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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.
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Agammaglobulinemia Tirosina Quinasa , Inhibidores de Proteínas Quinasas , Humanos , Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Femenino , Masculino , Persona de Mediana Edad , Anciano , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/administración & dosificación , Adulto , Anciano de 80 o más Años , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/patología , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Pirimidinas/uso terapéutico , Pirimidinas/administración & dosificación , Resultado del TratamientoRESUMEN
The amount of free ions, ion pairs, and higher aggregate of the possible species present in a solution during the gold(I)-catalyzed alkoxylation of unsaturated hydrocarbon, i.e., ISIP (inner sphere ion pair) [(NHC)AuX] and OSIP (outer sphere ion pairs) [(NHC)Au(TME)X] [NHC 1,3-bis(2,6-di-isopropylphenyl)-imidazol-2-ylidene; TME = tetramethylethylene (2,3-bis methyl-butene); X- = Cl-, BF4-, OTf-; and OTs- BArF4- (ArF = 3,5-(CF3)2C6H3)], has been determined. The 1H and 19F DOSY NMR measurements conducted in catalytic conditions indicate that the dissociation degree (α) of the equilibrium ion pair/free ions {[(NHC)Au(TME)X] [(NHC)Au(TME)]+ + X-} depends on the nature of the counterion (X-) when chloroform is the catalytic solvent: while the compounds containing OTs- and OTf- as the counterion gave a low α (which means a high number of ion pairs) of 0.13 and 0.24, respectively, the compounds containing BF4- and BArF4- showed higher α values of 0.36 and 0.32, respectively. These results experimentally confirm previous deductions based on catalytic and theoretical data: the lower the α value, the greater the catalytic activity because the anion that can activate methanol during a nucleophilic attack, although the lower propensity to activate methanol of BF4- and BArF4-, as suggested by the DFT calculations, cannot be completely overlooked. As for the effect of the solvent, α increases as the dielectric constant increases, as expected, and in particular, green solvents with high dielectric constants show a very high α (0.90, 0.84, 0.80, and 0.70 for propylene carbonate, γ-valerolactone, acetone, and methanol, respectively), thus confirming that the moderately high activity of NHC-Au-OTf in these solvents is due to the specific effect of polar functionalities (O-H, C=O, O-R) in activating methanol. Finally, the DOSY measurements conducted in p-Cymene show the formation of quadrupole species: under these conditions, the anion can better exercise its 'template' and 'activating' roles, giving the highest TOF.
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INTRODUCTION: Pirtobrutinib, a highly selective, noncovalent (reversible) Bruton tyrosine kinase inhibitor, has demonstrated promising efficacy in B-cell malignancies and is associated with low rates of discontinuation and dose reduction. Pirtobrutinib is administered until disease progression or toxicity, necessitating an understanding of the safety profile in patients with extended treatment. METHODS: Here we report the safety of pirtobrutinib in patients with relapsed/refractory B-cell malignancies with extended (≥12 months) drug exposure from the BRUIN trial. Assessments included median time-to-first-occurrence of adverse events (AEs), dose reductions, and discontinuations due to treatment-emergent AEs (TEAEs) and select AEs of interest (AESIs). RESULTS: Of 773 patients enrolled, 326 (42%) received treatment for ≥12 months. In the extended exposure cohort, the median time-on-treatment was 19 months. The most common all-cause TEAEs were fatigue (32%) and diarrhea (31%). TEAEs leading to dose reduction occurred in 23 (7%) and discontinuations in 11 (3%) extended exposure patients. One patient had a fatal treatment-related AE (COVID-19 pneumonia). Infections (73.0%) were the most common AESI with a median time-to-first-occurrence of 7.4 months. Majority of TEAEs and AESIs occurred during the first year of therapy. CONCLUSIONS: Pirtobrutinib therapy continues to demonstrate an excellent safety profile amenable to long-term administration without evidence of new or worsening toxicity signals.
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Protocolos de Quimioterapia Combinada Antineoplásica , Leucemia Linfocítica Crónica de Células B , Neoplasia Residual , Humanos , Leucemia Linfocítica Crónica de Células B/sangre , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/patología , Neoplasia Residual/sangre , Neoplasia Residual/diagnóstico , Ensayos Clínicos Controlados Aleatorios como Asunto , Ciclofosfamida/efectos adversos , Ciclofosfamida/uso terapéutico , Rituximab/efectos adversos , Rituximab/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Análisis de SupervivenciaRESUMEN
Pegcetacoplan significantly improves outcomes for patients with paroxysmal nocturnal hemoglobinuria (PNH) experiencing extravascular hemolysis (EVH) on eculizumab, leading to approval in 2021/2022 (USA/Europe). We report the first collaborative real-world evidence on pegcetacoplan use in UK and France. A total of 48 patients were either currently receiving or previously received pegcetacoplan (2019-2023). A total of 12 patients had participated in the PEGASUS clinical trial, continuing treatment after trial completion. Five patients were on combination treatment of C5 inhibition and pegcetacoplan. Mean pegcetacoplan duration was 20.2 months. Indication for pegcetacoplan was EVH on C5 inhibitors (Eculizumab, n = 29, Ravulizumab n = 16, others n = 3) with 35/48 patients requiring blood transfusion within the previous 12 months. Mean hemoglobin and reticulocyte count at pegcetacoplan commencement and after 3 months: 91 g/L and 205 × 109/L and 115.8 g/L and 107 × 109/L, respectively, resulting in mean Hb change of 22.3 g/L. Mean LDH pre- and post-pegcetacoplan was unchanged. Six patients have stopped pegcetacoplan. A total of 32 breakthrough hemolysis (BTH) events occurred in 13/48 patients. A total of 14 events were within clinical trials (reported separately). Six patients experienced 18 acute BTH events outside clinical trials, 7/18 associated with complement activating conditions. Successful clinical management included daily pegcetacoplan subcutaneously for 3 days or single eculizumab doses; these events are manageable with prompt intervention. Pegcetacoplan is effective for patients with PNH experiencing EVH. In this large patient cohort, treatment was well tolerated with improved hemoglobin and reticulocytes and maintained LDH control. Although BTH occurs, this is manageable by acute dose modification, with the majority of patients being maintained on pegcetacoplan.
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Hemoglobinuria Paroxística , Péptidos Cíclicos , Humanos , Hemoglobinas , Transfusión Sanguínea , HemólisisRESUMEN
BACKGROUND: The combination of ibrutinib and venetoclax has been shown to improve outcomes in patients with chronic lymphocytic leukemia (CLL) as compared with chemoimmunotherapy. Whether ibrutinib-venetoclax and personalization of treatment duration according to measurable residual disease (MRD) is more effective than fludarabine-cyclophosphamide-rituximab (FCR) is unclear. METHODS: In this phase 3, multicenter, randomized, controlled, open-label platform trial involving patients with untreated CLL, we compared ibrutinib-venetoclax and ibrutinib monotherapy with FCR. In the ibrutinib-venetoclax group, after 2 months of ibrutinib, venetoclax was added for up to 6 years of therapy. The duration of ibrutinib-venetoclax therapy was defined by MRD assessed in peripheral blood and bone marrow and was double the time taken to achieve undetectable MRD. The primary end point was progression-free survival in the ibrutinib-venetoclax group as compared with the FCR group, results that are reported here. Key secondary end points were overall survival, response, MRD, and safety. RESULTS: A total of 523 patients were randomly assigned to the ibrutinib-venetoclax group or the FCR group. At a median of 43.7 months, disease progression or death had occurred in 12 patients in the ibrutinib-venetoclax group and 75 patients in the FCR group (hazard ratio, 0.13; 95% confidence interval [CI], 0.07 to 0.24; P<0.001). Death occurred in 9 patients in the ibrutinib-venetoclax group and 25 patients in the FCR group (hazard ratio, 0.31; 95% CI, 0.15 to 0.67). At 3 years, 58.0% of the patients in the ibrutinib-venetoclax group had stopped therapy owing to undetectable MRD. After 5 years of ibrutinib-venetoclax therapy, 65.9% of the patients had undetectable MRD in the bone marrow and 92.7% had undetectable MRD in the peripheral blood. The risk of infection was similar in the ibrutinib-venetoclax group and the FCR group. The percentage of patients with cardiac serious adverse events was higher in the ibrutinib-venetoclax group than in the FCR group (10.7% vs. 0.4%). CONCLUSIONS: MRD-directed ibrutinib-venetoclax improved progression-free survival as compared with FCR, and results for overall survival also favored ibrutinib-venetoclax. (Funded by Cancer Research UK and others; FLAIR ISRCTN Registry number, ISRCTN01844152; EudraCT number, 2013-001944-76.).
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Protocolos de Quimioterapia Combinada Antineoplásica , Leucemia Linfocítica Crónica de Células B , Neoplasia Residual , Vidarabina , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/patología , Neoplasia Residual/patología , Rituximab/administración & dosificación , Rituximab/efectos adversos , Sulfonamidas/administración & dosificación , Sulfonamidas/efectos adversos , Factores de Tiempo , Vidarabina/administración & dosificación , Vidarabina/efectos adversos , Vidarabina/análogos & derivados , Duración de la TerapiaRESUMEN
ABSTRACT: Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematopoietic disorder that occurs on a background of bone marrow failure (BMF). In PNH, chronic intravascular hemolysis causes an increase in morbidity and mortality, mainly because of thromboses. Over the last 20 years, treatment of PNH has focused on the complement protein C5 to prevent intravascular hemolysis using the monoclonal antibody eculizumab and more recently ravulizumab. In the United Kingdom, all patients are under review at 1 of 2 reference centers. We report on all 509 UK patients with PNH treated with eculizumab and/or ravulizumab between May 2002 and July 2022. The survival of patients with eculizumab and ravulizumab was significantly lower than that of age- and sex-matched controls (P = .001). Only 4 patients died of thromboses. The survival of patients with PNH (n = 389), when those requiring treatment for BMF (clonal evolution to myelodysplastic syndrome or acute leukemia or had progressive unresponsive aplastic anemia) were excluded, was not significantly different from that of age- and sex-matched controls (P = .12). There were 11 cases of meningococcal sepsis (0.35 events per 100 patient-years). Extravascular hemolysis was evident in patients who received treatment, with 26.7% of patients requiring transfusions in the most recent 12 months on therapy. Eculizumab and ravulizumab are safe and effective therapies that reduce mortality and morbidity in PNH, but further work is needed to reduce mortality in those with concomitant BMF.
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Hemoglobinuria Paroxística , Trombosis , Humanos , Hemoglobinuria Paroxística/complicaciones , Hemólisis , Inactivadores del Complemento , Resultado del Tratamiento , Complemento C5 , Trombosis/complicaciones , Trastornos de Fallo de la Médula ÓseaRESUMEN
BACKGROUND: In the GLOW study, fixed-duration ibrutinib-venetoclax showed superior progression-free survival versus chlorambucil-obinutuzumab in patients with previously untreated chronic lymphocytic leukaemia who were older or had comorbidities, or both, at a median follow up of 27·7 months. In this Article, we report updated outcomes from GLOW after a 46-month median follow-up. METHODS: GLOW was a randomised, multicentre, phase 3 study done at 67 hospital centres across 14 countries. Patients aged 65 years and older or 18-64 years with previously untreated chronic lymphocytic leukaemia and a cumulative illness rating scale score of more than 6 or creatinine clearance less than 70 mL/min, or both, and an Eastern Cooperative Oncology Group performance status of 2 or less were randomly assigned (1:1) via an interactive web system with permuted blocks (block size of four) and stratified by IGHV mutational status and the presence of del11q aberration to the ibrutinib-venetoclax group (three cycles of ibrutinib lead-in [420 mg/day, orally], followed by 12 cycles of ibrutinib plus venetoclax [400 mg/day, orally, including a 5-week dose ramp-up]) or the chlorambucil-obinutuzumab group (six cycles of chlorambucil [0·5 mg/kg, orally, on days 1 and 15 of each cycle], and obinutuzumab [1000 mg, intravenously, on days 1 (or 100 mg on day 1 and 900 mg on day 2), 8, and 15 of cycle 1 and day 1 of cycles 2-6]). The primary endpoint was progression-free survival in the intention-to-treat population, assessed by an independent review committee. The safety population included all randomised patients who received at least one dose of the study treatment. This study is registered with ClinicalTrials.gov (NCT03462719) and the EU Clinical Trials Register (EudraCT 2017-004699-77). FINDINGS: Between May 4, 2018, and April 5, 2019, 211 patients (122 [58%] were male and 89 [42%] were female) were randomly assigned to receive ibrutinib-venetoclax (n=106) or chlorambucil-obinutuzumab (n=105). At a median of 46 months (IQR 43-47) of follow-up, progression-free survival remained superior for the ibrutinib-venetoclax group (hazard ratio 0·214 [95% CI 0·138-0·334]; p<0·0001); 42-month progression-free survival rates were 74·6% (95% CI 65·0-82·0) for ibrutinib-venetoclax and 24·8% (16·5-34·1) for chlorambucil-obinutuzumab. Following the primary analysis, one patient in the chlorambucil-obinutuzumab group had a serious adverse event of myelodysplastic syndrome. Treatment-related deaths were reported in one patient receiving ibrutinib-venetoclax (cardiac failure, pneumonia, and sinus node dysfunction) and in one patient receiving chlorambucil-obinutuzumab (pneumonia). There were 15 deaths in the ibrutinib-venetoclax group (of which three were due to post-treatment infections) and 30 deaths in the chlorambucil-obinutuzumab group (of which 10 were due to post-treatment infections). INTERPRETATION: After 4 years of follow-up, ibrutinib-venetoclax continues to significantly prolong progression-free survival (vs chemoimmunotherapy) in patients with previously untreated chronic lymphocytic leukaemia, supporting its use as a first-line option. FUNDING: Janssen Research & Development and Pharmacyclics.
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Leucemia Linfocítica Crónica de Células B , Neumonía , Femenino , Humanos , Masculino , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Clorambucilo/efectos adversos , Clorambucilo/uso terapéutico , Estudios de Seguimiento , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Neumonía/inducido químicamenteRESUMEN
Complement dysregulation underpins the physiopathology of paroxysmal nocturnal hemoglobinuria (PNH). Cemdisiran, an RNA interference investigational treatment, silences complement component 5 (C5) expression in the liver. Previously reported results showed sustained reduction in C5 levels following cemdisiran monotherapy, with >90% reduction in patients with PNH. This phase 1/2 study evaluated single (Part A, n = 32; 50-900 mg) or multiple (Part B, n = 24; 100-600 mg) ascending doses of cemdisiran or placebo (double-blind, randomized 3:1) in healthy adults, or cemdisiran in patients with PNH who were naive to, or receiving, eculizumab (Part C, n = 6; 200 or 400 mg weekly; open-label). The primary objective was to assess the safety and tolerability of cemdisiran. Other assessments included change in complement activity, lactate dehydrogenase levels, and inhibition of hemolysis following cemdisiran treatment. Cemdisiran was generally well tolerated in this study. Overall, 75%, 89%, and 100% of subjects in Parts A, B, and C, respectively, experienced ≥1 non-serious adverse event (AE). Most events were Grade 1 or 2 in severity and the most common AEs included nasopharyngitis and headache. Cemdisiran elicited robust, sustained reductions in the complement activity in healthy adults and patients with PNH. In Part C, exploratory analyses showed that cemdisiran monotherapy was insufficient to prevent hemolysis in patients with PNH as measured by serum lactate dehydrogenase levels. Cemdisiran and eculizumab combination therapy reduced the dose of eculizumab required to provide adequate control of intravascular hemolysis. These results demonstrate a potential benefit of cemdisiran coadministration in patients who are inadequate responders to eculizumab alone.
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Because most patients with lupus nephritis have a positive antinuclear antibody (ANA), ANA-negative lupus nephritis is a rare complication of systemic lupus erythematosus (SLE). In the 2019 European Alliance of Associations for Rheumatology/American College of Rheumatology (EULAR/ACR) classification criteria for SLE, a negative ANA precludes further work-up of SLE. The following case discusses a patient with multiple negative ANA titers but was diagnosed with SLE based on the findings of the kidney biopsy showing lupus nephritis. Though ANA was negative, anti-double-stranded DNA (anti-dsDNA) and anti-Sjogren's syndrome-A (anti-SS-A) antibodies were high. This case highlights the nuances of SLE and further illustrates the challenges in making a diagnosis of SLE when serology alone is relied on for screening.
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BACKGROUND: Patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) have poor outcomes after the failure of covalent Bruton's tyrosine kinase (BTK) inhibitor treatment, and new therapeutic options are needed. Pirtobrutinib, a highly selective, noncovalent (reversible) BTK inhibitor, was designed to reestablish BTK inhibition. METHODS: We conducted a phase 1-2 trial in which patients with relapsed or refractory B-cell cancers received pirtobrutinib. Here, we report efficacy results among patients with CLL or SLL who had previously received a BTK inhibitor as well as safety results among all the patients with CLL or SLL. The primary end point was an overall response (partial response or better) as assessed by independent review. Secondary end points included progression-free survival and safety. RESULTS: A total of 317 patients with CLL or SLL received pirtobrutinib, including 247 who had previously received a BTK inhibitor. Among these 247 patients, the median number of previous lines of therapy was 3 (range, 1 to 11), and 100 patients (40.5%) had also received a B-cell lymphoma 2 (BCL2) inhibitor such as venetoclax. The percentage of patients with an overall response to pirtobrutinib was 73.3% (95% confidence interval [CI], 67.3 to 78.7), and the percentage was 82.2% (95% CI, 76.8 to 86.7) when partial response with lymphocytosis was included. The median progression-free survival was 19.6 months (95% CI, 16.9 to 22.1). Among all 317 patients with CLL or SLL who received pirtobrutinib, the most common adverse events were infections (in 71.0%), bleeding (in 42.6%), and neutropenia (in 32.5%). At a median duration of treatment of 16.5 months (range, 0.2 to 39.9), some adverse events that are typically associated with BTK inhibitors occurred relatively infrequently, including hypertension (in 14.2% of patients), atrial fibrillation or flutter (in 3.8%), and major hemorrhage (in 2.2%). Only 9 of 317 patients (2.8%) discontinued pirtobrutinib owing to a treatment-related adverse event. CONCLUSIONS: In this trial, pirtobrutinib showed efficacy in patients with heavily pretreated CLL or SLL who had received a covalent BTK inhibitor. The most common adverse events were infections, bleeding, and neutropenia. (Funded by Loxo Oncology; BRUIN ClinicalTrials.gov number, NCT03740529.).
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Antineoplásicos , Leucemia Linfocítica Crónica de Células B , Inhibidores de Proteínas Quinasas , Humanos , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Hemorragia/inducido químicamente , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Neutropenia/inducido químicamente , Supervivencia sin Progresión , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidoresRESUMEN
ELEVATE-RR demonstrated noninferior progression-free survival and lower incidence of key adverse events (AEs) with acalabrutinib vs ibrutinib in previously treated chronic lymphocytic leukemia. We further characterize AEs of acalabrutinib and ibrutinib via post hoc analysis. Overall and exposure-adjusted incidence rate was assessed for common Bruton tyrosine kinase inhibitor-associated AEs and for selected events of clinical interest (ECIs). AE burden scores based on previously published methodology were calculated for AEs overall and selected ECIs. Safety analyses included 529 patients (acalabrutinib, n = 266; ibrutinib, n = 263). Among common AEs, incidences of any-grade diarrhea, arthralgia, urinary tract infection, back pain, muscle spasms, and dyspepsia were higher with ibrutinib, with 1.5- to 4.1-fold higher exposure-adjusted incidence rates. Incidences of headache and cough were higher with acalabrutinib, with 1.6- and 1.2-fold higher exposure-adjusted incidence rate, respectively. Among ECIs, incidences of any-grade atrial fibrillation/flutter, hypertension, and bleeding were higher with ibrutinib, as were exposure-adjusted incidence rates (2.0-, 2.8-, and 1.6-fold, respectively); incidences of cardiac events overall (the Medical Dictionary for Regulatory Activities system organ class) and infections were similar between arms. Rate of discontinuation because of AEs was lower for acalabrutinib (hazard ratio, 0.62; 95% confidence interval, 0.41-0.93). AE burden score was higher for ibrutinib vs acalabrutinib overall and for the ECIs atrial fibrillation/flutter, hypertension, and bleeding. A limitation of this analysis is its open-label study design, which may influence the reporting of more subjective AEs. Overall, event-based analyses and AE burden scores demonstrated higher AE burden overall and specifically for atrial fibrillation, hypertension, and hemorrhage with ibrutinib vs acalabrutinib. This trial was registered at www.clinicaltrials.gov as #NCT02477696.
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Fibrilación Atrial , Hipertensión , Leucemia Linfocítica Crónica de Células B , Humanos , Fibrilación Atrial/tratamiento farmacológico , Hemorragia/inducido químicamente , Hipertensión/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/efectos adversosRESUMEN
Background: Patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) have limited treatment options. Ceralasertib, a selective ataxia telangiectasia and Rad-3-related protein (ATR) inhibitor, demonstrated synergistic preclinical activity with a Bruton tyrosine kinase (BTK) inhibitor in TP53- and ATM-defective CLL cells. Acalabrutinib is a selective BTK inhibitor approved for treatment of CLL. Objectives: To evaluate ceralasertib ± acalabrutinib in R/R CLL. Design: Nonrandomized, open-label phase I/II study. Methods: In arm A, patients received ceralasertib monotherapy 160 mg twice daily (BID) continuously (cohort 1) or 2 weeks on/2 weeks off (cohort 2). In arm B, patients received acalabrutinib 100 mg BID continuously (cycle 1), followed by combination treatment with ceralasertib 160 mg BID 1 week on/3 weeks off from cycle 2. Co-primary objectives were safety and pharmacokinetics. Efficacy was a secondary objective. Results: Eleven patients were treated [arm A, n = 8 (cohort 1, n = 5; cohort 2, n = 3); arm B, n = 3 (acalabrutinib plus ceralasertib, n = 2; acalabrutinib only, n = 1)]. Median duration of exposure was 3.5 and 7.2 months for ceralasertib in arms A and B, respectively, and 15.9 months for acalabrutinib in arm B. Most common grade ⩾3 treatment-emergent adverse events (TEAEs) in arm A were anemia (75%) and thrombocytopenia (63%), with four dose-limiting toxicities (DLTs) of grade 4 thrombocytopenia. No grade ⩾3 TEAEs or DLTs occurred in arm B. Ceralasertib plasma concentrations were similar when administered as monotherapy or in combination. At median follow-up of 15.1 months in arm A, no responses were observed, median progression-free survival (PFS) was 3.8 months, and median overall survival (OS) was 16.9 months. At median follow-up of 17.2 months in arm B, overall response rate was 100%, and median PFS and OS were not reached. Conclusion: Ceralasertib alone showed limited clinical benefit. Acalabrutinib plus ceralasertib was tolerable with preliminary activity in patients with R/R CLL, though findings are inconclusive due to small sample size. Registration: NCT03328273.
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PURPOSE: In GLOW, fixed-duration ibrutinib + venetoclax showed superior progression-free survival (PFS) versus chlorambucil + obinutuzumab in older/comorbid patients with previously untreated chronic lymphocytic leukemia (CLL). The current analysis describes minimal residual disease (MRD) kinetics and any potential predictive value for PFS, as it has not yet been evaluated for ibrutinib + venetoclax treatment. METHODS: Undetectable MRD (uMRD) was assessed by next-generation sequencing at <1 CLL cell per 10,000 (<10-4) and <1 CLL cell per 100,000 (<10-5) leukocytes. PFS was analyzed by MRD status at 3 months after treatment (EOT+3). RESULTS: Ibrutinib + venetoclax achieved deeper uMRD (<10-5) rates in bone marrow (BM) and peripheral blood (PB), respectively, in 40.6% and 43.4% of patients at EOT+3 versus 7.6% and 18.1% of patients receiving chlorambucil + obinutuzumab. Of these patients, uMRD (<10-5) in PB was sustained during the first year post-treatment (EOT+12) in 80.4% of patients receiving ibrutinib + venetoclax and 26.3% receiving chlorambucil + obinutuzumab. Patients with detectable MRD (dMRD; ≥10-4) in PB at EOT+3 were more likely to sustain MRD levels through EOT+12 with ibrutinib + venetoclax versus chlorambucil + obinutuzumab. PFS rates at EOT+12 were high among patients treated with ibrutinib + venetoclax regardless of MRD status at EOT+3: 96.3% and 93.3% in patients with uMRD (<10-4) and dMRD (≥10-4) in BM, respectively, versus 83.3% and 58.7% for patients receiving chlorambucil + obinutuzumab. PFS rates at EOT+12 also remained high in patients with unmutated immunoglobulin heavy-chain variable region (IGHV) receiving ibrutinib + venetoclax, independent of MRD status in BM. CONCLUSION: Molecular and clinical relapses were less frequent during the first year post-treatment with ibrutinib + venetoclax versus chlorambucil + obinutuzumab regardless of MRD status at EOT+3 and IGHV status. Even for patients not achieving uMRD (<10-4), PFS rates remained high with ibrutinib + venetoclax; this is a novel finding and requires additional follow-up to confirm its persistence over time.
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Leucemia Linfocítica Crónica de Células B , Humanos , Anciano , Supervivencia sin Progresión , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Neoplasia Residual/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Compuestos Bicíclicos Heterocíclicos con Puentes/efectos adversos , Clorambucilo/efectos adversosRESUMEN
PURPOSE: Pirtobrutinib is a highly selective, noncovalent (reversible) Bruton tyrosine kinase inhibitor (BTKi). We report the safety and efficacy of pirtobrutinib in patients with covalent Bruton tyrosine kinase inhibitor (cBTKi) pretreated mantle-cell lymphoma (MCL), a population with poor prognosis. METHODS: Patients with cBTKi pretreated relapsed/refractory (R/R) MCL received pirtobrutinib monotherapy in a multicenter phase I/II trial (BRUIN; ClinicalTrials.gov identifier: NCT03740529). Efficacy was assessed in the first 90 consecutively enrolled patients who met criteria for inclusion in the primary efficacy cohort. The primary end point was overall response rate (ORR). Secondary end points included duration of response (DOR) and safety. RESULTS: The median patient age was 70 years (range, 46-87), the median prior lines of therapy was 3 (range, 1-8), 82.2% had discontinued a prior cBTKi because of disease progression, and 77.8% had intermediate- or high-risk simplified MCL International Prognostic Index score. The ORR was 57.8% (95% CI, 46.9 to 68.1), including 20.0% complete responses (n = 18). At a median follow-up of 12 months, the median DOR was 21.6 months (95% CI, 7.5 to not reached). The 6- and 12-month estimated DOR rates were 73.6% and 57.1%, respectively. In the MCL safety cohort (n = 164), the most common treatment-emergent adverse events (TEAEs) were fatigue (29.9%), diarrhea (21.3%), and dyspnea (16.5%). Grade ≥3 TEAEs of hemorrhage (3.7%) and atrial fibrillation/flutter (1.2%) were less common. Only 3% of patients discontinued pirtobrutinib because of a treatment-related adverse event. CONCLUSION: Pirtobrutinib is a first-in-class novel noncovalent (reversible) BTKi and the first BTKi of any kind to demonstrate durable efficacy after prior cBTKi therapy in heavily pretreated R/R MCL. Pirtobrutinib was well tolerated with low rates of treatment discontinuation because of toxicity.
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Linfoma de Células del Manto , Adulto , Humanos , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Linfoma de Células del Manto/tratamiento farmacológico , Linfoma de Células del Manto/patología , Recurrencia Local de Neoplasia/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/efectos adversosRESUMEN
BACKGROUND: The approval of Bruton tyrosine kinase (BTK) inhibitors in patients with previously untreated chronic lymphocytic leukaemia (CLL) was based on trials which compared ibrutinib with alkylating agents in patients considered unfit for fludarabine, cyclophosphamide, and rituximab, the most effective chemoimmunotherapy in CLL. We aimed to assess whether ibrutinib and rituximab is superior to fludarabine, cyclophosphamide, and rituximab in terms of progression-free survival. METHODS: This study is an interim analysis of FLAIR, which is an open-label, randomised, controlled, phase 3 trial in patients with previously untreated CLL done at 101 UK National Health Service hospitals. Eligible patients were between 18 and 75 years of age with a WHO performance status of 2 or less and disease status requiring treatment according to International Workshop on CLL criteria. Patients with greater than 20% of their CLL cells having the chromosome 17p deletion were excluded. Patients were randomly assigned (1:1) by means of minimisation (Binet stage, age, sex, and centre) with a random element in a web-based system to ibrutinib and rituximab (ibrutinib administered orally at 420 mg/day for up to 6 years; rituximab administered intravenously at 375 mg/m2 on day 1 of cycle 1 and at 500 mg/m2 on day 1 of cycles 2-6 of a 28-day cycle) or fludarabine, cyclophosphamide, and rituximab (fludarabine 24 mg/m2 per day orally on day 1-5, cyclophosphamide 150 mg/m2 per day orally on days 1-5; rituximab as above for up to 6 cycles). The primary endpoint was progression-free survival, analysed by intention to treat. Safety analysis was per protocol. This study is registered with ISRCTN, ISRCTN01844152, and EudraCT, 2013-001944-76, and recruiting is complete. FINDINGS: Between Sept 19, 2014, and July 19, 2018, of 1924 patients assessed for eligibility, 771 were randomly assigned with median age 62 years (IQR 56-67), 565 (73%) were male, 206 (27%) were female and 507 (66%) had a WHO performance status of 0. 385 patients were assigned to fludarabine, cyclophosphamide, and rituximab and 386 patients to ibrutinib and rituximab. After a median follow-up of 53 months (IQR 41-61) and at prespecified interim analysis, median progression-free survival was not reached (NR) with ibrutinib and rituximab and was 67 months (95% CI 63-NR) with fludarabine, cyclophosphamide, and rituximab (hazard ratio 0·44 [95% CI 0·32-0·60]; p<0·0001). The most common grade 3 or 4 adverse event was leukopenia (203 [54%] patients in the fludarabine, cyclophosphamide, and rituximab group and 55 [14%] patients in the ibrutinib and rituximab group. Serious adverse events were reported in 205 (53%) of 384 patients receiving ibrutinib and rituximab compared with 203 (54%) of 378 patients receiving fludarabine, cyclophosphamide, and rituximab. Two deaths in the fludarabine, cyclophosphamide, and rituximab group and three deaths in the ibrutinib and rituximab group were deemed to be probably related to treatment. There were eight sudden unexplained or cardiac deaths in the ibrutinib and rituximab group and two in the fludarabine, cyclophosphamide, and rituximab group. INTERPRETATION: Front line treatment with ibrutinib and rituximab significantly improved progression-free survival compared with fludarabine, cyclophosphamide, and rituximab but did not improve overall survival. A small number of sudden unexplained or cardiac deaths in the ibrutinib and rituximab group were observed largely among patients with existing hypertension or history of cardiac disorder. FUNDING: Cancer Research UK and Janssen.
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Leucemia Linfocítica Crónica de Células B , Humanos , Masculino , Femenino , Persona de Mediana Edad , Rituximab , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Medicina Estatal , Ciclofosfamida , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
BACKGROUND: Clinical outcomes in chronic lymphocytic leukemia (CLL) have improved with targeted therapy, including Bruton tyrosine kinase inhibitors such as acalabrutinib. METHODS: A semi-Markov model with three health states (progression-free, progressed disease, and death) estimated cost per quality-adjusted life-year (QALY) gained for acalabrutinib ± obinutuzumab vs chlorambucil + obinutuzumab in treatment-naive CLL (based on ELEVATE-TN). The model used direct costs and resource utilization from the US Medicare perspective and utility values sourced from literature. Sensitivity analyses tested the robustness of the model. RESULTS: Over a 30-year lifetime horizon, the model base case analysis suggested that acalabrutinib monotherapy had an incremental cost of $206,329 and 2.52 QALYs gained versus chlorambucil + obinutuzumab, resulting in an incremental cost-effectiveness ratio (ICER) of $81,960/QALY. Acalabrutinib + obinutuzumab had an incremental cost of $423,747 and 2.79 QALYs gained (ICER: $152,153/QALY). Probabilistic sensitivity analysis showed the probability of acalabrutinib monotherapy being cost-effective as 59% to 73% at a $100,000-to-150,000/QALY willingness-to-pay threshold; the probability of acalabrutinib + obinutuzumab being cost-effective ranged from 34% to 51%. CONCLUSIONS: Although the analysis is limited by uncertainty in postprogression survival outcomes, acalabrutinib monotherapy is likely cost-effective vs chlorambucil + obinutuzumab in treatment-naive CLL in the US Medicare setting.
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Leucemia Linfocítica Crónica de Células B , Anciano , Humanos , Estados Unidos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Análisis Costo-Beneficio , Medicare , Clorambucilo/uso terapéutico , Años de Vida Ajustados por Calidad de VidaRESUMEN
The GA101 (obinutuzumab) monocLonal Antibody as Consolidation Therapy In chronic lymphocytic leukaemia (CLL) (GALACTIC) was a seamless phase II/III trial designed to test whether consolidation with obinutuzumab is safe and eradicates minimal residual disease (MRD) and, subsequently, whether this leads to prolonged progression-free survival (PFS) in patients with CLL who have recently responded to chemo-immunotherapy. Patients with a response 3-24 months after chemotherapy were assessed for MRD. MRD-positive patients were randomised to receive consolidation therapy with obinutuzumab or no consolidation. The trial closed after the phase II part due to slow recruitment. In all, 48 patients enrolled of whom 19 were MRD negative and were monitored. Of the 29 MRD-positive patients, 14 were randomised to receive consolidation and 15 to no consolidation. At 6 months after randomisation, 10 and 13 consolidated patients achieved MRD negativity by flow cytometry (sensitivity 10-4 ) in bone marrow and peripheral blood respectively. PFS was significantly better in consolidated patients compared to non-consolidated patients (p = 0.001). No difference was observed in PFS, overall survival or duration of MRD negativity when comparing the 10 MRD-negative patients after consolidation with the 19 MRD-negative patients in the monitoring group. Common adverse events in the consolidation arm were thrombocytopenia, infection, and cough. Only 1% of events were infusion-related reactions. This observation provides further evidence that consolidation to achieve MRD negativity improves outcomes in CLL and that obinutuzumab is well tolerated in patients with low levels of disease.