiving first-line treatment added in a protocol amendment (version 9.0, Dec 15, 2021). Pirtobrutinib 200 mg was administered orally once a day in 28-day cycles. The primary endpoint of phase 1 of the BRUIN trial as a whole, which has been previously reported, was to establish the recommended phase 2 dose for pirtobrutinib monotherapy and the phase 2 primary endpoint was overall response rate. Safety and activity were measured in all patients who received at least one dose of pirtobrutinib monotherapy. This BRUIN phase 1/2 trial was registered with ClinicalTrials.gov and is closed to enrolment (NCT03740529). FINDINGS: Between Dec 26, 2019, and July 22, 2022, 82 patients were enrolled, of whom five were enrolled during phase 1 and 77 during phase 2. All but one patient received a starting dose of 200 mg pirtobrutinib once a day as the recommended phase 2 dose. The remaining patient received 150 mg pirtobrutinib once a day, which was not escalated to 200 mg. The median age of patients was 67 years (IQR 59-72). 55 (67%) of 82 patients were male and 27 (33%) were female. Most patients were White (65 [79%] of 82). 74 (90%) of 82 patients received at least one previous Richter transformation-directed therapy. Most patients (61 [74%] of 82) had received previous covalent BTK inhibitor therapy for chronic lymphocytic leukaemia or Richter transformation. The overall response rate was 50·0% (95% CI 38·7-61·3). 11 (13%) of 82 patients had a complete response and 30 (37%) of 82 patients had a partial response. Eight patients with ongoing response electively discontinued pirtobrutinib to undergo stem-cell transplantation. The most common grade 3 or worse adverse event was neutropenia (n=19). There were no treatment-related deaths. INTERPRETATION: Pirtobrutinib shows promising safety and activity among patients with Richter transformation, most of whom received previous Richter transformation-directed therapy, including covalent BTK inhibitors. These data suggest that further investigation is warranted of pirtobrutinib as a treatment option for patients with relapsed or refractory Richter transformation after treatment with a covalent BTK inhibitor. FUNDING: Loxo Oncology.