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1.
Transplant Cell Ther ; 2022 Aug 12.
Artículo en Inglés | MEDLINE | ID: mdl-35970300

RESUMEN

High dose melphalan and autologous stem cell transplant (HDM/SCT) induces deep hematologic responses (HR) in patients with newly diagnosed systemic immunoglobulin light chain (AL) amyloidosis. Modifying melphalan conditioning dose (mHDM <140 mg/m2) is considered in older patients due to concerns regarding tolerability. Age does not predict frailty and dose modification could compromise responses in an era where effective non-transplant regimens are available. We analyzed 43 patients ≥ 65 years with AL amyloidosis who underwent SCT at Boston University Amyloidosis Center between 2011 and 2020. Median age was 66 years (range 65 - 68) versus 69 years (range 65 - 76) in the HDM and mHDM groups, respectively. HR of ≥ VGPR at 12 months was 66.7% versus 42.3% for patients treated with HDM versus mHDM. Median progression free survival (PFS) from day 0 of SCT was not reached versus 12.0 months (p = 0.13); grade ≥ 3 non-hematologic transplant-related toxicities occurred in 87.5% versus 76.9%; and transplant-related mortality was 0% versus 2.3% in HDM versus mHDM group, respectively. In carefully selected older patients with AL amyloidosis, HDM is well tolerated. Use of mHDM results in reduced HR and PFS; an important consideration with the advent of highly effective non-transplant therapies.

2.
Am J Hematol ; 97(9): 1189-1199, 2022 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-35731907

RESUMEN

High-dose melphalan and stem cell transplantation (HDM/SCT) is an effective treatment for selected patients with AL amyloidosis. We report the long-term outcomes of 648 patients with AL amyloidosis treated with HDM/SCT over 25 years. Hematologic CR was achieved by 39% of patients. The median duration of hematologic CR was 12.3 years, and 45% of patients with a hematologic CR had no evidence of a recurrent plasma cell dyscrasia at 15 years after HDM/SCT. With a median follow-up interval of 8 years, the median event-free survival (EFS) and overall survival (OS) were 3.3 and 7.6 years, respectively. Patients with a hematologic CR had a median OS of 15 years, and 30% of these patients survived >20 years. On multivariable analysis, dFLC >180 mg/L and BM plasma cells >10% were independently associated with shorter EFS, whereas BNP >81 pg/mL, troponin I > 0.1 ng/mL, and serum creatinine >2.0 mg/dL were independently associated with shorter OS. We developed a prognostic score for EFS, which incorporated dFLC >180 mg/L and BMPC% >10% as adverse risk factors. Patients with low-risk (0 factors), intermediate-risk (1 factor), and high-risk (2 factors) disease had median EFS estimates of 5.3, 2.8, and 1.0 years, respectively (p < .001). The 100-day treatment-related mortality rate was 3% in the latest treatment period (2012-2021), and the 25-year risk of t-MDS/AML was 3%. We conclude that HDM/SCT induces durable hematologic responses and prolonged survival with improved safety in selected patients with AL amyloidosis.


Asunto(s)
Amiloidosis , Trasplante de Células Madre Hematopoyéticas , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas , Amiloidosis/complicaciones , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Estudios Longitudinales , Melfalán/uso terapéutico , Trasplante de Células Madre , Trasplante Autólogo , Resultado del Tratamiento
3.
Crit Rev Oncol Hematol ; 172: 103644, 2022 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-35227897

RESUMEN

Adverse events affecting Black patients, including skin hyperpigmentation, may be overlooked using existing clinical trial data on lenalidomide. The objective of this systematic review is to characterize the representation of Black participants and rate of skin hyperpigmentation in clinical trials. In this systematic review and pooled analysis of 21 clinical trials comprising 4539 participants, the proportion of Black participants in trials (6.9%, n = 315) was significantly less than the multiple myeloma population (p < 0.001). The rate of skin hyperpigmentation (0.066%, n = 3) and all skin changes (6.4%, n = 291) was significantly less compared to a 40.8% incidence in a recent retrospective study (p. <0.001). Among participants undergoing treatment with lenalidomide for multiple myeloma, Black patients were underrepresented and the adverse event of skin hyperpigmentation was underreported. Fair representation of Black patients in clinical trials is needed to better describe this adverse event and other events that may be underreported.


Asunto(s)
Mieloma Múltiple , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Dexametasona/efectos adversos , Humanos , Lenalidomida/efectos adversos , Mieloma Múltiple/tratamiento farmacológico , Estudios Retrospectivos
5.
Am J Hematol ; 97(1): 79-89, 2022 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-34739735

RESUMEN

Daratumumab as a single agent (sDARA) or in combination with chemotherapies (cDARA) leads to impressive hematologic and organ responses in AL amyloidosis. However, predictive factors associated with outcomes, and optimal duration of therapy remain unclear. We analyzed 107 patients with AL amyloidosis treated with daratumumab between 2017 and 2020. The median overall survival (OS) was not reached while the median major organ deterioration progression free survival (MOD-PFS) was 36 months in the sDARA cohort and not reached in the cDARA cohort, respectively. Hematologic response > VGPR was achieved in 81% of patients receiving sDARA and 86% of patients treated with cDARA. Several predictive factors were identified on a univariate analysis, including NTproBNP >8500 pg/mL but only achievement of at least VGPR and presence of 1q21 gain were independently associated with MOD-PFS and OS on a multivariate analysis. Finally, patients receiving > 12 cycles had significantly longer MOD-PFS (30 vs.13 months; (p = .0018) and OS (NR vs. 15 months; p < .0001). NTproBNP > 8500 pg/mL, presence of 1q21 gain and shorter duration of therapy (≤ 12 cycles) are strong negative predictive factors for outcomes with daratumumab therapy in AL amyloidosis.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Femenino , Humanos , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/diagnóstico , Masculino , Persona de Mediana Edad , Pronóstico , Supervivencia sin Progresión , Estudios Prospectivos , Análisis de Supervivencia , Resultado del Tratamiento
8.
ESMO Open ; 6(5): 100252, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34461483

RESUMEN

BACKGROUND: Immune checkpoint inhibitors (ICIs) can cause life-threatening cardiovascular adverse events (CVAEs) that may not be attributed to therapy. The outcomes of clinical trials may underestimate treatment-related adverse events due to restrictive eligibility, limited sample size, and failure to anticipate selected toxicities. We evaluated the incidence and clinical determinants of CVAEs in real-world population on ICI therapy. PATIENTS AND METHODS: Among 2 687 301 patients diagnosed with cancer from 2011 to 2018, 16 574 received ICIs for any cancer. Patients in the ICI and non-ICI cohorts were matched in a 1 : 1 ratio according to age, sex, National Cancer Institute comorbidity score, and primary cancer. The non-ICI cohort was stratified into patients who received chemotherapy (N = 2875) or targeted agents (N = 4611). All CVAEs, non-cardiac immune-related adverse events occurring after treatment initiation, baseline comorbidities, and treatment details were identified and analyzed using diagnosis and billing codes. RESULTS: Median age was 61 and 65 years in the ICI and non-ICI cohorts, respectively (P < 0.001). ICI patients were predominantly male (P < 0.001). Lung cancer (43.1%), melanoma (30.4%), and renal cell carcinoma (9.9%) were the most common cancer types. CVAE diagnoses in our dataset by incidence proportion (ICI cohort) were stroke (4.6%), heart failure (3.5%), atrial fibrillation (2.1%), conduction disorders (1.5%), myocardial infarction (0.9%), myocarditis (0.05%), vasculitis (0.05%), and pericarditis (0.2%). Anti-cytotoxic T-lymphocyte-associated protein 4 increased the risk of heart failure [versus anti-programmed cell death protein 1; hazard ratio (HR), 1.9; 95% confidence interval (CI) 1.27-2.84] and stroke (HR, 1.7; 95% CI 1.3-2.22). Pneumonitis was associated with heart failure (HR, 2.61; 95% CI 1.23-5.52) and encephalitis with conduction disorders (HR, 4.35; 95% CI 1.6-11.87) in patients on ICIs. Advanced age, primary cancer, nephritis, and anti-cytotoxic T-lymphocyte-associated protein 4 therapy were commonly associated with CVAEs in the adjusted Cox proportional hazards model. CONCLUSIONS: Our findings underscore the importance of risk stratification and cardiovascular monitoring for patients on ICI therapy.


Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Neoplasias Pulmonares , Melanoma , Anciano , Humanos , Inhibidores de Puntos de Control Inmunológico , Neoplasias Pulmonares/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Estados Unidos/epidemiología
13.
Blood Cancer J ; 10(8): 88, 2020 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-32873776

RESUMEN

Hematologic complete response (hemCR) in AL amyloidosis requires absence of monoclonal protein by immunofixation electrophoreses (IFE) and normal serum free light chain ratio (FLCR). Recent literature suggests that an involved free light chain (iFLC) <20 mg/L or difference in free light chains (dFLC) <10 mg/L may more accurately predict outcomes after treatment. We evaluated overall survival in 340 patients treated with high-dose melphalan and stem cell transplantation (SCT). Of 305 patients evaluable 6 months after SCT, 90 (30%) achieved hemCR, 132 (43%) dFLC <10 mg/L, 118 (39%) iFLC <20 mg/L, and 176 (58%) normal FLCR. Of 215 patients without hemCR, 65 (30%) had dFLC <10 mg/L and 86 (40%) had normal FLCR. Overall survival (OS) in those achieving dFLC <10 mg/L or normal FLCR without hemCR was inferior to those achieving hemCR (p = 0.013 and p = 0.001). OS was not significantly different in patients achieving iFLC <20 mg/L without hemCR compared with hemCR (p = 0.243). Of those with hemCR, OS was not significantly improved if dFLC <10 mg/L was also achieved (p = 0.852), but OS was improved for those with hemCR who also attained iFLC <20 mg/L (p = 0.009). Multivariate analysis demonstrated absence of monoclonal protein in IFE and iFLC <20 mg/L as independent predictors of survival. Attainment of hemCR remains a treatment goal, although achieving iFLC <20 mg/L may also predict improved OS.


Asunto(s)
Antineoplásicos Alquilantes/uso terapéutico , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/terapia , Melfalán/uso terapéutico , Trasplante de Células Madre , Adulto , Anciano , Antineoplásicos Alquilantes/administración & dosificación , Femenino , Humanos , Cadenas Ligeras de Inmunoglobulina/sangre , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/sangre , Masculino , Melfalán/administración & dosificación , Persona de Mediana Edad , Análisis de Supervivencia , Resultado del Tratamiento
14.
Am J Clin Pathol ; 154(4): 466-474, 2020 09 08.
Artículo en Inglés | MEDLINE | ID: mdl-32681166

RESUMEN

OBJECTIVES: A subset of coronavirus disease 2019 (COVID-19) patients exhibit clinical features of cytokine storm. However, clinicopathologic features diagnostic of hemophagocytic lymphohistiocytosis (HLH) have not been reported. We studied the reticuloendothelial organs of 4 consecutive patients who died of COVID-19 and correlated with clinical and laboratory parameters to detect HLH. METHODS: Autopsies were performed on 4 patients who died of COVID-19. Routine H&E staining and immunohistochemical staining for CD163 were performed to detect hemophagocytosis. Clinical and laboratory results from premortem blood samples were used to calculate H-scores. RESULTS: All 4 cases demonstrated diffuse alveolar damage within the lungs. Three of the 4 cases had histologic evidence of hemophagocytosis within pulmonary lymph nodes. One case showed hemophagocytosis in the spleen but none showed hemophagocytosis in liver or bone marrow. Lymphophagocytosis was the predominant form of hemophagocytosis observed. One patient showed diagnostic features of HLH with an H-score of 217, while a second patient likely had HLH with a partial H-score of 145 due to a missing triglyceride level. The remaining 2 patients had H-scores of 131 and 96. CONCLUSIONS: This is the first report of severe acute respiratory syndrome coronavirus 2-associated HLH. Identification of HLH in a subset of patients with severe COVID-19 will inform clinical trials of therapeutic strategies.


Asunto(s)
Betacoronavirus , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/patología , Linfohistiocitosis Hemofagocítica/patología , Linfohistiocitosis Hemofagocítica/virología , Neumonía Viral/diagnóstico , Neumonía Viral/patología , Anciano , Anciano de 80 o más Años , Autopsia , Médula Ósea/patología , COVID-19 , Infecciones por Coronavirus/complicaciones , Resultado Fatal , Femenino , Humanos , Hígado/patología , Pulmón/patología , Ganglios Linfáticos/patología , Linfohistiocitosis Hemofagocítica/diagnóstico , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/complicaciones , SARS-CoV-2 , Bazo/patología
16.
Amyloid ; 27(4): 244-249, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-32551974

RESUMEN

The proteasome inhibitor, bortezomib, has become a backbone for the first line treatment of patients with AL amyloidosis who are not eligible for high dose melphalan and stem cell transplantation. The presence of t(11;14), seen in up to 40-60% of patients with AL amyloidosis, may be associated with poorer response when treated with bortezomib based regimens. This remains a critical distinction in light of recent evidence demonstrating favourable responses to BCL-2 inhibition with venetoclax in patients with t(11;14) in multiple myeloma. We report on 135 patients with newly diagnosed AL amyloidosis treated with a bortezomib-based regimen as first line therapy between 2013 and 2017. Treatment outcomes were compared between a cohort of patients with t(11;14) and those without the translocation. Forty-four patients had the presence of t(11;14). Five-year overall survival was 46% for those with t(11;14) and 72% in patients without this translocation (p = .026). The median haematologic event free survival was 17 months for patients with t(11;14) compared to 34 months without (p = .068). Haematologic response of VGPR or better was achieved in 41% of patients with t(11;14) vs 66% without t(11;14) (p = .012). Cardiac and renal responses to first line treatment with bortezomib-based regimens were also higher in patients without t(11;14). In conclusion, patients with AL amyloidosis and the presence of t(11;14) have inferior outcomes with respect to survival, as well as haematologic and organ responses, when treated with bortezomib-based regimens as first line therapy.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cromosomas Humanos Par 11 , Cromosomas Humanos Par 14 , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/tratamiento farmacológico , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/genética , Translocación Genética , Biomarcadores/metabolismo , Bortezomib/administración & dosificación , Ciclofosfamida/administración & dosificación , Dexametasona/administración & dosificación , Femenino , Humanos , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/metabolismo , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/patología , Masculino , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del Tratamiento
17.
Kidney Int Rep ; 5(4): 485-493, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32274452

RESUMEN

INTRODUCTION: Monoclonal Ig deposition disease (MIDD) frequently leads to kidney failure, and a large proportion of these patients would greatly benefit from kidney transplantation. However, data on kidney transplantation outcomes in MIDD are limited. METHODS: This was a retrospective analysis of long-term renal outcomes of 23 patients with MIDD, including 6 patients who underwent kidney transplantation. RESULTS: The 1-, 5-, and 10-year overall survival (OS) from diagnosis were 95%, 78%, and 65%, respectively. Approximately half of the patients (n = 12) progressed to end-stage renal disease (ESRD) with a median time from diagnosis to ESRD of 3.4 years. The 1-, 5-, and 10-year renal survival from diagnosis were 77%, 48%, and 29% respectively. Renal response was observed only in 5 patients (22%), all of them after achieving hematologic complete response. Median OS from diagnosis was significantly better for those who underwent kidney transplantation versus those who remained on dialysis (19.8 years vs. 8.3 years, P = 0.016). Among patients who underwent kidney transplantation, the shortest survival from MIDD diagnosis was 13.7 years and the longest was 27.8 years. Of the 3 patients with kidney transplants who died, the time from the first kidney transplantation to death was 7.4, 18.8, and 20.4 years. Graft loss due to disease recurrence occurred at 4 months and 3.8 years after kidney transplantation in 2 patients who either were not treated or did not respond to treatment. CONCLUSION: As treatments for MIDD have dramatically improved, more patients are achieving sustained hematologic responses with longer patient and graft survival after kidney transplantation.

18.
Blood Adv ; 4(5): 880-884, 2020 03 10.
Artículo en Inglés | MEDLINE | ID: mdl-32130406

RESUMEN

Despite achieving a hematologic complete response after treatment, many patients with AL amyloidosis do not attain recovery of organ function and/or experience hematologic relapse. A persistent plasma cell clone producing amyloidogenic light chains at levels below the detection threshold of traditional serologic methods is hypothesized to impede organ response in some patients. Assessment of minimal residual disease (MRD) may therefore have clinical importance as a more stringent treatment response tool for patients in a hematologic complete response. We used 2-tube, 10-color combination multiparametric flow cytometry to assess for MRD at a minimum sensitivity of 1 in 105 nucleated cells. Of 65 patients in hematologic complete response, 36 (55%) were found to have a residual clonal plasma cell population in the bone marrow. Comparing the MRD-negative and MRD-positive groups, renal response was observed in 88% vs 64% (P = .06), cardiac response in 75% vs 59% (P = .45), and any organ response in 90% vs 75% (P = .20) of patients. Depth of organ response as measured by the percent decrease in 24-hour proteinuria and brain natriuretic peptide was 96% vs 91% (P = .16) and 55% vs 46% (P = .66), respectively. These data suggest a possible correlation between MRD negativity and higher probability of organ response after treatment in AL amyloidosis. Future prospective studies with a larger cohort are needed to determine the clinical relevance of these improvements. This trial was registered at www.clinicaltrials.gov as #NCT00898235.


Asunto(s)
Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas , Citometría de Flujo , Humanos , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/diagnóstico , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/tratamiento farmacológico , Recurrencia Local de Neoplasia , Neoplasia Residual , Estudios Prospectivos
19.
Blood ; 135(18): 1541-1547, 2020 04 30.
Artículo en Inglés | MEDLINE | ID: mdl-31978210

RESUMEN

Daratumumab, a monoclonal CD38 antibody, is approved in the treatment of myeloma, but its efficacy and safety in light-chain (AL) amyloidosis has not been formally studied. This prospective phase 2 trial of daratumumab monotherapy for the treatment of AL amyloidosis was designed to determine the safety, tolerability, and hematologic and clinical response. Daratumumab 16 mg/kg was administered by IV infusion once weekly for weeks 1 to 8, every 2 weeks for weeks 9 to 24, and every 4 weeks thereafter until progression or unacceptable toxicity, for up to 24 months. Twenty-two patients with previously treated AL amyloidosis were enrolled. The majority of the patients had received high-dose melphalan and stem cell transplantation and/or treatment with a proteasome inhibitor. The median time between prior therapy and trial enrollment was 9 months (range, 1-180 months). No grade 3-4 infusion-related reactions occurred. The most common grade ≥3 adverse events included respiratory infections (n = 4; 18%) and atrial fibrillation (n = 4, 18%). Hematologic complete and very-good-partial response occurred in 86% of patients. The median time to first and best hematologic response was 4 weeks and 3 months, respectively. Renal response occurred in 10 of 15 patients (67%) with renal involvement and cardiac response occurred in 7 of 14 patients (50%) with cardiac involvement. In summary, daratumumab is well tolerated in patients with relapsed AL amyloidosis and leads to rapid and deep hematologic responses and organ responses. This trial was registered at www.clinicaltrials.gov as #NCT02841033.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/tratamiento farmacológico , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/patología , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Biomarcadores , Femenino , Humanos , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/mortalidad , Masculino , Persona de Mediana Edad , Pronóstico , Recurrencia , Resultado del Tratamiento
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