RESUMEN
Venetoclax-obinutuzumab (Ven-Obi) is a standard-of-care for patients with previously untreated chronic lymphocytic leukemia (CLL). In the CLL14 study, patients with previously untreated CLL and coexisting conditions were randomized to 12 cycles of Ven-Obi (n=216) or chlorambucil-obinutuzumab (Clb-Obi, n=216). Progression-free survival (PFS) was the primary endpoint. Key secondary endpoints included time-to-next-treatment (TTNT), rates of undetectable minimal residual disease (uMRD), overall survival (OS) and rates of adverse events. Patient reported outcomes (PROs) of time until definitive deterioration (TUDD) in quality of life (QoL) were analyzed. At a median observation time of 76.4 months, PFS remained superior for Ven-Obi compared to Clb-Obi (median 76.2 vs 36.4 months; HR 0.40[95%CI 0.31-0.52], p<0.0001). Likewise, TTNT was longer after Ven-Obi (6-year-TTNT 65.2% vs 37.1%; HR 0.44, 95%CI 0.33-0.58, p<0.0001). In the Ven-Obi arm, presence of del(17p), unmutated-IGHV and lymph node size ≥5 cm were independent prognostic factors for shorter PFS. Five years after treatment, 17 patients (7.9% of intention-to-treat-population) in the Ven-Obi arm had uMRD (<10-4 in peripheral blood) compared to 4 (1.9%) in the Clb-Obi arm. 6-year-OS rate was 78.7% in the Ven-Obi and 69.2% in the Clb-Obi arm (HR 0.69[95%CI 0.48-1.01], p=0.052). A significantly longer TUDD in global health status/QoL was observed in the Ven-Obi compared to the Clb-Obi arm (median 82.1 vs 65.1 months; HR 0.70[95%CI 0.51-0.97]). Follow-up adjusted SPM incidence rates were 2.3 and 1.4/1000 patient-months in the Ven-Obi and Clb-Obi arm, respectively. The sustained long-term survival, uMRD and QoL benefits support the use of one-year fixed-duration Ven-Obi in CLL. NCT02242942, EudraCT 2014-001810-24.
RESUMEN
T-prolymphocytic leukemia (T-PLL) is a mature T-cell neoplasm associated with marked chemotherapy resistance and continued poor clinical outcomes. Current treatments, i.e. the CD52-antibody alemtuzumab, offer transient responses, with relapses being almost inevitable without consolidating allogeneic transplantation. Recent more detailed concepts of T-PLL's pathobiology fostered the identification of actionable vulnerabilities: (i) altered epigenetics, (ii) defective DNA damage responses, (iii) aberrant cell-cycle regulation, and (iv) deregulated pro-survival pathways, including TCR and JAK/STAT signaling. To further develop related pre-clinical therapeutic concepts, we studied inhibitors of (H)DACs, BCL2, CDK, MDM2, and clas-sical cytostatics, utilizing (a) single-agent and combinatorial compound testing in 20 well-characterized and molecularly-profiled primary T-PLL (validated by additional 42 cases), and (b) 2 independent murine models (syngeneic transplants and patient-derived xenografts). Overall, the most efficient/selective single-agents and combinations (in vitro and in mice) in-cluded Cladribine, Romidepsin ((H)DAC), Venetoclax (BCL2), and/or Idasanutlin (MDM2). Cladribine sensitivity correlated with expression of its target RRM2. T-PLL cells revealed low overall apoptotic priming with heterogeneous dependencies on BCL2 proteins. In additional 38 T-cell leukemia/lymphoma lines, TP53 mutations were associated with resistance towards MDM2 inhibitors. P53 of T-PLL cells, predominantly in wild-type configuration, was amenable to MDM2 inhibition, which increased its MDM2-unbound fraction. This facilitated P53 activa-tion and down-stream signals (including enhanced accessibility of target-gene chromatin re-gions), in particular synergy with insults by Cladribine. Our data emphasize the therapeutic potential of pharmacologic strategies to reinstate P53-mediated apoptotic responses. The identified efficacies and their synergies provide an informative background on compound and patient selection for trial designs in T-PLL.
RESUMEN
During the past 5 years, rapid therapeutic advances have changed the landscape of chronic lymphocytic leukemia (CLL) therapy. This disease has traditionally been treated using cytotoxic chemotherapy regimens in combination with anti-CD20 antibody treatment, and recent long-term follow-up data from multiple centers suggest that fit patients with CLL with favorable disease features-particularly mutated immunoglobulin heavy chain variable region (IGHV) genes-derive very long-term benefit from the most potent of these regimens, namely the fludarabine, cyclophosphamide, and rituximab (FCR) regimen. The advent of oral targeted therapies, particularly ibrutinib and idelalisib, has provided generally well-tolerated and highly effective additional options that have come into widespread use in the relapsed setting. Additional agents are advancing in clinical development, with the BCL-2 inhibitor venetoclax likely to be approved by the U.S. Food and Drug Administration (FDA) in 2016. With the development of these novel therapies for patients with relapsed CLL, many unanswered questions remain, including the optimal sequence (first vs. second line), duration, discontinuation, and combination of these agents. In addition, recent publications show the emergence of a pattern of treatment resistance in certain subgroups of patients with del(17p) and complex karyotype that needs further study and improvement. Because the field of CLL management has become much more complex, we focus here on understanding the recent data and discuss many of the questions and controversies important for how we approach patients with CLL.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Inmunoterapia , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Terapia Molecular Dirigida , Proteínas Proto-Oncogénicas c-bcl-2/inmunología , Adenina/análogos & derivados , Anticuerpos Monoclonales/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Ciclofosfamida/uso terapéutico , Humanos , Leucemia Linfocítica Crónica de Células B/inmunología , Leucemia Linfocítica Crónica de Células B/patología , Piperidinas , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Purinas/uso terapéutico , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Quinazolinonas/uso terapéutico , Rituximab/uso terapéutico , Sulfonamidas/uso terapéutico , Vidarabina/análogos & derivados , Vidarabina/uso terapéuticoRESUMEN
PURPOSE: To determine the clinical significance of flow cytometric minimal residual disease (MRD) quantification in chronic lymphocytic leukemia (CLL) in addition to pretherapeutic risk factors and to compare the prognostic impact of MRD between the arms of the German CLL Study Group CLL8 trial. PATIENTS AND METHODS: MRD levels were prospectively quantified in 1,775 blood and bone marrow samples from 493 patients randomly assigned to receive fludarabine and cyclophosphamide (FC) or FC plus rituximab (FCR). Patients were categorized by MRD into low- (< 10(-4)), intermediate- (≥ 10(-4) to <10(-2)), and high-level (≥ 10(-2)) groups. RESULTS: Low MRD levels during and after therapy were associated with longer progression-free survival (PFS) and overall survival (OS; P < .0001). Median PFS is estimated at 68.7, 40.5, and 15.4 months for low, intermediate, and high MRD levels, respectively, when assessed 2 months after therapy. Compared with patients with low MRD, greater risks of disease progression were associated with intermediate and high MRD levels (hazard ratios, 2.49 and 14.7, respectively; both P < .0001). Median OS was 48.4 months in patients with high MRD and was not reached for lower MRD levels. MRD remained predictive for OS and PFS in multivariate analyses that included the most important pretherapeutic risk markers in CLL. PFS and OS did not differ between treatment arms within each MRD category. However, FCR induced low MRD levels more frequently than FC. CONCLUSION: MRD levels independently predict OS and PFS in CLL. Therefore, MRD quantification might serve as a surrogate marker to assess treatment efficacy in randomized trials before clinical end points can be evaluated.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/mortalidad , Neoplasia Residual/tratamiento farmacológico , Neoplasia Residual/mortalidad , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Ciclofosfamida/administración & dosificación , Progresión de la Enfermedad , Citometría de Flujo , Humanos , Neoplasia Residual/diagnóstico , Pronóstico , Estudios Prospectivos , Rituximab , Tasa de Supervivencia , Vidarabina/administración & dosificación , Vidarabina/análogos & derivadosRESUMEN
BACKGROUND: Currently the majority of cancer patients are considered ineligible for intensive care treatment and oncologists are struggling to get their patients admitted to intensive care units. Critical care and oncology are frequently two separate worlds that communicate rarely and thus do not share novel developments in their fields. However, cancer medicine is rapidly improving and cancer is eventually becoming a chronic disease. Oncology is therefore characterized by a growing number of older and medically unfit patients that receive numerous novel drug classes with unexpected side effects. DISCUSSION: All of these changes will generate more medically challenging patients in acute distress that need to be considered for intensive care. An intense exchange between intensivists, oncologists, psychologists and palliative care specialists is warranted to communicate the developments in each field in order to improve triage and patient treatment. Here, we argue that "critical care of cancer patients" needs to be recognized as a medical subspecialty and that there is an urgent need to develop it systematically. CONCLUSION: As prognosis of cancer improves, novel therapeutic concepts are being introduced and more and more older cancer patients receive full treatment the number of acutely ill patients is growing significantly. This development a major challenge to current concepts of intensive care and it needs to be redefined who of these patients should be treated, for how long and how intensively.
Asunto(s)
Cuidados Críticos/métodos , Oncología Médica/métodos , Neoplasias/terapia , Instituciones Oncológicas , Continuidad de la Atención al Paciente , Humanos , Unidades de Cuidados Intensivos , Relaciones Interprofesionales , Cuidados Paliativos/métodos , Admisión del Paciente , Psicología/métodos , Recursos HumanosRESUMEN
Allogeneic hematopoietic stem cell transplantation is an established treatment modality for malignant and nonmalignant hematologic diseases. Acute and chronic graft-versus-host diseases (GVHDs) are a major cause of morbidity and mortality after allogeneic stem cell transplantation. T cells have been identified as key players in the graft-versus-host reaction and, therefore, most established drugs used against GVHD target T cells. Despite our knowledge on the pathogenesis of the GVH reaction, success of established therapies for prevention and treatment of GHVD is unsatisfactory. Recently, animal and human studies demonstrated that B cells are involved in the immunopathophysiology of acute and chronic GVHD. Early phase clinical trials of B-cell depletion with rituximab have shown beneficial effects on both acute and chronic GVHD. This review summarizes the current experimental and clinical evidence for the involvement of B cells in the pathogenesis of acute and chronic GVHD and discusses the clinical implications for the management of patients undergoing allogeneic stem cell transplantation.
Asunto(s)
Linfocitos B/inmunología , Enfermedad Injerto contra Huésped/inmunología , Animales , Trasplante de Células Madre Hematopoyéticas/efectos adversos , HumanosRESUMEN
A high incidence of autologous graft-versus-host-disease (auto-GVHD) was observed after an alemtuzumab-containing conditioning regimen and autologous stem cell transplantation (auto-SCT) for chronic lymphocytic leukemia (CLL). Skin rash developed in almost all surviving patients (87%). In 7 patients (58%), a diagnosis of auto-GVHD was made (compared with 0% after TBI/Cy; P = .01). All patients with auto-GVHD required immunosuppression, and 3 of 7 were hospitalized because of GVHD. The median duration of GVHD was 517 days (range, 60-867 days). Auto-GVHD was associated with an abnormally high CD4/CD8 ratio because of severe depletion of CD8(+) T cells, pointing to a potential pathomechanism. High non-relapse-related mortality led to the discontinuation of the trial. Current results do not support the use of high-dose alemtuzumab combined with total body irradiation (TBI) and autologous stem cell transplantation (auto-SCT). However, the addition of alemtuzumab led to improved disease control at the molecular level. Longer follow-up will show whether the GVHD-like syndrome may contribute to prolonged minimal residual disease (MRD) negativity.
Asunto(s)
Enfermedad Injerto contra Huésped/etiología , Leucemia Linfocítica Crónica de Células B/terapia , Trasplante de Células Madre/efectos adversos , Adulto , Anciano , Alemtuzumab , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Anticuerpos Antineoplásicos/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Acondicionamiento Pretrasplante , Trasplante AutólogoRESUMEN
BACKGROUND AND OBJECTIVES: Although bendamustine has been used for more than 30 years in the treatment of lymphoma, little is known about the optimal dosing schedule in relapsed or refractory B-cell chronic lymphocytic leukemia (CLL). Various dose and treatment schedules have been used empirically, and several phase II studies have shown impressive efficacy. To determine the maximal tolerated dose, dose-limiting toxicity and the optimal therapeutic dose of bendamustine for further phase III clinical trials the GCLLSG designed a phase I/II study for pre-treated CLL patients. DESIGN AND METHODS: Sixteen patients (median age 67 years) with relapsed or refractory CLL were enrolled. All patients had been pre-treated with a median of three different regimens. Bendamustine was given at a starting dose of 100 mg/m2 on day 1 and 2, repeated every 3-4 weeks. RESULTS: Major toxicities were leukocytopenia (CTC grade 3+4) in 8/16 and infections (CTC grade 3+4) in 7/16 patients. Six patients had dose-limiting toxicity which led to dose de-escalation from 100 to 70 mg/m2 in three patients. The maximum tolerated dose was 70 mg/m2. According to NCI-WG criteria, 9/16 patients (56%) responded to therapy, seven to doses Asunto(s)
Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico
, Leucemia Linfocítica Crónica de Células B/prevención & control
, Compuestos de Mostaza Nitrogenada/uso terapéutico
, Anciano
, Anciano de 80 o más Años
, Clorhidrato de Bendamustina
, Relación Dosis-Respuesta a Droga
, Femenino
, Estudios de Seguimiento
, Alemania/epidemiología
, Humanos
, Leucemia Linfocítica Crónica de Células B/epidemiología
, Masculino
, Persona de Mediana Edad
, Recurrencia Local de Neoplasia/prevención & control
, Análisis de Supervivencia