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1.
Int J Infect Dis ; 103: 507-513, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33333254

RESUMEN

OBJECTIVES: The aim was to evaluate the safety and effectiveness of thalidomide, an immunomodulatory agent, in combination with glucocorticoid, for the treatment of COVID-19 patients with life-threatening symptoms. METHODS: A nonrandomized comparative case series study was performed. Six patients received thalidomide 100 mg per day (with therapy lasting for ≥7 days) plus low-dose short-term dexamethasone, and 6 control patients matched with patients in the thalidomide group, received low-dose short-term treatment with dexamethasone alone. The main outcomes were: the duration of SARS-CoV-2 negative conversion from admission; length of hospital stay; and changes in inflammatory cytokine concentrations and lymphocyte subsets. RESULTS: The median thalidomide treatment time was 12.0 days. The median duration of SARS-CoV-2 negative conversion from admission and hospital stay length were briefer in the thalidomide group compared to the control group (respectively, 11.0 vs 23.0 days, P = 0.043; 18.5 vs 30.0 days, P = 0.043). The mean reduction rates at 7-10 days after treatment for serum interleukin-6 and interferon-γ concentrations were greater in the thalidomide group compared to the control group. Alterations in lymphocyte numbers in the subsets between the 2 groups were similar. CONCLUSIONS: Thalidomide plus short-term glucocorticoid therapy is an effective and safe regimen for the treatment of severely ill COVID-19 patients. The mechanism of action is most likely inhibition of inflammatory cytokine production.


Asunto(s)
/tratamiento farmacológico , Dexametasona/administración & dosificación , Talidomida/administración & dosificación , Anciano , Anciano de 80 o más Años , Quimioterapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad
2.
N Z Med J ; 133(1527): 104-110, 2020 12 18.
Artículo en Inglés | MEDLINE | ID: mdl-33332332

RESUMEN

Multiple myeloma is the second most common blood cancer in New Zealand with higher incidence in Maori and Pacific Island populations. It remains an incurable disease but the rapidly changing treatment landscape has led to improved outcome. In response to recent changes in funding of anti-myeloma therapy in New Zealand, the New Zealand Myeloma Interest Group has reviewed the latest literature and updated the treatment pathway of transplant-eligible patients with newly diagnosed multiple myeloma.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Médula Ósea , Quimioterapia de Consolidación , Quimioterapia de Inducción , Quimioterapia de Mantención , Mieloma Múltiple/terapia , Trasplante de Médula Ósea/métodos , Bortezomib/administración & dosificación , Consenso , Quimioterapia de Consolidación/métodos , Ciclofosfamida/administración & dosificación , Dexametasona/administración & dosificación , Quimioterapia de Inducción/métodos , Lenalidomida , Nueva Zelanda , Guías de Práctica Clínica como Asunto , Talidomida/administración & dosificación
3.
Ann Hematol ; 99(11): 2589-2598, 2020 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-32892275

RESUMEN

The induction therapy containing ixazomib, an oral proteasome inhibitor, has shown favorable efficacy and safety in clinical trials, but its experience in real-life remains limited. In routine practice, few patients received ixazomib-based induction therapy due to reasons including (1) patients' preference on oral regimens, (2) concerns on adverse events (AEs) of other intravenous/subcutaneous regimens, (3) requirements for less center visits, and (4) fears of COVID-19 and other infectious disease exposures. With the aim of assessing the real-life effectiveness and safety of ixazomib-based induction therapy, we performed this multi-center, observational study on 85 newly diagnosed multiple myeloma (NDMM) patients from 14 medical centers. Ixazomib-based regimens included ixazomib-lenalidomide-dexamethasone (IRd) in 44.7% of patients, ixazomib-dexamethasone (Id) in 29.4%, and Id plus another agent (doxorubicin, cyclophosphamide, thalidomide, or daratumumab) in 25.9%. Different ixazomib-based therapies were applied due to (1) financial burdens or limitations on local health insurance coverage, (2) concerns on treatment tolerance, and (3) drug accessibility issue. Ten patients received ixazomib maintenance. The median age was 67 years; 43.5% had ISS stage III disease; 48.2% had an Eastern Cooperative Oncology Group performance score ≥ 2; and 17.6% with high-risk cytogenetic abnormalities. Overall response rate for all 85 patients was 95.3%, including 65.9% very good partial response or better and 29.5% complete responses. The median time to response was 30 days. The response rate was similar across different ixazomib-based regimens. Median progression-free survival was not reached. Severe AEs (≥ grade 3) were reported in 29.4% of patients. No grade 3/4 peripheral neuropathy (PN) occurred. Patients received a median of 6 (range 1-20) cycles of ixazomib treatment; 56.6% remained on treatment at data cutoff; 15.3% discontinued treatment due to intolerable AEs. These results support that the ixazomib-based frontline therapy was highly effective with acceptable toxicity in routine practice and the ixazomib oral regimens could be good alternative options for NDMM patients.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Compuestos de Boro/administración & dosificación , Glicina/análogos & derivados , Mieloma Múltiple/tratamiento farmacológico , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Adolescente , Adulto , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Compuestos de Boro/efectos adversos , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Dexametasona/administración & dosificación , Dexametasona/efectos adversos , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Esquema de Medicación , Femenino , Glicina/administración & dosificación , Glicina/efectos adversos , Humanos , Lenalidomida/administración & dosificación , Lenalidomida/efectos adversos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/mortalidad , Mieloma Múltiple/patología , Estadificación de Neoplasias , Enfermedades del Sistema Nervioso Periférico/diagnóstico , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Inducción de Remisión , Análisis de Supervivencia , Talidomida/administración & dosificación , Talidomida/efectos adversos , Resultado del Tratamiento
4.
Eur J Haematol ; 105(6): 751-754, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-32745304

RESUMEN

COVID-19 has emerged as a global pandemic. Cancer patients have been reported to be at higher risk for adverse outcome of COVID-19. Studies are ongoing to decipher the risk factors and risk groups among cancer patients as well as strategies to refine treatment approaches. Here, we report eight patients with multiple myeloma that underwent immunomodulatory therapies with daratumumab or lenalidomide-based combination treatments and one patient with smoldering multiple myeloma, all of which presented with symptomatic COVID-19. We report that patients that succumbed to COVID-19 presented with either progressive tumor disease under daratumumab treatment or were in remission under lenalidomide-dexamethasone treatment.


Asunto(s)
Anticuerpos Monoclonales/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Infecciones por Coronavirus/diagnóstico , Dexametasona/efectos adversos , Lenalidomida/efectos adversos , Mieloma Múltiple/diagnóstico , Neumonía Viral/diagnóstico , Talidomida/efectos adversos , Anticuerpos Monoclonales/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Betacoronavirus/patogenicidad , Estudios de Cohortes , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/mortalidad , Dexametasona/administración & dosificación , Progresión de la Enfermedad , Femenino , Humanos , Inmunomodulación , Lenalidomida/administración & dosificación , Masculino , Persona de Mediana Edad , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/inmunología , Mieloma Múltiple/mortalidad , Pandemias , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/inmunología , Neumonía Viral/mortalidad , Pronóstico , Inducción de Remisión , Índice de Severidad de la Enfermedad , Análisis de Supervivencia , Talidomida/administración & dosificación , Resultado del Tratamiento
5.
Drugs Aging ; 37(9): 657-663, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32696432

RESUMEN

INTRODUCTION: Apremilast is a drug recently developed for psoriasis. Few data are available on its use in the elderly. We evaluated the tolerance and effectiveness of apremilast used in daily practice for psoriasis treatment in older patients. METHODS: We performed a multicenter, retrospective study involving patients aged ≥ 65 years who had received apremilast as a psoriasis treatment. Demographic data and details regarding psoriasis and adverse events (AEs) were collected from patient medical records. RESULTS: 135 patients were included (mean age: 73.5 years). Treatment was stopped in 74 patients (54.8%) for AEs (n = 43, 56.6%), primary failures (n = 18, 23.4%), and relapses (n = 7, 9.2%). When patients were stratified by age at treatment initiation, the main cause of discontinuation in patients ≥ 75 years was AEs, whereas in patients aged 65-74 years it was primary failures (28.3%). Sixty-one patients reported AEs, mainly digestive (n = 49). Regarding effectiveness, 45.2% of patients reached PGA 0/1 between 3 and 6 months after treatment initiation. One-year apremilast continuation rates were better in the 65-74 and 75-84 years subgroups than in the > 85 years subgroup (p = 0.01). CONCLUSION: Apremilast seems to be an effective and safe therapeutic option for psoriasis in the elderly. The main AEs reported by patients did not seem to differ from those reported previously in younger populations. However, AEs were more frequent in patients > 75 years old leading to more frequent discontinuation of apremilast compared with younger patients, suggesting a higher level of vigilance is needed in the elderly.


Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Inhibidores de Fosfodiesterasa 4/uso terapéutico , Psoriasis/tratamiento farmacológico , Talidomida/análogos & derivados , Administración Oral , Factores de Edad , Anciano , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/efectos adversos , Femenino , Humanos , Masculino , Registros Médicos , Persona de Mediana Edad , Inhibidores de Fosfodiesterasa 4/administración & dosificación , Inhibidores de Fosfodiesterasa 4/efectos adversos , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Talidomida/administración & dosificación , Talidomida/efectos adversos , Talidomida/uso terapéutico , Resultado del Tratamiento
6.
Scott Med J ; 65(3): 72-75, 2020 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-32638647

RESUMEN

Cytokine storm is a life-threatening complication of Covid-19 infection. Excessive cytokines are the products of hyperactive immune inflammatory response mounted by the host against the virus. There is no agreed treatment for cytokine storm. Three therapeutic agents with proven immune-modulatory properties in regular use in a wide range of inflammatory disorders (high dose intravenous immunoglobulin, Rituximab and thalidomide) are proposed for the treatment of cytokine storm. Safety and efficacy of the proposed treatment should be assessed by randomised controlled clinical trials. The use of the proposed treatment is expected to reduce the mortality rate and alter the overall management of the pandemic.


Asunto(s)
Betacoronavirus , Infecciones por Coronavirus/tratamiento farmacológico , Inmunoglobulinas Intravenosas/uso terapéutico , Factores Inmunológicos/uso terapéutico , Neumonía Viral/tratamiento farmacológico , Rituximab/uso terapéutico , Talidomida/uso terapéutico , Administración Intravenosa , Infecciones por Coronavirus/complicaciones , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Síndrome de Liberación de Citoquinas/etiología , Quimioterapia Combinada/métodos , Humanos , Inmunoglobulinas Intravenosas/administración & dosificación , Factores Inmunológicos/administración & dosificación , Pandemias , Neumonía Viral/complicaciones , Rituximab/administración & dosificación , Talidomida/administración & dosificación
7.
Medicine (Baltimore) ; 99(21): e20221, 2020 May 22.
Artículo en Inglés | MEDLINE | ID: mdl-32481292

RESUMEN

RATIONALE: Behcets disease (BD) is a type of chronic systemic vasculitis that typically manifests as a mucocutaneous disease with orogenital ulcers, skin damage, and uveitis. The clinical diagnosis is often difficult because of the diversity of organs that may be involved and lack of specific pathological diagnosis. PATIENT CONCERNS: A 26-year-old woman presented as a nearly 2-week history of hoarseness with throat pain. DIAGNOSES: In the present case, Fiber laryngoscopy showed multiple ulcers involving the epiglottic tubercle, bilateral false vocal cord, middle area of the left vocal cord, and full length of the right vocal cord. Multidisciplinary physicians combined the patients clinical manifestations and pathological findings to make the Behcets disease diagnosis. INTERVENTIONS: As the diagnosis confirmed, immediately began appropriate medical therapy (prednisolone at 30 mg once per day and thalidomide at 50 mg once per night in a month). OUTCOMES: The ulcer on the right vocal cord disappeared but left a scar. Therefore, the patient experienced only partial recovery from the hoarseness. LESSONS: Behcets disease can cause damage to multiple organs. Although the combination of vocal cord ulcers and hoarseness is rare in patients with BD and has not been previously reported to date, such patients should be treated with caution in clinical practice.


Asunto(s)
Síndrome de Behçet/complicaciones , Ronquera/etiología , Faringitis/etiología , Pliegues Vocales/patología , Adulto , Síndrome de Behçet/diagnóstico por imagen , Síndrome de Behçet/tratamiento farmacológico , Quimioterapia Combinada/métodos , Femenino , Glucocorticoides/administración & dosificación , Glucocorticoides/uso terapéutico , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/uso terapéutico , Laringoscopía/métodos , Faringitis/diagnóstico , Prednisolona/administración & dosificación , Prednisolona/uso terapéutico , Talidomida/administración & dosificación , Talidomida/uso terapéutico , Resultado del Tratamiento , Pliegues Vocales/diagnóstico por imagen
8.
Cancer Sci ; 111(6): 2116-2122, 2020 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-32297407

RESUMEN

In the phase 3 OPTIMISMM trial, pomalidomide, bortezomib and dexamethasone (PVd) significantly improved the progression-free survival (PFS) and the overall response rate (ORR) vs bortezomib and dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma. All patients were previously treated with lenalidomide (70% refractory to lenalidomide) and had received one to three prior regimens. Here we report the first efficacy and safety analysis of PVd vs Vd in Japanese patients with relapsed or refractory multiple myeloma. Seventeen patients enrolled in the OPTIMISMM trial in Japan. With a median follow-up of 14.8 months, the median PFS was 17.6 months with PVd (n = 12) vs 4.4 months with Vd (n = 5), and the ORR was 100% vs 60.0%, respectively. The safety profile was as expected for PVd. Toxicities were managed with dose reductions and interruptions, and no patients discontinued PVd due to treatment-emergent adverse events. These results are consistent with those in the overall OPTIMISMM patient population and confirm the clinical benefit of PVd in Japanese patients.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Bortezomib/administración & dosificación , Dexametasona/administración & dosificación , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Humanos , Japón , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Supervivencia sin Progresión , Talidomida/administración & dosificación , Talidomida/análogos & derivados , Resultado del Tratamiento
9.
Hematol Oncol ; 38(3): 363-371, 2020 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-32196120

RESUMEN

Data about treatment outcomes and toxicity in Latin America are scarce. There are differences with central countries based on access to healthcare system and socioeconomic status. Argentinean Society of Hematology recommends bortezomib-based triplets for induction treatment of transplant eligible newly diagnosed multiple myeloma patients. Most common options are CyBorD (cyclophosphamide, bortezomib and dexamethasone) and VTD (bortezomib, thalidomide and dexamethasone). Main goal of our retrospective, multicentric study was to compare very good partial response rate (VGPR) or better after induction treatment in a real-world setting in Argentina. Secondary objectives included comparison of complete response (CR) post-induction and after bone marrow transplantation, grade 3-4 adverse events (AEs), progression-free survival (PFS) and overall survival (OS). Three hundred twenty-two patients were included (median age at diagnosis: 57 years; 52% male; 28% had ISS3; 14% with high-risk cytogenetics; median follow up: 34 months). CyBorD was indicated in 74% and 26% received VTD. In VTD arm, 72.62% of patients achieved at least VGPR vs 53.36% receiving CyBorD (odds ratio, OR: 1.96 [95% confidence interval, CI: 1.08-3.57; P = .026] after adjusting by age, ISS [International Staging System], lactate dehydrogenase levels (LDH) and cytogenetic risk. Difference in VGPR was 19.26% (95% CI: 15-24). CR rate were 35.92% (VTD) vs 22.55% (CyBorD) (adjusted OR: 2.13 [95% CI: 1.12-4.05]). Difference in CR was 13.37% (95% CI: 9.6-17.53). Adverse events (AEs) were more common with VTD (69.05% vs 55.46% for CyBorD; P = .030), especially grade 3-4 neuropathy (P = .005) and thrombosis (P = .001). Thromboprophylaxis was inadequate in 20.24% of patients. Hematological AEs were more common with CyBorD, especially thrombocytopenia (P = .017). PFS and OS at 24 months were not different between treatments. In this real-world setting, VTD was associated with better CR and VGPR than CyBorD. Nevertheless, CyBorD continues to be the preferred induction regimen in Argentina, based on safety profile. Frontline autologous stem cell transplantation improves quality of responses, especially in countries with limited access to new drugs.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioterapia de Inducción/mortalidad , Mieloma Múltiple/mortalidad , Anciano , Bortezomib/administración & dosificación , Ciclofosfamida/administración & dosificación , Dexametasona/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/patología , Pronóstico , Inducción de Remisión , Estudios Retrospectivos , Tasa de Supervivencia , Talidomida/administración & dosificación
10.
Intern Med ; 59(9): 1149-1153, 2020 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-32009091

RESUMEN

Objective A randomized controlled trial has shown the efficacy of thalidomide against polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome; however, there are still refractory patients. We studied the effects of lenalidomide, a derivative of thalidomide, on patients refractory to thalidomide. Methods This prospective single-arm trial evaluated the safety and efficacy of lenalidomide plus dexamethasone in refractory or recurrent patients with POEMS syndrome. The regimen was administered as six 28-day cycles with lenalidomide on days 1-21 (15 mg in cycle 1, and 25 mg in cycle 2-6) plus dexamethasone once a week (20 mg). The primary endpoints were the rate of reduction in the serum vascular endothelial growth factor (VEGF) level at 24 weeks and the incidence of adverse events. This trial was registered with ClinicalTrial.gov, NCT02193698. Results Between July 2014 and December 2015, five men were enrolled. All patients had been refractory to thalidomide plus dexamethasone for more than 24 weeks. The mean rate of reduction in the serum VEGF level at 24 weeks was 59.6%±8.3% (p=0.0003). The mean serum VEGF level decreased from 2,466±771 pg/mL to 974±340 pg/mL. No serious adverse events were observed, and all patients completed six cycles treatment. Discussion Lenalidomide is a therapeutic option for thalidomide-refractory patients with POEMS syndrome.


Asunto(s)
Lenalidomida/uso terapéutico , Síndrome POEMS/tratamiento farmacológico , Dexametasona/administración & dosificación , Dexametasona/uso terapéutico , Quimioterapia Combinada , Femenino , Humanos , Factores Inmunológicos , Lenalidomida/administración & dosificación , Masculino , Persona de Mediana Edad , Síndrome POEMS/sangre , Estudios Prospectivos , Talidomida/administración & dosificación , Talidomida/uso terapéutico , Resultado del Tratamiento , Factor A de Crecimiento Endotelial Vascular/sangre , Adulto Joven
11.
Leukemia ; 34(7): 1853-1865, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32034285

RESUMEN

The MM5 trial aimed at demonstrating a progression-free survival (PFS) difference in continued vs. response-adapted (in case of complete response, CR) lenalidomide (LEN) maintenance therapy (MT) in newly diagnosed, transplant-eligible multiple myeloma (MM). Patients were equally randomized to receive induction therapy with PAd (bortezomib/doxorubicin/dexamethasone) or VCD (bortezomib/cyclophosphamide/dexamethasone), high-dose melphalan and autologous blood stem cell transplantation, and LEN consolidation, followed by either LEN MT for a fixed duration of 2 years (LEN-2Y) or until achievement of CR (LEN-CR, intention-to-treat population n = 502): arms A1:PAd + LEN-2Y (n = 125), B1:PAd + LEN-CR (n = 126), A2:VCD + LEN-2Y (n = 126), B2:VCD + LEN-CR (n = 125). In the LEN-CR group (B1 + B2), n = 88/17.5% patients did not start or discontinued LEN MT due to CR. There was no PFS (p = 0.60, primary endpoint) nor overall survival (OS) (p = 0.15) difference between the four study arms. On pooled LEN MT strategies, OS (hazard ratio, hazard ratio [HR] = 1.42, p = 0.03) but not PFS (HR = 1.15, p = 0.20) was shorter in LEN-CR (B1 + B2) vs. LEN-2Y (A1 + A2) groups. PFS was shortened on landmark analyses from the start of LEN MT in patients being in CR in the LEN-CR group (LEN-CR vs. LEN-2Y, HR = 1.84, p = 0.02). OS from first progression was shortened in the LEN-CR vs. LEN-2Y group (HR = 1.60, p = 0.01). LEN MT should be applied beyond CR for at least 2 years.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioterapia de Consolidación/mortalidad , Trasplante de Células Madre Hematopoyéticas/mortalidad , Quimioterapia de Mantención/mortalidad , Mieloma Múltiple/terapia , Anciano , Bortezomib/administración & dosificación , Terapia Combinada , Ciclofosfamida/administración & dosificación , Dexametasona/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Lenalidomida/administración & dosificación , Masculino , Melfalán/administración & dosificación , Mieloma Múltiple/patología , Pronóstico , Estudios Prospectivos , Inducción de Remisión , Tasa de Supervivencia , Talidomida/administración & dosificación , Trasplante Autólogo
12.
Leukemia ; 34(7): 1875-1884, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32001798

RESUMEN

In POLLUX, daratumumab (D) plus lenalidomide/dexamethasone (Rd) reduced the risk of disease progression or death by 63% and increased the overall response rate (ORR) versus Rd in relapsed/refractory multiple myeloma (RRMM). Updated efficacy and safety after >3 years of follow-up are presented. Patients (N = 569) with ≥1 prior line received Rd (lenalidomide, 25 mg, on Days 1-21 of each 28-day cycle; dexamethasone, 40 mg, weekly) ± daratumumab at the approved dosing schedule. Minimal residual disease (MRD) was assessed by next-generation sequencing. After 44.3 months median follow-up, D-Rd prolonged progression-free survival (PFS) in the intent-to-treat population (median 44.5 vs 17.5 months; HR, 0.44; 95% CI, 0.35-0.55; P < 0.0001) and in patient subgroups. D-Rd demonstrated higher ORR (92.9 vs 76.4%; P < 0.0001) and deeper responses, including complete response or better (56.6 vs 23.2%; P < 0.0001) and MRD negativity (10-5; 30.4 vs 5.3%; P < 0.0001). Median time to next therapy was prolonged with D-Rd (50.6 vs 23.1 months; HR, 0.39; 95% CI, 0.31-0.50; P < 0.0001). Median PFS on subsequent line of therapy (PFS2) was not reached with D-Rd versus 31.7 months with Rd (HR, 0.53; 95% CI, 0.42-0.68; P < 0.0001). No new safety concerns were reported. These data support using D-Rd in patients with RRMM after first relapse.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Mieloma Múltiple/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Terapia Recuperativa , Anciano , Anticuerpos Monoclonales/administración & dosificación , Dexametasona/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Lenalidomida/administración & dosificación , Masculino , Mieloma Múltiple/patología , Recurrencia Local de Neoplasia/patología , Pronóstico , Tasa de Supervivencia , Talidomida/administración & dosificación
13.
PLoS One ; 15(2): e0229469, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32084254

RESUMEN

Treatment of transplant-ineligible (TNE) newly diagnosed multiple myeloma (NDMM) requires a balance between disease control and maintaining quality of life (QoL). Patients value treatment-free remission periods in this incurable condition, as they are associated with better QoL. We set out to study clinical outcomes of consecutive TNE NDMM patients in routine care treated in Thames Valley Cancer Network between 2009 and 2017. The primary outcome was the evaluation of the treatment-free interval (TFI) after 1st and subsequent lines of therapy in the total cohort and in individual subgroups, according to age (≤75 vs. >75 years), and co-morbidities using Charlson Co-morbidity Index (CCI): mild: 0-2 vs. moderate: 3-4 vs. severe: ≥5). Secondary outcomes include response rates, overall survival (OS) and progression-free survival (PFS) between subgroups: according to age and according to co-morbidities. In a total cohort of 292 patients, median TFI (IQR) was longest after first-line therapy 6.9 months (1.4-16.9), reducing after second line therapy to 1.8 months (.7-6.9), and after third line therapy to 0.6 months (0.2-1.5). Median TFI followed the same trend across the different subgroups, by age (≤75, >75 years) and by CCI (0-2, 3-4, ≥5). Overall response rate (ORR) to first line therapy for total cohort was 67%, with responses categorised as complete response (CR): 21%, very good partial response: 16%, partial response: 30%, stable disease: 18%, and progressive disease: 8%. ORR in individual subgroups by age were (≤75: 70% vs. >75: 63%), and by CCI (0-2: 65% vs. 3-4: 71% vs. ≥5: 77%). Median OS and PFS for the total cohort were (30.2 months, 95% CI: 23.8-36.9), and (9 months, 95% CI: 7.9-9.8), respectively. Patients aged >75 years showed a significant reduction in OS and PFS compared to those ≤75 years of age: OS (49.0 vs. 22.4 months, p<0.0001, HR: 2.08, 95% CI: 1.5-2.8), PFS (9.7 vs. 8.0 months, p<0.01, HR: 1.47, 95% CI: 1.1-1.9). Median OS was significantly reduced with worsening co-morbidities: (CCI 0-2: 52.4 months vs. CCI 3-4: 33.0 months vs. CCI ≥5: 24.0 months, p = 0.01, HR: 1.43, 95% CI: 1.1-1.9). Median PFS was significantly reduced in the severely co-morbid subgroup (CCI 0-2: 9.4 months vs. CCI 3-4: 9.6 months vs. CCI ≥5: 7.1 months, p = 0.025, HR: 1.3, 95% CI: 1.0-1.6). This study demonstrated that first line therapy in the TNE NDMM setting resulted in the longest TFI which was modest at a median of 6.9 months, and decreased significantly following subsequent lines of therapy and across the different subgroups by age and by co-morbidities. Therapy objective should be to maximise the benefit of first line treatment. We envisage that the recent shift towards a continuous therapeutic approach will benefit TNE patients in view of improved survival data demonstrated by a number phase 3 trials. When continuous therapy is not appropriate due to patient choice or toxicities, an efficacious (not limited to thalidomide and bortezomib) but tolerable first line FDT strategy, which can maximise TFI and maintain a good QoL, remains a reasonable alternative approach.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Calidad de Vida , Anciano , Anciano de 80 o más Años , Bortezomib/administración & dosificación , Esquema de Medicación , Femenino , Estudios de Seguimiento , Humanos , Lenalidomida/administración & dosificación , Masculino , Mieloma Múltiple/epidemiología , Mieloma Múltiple/patología , Inducción de Remisión , Estudios Retrospectivos , Tasa de Supervivencia , Talidomida/administración & dosificación , Factores de Tiempo , Resultado del Tratamiento , Reino Unido/epidemiología
15.
Sci Rep ; 10(1): 605, 2020 01 17.
Artículo en Inglés | MEDLINE | ID: mdl-31953524

RESUMEN

Finding biomarkers that provide shared link between disease severity, drug-induced pharmacodynamic effects and response status in human trials can provide number of values for patient benefits: elucidating current therapeutic mechanism-of-action, and, back-translating to fast-track development of next-generation therapeutics. Both opportunities are predicated on proactive generation of human molecular profiles that capture longitudinal trajectories before and after pharmacological intervention. Here, we present the largest plasma proteomic biomarker dataset available to-date and the corresponding analyses from placebo-controlled Phase III clinical trials of the phosphodiesterase type 4 inhibitor apremilast in psoriasis (PSOR), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) from 526 subjects overall. Using approximately 150 plasma analytes tracked across three time points, we identified IL-17A and KLK-7 as biomarkers for disease severity and apremilast pharmacodynamic effect in psoriasis patients. Combined decline rate of KLK-7, PEDF, MDC and ANGPTL4 by Week 16 represented biomarkers for the responder subgroup, shedding insights into therapeutic mechanisms. In ankylosing spondylitis patients, IL-6 and LRG-1 were identified as biomarkers with concordance to disease severity. Apremilast-induced LRG-1 increase was consistent with the overall lack of efficacy in ankylosing spondylitis. Taken together, these findings expanded the mechanistic knowledge base of apremilast and provided translational foundations to accelerate future efforts including compound differentiation, combination, and repurposing.


Asunto(s)
Antiinflamatorios no Esteroideos/administración & dosificación , Biomarcadores/sangre , Proteómica/métodos , Psoriasis/tratamiento farmacológico , Espondilitis Anquilosante/tratamiento farmacológico , Talidomida/análogos & derivados , Antiinflamatorios no Esteroideos/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Glicoproteínas/sangre , Humanos , Interleucina-17/sangre , Interleucina-6/sangre , Calicreínas/sangre , Psoriasis/metabolismo , Índice de Severidad de la Enfermedad , Espondilitis Anquilosante/metabolismo , Talidomida/administración & dosificación , Talidomida/farmacología , Resultado del Tratamiento
16.
Drugs ; 80(2): 181-188, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31933168

RESUMEN

The oral phosphodiesterase 4 inhibitor apremilast (Otezla®) is indicated for the treatment of oral ulcers associated with Behçet's disease in some countries, including the USA (where it is the first agent approved for the disease) and Japan. In phase 2 and 3 trials in adults with this chronic and debilitating disorder, 12 weeks of treatment with apremilast 30 mg twice daily reduced the number and pain of oral ulcers and disease activity relative to placebo, with these clinical benefits being accompanied by improvements in health-related quality of life (HR-QOL). Benefits of apremilast were seen regardless of baseline patient/disease characteristics and in Japanese patients, and were sustained over up to 64 weeks of treatment. Apremilast was generally well tolerated, with gastrointestinal adverse events being among the most common tolerability issues. Emerging real-world data also support the drug's use in this setting. Thus, for patients with oral ulcers associated with Behçet's disease, apremilast provides an effective and generally well tolerated approved treatment option.


Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Síndrome de Behçet/tratamiento farmacológico , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Úlceras Bucales/tratamiento farmacológico , Inhibidores de Fosfodiesterasa 4/farmacología , Talidomida/análogos & derivados , Administración Oral , Antiinflamatorios no Esteroideos/administración & dosificación , Síndrome de Behçet/enzimología , Humanos , Úlceras Bucales/enzimología , Inhibidores de Fosfodiesterasa 4/administración & dosificación , Talidomida/administración & dosificación , Talidomida/farmacología
18.
Prostate ; 80(4): 336-344, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31899823

RESUMEN

BACKGROUND: Immunosuppressive cytokines have the potential to promote prostate cancer progression. Assessing their longitudinal changes may implicate mechanisms of progression, treatment resistance, and suggest new therapeutic targets. METHODS: Thirty-seven men with biochemically recurrent (BCR) prostate cancer who received 6 months of androgen deprivation therapy (ADT) and were monitored until the time to prostate-specific antigen progression (TTPP) were identified from a completed phase III trial (NCT00020085). Serum samples were archived at baseline, 3 months after ADT, and at TTPP. Cytokine concentrations were quantified using a 36-parameter electrochemiluminescence assay. The Wilcoxon signed-rank sum test was used to compare observations between time points. Kaplan-Meier analysis was used to calculate TTPP dichotomized by cytokine values above or below the median. Pearson's rank correlation coefficient was used to compare continuous variables. RESULTS: Median TTPP was 399 days (range, 114-1641). Median prostate-specific antigen (PSA) at baseline and progression were 8.5 and 5.3 ng/mL, respectively. Twenty-three patients (62%) achieved undetectable PSA with ADT. Castrate levels of testosterone (<50 ng/dL) after 3 months of ADT occurred in 35 patients (95%). TNF-α (P = .002), IL-23 (P = .002), and CXCL10 (P = .001) significantly increased from baseline to post ADT. Certain cytokines correlated longitudinally: TNF-α correlated with IL-23 (r = .72; P < .001) and IL-8 (r = .59; P < .001) from baseline to post ADT and to PSA progression. Neutrophil-to-lymphocyte ratio correlated with IL-27 (r = .57; P < .001) and MIP-3α (r = .56; P < .001). Patients with a detectable PSA after ADT had elevated levels of IL-6 (P = .049) and IL-8 (P = .013) at PSA progression as compared with those with an undetectable PSA. There was a trend toward shorter TTPP in patients with TNF-α levels above the median (P = .042). CONCLUSIONS: Several innate cytokines were associated with biochemically recurrent prostate cancer.


Asunto(s)
Antineoplásicos Hormonales/administración & dosificación , Citocinas/inmunología , Calicreínas/sangre , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/inmunología , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/inmunología , Anciano , Biomarcadores de Tumor/sangre , Estudios de Cohortes , Citocinas/sangre , Progresión de la Enfermedad , Método Doble Ciego , Goserelina/administración & dosificación , Humanos , Tolerancia Inmunológica , Inmunidad Innata , Inmunosupresores/administración & dosificación , Leuprolida/administración & dosificación , Estudios Longitudinales , Masculino , Recurrencia Local de Neoplasia/sangre , Neoplasias de la Próstata/sangre , Talidomida/administración & dosificación
19.
Leukemia ; 34(6): 1563-1576, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-31900407

RESUMEN

An immunosuppressive microenvironment promoting leukemia cell immune escape plays an important role in the pathogenesis of AML. Through its interaction with cereblon, a substrate receptor for the E3 ubiquitin ligase complex, pomalidomide leads to selective ubiquitination of transcription factors Aiolos and Ikaros thereby promoting immune modulation. In this phase I trial, 51 newly diagnosed non-favorable risk AML and high-risk MDS patients were enrolled and treated with AcDVP16 (cytarabine 667 mg/m2/day IV continuous infusion days 1-3, daunorubicin 45 mg/m2 IV days 1-3, etoposide 400 mg/m2 IV days 8-10) induction therapy followed by dose- and duration-escalation pomalidomide beginning at early lymphocyte recovery. Forty-three patients (AML: n = 39, MDS: n = 4) received pomalidomide. The maximum tolerated dose of pomalidomide was 4 mg for 21 consecutive days. The overall complete remission (CR + CRi) rate, median overall survival, and disease-free survival were 75%, 27.1 and 20.6 months, respectively. Subset analyses revealed 86% CR/CRi rate in AML patients with unfavorable-risk karyotype treated with pomalidomide. Pomalidomide significantly decreased Aiolos expression in both CD4+ and CD8+ peripheral blood and bone marrow T cells, promoted T cell differentiation, proliferation, and heightened their cytokine production. Finally, pomalidomide induced distinct gene expression changes in immune function-related ontologies in CD4+ and CD8+ T cells.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Factores Inmunológicos/administración & dosificación , Leucemia Mieloide Aguda/tratamiento farmacológico , Síndromes Mielodisplásicos/tratamiento farmacológico , Talidomida/análogos & derivados , Adulto , Anciano , Citarabina/administración & dosificación , Supervivencia sin Enfermedad , Etopósido/administración & dosificación , Femenino , Hexosaminas/administración & dosificación , Humanos , Inmunomodulación/efectos de los fármacos , Quimioterapia de Inducción/métodos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Inducción de Remisión , Talidomida/administración & dosificación , Resultado del Tratamiento , Adulto Joven
20.
Int J Hematol ; 111(6): 888-890, 2020 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-31900879
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