RESUMEN
Coronavirus-19 (COVID-19) mortality rates among haemopoietic stem cell transplant (HSCT) patients are high, ranging between 20% and 40%. We prospectively evaluated the mortality outcomes of COVID-19 in Western Australian HSCT patients. A total of 32/492 (6.5%) HSCT recipients contracted COVID-19 during the study, of whom 30/32 (94%) developed mild or asymptomatic disease. Two allogeneic HSCT patients were hospitalised for severe COVID-19; one patient died. Stringent healthcare, social isolation practices, aggressive vaccination programmes and rapid access to COVID-19 antivirals may have promoted mild COVID-19 illness in Western Australian HSCT patients, resulting in one of the lowest COVID-19 mortality rates in HSCT recipients worldwide.
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COVID-19 , Trasplante de Células Madre Hematopoyéticas , Humanos , Australia Occidental/epidemiología , Australia , Antivirales/uso terapéutico , Vacunación , Receptores de TrasplantesRESUMEN
BACKGROUND: Cytomegalovirus (CMV) is a common cause of morbidity after allogeneic haematopoietic cell transplantation (alloHCT). Pre-emptive therapy (PET) with valganciclovir (VGC) is associated with haematological toxicity. METHODS: We included alloHCT patients from 2018 to 2021 where letermovir (LTV) was used for CMV PET because of cytopenias. RESULTS: Ten patients were included. Six received VGC prior to LTV. VGC was commenced at median d42, given for median 40 days. LTV was commenced at median d90, given for median 54 days. At commencement of antiviral, CMV viral load was higher for VGC at 3.7 log10 IU/mL, compared to LTV at 2.9 log10 IU/mL. Viral load reduction occurred at 0.18 log10 IU/mL per week for VGC, compared to 0.17 log10 IU/mL per week for LTV. There was no clinically significant CMV viremia after stopping LTV. Cytopenias improved on LTV. CONCLUSION: LTV was effective in controlling CMV viremia when it was given at a lower starting CMV viral load and later post alloHCT than VGC. Further study is required of LTV as upfront PET following alloHCT.
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Infecciones por Citomegalovirus , Citopenia , Trasplante de Células Madre Hematopoyéticas , Humanos , Citomegalovirus , Antivirales/uso terapéutico , Viremia/tratamiento farmacológico , Resultado del Tratamiento , Valganciclovir/uso terapéutico , Infecciones por Citomegalovirus/tratamiento farmacológico , Infecciones por Citomegalovirus/prevención & control , Infecciones por Citomegalovirus/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversosRESUMEN
BACKGROUND: Prescription-related errors and misinterpretation of oral cancer treatment instructions can lead to significant harm or fatal outcomes for patients. The impact of specialist pharmacist-led consultation for patients taking oral antineoplastic medicines (OAMs) across a range of cancer types in an Australian setting has not been studied. AIM: To evaluate the impact of specialist cancer pharmacist patient consultation in a pharmacist-led anticancer clinic across a range of cancer types and evaluate health service staff perceptions of these consultations. METHOD: Retrospective data were collected from electronic patient medical records from 2017 to 2020 at a Western Australian quaternary hospital. The impacts of pharmacist clinical interventions were classified using a validated tool and specialist interdisciplinary panel consensus. An online staff survey was conducted using Qualtrics. RESULTS: Of 246 patients reviewed, 76 (30.8%, p < .001) had received a clinical intervention of which 48 (63.2%) were classified as high-extreme and 28 (36.8%) as low-moderate impact (p = .021). Patients on ≥5 concurrent medications or > 65 years may represent high risk groups. Thirty-seven clinical staff were surveyed (37/55; 67.3%) and all strongly agreed/ agreed pharmacist consultation improved patient understanding and medication management confidence (p < .001). All cancer center staff (26/26) strongly agreed/agreed the clinic added value to the cancer service (p < .001), and 96.2% perceived it improved patient outcomes (p < .001). CONCLUSIONS: Specialist pharmacist-led patient consultation for patients on OAM regimens may protect patients from high and extreme risk of harm. Specialist interdisciplinary staff supported this service.
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Neoplasias , Farmacéuticos , Humanos , Estudios Retrospectivos , Australia , Derivación y Consulta , Encuestas y Cuestionarios , Neoplasias/tratamiento farmacológicoRESUMEN
BACKGROUND: Controlling cytomegalovirus (CMV) infection through prophylaxis or pre-emptive therapy remains an important contributor to outcomes after allogeneic hematopoetic stem cell transplant (alloHCT). Predicting clinically significant CMV infection (csCMVi) after day 100 remains a challenge. METHODS: We examined the abilty of the QuantiFERON-CMV assay (QFN-CMV) at day 100 (d100) and day 150 (d150) after alloHCT to predict csCMVi after these time points, with median follow-up of 3.1 years (range 1.3-4.3 years). RESULTS: In 46 transplants (donor seropositive (D+) recipient seronegative (R-) = 12, D+R+ = 25, D-R+ = 9; matched related = 13, unrelated donor = 32, haploidentical = 1), for the prediction of freedom from csCMVi >d100, QFN-CMVd100 (positive compared to negative/indeterminate) had sensitivity 62% (23/37), specificity 100% (9/9), positive predictive value 100% (23/23), and negative predictive value 39% (9/23). For the prediction of freedom from csCMVi >d150, QFN-CMVd150 (positive compared to negative/indeterminate) had sensitivity 62% (18/29), specificity 83% (5/6), positive predictive value 95% (18/19), and negative predictive value 31% (5/16). CONCLUSION: Positive QFN-CMV at d100 and d150 strongly predicted freedom from csCMVi after these time points. QFN-CMV could be utilized to predict the need for pre-emptive therapy and CMV viral load monitoring after day 100 post-alloHCT.
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Infecciones por Citomegalovirus , Trasplante de Células Madre Hematopoyéticas , Trasplantes , Antivirales/uso terapéutico , Citomegalovirus , Infecciones por Citomegalovirus/diagnóstico , Infecciones por Citomegalovirus/tratamiento farmacológico , Infecciones por Citomegalovirus/prevención & control , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Valor Predictivo de las PruebasRESUMEN
Background: Oral busulfan and intravenous cyclophosphamide (Bu/Cy) are common myeloablative preparations used in allogeneic hematopoietic stem cell transplantation (HSCT). Herein, we investigated the safety of (Bu/Cy) administration during HSCT. Methods: Patients administered Bu/Cy for allogeneic HSCT at Royal Perth Hospital and Fiona Stanley Hospital between 2007 and 2017 were reviewed for inclusion in the study. We performed busulfan pharmacokinetic (PK) testing for a subset of patients and allometric scaling modeling to assess the best method of busulfan dosing in patients at extremes of weight. Results: Sixty-nine patients were included in the clinical outcome analysis. The median follow-up period was 32 months (range, 9-114 months). The three-year overall survival rate was 62% (95% confidence interval (CI), 51%-75%), and transplant-related mortality was 4% at 6 months (95% CI, 1-7%), with a low rate of sinusoidal obstruction syndrome of the liver being observed. In addition, relapse was 38% (95% CI, 30%-44%) at 3 years. The PK information of 15 patients receiving busulfan was available after oral dosing. The average per-dose busulfan exposure was 1,350 µmol.min/L (range, 878-1,717 µmol.min/L), and the within target range was 1,000-1,500 µmol.min/L in 73% of patients. Of the size measures investigated, ideal and adjusted body weight (ABW40) provided the best fit. No association was observed between busulfan exposure, toxicity, and relapse. Conclusions: Overall, Bu/Cy administration appeared safe when dosed in relation to weight, showing a low early transplant-related mortality rate following adequate busulfan exposure in majority of the cases. Body size measures, such as ideal body weight or ABW40, are likely more suitable for use during busulfan dosing, particularly at high extremes of the body mass index classification.
RESUMEN
We report the case of a 59-year-old woman with stage IV erythrodermic mycosis fungoides (MF) and large cell transformation who, despite failing multiple previous treatments, achieved complete remission through a combination of pralatrexate and romidepsin followed by allogeneic hematopoietic stem cell transplantation (alloSCT). Further studies are needed in focussing on this combined regimen in treating cutaneous T-cell lymphoma (CTCL) and its efficacy as a bridging regimen in facilitating successful alloSCT.
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Aminopterina/análogos & derivados , Antibióticos Antineoplásicos/uso terapéutico , Depsipéptidos/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Micosis Fungoide/terapia , Neoplasias Cutáneas/terapia , Aminopterina/uso terapéutico , Femenino , Humanos , Persona de Mediana Edad , Micosis Fungoide/patología , Inducción de Remisión , Neoplasias Cutáneas/patología , Resultado del TratamientoRESUMEN
Cytomegalovirus (CMV) infection causes morbidity and mortality after allogeneic haematopoietic stem cell transplantation (HSCT). We investigated whether prophylaxis with high dose valaciclovir is effective at reducing the incidence of clinically significant CMV infection (csCMVi) within six months of allogeneic HSCT. Consecutive allogeneic HSCT recipients who received 2g valaciclovir orally four times daily from transplant until day 100 (prophylaxis group) were compared to subsequent patients who received no CMV prophylaxis (control group). Forty-nine patients in the prophylaxis group and 59 in the control group were included. The cumulative incidence of csCMVi at 6 months was 20% (95% confidence interval (CI): 9%-27%) in the prophylaxis group and 39% (95% CI: 26%-47%) in the control group (P = .009). There was no CMV disease in the prophylaxis group and three cases in the control group. There was no difference in time to neutrophil or platelet recovery nor graft failure between groups. On multivariable analysis, lack of high dose valaciclovir prophylaxis, positive recipient CMV IgG and age were associated with greater likelihood of csCMVi. There was no significant difference in acute graft versus host disease, non-relapse mortality or overall survival between groups. In this retrospective cohort study, high dose valaciclovir prophylaxis resulted in a lower incidence of csCMVi within six months of HSCT.
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Infecciones por Citomegalovirus , Trasplante de Células Madre Hematopoyéticas , Antivirales/uso terapéutico , Citomegalovirus , Infecciones por Citomegalovirus/tratamiento farmacológico , Infecciones por Citomegalovirus/epidemiología , Infecciones por Citomegalovirus/prevención & control , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Estudios Retrospectivos , Receptores de Trasplantes , Trasplante Homólogo/efectos adversos , Valaciclovir/uso terapéuticoRESUMEN
In a phase 3 clinical study of heavily pretreated adults with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL), overall survival (OS) following blinatumomab, a BiTE (bispecific T-cell engager) immunooncology therapy, was significantly improved vs chemotherapy following induction (cycles 1 to 2). Here we report the efficacy and safety of those who received additional cycles of blinatumomab. Blinatumomab was administered as a continuous IV infusion for 4 weeks in a 6-week cycle. Patients who achieved a bone marrow response (≤5% blasts) or complete remission (full, partial, or incomplete hematological recovery) during induction could receive additional cycles of blinatumomab. OS and relapse-free survival (RFS) for consolidation (cycles 3 to 5) vs no consolidation, and maintenance (cycles ≥6) vs no maintenance were analyzed using Simon-Makuch and Mantel-Byar odds ratios. Of 267 patients who received blinatumomab induction, 86 (32%) entered consolidation and 36 (13%) entered maintenance. Evidence of longer OS was demonstrated among the maintenance group compared with no-maintenance (median OS [95% confidence interval, CI]: not reached for maintenance vs 15.5 months for no maintenance). Median RFS (months; 95% CI) was numerically longer among maintenance group (14.5; 7.1 to 21.9) compared with no-maintenance (9.8; 8.5 to 11.1). A lower incidence of adverse events was seen during maintenance (72.2%) compared with induction (97.2%) and consolidation (86.1%). Adults with R/R ALL who achieved remission following blinatumomab induction had longer survival on continuation therapy than those who discontinued blinatumomab early, supporting the use of blinatumomab as long-term therapy. No new safety signals were reported. This trial was registered at www.clinicaltrials.gov as #NCT02013167.
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Anticuerpos Biespecíficos , Antineoplásicos , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto , Anticuerpos Biespecíficos/uso terapéutico , Antineoplásicos/uso terapéutico , Quimioterapia de Consolidación , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológicoRESUMEN
The randomized phase III ADMYRE trial evaluated plitidepsin plus dexamethasone (DXM) versus DXM alone in patients with relapsed/refractory multiple myeloma after at least three but not more than six prior regimens, including at least bortezomib and lenalidomide or thalidomide. Patients were randomly assigned (2:1) to receive plitidepsin 5 mg/m2 on D1 and D15 plus DXM 40 mg on D1, D8, D15, and D22 (arm A, n = 171) or DXM 40 mg on D1, D8, D15, and D22 (arm B, n = 84) q4wk. The primary endpoint was progression-free survival (PFS). Median PFS without disease progression (PD) confirmation (IRC assessment) was 2.6 months (arm A) and 1.7 months (arm B) (HR = 0.650; p = 0.0054). Median PFS with PD confirmation (investigator's assessment) was 3.8 months (arm A) and 1.9 months (arm B) (HR = 0.611; p = 0.0040). Median overall survival (OS, intention-to-treat analysis) was 11.6 months (arm A) and 8.9 months (arm B) (HR = 0.797; p = 0.1261). OS improvement favoring arm A was found when discounting a crossover effect (37 patients crossed over from arm B to arm A) (two-stage method; HR = 0.622; p = 0.0015). The most common grade 3/4 treatment-related adverse events (% of patients arm A/arm B) were fatigue (10.8%/1.2%), myalgia (5.4%/0%), and nausea (3.6%/1.2%), being usually transient and reversible. The safety profile does not overlap with the toxicity observed with other agents used in multiple myeloma. In conclusion, efficacy data, the reassuring safety profile, and the novel mechanism of action of plitidepsin suggest that this combination can be an alternative option in patients with relapsed/refractory multiple myeloma after at least three prior therapy lines.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Bortezomib/administración & dosificación , Depsipéptidos/administración & dosificación , Dexametasona/administración & dosificación , Supervivencia sin Enfermedad , Femenino , Humanos , Lenalidomida/administración & dosificación , Masculino , Persona de Mediana Edad , Péptidos Cíclicos , Tasa de Supervivencia , Talidomida/administración & dosificaciónRESUMEN
Purpose The GALLIUM study ( ClinicalTrials.gov identifier: NCT01332968) showed that obinutuzumab (GA101; G) significantly prolonged progression-free survival (PFS) in previously untreated patients with follicular lymphoma relative to rituximab (R) when combined with cyclophosphamide (C), doxorubicin, vincristine (V), and prednisone (P; CHOP); CVP; or bendamustine. This report focuses on the impact of chemotherapy backbone on efficacy and safety. Patients and Methods A total of 1,202 patients with previously untreated follicular lymphoma (grades 1 to 3a), advanced disease (stage III or IV, or stage II with tumor diameter ≥ 7 cm), Eastern Cooperative Oncology Group performance status 0 to 2, and requiring treatment were randomly assigned 1:1 to G 1,000 mg on days 1, 8, and 15 of cycle 1 and day 1 of subsequent cycles or R 375 mg/m2 on day 1 of each cycle, for six to eight cycles, depending on chemotherapy (allocated nonrandomly by center). Responding patients received G or R for 2 years or until disease progression. Results Baseline Follicular Lymphoma International Prognostic Index risk, bulky disease, and comorbidities differed by chemotherapy. After 41.1 months median follow-up, PFS (primary end point) was superior for G plus chemotherapy (overall hazard ratio [HR], 0.68; 95% CI, 0.54 to 0.87; P = .0016), with consistent results across chemotherapy backbones (bendamustine: HR, 0.63; 95% CI, 0.46 to 0.88; CHOP: HR, 0.72; 95% CI, 0.48 to 1.10; CVP: HR, 0.79; 95% CI, 0.42 to 1.47). Grade 3 to 5 adverse events, notably cytopenias, were most frequent with CHOP. Grade 3 to 5 infections and second neoplasms were most frequent with bendamustine, which was associated with marked and prolonged reductions in T-cell counts. Fatal events were more frequent in patients treated with bendamustine, possibly reflecting differences in patient risk profiles. Conclusion Improved PFS was observed for G plus chemotherapy for all three chemotherapy backbones. Safety profiles differed, although comparisons are confounded by nonrandom chemotherapy allocation.
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Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma Folicular/tratamiento farmacológico , Rituximab/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/efectos adversos , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Clorhidrato de Bendamustina/administración & dosificación , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prednisona/administración & dosificación , Prednisona/efectos adversos , Supervivencia sin Progresión , Rituximab/efectos adversos , Vincristina/administración & dosificación , Vincristina/efectos adversos , Adulto JovenRESUMEN
In the phase 3 TOWER study, blinatumomab significantly improved overall survival in adults with relapsed or refractory (R/R) Philadelphia chromosome-negative (Ph-) B-cell precursor acute lymphoblastic leukemia (BCP-ALL) relative to standard-of-care chemotherapy. A secondary objective of this study was to assess the impact of blinatumomab on health-related quality of life (HRQL) as measured by the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30). This analysis included the 342 of 405 randomized patients for whom baseline and ≥1 postbaseline result were available in any EORTC multi-item scale or single-item measure. In general, patients receiving blinatumomab (n = 247) reported better posttreatment HRQL across all QLQ-C30 subscales, based on descriptive mean change from baseline, than did those receiving chemotherapy (n = 95). The hazard ratios for time to deterioration (TTD) of ≥10 points from baseline in HRQL or death ranged from 0.42 to 0.81 in favor of blinatumomab, with the upper bounds of the 95% confidence interval <1.0 across all measures, except insomnia, social functioning, and financial difficulties; sensitivity analysis of TTD in HRQL without the event of death were consistent with these findings. When treatment effect over time was tested using a restricted maximum likelihood-based mixed model for repeated measures analysis, P < .05 was reached for blinatumomab vs chemotherapy for all subscale measures except financial difficulties. The clinically meaningful benefits in overall survival and HRQL support the clinical value of blinatumomab in patients with R/R Ph- BCP-ALL when compared with chemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT02013167.
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Anticuerpos Biespecíficos/uso terapéutico , Antineoplásicos/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Calidad de Vida , Adulto , Femenino , Humanos , Masculino , Recurrencia Local de Neoplasia/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patología , Estudios Prospectivos , Análisis de SupervivenciaRESUMEN
OBJECTIVES: Haematopoetic autologous stem cell transplantation (ASCT) has emerged as a treatment option for patients with refractory, severe autoimmune disease. This is a systematic review of the current literature on ASCT in adult patients with systemic sclerosis (SSc). METHODS: Original articles published between 2005 and 2016 that evaluated the use of ASCT in patients with SSc were reviewed with respect to the primary outcomes of overall and transplant related mortality (TRM) rates, and secondary outcomes of changes in modified Rodnan Skin Score (mRSS), forced vital capacity (FVC), progression/event free survival (P/EFS) and quality of life measures. We also focussed on patient characteristics, the ASCT conditioning and mobilisation regimens used, and their relationship to patient outcome in each study. RESULTS: Of the 155 articles found, only 9 articles were suitable for review. There were 2 placebo-controlled trials (RCTs), ASTIS and ASSIST, and 7 observational and cohort studies. In general, patients undergoing ASCT had diffuse SSc with mRSS >14, and interstitial lung disease. The 2 RCTs showed a benefit in P/EFS (80-81%), FVC and quality of life measures in ASCT compared to monthly cyclophosphamide. All the studies showed an improvement in mRSS. TRM rates varied among studies, from 0 to 23%, with a trend to higher mortality rates in studies using higher doses of cyclophosphamide or myeloablative conditioning regimens. CONCLUSIONS: We conclude that ASCT is beneficial in some patients with SSc and that patient selection and conditioning regimens are critical determinants of prognosis and mortality post-ASCT.
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Trasplante de Células Madre Hematopoyéticas , Esclerodermia Sistémica/terapia , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Humanos , Selección de Paciente , Ensayos Clínicos Controlados Aleatorios como Asunto , Esclerodermia Sistémica/mortalidad , Esclerodermia Sistémica/fisiopatología , Acondicionamiento Pretrasplante , Trasplante Autólogo , Capacidad VitalRESUMEN
Purpose Higher doses of the anthracycline daunorubicin during induction therapy for acute myeloid leukemia (AML) have been shown to improve remission rates and survival. We hypothesized that improvements in outcomes in adult AML may be further achieved by increased anthracycline dose during consolidation therapy. Patients and Methods Patients with AML in complete remission after induction therapy were randomly assigned to receive two cycles of consolidation therapy with cytarabine 100 mg/m2 daily for 5 days, etoposide 75 mg/m2 daily for 5 days, and idarubicin 9 mg/m2 daily for either 2 or 3 days (standard and intensive arms, respectively). The primary end point was leukemia-free survival (LFS). Results Two hundred ninety-three patients 16 to 60 years of age, excluding those with core binding factor AML and acute promyelocytic leukemia, were randomly assigned to treatment groups (146 to the standard arm and 147 to the intensive arm). Both groups were balanced for age, karyotypic risk, and FLT3-internal tandem duplication and NPM1 gene mutations. One hundred twenty patients in the standard arm (82%) and 95 patients in the intensive arm (65%) completed planned consolidation ( P < .001). Durations of severe neutropenia and thrombocytopenia were prolonged in the intensive arm, but there were no differences in serious nonhematological toxicities. With a median follow-up of 5.3 years (range, 0.6 to 9.9 years), there was a statistically significant improvement in LFS in the intensive arm compared with the standard arm (3-year LFS, 47% [95% CI, 40% to 56%] v 35% [95% CI, 28% to 44%]; P = .045). At 5 years, the overall survival rate was 57% in the intensive arm and 47% in the standard arm ( P = .092). There was no evidence of selective benefit of intensive consolidation within the cytogenetic or FLT3-internal tandem duplication and NPM1 gene mutation subgroups. Conclusion An increased cumulative dose of idarubicin during consolidation therapy for adult AML resulted in improved LFS, without increased nonhematologic toxicity.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Quimioterapia de Consolidación , Citarabina/administración & dosificación , Citarabina/efectos adversos , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Etopósido/administración & dosificación , Etopósido/efectos adversos , Femenino , Humanos , Idarrubicina/administración & dosificación , Idarrubicina/efectos adversos , Masculino , Persona de Mediana Edad , Nucleofosmina , Tasa de Supervivencia , Adulto JovenRESUMEN
BRAF mutation testing to determine eligibility for treatment with vemurafenib was performed on archival skin lesions of a 54-year-old patient diagnosed with Erdheim-Chester disease (ECD) in 1999. Sanger sequencing of DNA extracted from a 2008 skin lesion identified two non-contiguous base substitutions in BRAF, which were shown by next-generation sequencing (NGS) to be located in the same allele. Due to its long-standing duration, molecular evolution of disease was possible; however, both Sanger and NGS of a 2000 skin lesion were unsuccessful due to the poor quality of DNA. Finally, droplet digital PCR using a probe specific for this novel mutation detected the complex BRAF mutation in both the 2000 and 2008 lesions, indicating this case to be ECD with a novel underlying BRAF p.Thr599_Val600delinsArgGlu mutation. Although well at present, molecular modelling of the mutant BRAF suggests suboptimal binding of vemurafenib and hence reduced therapeutic effectiveness.
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Enfermedad de Erdheim-Chester/genética , Histiocitosis de Células de Langerhans/genética , Mutación , Proteínas Proto-Oncogénicas B-raf/genética , Inhibidores Enzimáticos/uso terapéutico , Enfermedad de Erdheim-Chester/etiología , Enfermedad de Erdheim-Chester/patología , Histiocitosis de Células de Langerhans/patología , Humanos , Indoles/uso terapéutico , Masculino , Persona de Mediana Edad , Evaluación del Resultado de la Atención al Paciente , Piel/patología , Neoplasias Cutáneas/genética , Sulfonamidas/uso terapéutico , VemurafenibRESUMEN
The combination of lenalidomide and dexamethasone is an established treatment for patients with multiple myeloma (MM). Increasingly, treatment attenuation is advocated for frail/elderly patients to minimize toxicity even though there have been no prospective studies to demonstrate whether lenalidomide dose attenuation impacts on response and survival outcome. This prospective multicentre phase II study assessed the efficacy and tolerability of lower dose lenalidomide (15 mg) and dexamethasone (20 mg) in 149 eligible patients with relapsed/refractory MM aged over 59 years and/or with renal impairment. The overall response rate was 71% (complete response 15%). Median (range) progression-free survival (PFS) and overall survival (OS) were 8·9 (6·9-11·5) and 30·5 (20·0-36·2) months, respectively. Upon formal statistical comparison of these endpoints to that of a matched cohort of patients from the pivotal phase III MM009/MM010 studies who received standard-dose lenalidomide (25 mg) and high-dose dexamethasone (40 mg) no difference was seen in PFS (P = 0·34) and OS (P = 0·21). Importantly, grade 3-4 toxicities were reduced with low-dose lenalidomide, mainly lower neutropenia (29% vs. 41%), infections (23% vs. 31%) and venous thromboembolism (3% vs. 13%). This study supports a strategy of lenalidomide dose reduction at the outset for at-risk patients, and prospectively confirms that such an approach reduces adverse events while not compromising patient response or survival outcomes.
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Inhibidores de la Angiogénesis/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Mieloma Múltiple/tratamiento farmacológico , Talidomida/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Inhibidores de la Angiogénesis/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Dexametasona/administración & dosificación , Progresión de la Enfermedad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Lenalidomida , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Recurrencia , Talidomida/administración & dosificación , Talidomida/efectos adversosRESUMEN
PURPOSE: Marizomib (NPI-0052) is an irreversible proteasome inhibitor, derived from a marine actinomycete, with activity and specificity that is distinct from other proteasome inhibitors. EXPERIMENTAL DESIGN: Phase I study (NPI-0052-102) evaluated the MTD, pharmacokinetics, and pharmacodynamics of marizomib intravenously on two dosing schedules. RESULTS: Forty-two patients with advanced malignancies received Schedule A (0.1-0.9 mg/m(2) over 1-10 minutes on days 1, 8, 15 in 4-week cycles); 44 patients with relapsed and/or refractory multiple myeloma (RRMM) and other hematologic malignancies received Schedule B (0.075-0.6 mg/m(2) over 1 minute to 2 hours on days 1, 4, 8, 11, in 3-week cycles). The Schedule A recommended phase II dose was 0.7 mg/m(2) over 10 minutes; Schedule B was 0.5 mg/m(2) over 2 hours. The most common (>25% of patients) related adverse events were fatigue, nausea, diarrhea, and infusion site pain (Schedule A); and fatigue (Schedule B). Overall response rate of 11% was seen in 27 efficacy-evaluable RRMM Schedule B patients (1 very good partial response, 3 partial responses, 4 minimal responses, and 12 stable disease). One Schedule A patient with transformed marginal zone lymphoma had complete response. Marizomib has a short half-life (<30 minutes), with high volume of distribution (â¼15-416 L) and clearance (â¼0.9-22 L/minutes). CONCLUSIONS: Marizomib does not exhibit the severe peripheral neuropathy or hematologic toxicity observed with other proteasome inhibitors. Marizomib was generally well tolerated with low-dose dexamethasone, demonstrated activity in heavily pretreated RRMM patients, and warrants further evaluation. Clin Cancer Res; 22(18); 4559-66. ©2016 AACR.
Asunto(s)
Antineoplásicos/uso terapéutico , Lactonas/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/patología , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Inhibidores de Proteasoma/uso terapéutico , Pirroles/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Esquema de Medicación , Femenino , Humanos , Lactonas/administración & dosificación , Lactonas/efectos adversos , Lactonas/farmacocinética , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Inhibidores de Proteasoma/administración & dosificación , Inhibidores de Proteasoma/efectos adversos , Inhibidores de Proteasoma/farmacocinética , Pirroles/administración & dosificación , Pirroles/efectos adversos , Pirroles/farmacocinética , Recurrencia , Retratamiento , Resultado del Tratamiento , Adulto JovenRESUMEN
An intensive induction regimen, consisting of idarubicin and high dose cytarabine, was assessed in 19 adult patients, median age 44 years, with newly diagnosed precursor-B acute lymphoblastic leukemia (ALL). Patients achieving a complete response (CR) were given an attenuated consolidation course. The primary endpoints were induction death rate and incidence of serious non-hematological toxicity. Grades 3-4 diarrhoea occurred in 47% of patients during induction. Two patients (11%) died during induction therapy, and 2 were withdrawn due to resistant disease or prolonged marrow hypoplasia. Fifteen patients achieved CR (79%), but levels of minimal residual disease (MRD) after induction were comparable with those previously observed using a modified pediatric protocol. Overall survival at 5 years was 36.8% while leukemia-free survival was 44.1%. An intensive AML protocol used in adults with ALL resulted in substantial toxicity and provided similar levels of cytoreduction to conventional ALL protocols, without improving long-term outcomes.