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Bruton's tyrosine kinase inhibitors (BTKi) have dramatic efficacy against B-cell malignancies, but link with cardiotoxicity, including atrial fibrillation (AF). Burden, severity, and implications of BTKi-related AF are unknown. Leveraging a large-cohort of consecutive B-cell malignancy patients initiated on BTKi from 2009-2020, we identified patients with extended ambulatory rhythm monitoring. The primary outcome was AF burden after BTKi-initiation. Secondary outcomes included ventricular arrhythmia burden and other arrhythmias. Observed incident-AF rates and burden with next-generation BTKi's were compared to ibrutinib. Multivariable regression defined association between rhythm measures and major adverse cardiac events (MACE), and mortality. There were 98 BTKi-treated patients [38.8% next-generation BTKi's, 14.3% prior-AF], with 28,224 h of monitoring. Median duration BTKi-use was 34 months. Over mean duration 12 days monitoring, 72.4% developed arrhythmias (16.3% incident-AF, 31.6% other SVTs, 14.3% ventricular tachycardia). 14.3% had high AF-burden. AF-burden was similar between ibrutinib and next-generation BTKi's. No single antiarrhythmic-therapy prevented BTKi-related AF. However, antiarrhythmic initiation associated with reduction in arrhythmic burden (P = 0.009). In a multivariable model accounting for traditional cardiovascular risk factors, prior-AF associated with increased post-BTKi AF-burden. In follow-up, high AF burden associated with MACE (HR 3.12, P = 0.005) and mortality (HR 2.97, P = 0.007). Among BTKi-treated patients, high AF burden prognosticates future MACE and mortality risk.
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Kaplan-Meier curve depicting overall survival from CLL treatment start by race. For patients with CLL, no overall survival difference was observed between races in this real-world US database.
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Leucemia Linfocítica Crónica de Células B , Humanos , Estudios de CohortesRESUMEN
Background: Heat shock protein 90 (HSP90) is a molecular chaperone required for stabilization of client proteins over-activated in triple-negative breast cancer (TNBC). Over-expression of HSP90 client proteins has been implicated in paclitaxel resistance. Onalespib (AT13387) is a potent inhibitor of HSP90 that could improve paclitaxel efficacy when administered in combination. Design: This phase Ib trial administered onalespib with paclitaxel in patients with advanced TNBC to assess safety and establish a recommended phase II dose (RP2D). Objectives: The primary objectives were determining the dose-limiting toxicities and maximum tolerated dose of combination therapy. Secondary objectives included pharmacokinetic (PK) analysis and determination of overall response rate (ORR), duration of response (DOR), and progression-free survival (PFS). Methods: Patients with advanced TNBC were treated with standard dose intravenous paclitaxel in combination with intravenous onalespib at doses ranging from 120 to 260 mg/m2 administered on days 1, 8, and 15 of a 28-day cycle using a standard 3 + 3 design. A total of 15 patients were enrolled to dose expansion cohort at RP2D to confirm safety profile. Results: Thirty-one patients were enrolled in the study, of which over 90% had received prior taxane therapy. Paclitaxel was given for metastatic disease in 23% of patients. Adverse events (AEs) included anemia (grade 3: 20%), lymphopenia (grade 3: 17%), and neutropenia (grade 3: 33%, grade 4: 4%). The most frequent grade ⩾3 non-hematologic AE was diarrhea (7%). The established RP2D was 260 mg/m2 onalespib when given with paclitaxel at 80 mg/m2. PK analysis revealed a modest drug interaction profile for onalespib in the combination regimen. ORR was 20%. Three patients achieved complete responses, all of whom had received prior taxane therapy. Median DOR was 5.6 months; median PFS was 2.9 months. Conclusion: Combination treatment with onalespib and paclitaxel had an acceptable toxicity profile and RP2D was determined to be 260 mg/m2 of onalespib. Combination therapy showed antitumor activity in patients with advanced TNBC. Trial registration: Onalespib and paclitaxel in treating patients with advanced TNBC https://clinicaltrials.gov/ct2/show/NCT02474173.
Phase 1b study of HSP90 inhibitor called onalespib in combination with paclitaxel in patients with advanced triple-negative breast cancer This Phase 1b study demonstrated that treatment with a combination of onalespib and paclitaxel was reasonably well tolerated by most patients. Onalespib at 260 mg/m2 given intravenously on days 1, 8 and 15 on 28-day cycles in combination with standard dose and schedule of paclitaxel was established as the recommended phase 2 dose for further clinical development. Despite minor drug-drug interactions between these 2 agents, onalespib did not alter paclitaxel exposure and paclitaxel did not affect exposure to onalespib. While onalespib with paclitaxel combination therapy did not yield durable objective responses or prolonged progression-free survival, there were several patients with long-lasting benefit from this combination including patients who previously experienced progression on taxane therapy.
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Over the past decade, the treatment landscape of chronic lymphocytic leukemia (CLL) has dramatically changed, shifting from cytotoxic chemotherapy to targeted therapies. Bruton's tyrosine kinase (BTK) inhibitors have revolutionized the treatment of CLL and are increasingly applied in many other malignancies. However, ibrutinib, the first BTK inhibitor approved, is associated with serious toxicities, including atrial fibrillation in up to 38% of patients, ventricular arrhythmias, and other cardiovascular toxicities. Emerging data suggest several newer BTK inhibitors (eg, acalabrutinib, zanubrutinib) are still associated with cardiotoxic risks. This review examines the current state of evidence, including incidence rates, risk factors, mechanisms, and management strategies of cardiovascular toxicities with BTK inhibitors and other CLL therapies. We specifically focus on atrial fibrillation, ventricular arrhythmias/sudden death, hypertension, heart failure, bleeding, and stroke. We also touch on other emerging BTK therapies (eg, pirtobrutinib). Finally, we highlight key unanswered questions and future directions of research.
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Leucemia Linfocítica Crónica de Células B , Humanos , Hibridación Fluorescente in Situ , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/genética , Deleción Cromosómica , Eliminación de Gen , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genéticaRESUMEN
Fluorescence in situ hybridization (FISH) to detect the recurrent cytogenetics abnormalities deletion 13q, trisomy 12, deletion 11q, and deletion 17p is important for prognostication in chronic lymphocytic leukemia (CLL). A subset of patients are negative for each of these abnormalities (normal 12/13/11/17 FISH), and outcomes are heterogenous within this group. To elucidate variables important for prognostication in this subgroup we conducted a retrospective analysis of 280 treatment-naïve CLL patients with normal standard CLL FISH results. In a multivariable model, advanced Rai stage (p = 0.04, hazard ratio [HR] 1.24 (95% confidence interval [CI] 1.01-1.53)), unmutated immunoglobulin heavy chain gene (IGHV) (p < 0.0001, HR 5.59 (95% CI 3.63-8.62)) and IGH rearrangement by FISH (p = 0.02, HR 2.56 (95% CI 1.20-5.48)) were significantly associated with shorter time to first treatment. In a multivariable model for overall survival, increasing age at 5-year increments (p < 0.0001, HR 1.55 (95% CI 1.25-1.93)), unmutated IGHV (p = 0.01, HR 5.28 (95% CI 1.52-18.35)) and gain of REL (p = 0.01, HR 4.08 (5% CI 1.45-11.49)) were significantly associated with shorter survival. Our study identifies variables important for refining prognosis for CLL patients with normal standard CLL FISH results.
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Leucemia Linfocítica Crónica de Células B , Humanos , Preescolar , Hibridación Fluorescente in Situ/métodos , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/genética , Estudios Retrospectivos , Aberraciones Cromosómicas , PronósticoRESUMEN
Chronic lymphocytic leukemia (CLL) transformation to aggressive lymphoma, known as Richter's Transformation (RT), has a dismal prognosis. There are limited data evaluating risk of RT in patients treated with ibrutinib. We performed a retrospective analysis to determine prognostic variables associated with development of RT and overall survival (OS) at progression after treatment with ibrutinib. We identified 559 patients with CLL treated with ibrutinib from 2010-2019. After a median follow-up of 44.5 months from ibrutinib start, 179 patients progressed and were included in our analysis. After a median follow-up of 20.8 months from progression, 54 out of 179 patients developed RT. Progression on treatment (hazard ratio [HR] 4.01 [1.60-10.00], p = .003), higher LDH (HR 1.80 for 2-fold increase [1.33-2.43], p = .0001), and lymphadenopathy without lymphocytosis (HR 2.88 [1.15-7.20], p = .02) were independent prognostic variables for the development of RT at progression. Progression with lymphadenopathy without lymphocytosis continued to be an independent prognostic variable of worse OS post-progression. In a subset analysis of 50 patients who obtained a PET-CT at progression, the median SUVmax for patients who would develop RT was 15.2 (n = 30, range: 4.0-46.3) versus those patients who did not develop RT with a SUVmax of 7.7 (n = 20, range: 2.3-27.2) (p = .0030). Median OS from date of RT was 4.0 months, suggesting that prognosis for RT remains poor. A lymph node biopsy to rule out RT should be considered in patients who received ibrutinib who progress on treatment, have an elevated LDH, or progress with lymphadenopathy without lymphocytosis.
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Leucemia Linfocítica Crónica de Células B , Linfadenopatía , Linfocitosis , Linfoma de Células B Grandes Difuso , Humanos , Tomografía Computarizada por Tomografía de Emisión de Positrones , Estudios RetrospectivosRESUMEN
A significant body of literature has been generated related to the detection of measurable residual disease (MRD) at the time of achieving complete remission (CR) in patients with hairy cell leukemia (HCL). However, due to the indolent nature of the disease as well as reports suggesting long-term survival in patients treated with a single course of a nucleoside analog albeit without evidence of cure, the merits of detection of MRD and attempts to eradicate it have been debated. Studies utilizing novel strategies in the relapse setting have demonstrated the utility of achieving CR with undetectable MRD (uMRD) in prolonging the duration of remission. Several assays including immunohistochemical analysis of bone marrow specimens, multi-parameter flow cytometry and molecular assays to detect the mutant BRAF V600E gene or the consensus primer for the immunoglobulin heavy chain gene (IGH) rearrangement have been utilized with few comparative studies. Here we provide a consensus report on the available data, the potential merits of MRD assessment in the front-line and relapse settings and recommendations on future role of MRD assessment in HCL.
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Leucemia de Células Pilosas , Humanos , Leucemia de Células Pilosas/diagnóstico , Leucemia de Células Pilosas/genética , Leucemia de Células Pilosas/terapia , Neoplasia Residual/diagnóstico , Neoplasia Residual/genética , Inducción de Remisión , Genes de las Cadenas Pesadas de las Inmunoglobulinas , Citometría de FlujoRESUMEN
Hairy cell leukemia (HCL) is a rare lymphoproliferative disorder, comprising only 2% of all leukemias. The Hairy Cell Leukemia Foundation (HCLF) has developed a patient data registry to enable investigators to better study the clinical features, treatment outcomes, and complications of patients with HCL. This system utilizes a centralized registry architecture. Patients are enrolled at HCL Centers of Excellence (COE) or via a web-based portal. All data are de-identified, which reduces regulatory burden and increases opportunities for data access and re-use. To date, 579 patients have been enrolled in the registry. Efforts are underway to engage additional COE's to expand access to patients across the globe. This international PDR will enable researchers to study outcomes in HCL in ways not previously possible due to the rarity of the disease and will serve as a platform for future prospective research.
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Leucemia de Células Pilosas , Humanos , Leucemia de Células Pilosas/diagnóstico , Leucemia de Células Pilosas/epidemiología , Leucemia de Células Pilosas/terapia , Resultado del Tratamiento , Sistema de RegistrosRESUMEN
Vemurafenib, an oral BRAF inhibitor, has demonstrated high response rates in relapsed/refractory (R/R) hairy cell leukemia (HCL). However, little is known about long-term outcomes and response to retreatment. Herein, we report the results of 36 patients with R/R HCL treated with vemurafenib from the United States arm of the phase 2 clinical trial (NCT01711632). The best overall response rate was 86%, including 33% complete response (CR) and 53% partial response (PR). After a median follow-up of 40 months, 21 of 31 responders (68%) experienced relapse with a median relapse-free survival (RFS) of 19 months (range, 12.5-53.9 months). There was no significant difference in the RFS for patients with CR vs PR. Fourteen of 21 (67%) relapsed patients were retreated with vemurafenib, with 86% achieving complete hematologic response. Two patients acquired resistance to vemurafenib with the emergence of new KRAS and CDKN2A mutations, respectively. Six of 12 (50%) responders to vemurafenib retreatment experienced another relapse with a median RFS of 12.7 months. Overall survival (OS) was 82% at 4 years, with a significantly shorter OS in patients who relapsed within 1 year of initial treatment with vemurafenib. Higher cumulative doses or a longer duration of treatment did not lengthen the durability of response. All adverse events in the retreatment cohort were grade 1/2 except for 1 case of a grade 3 rash and 1 grade 3 fever/pneumonia. Our data suggest that vemurafenib retreatment is a safe and effective option for patients with R/R HCL.
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Antineoplásicos , Leucemia de Células Pilosas , Humanos , Vemurafenib/uso terapéutico , Leucemia de Células Pilosas/tratamiento farmacológico , Leucemia de Células Pilosas/genética , Proteínas Proto-Oncogénicas B-raf/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Inducción de Remisión , Antineoplásicos/efectos adversosRESUMEN
Acalabrutinib, a next-generation Bruton's tyrosine kinase inhibitor (BTKi), associates with dramatic efficacy against B-cell malignancies. Recently, unexplained ventricular arrhythmias (VAs) with next-generation BTKi-therapy have been reported. Yet, whether acalabrutinib associates with VAs in long-term follow-up is unknown. Leveraging a large-cohort of 290 consecutive B-cell malignancy patients treated with acalabrutinib from 2014 to 2020, we assessed the incidence of VAs. The primary-endpoint was incident VA development (ventricular fibrillation, ventricular tachycardia, and symptomatic premature ventricular contractions). Probability-scores were assessed to determine likelihood of acalabrutinib-association. Incident rates as function of time-on-therapy were calculated. Weighted average observed incidence rates were compared with expected population rates using relative-risks. Absolute excess risk (AER) for acalabrutinib-associated VAs was estimated. Over 1063 person-years of follow-up, there were 8 cases of incident-VAs, including 6 in those without coronary disease (CAD) or heart failure (HF) and 1 sudden-death; median time-to-event 14.9 months. Among those without prior ibrutinib-use, CAD, or HF, the weighted average incidence was 394 per 100 000 person years compared with a reported incidence of 48.1 among similar-aged non-BTKi-treated subjects (relative risk, 8.2; P < .001; AER, 346). Outside of age, no cardiac or electrocardiographic variables associated with VA development. Collectively, these data suggest VAs may be a class-effect of BTKi therapies.
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Benzamidas , Insuficiencia Cardíaca , Humanos , Anciano , Pirazinas , Arritmias Cardíacas/inducido químicamente , Arritmias Cardíacas/epidemiología , Muerte SúbitaRESUMEN
BACKGROUND: Post-market analyses revealed unanticipated links between first-generation Bruton's tyrosine kinase inhibitor (BTKi) therapy, ibrutinib, and profound early hypertension. Yet, whether this is seen with novel selective second (next)-generation BTKi therapy, acalabrutinib, is unknown. METHODS: Leveraging a large cohort of consecutive B cell cancer patients treated with acalabrutinib from 2014 to 2020, we assessed the incidence and ramifications of new or worsened hypertension [systolic blood pressure (SBP) ≥ 130 mmHg] after acalabrutinib initiation. Secondary endpoints were major cardiovascular events (MACE: arrhythmias, myocardial infarction, stroke, heart failure, cardiac death) and disease progression. Observed incident hypertension rates were compared to Framingham heart-predicted and ibrutinib-related rates. Multivariable regression and survival analysis were used to define factors associated with new/worsened hypertension and MACE, and the relationship between early SBP increase and MACE risk. Further, the effect of standard antihypertensive classes on the prevention of acalabrutinib-related hypertension was assessed. RESULTS: Overall, from 280 acalabrutinib-treated patients, 48.9% developed new/worsened hypertension over a median of 41 months. The cumulative incidence of new hypertension by 1 year was 53.9%, including 1.7% with high-grade (≥ 3) hypertension. Applying the JNC 8 cutoff BP of ≥ 140/90 mmHg, the observed new hypertension rate was 20.5% at 1 year, > eightfold higher than the Framingham-predicted rate of 2.4% (RR 8.5, P < 0.001), yet 34.1% lower than ibrutinib (12.9 observed-to-expected ratio, P < 0.001). In multivariable regression, prior arrhythmias and Black ancestry were associated with new hypertension (HR 1.63, HR 4.35, P < 0.05). The degree of SBP rise within 1 year of treatment initiation predicted MACE risk (42% HR increase for each + 5 mmHg SBP rise, P < 0.001). No single antihypertensive class prevented worsened acalabrutinib-related hypertension. CONCLUSIONS: Collectively, these data suggest that hypertension may be a class effect of BTKi therapies and precedes major cardiotoxic events.