RESUMEN
Intolerance is the most common reason for kinase inhibitor (KI) discontinuation in chronic lymphocytic leukemia (CLL). Umbralisib, a novel highly selective phosphatidylinositol 3-kinase δ (PI3Kδ)/CK1ε inhibitor, is active and well tolerated in CLL patients. In this phase 2 trial (NCT02742090), umbralisib was initiated at 800 mg/d in CLL patients requiring therapy, who were intolerant to prior BTK inhibitor (BTKi) or PI3K inhibitor (PI3Ki) therapy, until progression or toxicity. Primary end point was progression-free survival (PFS). Secondary end points included time to treatment failure and safety. DNA was genotyped for CYP3A4, CYP3A5, and CYP2D6 polymorphisms. Fifty-one patients were enrolled (44 BTKi intolerant and 7 PI3Kδi intolerant); median age was 70 years (range, 48-96), with a median of 2 prior lines of therapy (range, 1-7), 24% had del17p and/or TP53 mutation, and 65% had unmutated IGHV. Most common adverse events (AEs) leading to prior KI discontinuation were rash (27%), arthralgia (18%), and atrial fibrillation (16%). Median PFS was 23.5 months (95% CI, 13.1-not estimable), with 58% of patients on umbralisib for a longer duration than prior KI. Most common (≥5%) grade ≥3 AEs on umbralisib (all causality) were neutropenia (18%), leukocytosis (14%), thrombocytopenia (12%), pneumonia (12%), and diarrhea (8%). Six patients (12%) discontinued umbralisib because of an AE. Eight patients (16%) had dose reductions and were successfully rechallenged. These are the first prospective data to confirm that switching from a BTKi or alternate PI3Ki to umbralisib in this BTKi- and PI3Ki-intolerant CLL population can result in durable well-tolerated responses.
Asunto(s)
Antineoplásicos/uso terapéutico , Fosfatidilinositol 3-Quinasa Clase I/antagonistas & inhibidores , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Proteínas de Neoplasias/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/uso terapéutico , Adenina/efectos adversos , Adenina/análogos & derivados , Adenina/uso terapéutico , Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Enfermedades Cardiovasculares/inducido químicamente , Erupciones por Medicamentos/etiología , Resistencia a Antineoplásicos , Femenino , Enfermedades Gastrointestinales/inducido químicamente , Compuestos Heterocíclicos de 4 o más Anillos/efectos adversos , Humanos , Estimación de Kaplan-Meier , Leucemia Linfocítica Crónica de Células B/enzimología , Leucemia Linfocítica Crónica de Células B/mortalidad , Masculino , Persona de Mediana Edad , Piperidinas/efectos adversos , Piperidinas/uso terapéutico , Supervivencia sin Progresión , Inhibidores de Proteínas Quinasas/efectos adversosRESUMEN
As part of a randomized, prospective clinical trial in large cell lymphoma, we conducted serial fluorodeoxyglucose positron emission tomography (FDG-PET) at baseline, after 2 cycles of chemotherapy (interim PET [i-PET]), and at end of treatment (EoT) to identify biomarkers of response that are predictive of remission and survival. Scans were interpreted in a core laboratory by 2 imaging experts, using the visual Deauville 5-point scale (5-PS), and by calculating percent change in FDG uptake (change in standardized uptake value [ΔSUV]). Visual scores of 1 through 3 and ΔSUV ≥66% were prospectively defined as negative. Of 524 patients enrolled in the parent trial, 169 agreed to enroll in the PET substudy and 158 were eligible for final analysis. In this selected population, all had FDG-avid disease at baseline; by 5-PS, 55 (35%) remained positive on i-PET and 28 (18%) on EoT PET. Median ΔSUV on i-PET was 86.2%. With a median follow-up of 5 years, ΔSUV, as continuous variable, was associated with progression-free survival (PFS) (hazard ratio [HR] = 0.99; 95% confidence interval [CI], 0.97-1.00; P = .02) and overall survival (OS) (HR, 0.98; 95% CI, 0.97-0.99; P = .03). ΔSUV ≥66% was predictive of OS (HR, 0.31; 95% CI, 0.11-0.85; P = .02) but not PFS (HR, 0.47; 95% CI, 0.19-1.13; P = .09). Visual 5-PS on i-PET did not predict outcome. ΔSUV, but not visual analysis, on i-PET predicted OS in DLBCL, although the low number of events limited the statistical analysis. These data may help guide future clinical trials using PET response-adapted therapy. This trial was registered at www.clinicaltrials.gov as #NCT00118209.
Asunto(s)
Linfoma de Células B Grandes Difuso/diagnóstico por imagen , Tomografía de Emisión de Positrones , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ciclofosfamida/administración & dosificación , Etopósido/administración & dosificación , Femenino , Radioisótopos de Flúor , Fluorodesoxiglucosa F18 , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/mortalidad , Masculino , Persona de Mediana Edad , Prednisona/administración & dosificación , Pronóstico , Supervivencia sin Progresión , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Radiofármacos , Rituximab/administración & dosificación , Vincristina/administración & dosificación , Adulto JovenRESUMEN
The treatment landscape for chronic lymphocytic leukemia (CLL) is rapidly evolving. Targeted agents (TAs) have demonstrated impressive single agent activity and therefore have been replacing chemoimmunotherapy (CIT). Despite their efficacy, the optimal use of the current TAs remains challenging. Perhaps the major dilemma is whether these drugs are best used in sequence or in combinations. Most patients tolerate TA well, notably early during treatment; however, a substantial number discontinue therapy because of toxicities. Therefore, the reasons for discontinuation and, subsequently, the preferred sequence of these agents become critical issues. Although TA monotherapy has revolutionized the treatment of CLL, residual disease, acquired resistance, suboptimal durability of response in patients with high-risk disease, indefinite treatment duration, and decreased compliance over time are issues of concern. To address these challenges, an increasing number of studies are evaluating different combinations of TAs; however, these studies have been mostly small single arm trials in heterogeneous patient populations using different methods for response assessment. A number of questions remain regarding the predictive value of minimal residual disease (MRD) status, durability of response, fixed treatment durations, and importantly, criteria for selection of patients for the optimal combinations. Medical comorbidities, performance status, prior therapies, and disease risk profile are fundamental in determining the treatment plan for each individual patient. Furthermore, utilizing prognostic and predictive markers along with monitoring MRD can guide the development of individualized, better-tolerated, time-limited, and potentially curative chemo-free treatment regimens.
Asunto(s)
Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Humanos , Leucemia Linfocítica Crónica de Células B/patología , PronósticoRESUMEN
B-cell receptor signalling inhibition by targeting Bruton tyrosine kinase (BTK) is effective in treating chronic lymphocytic leukemia (CLL). The BTK inhibitor ibrutinib may be intolerable for some patients. Acalabrutinib is a more selective BTK inhibitor that may be better tolerated by patients who are intolerant to ibrutinib. A phase 2 study of acalabrutinib was conducted in patients with relapsed/refractory CLL who were ibrutinib-intolerant and had continued disease activity. Intolerance was defined as having discontinued ibrutinib due to persistent grade 3/4 adverse events (AEs) or persistent/recurrent grade 2 AEs despite dose modification/interruption. Patients received oral acalabrutinib 100 mg twice daily until disease progression or intolerance. Sixty patients were treated. Overall response rate to acalabrutinib was 73% and three patients (5%) achieved complete remission. At median follow-up of 35 months, the median progressionfree and overall survival were not reached; 24-month estimates were 72% and 81%, respectively. The most frequent AEs with acalabrutinib were diarrhea (53%), headache (42%), contusion (40%), dizziness (33%), upper respiratory tract infection (33%), and cough (30%). Most common reasons for acalabrutinib discontinuation were progressive disease (23%) and AEs (17%). Most patients with baseline samples (49/52; 94%) and all with on-treatment samples (3/3; 100%) had no detectable BTK and/or PLCG2 mutations. Acalabrutinib is effective and tolerable in most patients with relapsed/refractory CLL who are intolerant of ibrutinib. Acalabrutinib may be useful for patients who may benefit from BTK inhibitor therapy but are ibrutinib intolerant.
Asunto(s)
Leucemia Linfocítica Crónica de Células B , Adenina/análogos & derivados , Benzamidas , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Piperidinas , Inhibidores de Proteínas Quinasas/efectos adversos , PirazinasRESUMEN
PURPOSE OF REVIEW: Functional imaging with 18FDG-PET-CT has transformed the staging and response assessment of patients with Hodgkin (HL) and non-Hodgkin lymphoma (NHL). Herein, we review the current role and future directions for functional imaging in the management of patients with lymphoma. RECENT FINDINGS: Because of its increased sensitivity, PET-CT is the preferred modality for staging of FDG-avid lymphomas. It appears to have a role for interim assessment in patients with HL with adaptive strategies that reduce toxicity in lower risk patients and increase efficacy in those at high risk. Such a role has yet to be demonstrated in other histologies. FDG-PET-CT is also the gold standard for response assessment posttreatment. Newer uses include assessment of total metabolic tumor volume and radiomics in pretreatment prognosis. Whereas PET-CT is more sensitive than other current modalities for staging and response assessment, the future of PET-CT will be in conjunction with other modalities, notably assessment of minimal residual disease and microenvironmental markers to develop risk adaptive strategies to improve the outcome of patients with lymphoma.
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Fluorodesoxiglucosa F18/administración & dosificación , Enfermedad de Hodgkin/diagnóstico por imagen , Linfoma no Hodgkin/diagnóstico por imagen , Enfermedad de Hodgkin/patología , Humanos , Linfoma no Hodgkin/patología , Estadificación de Neoplasias , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Tomografía de Emisión de Positrones/métodos , Guías de Práctica Clínica como AsuntoRESUMEN
CALGB (Alliance) 100001 was a phase II study evaluating autologous stem cell transplant (ASCT) followed by nonmyeloablative allogeneic stem cell transplant (alloSCT) in patients with multiple myeloma who had received no more than 18 months of prior therapy and had experienced no more than 1 prior progression event. Conditioning for ASCT was with high-dose melphalan (200 mg/m2). The alloSCT reduced-intensity conditioning (RIC) regimen consisted of fludarabine (30 mg/m2/d i.v. on days -7 through -3) and cyclophosphamide (1 g/m2/d i.v. on days -4 through -3). The primary objective was to determine the 6-month post-alloSCT treatment-related mortality (TRM) rate. Additional objectives included determining the proportion of patients who could complete this tandem ASCT-alloSCT approach in a cooperative group setting, overall response rates, rates of donor chimerism, rates of graft-versus-host disease (GVHD), disease-free survival, and overall survival (OS). Sixty patients were enrolled, of whom 57 (95%) completed ASCT and 49 (82%) completed tandem ASCT-alloSCT. The TRM rate was 2% (1/49; 90% confidence interval, 0.10% to 9.3%). Moderate to severe (grades 2 to 3) acute GVHD was observed in 13 of 49 alloSCT patients (27%). One patient died due to GVHD within 9 months of alloSCT. Twenty-seven of the 49 patients (55%) who underwent alloSCT reported chronic GVHD as either limited (15/49; 31%) or extensive (12/49; 24%) in the first year post-alloSCT and prior to the start of nonprotocol therapy for progressive disease. With a median follow-up for survival of 11 years, the median OS time is 6.6 years and the median time to disease progression is 3.6 years. Similar to other studies, this study confirmed that tandem ASCT/alloSCT is associated with durable disease control in a subset of patients. This study demonstrated the feasibility of performing tandem ASCT/alloSCT in a cooperative group setting and determined that a fludarabine/cyclophosphamide RIC regimen is associated with a very low TRM rate.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Mieloma Múltiple , Aloinjertos , Estudios de Seguimiento , Enfermedad Injerto contra Huésped/etiología , Humanos , Mieloma Múltiple/terapia , Acondicionamiento Pretrasplante , Trasplante Autólogo , Trasplante Homólogo , Resultado del TratamientoRESUMEN
Elderly chronic lymphocytic leukaemia (CLL) patients treated outside of trials have notably greater toxicity with the Bruton's tyrosine kinase inhibitor ibrutinib compared to younger patients. It is not known whether the same holds true for the B-cell lymphoma 2 inhibitor venetoclax. We provide a comprehensive analysis of key safety measures and efficacy in 342 patients comparing age categories ≥75 and <75 years treated in the relapsed, refractory non-trial setting. We demonstrate that venetoclax has equivalent efficacy and safety in relapsed/refractory CLL patients who are elderly, the majority of whom are previous ibrutinib-exposed and therefore may otherwise have few clear therapeutic options.
Asunto(s)
Antineoplásicos/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Sulfonamidas/uso terapéutico , Anciano , Antineoplásicos/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Humanos , Recurrencia , Sulfonamidas/farmacologíaRESUMEN
A negative interim positron emission tomography/computerized tomography (PET/CT) after 1 to 3 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in patients with newly diagnosed, nonbulky stage I or II Hodgkin lymphoma (HL) predicts a low relapse rate. This phase 2 trial was designed to determine if a population of patients with early-stage disease can be treated with short-course ABVD without radiation therapy (RT) on the basis of a negative interim PET/CT, thereby limiting the risks of treatment. Between 15 May 2010 and 21 February 2013, 164 previously untreated patients with nonbulky stage I/II HL were enrolled, and 149 were included in the final analysis. Patients received 2 cycles of ABVD followed by PET. Deauville scores 1 to 3 were negative (≤ liver uptake) based on central review. PET- patients received 2 more cycles of ABVD, and PET+ patients received 2 cycles of dose-intense bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (escalated BEACOPP) plus 3060-cGy involved-field RT. The primary objective was to determine 3-year progression-free survival (PFS) for the PET- group. One hundred thirty-five patients (91%) were interim PET-, and 14 patients (9%) were PET+ With median follow-up time of 3.8 years, the estimated 3-year PFS was 91% for the PET- group and 66% for the PET+ group (hazard ratio, 3.84; 95% confidence interval, 1.50-9.84; P = .011). There was 1 death as a result of suicide. Four cycles of ABVD resulted in durable remissions for a majority of patients with early-stage nonbulky HL and a negative interim PET. This trial was registered at www.clinicaltrials.gov as #NCT01132807.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Enfermedad de Hodgkin , Tomografía Computarizada por Tomografía de Emisión de Positrones , Adolescente , Adulto , Bleomicina/administración & dosificación , Ciclofosfamida/administración & dosificación , Dacarbazina/administración & dosificación , Supervivencia sin Enfermedad , Doxorrubicina/administración & dosificación , Etopósido/administración & dosificación , Femenino , Estudios de Seguimiento , Enfermedad de Hodgkin/diagnóstico por imagen , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Prednisona/administración & dosificación , Procarbazina/administración & dosificación , Tasa de Supervivencia , Vinblastina/administración & dosificación , Vincristina/administración & dosificaciónRESUMEN
The previous edition of the consensus guidelines of the International Workshop on Chronic Lymphocytic Leukemia (iwCLL), published in 2008, has found broad acceptance by physicians and investigators caring for patients with CLL. Recent advances including the discovery of the genomic landscape of the disease, the development of genetic tests with prognostic relevance, and the detection of minimal residual disease (MRD), coupled with the increased availability of novel targeted agents with impressive efficacy, prompted an international panel to provide updated evidence- and expert opinion-based recommendations. These recommendations include a revised version of the iwCLL response criteria, an update on the use of MRD status for clinical evaluation, and recommendations regarding the assessment and prophylaxis of viral diseases during management of CLL.
Asunto(s)
Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/terapia , Ensayos Clínicos como Asunto , Manejo de la Enfermedad , Pruebas Genéticas/métodos , Humanos , Inmunofenotipificación/métodos , Cariotipificación/métodos , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/patología , Mutación , Estadificación de Neoplasias/métodos , Neoplasia Residual/diagnóstico , Neoplasia Residual/genética , Neoplasia Residual/patología , Neoplasia Residual/terapia , PronósticoRESUMEN
Immunochemotherapy followed by autologous transplant (ASCT) in CALGB/Alliance 59909 achieved a median progression-free survival (PFS) in mantle cell lymphoma (MCL) of 5 years, but late recurrences occurred. We evaluated tolerability and efficacy of adding post-transplant bortezomib consolidation (BC) or maintenance (BM) to this regimen in CALGB/Alliance 50403, a randomized phase II trial. Following augmented-dose R-CHOP/ methotrexate, high-dose cytarabine-based stem cell mobilization, cyclophosphamide/carmustine/etoposide (CBV) autotransplant, and rituximab, patients were randomized to BC (1.3 mg/m2 IV days 1, 4, 8, 11 of a 3-week cycle for four cycles) or BM (1.6 mg/m2 IV once weekly × 4 every 8 weeks for 18 months) beginning day 90. The primary endpoint was PFS, measured from randomization for each arm. Proliferation signature, Ki67, and postinduction minimal residual disease (MRD) in bone marrow were assessed. Of 151 patients enrolled; 118 (80%) underwent ASCT, and 102 (68%) were randomized. Both arms met the primary endpoint, with median PFS significantly greater than 4 years (P < .001). The 8-year PFS estimates in the BC and BM arms were 54.1% (95% CI 40.9%-71.5%) and 64.4% (95% 51.8%-79.0%), respectively. Progression-free survival was significantly longer for transplanted patients on 50403 compared with those on 59909. Both the PFS and OS were significantly better for those who were MRD-negative post-induction. The high risk proliferation signature was associated with adverse outcome. Both BM and BC were efficacious and tolerable, although toxicity was significant. The comparison between studies 50403 and 59909 with long-term follow up suggests a PFS benefit from the addition of BC or BM post- transplant.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Bortezomib/administración & dosificación , Quimioterapia de Consolidación , Linfoma de Células del Manto/terapia , Quimioterapia de Mantención , Rituximab/administración & dosificación , Adolescente , Adulto , Anciano , Autoinjertos , Bortezomib/efectos adversos , Carmustina/administración & dosificación , Ciclofosfamida/administración & dosificación , Etopósido/administración & dosificación , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
B-cell receptor signaling is important in the pathogenesis of non-Hodgkin lymphoma. The PI3K pathway is activated by B-cell receptor signaling. Recently, several PI3K inhibitors have been in development for the treatment of indolent non-Hodgkin lymphomas. Copanlisib is a PI3Kα and PI3Kδ inhibitor that has been approved for its use as third-line therapy in the treatment of relapsed or refractory follicular lymphoma. The two other PI3k inhibitors approved by the US FDA in this setting are idelalisib and duvelisib. In this review, we compare the efficacy and adverse event profile of these different PI3K inhibitors and discuss the advantages and challenges of using copanlisib along with a guide on managing routinely encountered adverse events in the clinics.
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Linfoma no Hodgkin/tratamiento farmacológico , Terapia Molecular Dirigida , Inhibidores de las Quinasa Fosfoinosítidos-3/uso terapéutico , Pirimidinas/uso terapéutico , Quinazolinas/uso terapéutico , Biomarcadores , Ensayos Clínicos como Asunto , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Humanos , Hiperglucemia/etiología , Hiperglucemia/terapia , Hipertensión/etiología , Hipertensión/terapia , Linfoma no Hodgkin/diagnóstico , Linfoma no Hodgkin/etiología , Linfoma no Hodgkin/mortalidad , Fosfatidilinositol 3-Quinasa/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Pronóstico , Pirimidinas/farmacología , Quinazolinas/farmacología , Transducción de Señal/efectos de los fármacos , Resultado del TratamientoRESUMEN
The treatment of chronic lymphocytic leukemia (CLL) has changed remarkably throughout the past decade, with patients achieving deeper and more durable responses. Importantly, this clinical activity has been found to translate to prolonged survival. With some treatments, these responses are now allowing patients to stop therapy after 1 or 2 years, a concept referred to as "fixed duration." However, not all patients experience these outcomes. How to determine which patients can safely stop treatment remains unclear. Minimal residual disease (MRD) is emerging as a prognostic biomarker. In CLL, undetectable MRD has been shown to correlate with prolonged progression-free survival and, in some cases, overall survival. The incorporation of MRD status into clinical decision-making is not yet widely done, primarily based on the lack of prospective clinical trial data. As the endpoint of MRD status becomes more common in clinical trials of CLL, the role in the clinical setting will become more clear. Furthermore, prognostic models will help to determine the utility of MRD as a surrogate endpoint in clinical studies. This monograph examines clinical trial data regarding the role of MRD in CLL, and provides recommendations on how to incorporate MRD assessment into clinical management.
Asunto(s)
Leucemia Linfocítica Crónica de Células B/diagnóstico , Neoplasia Residual/diagnóstico , Toma de Decisiones Clínicas , Ensayos Clínicos como Asunto , Manejo de la Enfermedad , Humanos , Leucemia Linfocítica Crónica de Células B/terapia , Neoplasia Residual/terapia , PronósticoRESUMEN
BACKGROUND: This multicenter, randomized phase 2 trial evaluated complete responses (CRs), efficacy, and safety with ofatumumab and bendamustine and with ofatumumab, bendamustine, and bortezomib in patients with untreated, high-risk follicular lymphoma (FL). METHODS: Patients with grade 1 to 3a FL and either a Follicular Lymphoma International Prognostic Index (FLIPI) score of 2 with 1 lymph node >6 cm or an FLIPI score of 3 to 5 were randomized to arm A (ofatumumab, bendamustine, and maintenance ofatumumab) or to arm B (ofatumumab, bendamustine, bortezomib, and maintenance ofatumumab and bortezomib). RESULTS: One hundred twenty-eight patients (66 in arm A and 62 in arm B) received treatment. The median age was 61 years, and 61% had disease >6 cm; 29% had an FLIPI score of 2, and 71% had an FLIPI score of 3 to 5. In arm A, 86% completed induction, and 64% completed maintenance. In arm B, 66% and 52% completed induction and maintenance, respectively. Dose modifications were required in 65% and 89% in arms A and B, respectively. Clinically significant grade 3 to 4 toxicities included neutropenia (A, 36%; B, 31%), nausea/vomiting (A, 0%; B, 8%), diarrhea (A, 5%; B, 11%), and sensory neuropathy (A, 0%; B, 5%). The estimated CR rates were 62% (95% confidence interval [CI], 50%-74%) and 60% (95% CI, 47%-72%) in arms A and B, respectively (P = .68). With a median follow-up of 3.3 years, the estimated 2-year progression-free survival (PFS) and overall survival (OS) rates were 80% and 97%, respectively, for arm A and 76% and 91%, respectively, for arm B. CONCLUSIONS: The CR rates, PFS, and OS were not improved with the addition of bortezomib to ofatumumab and bendamustine in patients with high-risk FL. Although grade 3 to 4 toxicities were similar, more patients treated with bortezomib required dose modifications and early discontinuation.
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Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Clorhidrato de Bendamustina/administración & dosificación , Bortezomib/administración & dosificación , Linfoma Folicular/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Clorhidrato de Bendamustina/efectos adversos , Bortezomib/efectos adversos , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Linfoma Folicular/mortalidad , Linfoma Folicular/patología , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Supervivencia sin Progresión , Inducción de Remisión/métodosRESUMEN
Rituximab monotherapy has proven efficacy in treatment-naïve, asymptomatic advanced-stage follicular lymphoma (FL). Ofatumumab is a fully humanized anti-CD20 monoclonal antibody with increased CD20 affinity and complement-dependent cytotoxicity. This phase 2 trial (NCT01190449) evaluated ofatumumab in patients with untreated, low/intermediate-risk FL International Prognostic Index (FLIPI), advanced-stage FL to determine single-agent efficacy. Patients with measurable disease in stages III/IV or bulky stage II, regardless of Groupe d'Etude des Lymphomes Folliculaires criteria, received 4 weekly 1000 mg doses followed by four extended induction doses once every 8 weeks. Primary endpoint was overall response rate (ORR) to 1000 mg; secondary endpoints were progression-free survival (PFS) and safety. Fifty-one patients were enrolled. Fifteen patients were randomized to 500 mg prior to discontinuing that arm for slow accrual. Among 36 patients on the 1000 mg arm, ORR was 84%, median PFS was 1·9 years and median response duration was 23·7 months. All patients remain alive. No grade 4 infusion reactions or grade 3/4 infections occurred. Grade 3 infusion reactions occurred in 25% in the 1000 mg arm only (all first infusion); all but two patients continued on study. Discontinuation was 6% for the total study population. Ofatumumab monotherapy administered by extended induction in untreated, low/intermediate-risk FLIPI, advanced-stage FL is well tolerated and active. Activity appears similar to that reported with single-agent rituximab.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Linfoma Folicular/tratamiento farmacológico , Adulto , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/efectos adversos , Biomarcadores , Femenino , Humanos , Linfoma Folicular/diagnóstico , Linfoma Folicular/mortalidad , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Resultado del TratamientoRESUMEN
The utility of positron emission tomography-computed tomography (PET-CT) in distinguishing Richter's transformation versus chronic lymphocytic leukemia (CLL) progression after ibrutinib and/or idelalisib was assessed in a post hoc analysis of a phase II study of venetoclax. Patients underwent PET-CT at screening and were not enrolled/treated if Richter's transformation was confirmed pathologically. Of 167 patients screened, 57 met criteria for biopsy after PET-CT. Of 35 patients who underwent biopsy, eight had Richter's transformation, two had another malignancy, and 25 had CLL. A PET-CT maximum standardized uptake value (SUVmax) ≥10 had 71% sensitivity and 50% specificity for detecting Richter's transformation [Odds Ratio (OR): 2.5, 95%CI: 0.4-15; P=0.318]. Response rate to venetoclax was similar for screening SUVmax <10 versus ≥10 (65% vs. 62%) (n=127 enrolled), though median progression-free survival was longer at <10 months (24.7 vs. 15.4 months; P=0.0335). Six patients developed Richter's transformation on venetoclax, of whom two had screening biopsy demonstrating CLL (others did not have a biopsy) and five had screening SUVmax <10. We have defined the test characteristics for PET-CT to distinguish progression of CLL as compared to Richter's transformation when biopsied in patients treated with B-cell receptor signaling pathway inhibitors. Overall diminished sensitivity and specificity as compared to prior reports of patients treated with chemotherapy/chemoimmunotherapy suggest it has diminished ability to discriminate these two diagnoses using a SUVmax ≥10 cutoff. This cutoff did not identify venetoclax-treated patients with an inferior response but may be predictive of inferior progression-free survival. (Registered at clinicaltrials.gov identifier: 02141282).
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Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/terapia , Terapia Molecular Dirigida , Tomografía Computarizada por Tomografía de Emisión de Positrones , Receptores de Antígenos de Linfocitos B/metabolismo , Transducción de Señal/efectos de los fármacos , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Progresión de la Enfermedad , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/etiología , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida/efectos adversos , Terapia Molecular Dirigida/métodos , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Therapy targeting Bruton's tyrosine kinase (BTK) with ibrutinib has transformed the treatment of chronic lymphocytic leukaemia. However, patients who are refractory to or relapse after ibrutinib therapy have poor outcomes. Venetoclax is a selective, orally bioavailable inhibitor of BCL-2 active in previously treated patients with relapsed or refractory chronic lymphocytic leukaemia. In this study, we assessed the activity and safety of venetoclax in patients with chronic lymphocytic leukaemia who are refractory to or relapse during or after ibrutinib therapy. METHODS: In this interim analysis of a multicentre, open-label, non-randomised, phase 2 trial, we enrolled patients aged 18 years or older with a documented diagnosis of chronic lymphocytic leukaemia according to the 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria and an Eastern Cooperative Oncology Group performance score of 2 or lower. All patients had relapsed or refractory disease after previous treatment with a BCR signalling pathway inhibitor. All patients were screened for Richter's transformation and cases confirmed by biopsy were excluded. Eligible patients received oral venetoclax, starting at 20 mg per day with stepwise dose ramp-up over 5 weeks to 400 mg per day. Patients with rapidly progressing disease received an accelerated dosing schedule (to 400 mg per day by week 3). The primary endpoint was overall response, defined as the proportion of patients with an overall response per investigator's assessment according to IWCLL criteria. All patients who received at least one dose of venetoclax were included in the activity and safety analyses. This study is ongoing; data for this interim analysis were collected per regulatory agencies' request as of June 30, 2017. This trial is registered with ClinicalTrials.gov, number NCT02141282. FINDINGS: Between September, 2014, and November, 2016, 127 previously treated patients with relapsed or refractory chronic lymphocytic leukaemia were enrolled from 15 sites across the USA. 91 patients had received ibrutinib as the last BCR inhibitor therapy before enrolment, 43 of whom were enrolled in the main cohort and 48 in the expansion cohort recruited later after a protocol amendment. At the time of analysis, the median follow-up was 14 months (IQR 8-18) for all 91 patients, 19 months (9-27) for the main cohort, and 12 months (8-15) for the expansion cohort. 59 (65%, 95% CI 53-74) of 91 patients had an overall response, including 30 (70%, 54-83) of 43 patients in the main cohort and 29 (60%, 43-72) of 48 patients in the expansion cohort. The most common treatment-emergent grade 3 or 4 adverse events were neutropenia (46 [51%] of 91 patients), thrombocytopenia (26 [29%]), anaemia (26 [29%]), decreased white blood cell count (17 [19%]), and decreased lymphocyte count (14 [15%]). 17 (19%) of 91 patients died, including seven because of disease progression. No treatment-related deaths occurred. INTERPRETATION: The results of this interim analysis show that venetoclax has durable clinical activity and favourable tolerability in patients with relapsed or refractory chronic lymphocytic leukaemia whose disease progressed during or after discontinutation of ibrutinib therapy. The durability of response to venetoclax will be assessed in the final analysis in 2019. FUNDING: AbbVie, Genentech.
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Antineoplásicos/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/administración & dosificación , Pirazoles/administración & dosificación , Pirimidinas/administración & dosificación , Sulfonamidas/administración & dosificación , Adenina/análogos & derivados , Administración Oral , Adulto , Agammaglobulinemia Tirosina Quinasa , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Compuestos Bicíclicos Heterocíclicos con Puentes/efectos adversos , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Esquema de Medicación , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/enzimología , Leucemia Linfocítica Crónica de Células B/mortalidad , Leucemia Linfocítica Crónica de Células B/patología , Masculino , Persona de Mediana Edad , Piperidinas , Inhibidores de Proteínas Quinasas/efectos adversos , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Pirazoles/efectos adversos , Pirimidinas/efectos adversos , Sulfonamidas/efectos adversos , Factores de Tiempo , Resultado del Tratamiento , Estados UnidosRESUMEN
With the increasing number of targeted agents for the treatment of patients with lymphoid malignancies comes the promise of safe and effective chemotherapy-free treatment strategies. A number of single agents, such as ibrutinib and idelalisib, have demonstrated impressive efficacy with a favorable toxicity profile. The observations that most responses are, however, partial and treatment duration is indefinite have stimulated interest in combinations of these agents with chemotherapy as well as with each other. Despite the promise of this approach, several recent trials of combinations of agents have been terminated as the result of life-threatening and fatal complications. Such outcomes have generated a cautionary note of the potential for unforeseen adverse effects that challenge drug development and mitigate against the empiric combination of such drugs outside of a clinical trial setting.
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Linfoma/tratamiento farmacológico , Purinas/uso terapéutico , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Quinazolinonas/uso terapéutico , Adenina/análogos & derivados , Ensayos Clínicos como Asunto , Diseño de Fármacos , Humanos , Linfoma/mortalidad , PiperidinasRESUMEN
Uniformly adopted response criteria are essential for assessment of therapies incorporating conventional chemotherapy and chemoimmunotherapy regimens. Recently, immunomodulatory agents, such as immune checkpoint inhibitors, have demonstrated impressive activity in a broad range of lymphoma histologies. However, these agents may be associated with clinical and imaging findings during treatment suggestive of progressive disease (PD) despite evidence of clinical benefit (eg, tumor flare or pseudo-progression). Considering this finding as PD could lead to patients being prematurely removed from a treatment from which they actually stand to benefit. This phenomenon has been well described with checkpoint blockade therapy in solid tumors and anecdotally seen in lymphoma as well. To address this issue in the context of lymphoma immunomodulatory therapy, a workshop was convened to provide provisional recommendations to modify current response criteria in patients receiving these and future agents in clinical trials. The term "indeterminate response" was introduced to identify such lesions until confirmed as flare/pseudo-progression or true PD by either biopsy or subsequent imaging.
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Factores Inmunológicos/uso terapéutico , Inmunoterapia/métodos , Linfoma/clasificación , Linfoma/terapia , HumanosRESUMEN
Chemoimmunotherapy in follicular lymphoma is associated with significant toxicity. Targeted therapies are being investigated as potentially more efficacious and tolerable alternatives for this multiply-relapsing disease. Based on promising activity with rituximab and lenalidomide in previously untreated follicular lymphoma (overall response rate [ORR] 90%-96%) and ibrutinib in relapsed disease (ORR 30%-55%), the Alliance for Clinical Trials in Oncology conducted a phase 1 trial of rituximab, lenalidomide, and ibrutinib. Previously untreated patients with follicular lymphoma received rituximab 375 mg/m2 on days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 4, 6, 8, and 10; lenalidomide as per cohort dose on days 1 to 21 of 28 for 18 cycles; and ibrutinib as per cohort dose daily until progression. Dose escalation used a 3+3 design from a starting dose level (DL) of lenalidomide 15 mg and ibrutinib 420 mg (DL0) to DL2 (lenalidomide 20 mg, ibrutinib 560 mg). Twenty-two patients were enrolled; DL2 was determined to be the recommended phase II dose. Although no protocol-defined dose-limiting toxicities were reported, a high incidence of rash was observed (all grades 82%, grade 3 36%). Eleven patients (50%) required dose reduction, 7 because of rash. The ORR for the entire cohort was 95%, and the 12-month progression-free survival was 80% (95% confidence interval, 57%-92%). Five patients developed new malignancies; 3 had known risk factors before enrollment. Given the increased toxicity and required dose modifications, as well as the apparent lack of additional clinical benefit to the rituximab-lenalidomide doublet, further investigation of the regimen in this setting seems unwarranted. The study was registered with www.ClinicalTrials.gov as #NCT01829568.