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OBJECTIVES: To compare the capacity of ibrutinib (IB) and idelalisib-rituximab (IDELA-R) of prolonging overall survival (OS) as in CLL patients, previously treated with chemotherapy only. METHODS: A real-life cohort of 675 cases has been identified and investigated in the database of the groups participating in the study. RESULTS: At an unadjusted univariate analysis, a significant death risk reduction was observed favoring IB (IDELA-R vs IB HR = 0.5, 95% CI = 0.36-0.71) although with some limitations due to the non-randomized and retrospective nature of the study and to the lower number of patients in the IDELA-R group (112 cases) related to the current prescribing practice. To overcome the potential problem of confounding by indication, we adjusted the association between the type of therapy and mortality for all variables significantly associated with OS at Cox univariate analysis. Furthermore, those variables, differently distributed between the two study groups, were introduced into the multivariate Cox model to improve the effectiveness of the analysis. By introducing all these variables into the multiple Cox regression model, we confirmed the protective effect of IB vs IDELA-R (HR = 0.67, 95% CI = 0.45-0.98, P = .04) independent of potential confounders. CONCLUSIONS: Although our analysis presents some constraints, that is, the unavailability of additional potential confounders, and the retrospective nature of the study, this observation may be of help for the daily clinical practice, particularly in the absence of randomized trials comparing the two schedules.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Adenina/administración & dosificación , Adenina/análogos & derivados , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores de Tumor , Resistencia a Antineoplásicos , Femenino , Humanos , Inmunoglobulinas/genética , Hibridación Fluorescente in Situ , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/etiología , Leucemia Linfocítica Crónica de Células B/mortalidad , Masculino , Persona de Mediana Edad , Mutación , Piperidinas/administración & dosificación , Modelos de Riesgos Proporcionales , Purinas/administración & dosificación , Quinazolinonas/administración & dosificación , Recurrencia , Retratamiento , Rituximab/administración & dosificación , Resultado del TratamientoAsunto(s)
Adenina/análogos & derivados , Clorhidrato de Bendamustina/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Piperidinas/uso terapéutico , Rituximab/uso terapéutico , Adenina/farmacología , Adenina/uso terapéutico , Anciano , Clorhidrato de Bendamustina/farmacología , Humanos , Piperidinas/farmacología , Supervivencia sin Progresión , Rituximab/farmacologíaAsunto(s)
Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/terapia , Proteína p53 Supresora de Tumor/genética , Deleción Cromosómica , Cromosomas Humanos Par 17 , Humanos , Terapia Molecular Dirigida , Mutación , Pronóstico , Estudios Retrospectivos , Factores de RiesgoRESUMEN
BACKGROUND: Chronic myelogenous leukemia (CML) is a chronic myeloproliferative disease characterized by a massive overproduction of myeloid cells. It is associated with the Philadelphia chromosome [Ph1, t (9; 22) (q34; q11)] or BCR-ABL fusion gene. CML usually undergoes a triphasic clinical course ending in a blast crisis, an accelerated phase of blasts and promyelocyte production. Ten percent of CML patients reach the blast crisis phase, with 20-30% of leukemias belonging to B-cell lymphoid lineage. However, a transformation of CML into T-cell acute lymphoblastic leukemia (T-ALL) is rare. CASE PRESENTATION: We present a 56-year-old male patient, known case of hypertension and Ph1 CML of eight years with a family history of Gaucher disease who developed T-ALL. The patient presented with lymphadenopathy and severe anemia, needing packed RBC transfusion, neutropenia and thrombocytopenia at the admission. However, the monocytes and basophils percentage were high. The patient underwent a cervical lymph node core biopsy, and the immunohistochemistry stains showed an invasion of neoplastic cells positive for CD3, CD5, BCL2, CD34, TdT and focally positive for C-Kit and negative for CD20, CD56 and pan-CK. These histopathology features were consistent with T-cell acute lymphoblastic leukemia (T-ALL). CONCLUSION: Blast crisis remain a challenge in CML management. It's of great importance to do a full proper workup including lymph nodes biopsies. The aim is to reverse blast crisis and restore the chronic phase.
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BACKGROUND: Transverse myelitis is a rare spinal cord inflammation with absence of a compression. It varies in presentation based on the pathology location, and mainly causes a combined deficit of motor, sensory, and autonomic functions. History, physical examination, and other diagnostic tests including blood tests and an MRI are important tools to establish a diagnosis.A thorough neurological evaluation helps localize the affected region of the spinal cord. The management includes rehabilitation as any other spinal cord injury. If very severe, a multidisciplinary rehabilitation program will be required. PRESENTATION: We explain a case in which a 43-year-old male patient, known to have chronic myelogenous leukemia (CML), on Imatinib (a tyrosine kinase inhibitor), started complaining of back pain at the level of the 10th rib. Different tests were made including a PET-CT (Positron Emission Tomography-Computed Tomography) which showed hypermetabolic bony lytic lesion in the left mandible at the level of temporomandibular joint, destruction of the 10th rib, and no evidence of spinal cord compression. Other etiologies were excluded, making transverse myelitis due to radiation for the patient's CML on top of the differential diagnosis. CONCLUSION: A thorough physical examination and diagnostic tests are important tools to exclude other etiologies of complex neurological deficit in a patient with CML.
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Despite recent therapeutic advances, multiple myeloma (MM) patients experience relapses as they become resistant to various classes and combinations of treatment. Melphalan (L-PAM) is an ageless drug. However, its use in the autologous stem cell transplantation (ASCT) setting and the innovative quadruplet regimen as well as daratumumab, bortezomib, and prednisone make this old drug current yet. Melflufen is a peptide-conjugated alkylator belonging to a novel class of compounds, representing an overcoming of L-PAM in terms of mechanism of action and effectiveness. The improved melflufen cytotoxicity is related to aminopeptidase activity, notably present in normal and neoplastic cells and remarkably heavily overexpressed in MM cells. Upon entering a cell, melflufen is cleaved by aminopeptidases, ultimately releasing the L-PAM payload and eliciting further the inflow and cleavage of the conjugated peptide. This virtuous loop persists until all extracellular melflufen has been utilized. The aminopeptidase-driven accumulation results in a 50-fold increase in L-PAM cell enrichment as compared with free alkylator. This condition produces selective cytotoxicity, increased on-target cell potency, and decreased off-target cell toxicity, ultimately overcoming resistance pathways triggered by previous treatments, including alkylators. Due to its distinct mechanism of action, melflufen plus dexamethasone as a doublet, and in combination with other novel drugs, has the potential to be beneficial for a broad range of patients with relapsed/refractory (RR) MM in third- or even in second-line therapy. The safety profile of melflufen has been consistent across studies, and no new safety concerns have been identified when melflufen was administered in doublet and triplet combinations. Based on growing clinical evidence, melflufen could be not only a good addition in the fight against RRMM but also a drug with a very favorable tolerability profile.
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Antineoplásicos Alquilantes/administración & dosificación , Melfalán/análogos & derivados , Mieloma Múltiple/tratamiento farmacológico , Fenilalanina/análogos & derivados , Antineoplásicos Alquilantes/efectos adversos , Antineoplásicos Alquilantes/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Resistencia a Antineoplásicos , Humanos , Melfalán/administración & dosificación , Melfalán/efectos adversos , Melfalán/farmacología , Mieloma Múltiple/patología , Fenilalanina/administración & dosificación , Fenilalanina/efectos adversos , Fenilalanina/farmacologíaRESUMEN
Introduction: Regimens involving intensive immuno-chemotherapy, followed by high-dose therapy and autologous stem cell transplant represent the standard treatment for younger fit patients with mantle cell lymphoma (MCL). Targeted approaches (i.e. ibrutinib, bortezomib, and lenalidomide) represent the backbone of therapy for relapsed cases.Areas covered: Acalabrutinib is a novel small molecule with a butynamide moiety specifically designed to irreversibly inhibit Bruton tyrosine kinase (BTK), which is more potent and selective than ibrutinib. Relevant publications have been identified through literature searches using the terms 'mantle cell lymphoma' and 'acalabrutinib'.Expert opinion: Acalabrutinib has been approved for the treatment of relapsed/refractory (RR) MCL patients. To date, clinical trials have reported some adverse effects such as cardiac toxicity or atrial fibrillation. Acalabrutinib in combination with other drugs, either in chemo-containing or chemo-free schedules, represent a valid option for MCL. However, none of the treatment schedules containing BTK inhibitors have been shown to be curative in MCL. Acalabrutinib may ultimately represent an option for patients who are 'fit' and exhibit well-controlled disease, which often characterizes only a limited 'niche' among MCL patients.
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Antineoplásicos/uso terapéutico , Benzamidas/administración & dosificación , Linfoma de Células del Manto/tratamiento farmacológico , Pirazinas/administración & dosificación , Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Humanos , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
INTRODUCTION: Patients with TP53 dysfunction, assessed by del(17p) or TP53 mutations, respond poorly to chemo-immunotherapy and fare better with the new therapies (BCR and BCL-2 inhibitors); however, it is unclear whether their response is similar to that of patients without anomalies or whether there is currently an adequate determination of TP53 dysfunction. AREA COVERED: A literature search was undertaken on clinical trials and real-world experience data on patients with TP53 dysfunction treated with different protocols. Moreover, data on the TP53 biological function and on the tests currently employed for its assessment were reviewed. EXPERT OPINION: Although TP53 dysfunction has less negative influence on the new biological therapies, patients with these alterations, particularly those with biallelic inactivation of TP53, have a worst outcome with these therapies than those without alterations. At present, a determination of TP53, particularly with next generation sequencing (NGS) methodologies, may be sufficient for the identifications of the patients unsuitable for chemo-immunotherapy, although integration with del(17p) would be advisable. For the future, more extensive determinations of the TP53 status, including functional assays, may become part of the current armamentarium for a better patient stratification and treatment with newer protocols.