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While cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome are well-recognized acute toxicities of chimeric antigen receptor (CAR) T cell therapy, these complications have become increasingly manageable by protocolized treatment algorithms incorporating the early administration of tocilizumab and corticosteroids. As CAR-T cell therapy expands to new disease indications and the number of long-term survivors steadily increases, there is growing recognition of the need to appropriately evaluate and manage the late effects of CAR-T cell therapy, including late-onset or persistent neurotoxicity, prolonged cytopenias, delayed immune reconstitution and infections, subsequent malignancies, organ dysfunction, psychological distress, and fertility implications. In this review, we provide a practical approach to the long-term survivorship care of the CAR-T cell recipient, with a focus on the optimal strategies to address the common and challenging late complications affecting this unique population.
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Receptores de Antígenos Quiméricos , Humanos , Sobrevivência , Imunoterapia Adotiva/efeitos adversos , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/terapia , Terapia Baseada em Transplante de Células e Tecidos/efeitos adversos , Receptores de Antígenos de Linfócitos TRESUMO
INTRODUCTION: Although daratumumab-containing regimens improve multiple myeloma (MM) outcomes, recurrence is inevitable. METHODS AND OBJECTIVE: We performed a retrospective study using the Canadian Myeloma Research Group Database to benchmark the efficacy of carfilzomib- or pomalidomide-based therapies immediately following progression on daratumumab treatment. RESULTS: We identified 178 such patients; median number of prior lines of therapy was 3, 97% triple-class exposed, and 60% triple-class refractory. In our cohort, 75 received a subsequent carfilzomib-based therapy, 79 received a pomalidomide-based therapy, and 24 received a treatment with both immunomodulatory drug (IMiD) and proteasome inhibitor (PI) using carfilzomib and/or pomalidomide. The median progression-free survival (PFS) and overall survival (OS) for the entire cohort were 4.5 and 14.2 months, respectively. Carfilzomib-based therapy yielded a median PFS and OS of 4.5 and 10.2 months, respectively, compared to 5.2 and 21.7 months for pomalidomide-based therapy. Patients who received both IMiD and PI with carfilzomib and/or pomalidomide had a median PFS and OS of 4.1 and 14.5 months, respectively. CONCLUSION: Our observations demonstrate the poor outcome of MM patients when standard regimens based on carfilzomib and/or pomalidomide are utilized directly after daratumumab-based therapy given in the relapsed setting. Novel therapies, including immune therapies, are urgently needed to improve the outcomes of these daratumumab-exposed patients.
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BACKGROUND: Bone scintigraphy imaging is frequently used to investigate patients with suspected transthyretin cardiac amyloidosis (ATTR-CM). However, the reported accuracy for interpretation approaches has changed over time. We performed a systematic review and meta-analysis to determine the diagnostic accuracy of visual planar grading, heart-to-contralateral (HCL) ratio, and quantitative analysis of SPECT imaging and evaluate reasons for shifts in reported accuracy. METHODS: We performed a systematic review to identify studies of the diagnostic accuracy of bone scintigraphy for ATTR-CM from 1990 until February 2023 using PUBMED and EMBASE. Studies were reviewed separately by two authors for inclusion and for risk of bias assessment. Summary receiver operating characteristic curves and operating points were determined with hierarchical modeling. RESULTS: Out of a total of 428 identified studies, 119 were reviewed in detail and 23 were included in the final analysis. The studies included a total of 3954 patients, with ATTR-CM diagnosed in 1337 (39.6%) patients and prevalence ranging from 21 to 73%. Visual planar grading and quantitative analysis had higher diagnostic accuracy (.99) than HCL ratio (.96). Quantitative analysis of SPECT imaging had the highest specificity (97%) followed by planar visual grade (96%) and HCL ratio (93%). ATTR-CM prevalence accounted for some of the observed between study heterogeneity. CONCLUSIONS: Bone scintigraphy imaging is highly accurate for identifying patients with ATTR-CM, with between study heterogeneity in part explained by differences in disease prevalence. We identified small differences in specificity, which may have important clinical implications when applied to low-risk screening populations.
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Neuropatias Amiloides Familiares , Cardiomiopatias , Humanos , Pré-Albumina , Neuropatias Amiloides Familiares/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Cintilografia , Cardiomiopatias/diagnóstico por imagemRESUMO
Daratumumab (dara) has significantly altered the therapeutic landscape of multiple myeloma (MM), especially in the relapsed setting. This study aimed to evaluate the outcomes of dara-containing regimens in the Canadian real-world setting among relapsed and refractory MM available within the national Canadian Myeloma Research Group Database (CMRG-DB). A total of 583 MM patients who received dara-based therapy in second-line or later treatment were included. After a median follow-up of 17.5 months, the median progression-free survival (PFS) and overall survival (OS) for the entire cohort were 13.1 and 32.9 months, respectively. The median PFS and OS were 23.5 and 49.1 months in second-line treatment and decreased to 12.8 and 43.0 months in third-line and 7.0 and 20.5 months in fourth-line treatment respectively. Dara in monotherapy with or without corticosteroids after a median of four prior lines of therapy resulted in a median PFS of 3.9 months and a median OS of 17.1 months. The addition of bortezomib, lenalidomide or pomalidomide to dara resulted in an improved median PFS and OS of 8.3 and 26.2 months; 26.8 and 43.0 months; and 9.7 and 31.4 months respectively. These retrospective data from the CMRG-DB suggest that outcomes are superior when dara is used in combination and in earlier lines of treatment.
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Mieloma Múltiplo , Anticorpos Monoclonais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Canadá/epidemiologia , Estudos de Coortes , Dexametasona , Humanos , Mieloma Múltiplo/tratamento farmacológico , Estudos RetrospectivosRESUMO
BACKGROUND AIMS: The value of routine chimerism determination after myeloablative hematopoietic cell transplantation (HCT) is unclear, particularly in the setting of anti-thymocyte globulin (ATG)-based graft-versus-host disease (GVHD) prophylaxis. METHODS: Blood samples were collected at 3 months post-HCT from 558 patients who received myeloablative conditioning and ATG-based GVHD prophylaxis. Chimerism was assessed using multiplex polymerase chain reaction of short tandem repeats in sorted T cells (CD3+) and leukemia lineage cells (CD13+CD33+ for myeloid malignancies and CD19+ for B-lymphoid malignancies). ATG exposure was determined using a flow cytometry-based assay. The primary outcomes of interest were relapse and chronic GVHD (cGVHD). RESULTS: Incomplete (<95%) T-cell chimerism and leukemia lineage chimerism were present in 17% and 4% of patients, respectively. Patients with incomplete T-cell chimerism had a significantly greater incidence of relapse (36% versus 22%, subhazard ratio [SHR] = 2.03, P = 0.001) and lower incidence of cGVHD (8% versus 25%, SHR = 0.29, P < 0.001) compared with patients with complete chimerism. In multivariate modeling, patients with high post-transplant ATG area under the curve and any cytomegalovirus (CMV) serostatus other than donor/recipient seropositivity (non-D+R+) had an increased likelihood of incomplete T-cell chimerism. Patients with incomplete leukemia lineage chimerism had a significantly greater incidence of relapse (50% versus 23%, SHR = 2.70, P = 0.011) and, surprisingly, a greater incidence of cGVHD (45% versus 20%, SHR = 2.64, P = 0.003). CONCLUSIONS: High post-transplant ATG exposure and non-D+R+ CMV serostatus predispose patients to incomplete T-cell chimerism, which is associated with an increased risk of relapse. The increased risk of cGVHD with incomplete B-cell/myeloid chimerism is a novel finding that suggests an important role for recipient antigen-presenting cells in cGVHD pathogenesis.
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Infecções por Citomegalovirus , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia , Humanos , Doença Enxerto-Hospedeiro/prevenção & controle , Soro Antilinfocitário , Quimerismo , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Fatores de Risco , Doença Crônica , Citomegalovirus , RecidivaRESUMO
Severe acute respiratory syndrome coronavirus (SARS-CoV2) and associated COVID-19 infection continue to impact patients globally. Patients with underlying health conditions are at heightened risk of adverse outcomes from COVID-19; however, research involving patients with rare health conditions remains scarce. The amyloidoses are a rare grouping of protein deposition diseases. Light-chain and transthyretin amyloidosis are the most common disease forms, often present with systemic involvement of vital organs including the heart, nerves, kidneys, and GI tracts of affected individuals. The Amyloidosis Program of Calgary examined 152 ATTR patients and 103 AL patients analyzing rates of vaccination, COVID-19 testing, infection outcomes, influence referrals, and excess deaths. Results showed 15 total PCR-confirmed COVID-19 infections in the tested population of amyloid patients, with a higher frequency of infections among patient with AL compared to the ATTR cohort (26.2% vs 5.1%). Four patients (26.6%) required hospital admission for COVID-19 infection, 2 ATTR, and 2 AL patients. Of the confirmed cases, 1 (0.07%) unvaccinated ATTR patient died of a COVID-19 infection. An excess of deaths was found in both the ATTR and AL cohorts when comparing pre-pandemic years 2018 and 2019 to the pandemic years of 2020 and 2021. The finding suggests that amyloidosis patients are likely at a high risk for severe COVID-19 infection and mortality, especially those of advanced age, those on an active treatment with chemotherapy, and those with concomitant B-cell or plasma cell disorder. The impact of virtual healthcare visits and pandemic measures on the excess of deaths observed requires further research.
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Neuropatias Amiloides Familiares , COVID-19 , Amiloide/metabolismo , Teste para COVID-19 , Humanos , RNA Viral , SARS-CoV-2RESUMO
BACKGROUND: Quantitation of myocardial 99m Tc-pyrophosphate activity may have high diagnostic accuracy, but its correlation with disease burden is unknown. We examined the relationship between 99m Tc-pyrophosphate quantitation and cardiac magnetic resonance (CMR) measures in patients with suspected transthyretin cardiac amyloidosis (ATTR-CM) or light chain cardiac amyloidosis (AL-CM). METHODS: Consecutive patients who underwent 99mTc-pyrophosphate imaging and CMR were included. ATTR-CM and AL-CM were diagnosed using standard criteria. 99mTc-pyrophosphate images were assessed with standard parameters and quantified with cardiac pyrophosphate activity (CPA) and volume of involvement (VOI). We assessed the association between 99mTc-pyrophosphate image interpretation and CMR tissue characteristics. RESULTS: Seventy patients were identified, mean age 70.4 ± 11.4 years, with ATTR-CM and AL-CM diagnosed in 22 (31%) and 11 (16%) patients, respectively. In patients with ATTR-CM, there were significant correlations between CPA (r2 = 0.509, P < 0.001) and VOI (r2 = 0.586, P < 0.001) with native myocardial T1 mapping values. Additionally, CPA (adjusted hazard ratio (aHR) 1.04, P = 0.016), VOI (aHR 1.12, P = 0.034), and average myocardial T1 (aHR 1.12, P = 0.025) were associated with incidence of heart failure hospitalization or death. CONCLUSION: CPA and VOI were correlated with CMR measures of myocardial fibrosis in patients with ATTR-CM. 99mTc-pyrophosphate quantitation may have a role in ATTR-CM disease staging, guiding treatment, or following response to therapy.
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Amiloidose , Cardiomiopatias , Idoso , Idoso de 80 Anos ou mais , Amiloidose/diagnóstico por imagem , Cardiomiopatias/diagnóstico por imagem , Difosfatos , Humanos , Espectroscopia de Ressonância Magnética , Pessoa de Meia-Idade , Pré-Albumina , Tecnécio , Pirofosfato de Tecnécio Tc 99mRESUMO
BACKGROUND: The impact of coronavirus disease-19 on the management of multiple myeloma (MM) has been recognized. However, the real effect on clinical outcomes remains poorly understood. OBJECTIVE: We describe a local experience of the management of MM patients and report their outcomes during the current pandemic. METHODS: All consecutive symptomatic MM patients seen at our center since 03/20 were evaluated. RESULTS: A cohort of 156 patients diagnosed from 01/19 to 12/20 was analyzed to interrogate differences in presentation patterns. A total of 553 MM patients were seen and/or treated at Tom Baker Cancer Center in the year of 2020. From those, 47.1% (n = 261) were tested for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Sixteen patients tested positive and data are presented. In addition, a decrease of 21.7% in the rate of new smoldering MM/MM diagnosis was observed in 2020 as compared to 2019. Further, an increase in deaths was also observed in 2020. CONCLUSIONS: Our study confirms an increase lethality for MM patients infected with SARS-CoV-2. A balance between safety and need for cancer control should be emphasized.
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COVID-19 , Mieloma Múltiplo , COVID-19/complicações , COVID-19/mortalidade , Canadá/epidemiologia , Humanos , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/epidemiologia , Pandemias , SARS-CoV-2RESUMO
Bortezomib-containing regimens (BCRs) represented standard, first-line therapy for transplant-ineligible multiple myeloma (TIMM) in Canada until the introduction of lenalidomide and low-dose dexamethasone (Ld). However, little comparative data exist to inform the selection of regimens. We assessed the outcomes for TIMM patients treated with cyclophosphamide, bortezomib and dexamethasone or prednisone (CyBorD/P), bortezomib, melphalan and prednisone (VMP), bortezomib and dexamethasone or prednisone (VD/P) and lenalidomide and low-dose dexamethasone (Ld) using the Canadian Myeloma Research Group database. Of 1156 TIMM patients evaluated, 82% received bortezomib combinations while 18% received Ld. Median progression-free survival (PFS) was 21·0, 21·1, 13·2 and 28·5 months (P = 0·0002) and median overall survival (OS) was 52·0, 63·6, 30·8 and 65·7 months (P < 0·0001) in the CyBorD/P, VMP, VD/P and Ld groups respectively. There was no significant difference in PFS and OS between the two triplet bortezomib regimens (VMP and CyBorD/P). Ld was associated with a longer PFS but not a significantly superior OS to date. Outcomes with the bortezomib-steroid doublet were inferior (VD/P). However, multivariable analysis identified features related to disease biology as the most important prognostic factors for PFS and OS. Such factors, as well as those affecting the physician's choice of regimen, are likely to influence the results observed with different regimens. This study demonstrated real-world outcomes in TIMM similar to those reported in clinical trials.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bases de Dados Factuais , Mieloma Múltiplo/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Bortezomib/administração & dosagem , Canadá/epidemiologia , Dexametasona/administração & dosagem , Feminino , Seguimentos , Humanos , Lenalidomida/administração & dosagem , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidadeRESUMO
Elevated levels of serum cardiovascular markers including natriuretic peptides (NPs) such as amino terminal pro-brain natriuretic peptide (NTproBNP) have been associated with disease severity and survival in cancer patients and more recently in multiple myeloma (MM). In the present study, we retrospectively reviewed 87 consecutive symptomatic TEMM (transplant-eligible) and 126 TIMM (transplant-ineligible) patients treated at our institution that did undergo NTproBNP testing from 2017 to 2020. Median age at diagnosis was 59.3 years and 75.4 years for the TEMM and TIMM groups, respectively (p = 0.0001). NTproBNP ≥ 300 ng/L was used to assess survival outcomes in the group of symptomatic MM. Patients with AL amyloidosis and symptomatic MM were excluded from the study. Median OS for patients with NTproBNP ≥ 300 ng/L was shorter (45.9 months) as compared to those with NTproBNP of < 300 ng/L (non-reached) (p = 0.0001). In addition, OS was shorter for those with CCI > 2, ISS2-3, and high-risk cytogenetics by FISH and ≥ 70 years of age. Multivariate analysis showed that HR cytogenetics and ISS2-3 were independent predictors for OS in the entire cohort of MM patients. When restricted to TIMM, age ≥ 80 years and NTproBNP ≥ 800 ng/L were predictors for OS in univariate and multivariate analyses. In conclusion, NTproBNP appears to be an independent predictor factor for OS in symptomatic TIMM patients. The use of NTproBNP as a frailty marker remains to be elucidated. However, NTproBNP could potentially be used to guide treatment decisions aimed to minimize cardiovascular and renal toxicity for myeloma therapies that potentially do have cardio-renal implications.
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Mieloma Múltiplo/sangue , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Adulto , Idoso , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/epidemiologia , Prognóstico , Estudos Retrospectivos , Análise de SobrevidaRESUMO
INTRODUCTION: Patients with AL amyloidosis and immunoglobulin deposition diseases (IDD) are vulnerable during the COVID-19 pandemic due to the immune compromise from the plasma cell disorder and therapy-related immune defects. We describe a local experience in providing care for patients with AL amyloidosis and IDD. METHOD: Patient treatment and disease status since the beginning of the pandemic on March 11, 2020, as declared by WHO, were collected and analyzed. RESULTS: Ninety-six patients with AL amyloidosis and IDD were included. Four patients with IDD and 22 patients with systemic AL amyloidosis were receiving treatment during the pandemic. Since the pandemic, patients' treatments were discontinued if they achieved VGPR or better postinduction. Seven patients discontinued all treatment after achieving VGPR, and others required treatment modifications. 28 patients have been tested for COVID-19, and all tests have been negative. Three patients died since the pandemic, two from organ complications of systemic AL amyloidosis and one from an unrelated cause. CONCLUSION: The management of AL amyloidosis and IDD must be individualized on the clinical characteristics, centers' access to care under the pandemic restrictions, and the epidemiological aspects of the outbreak.
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COVID-19 , Cadeias Leves de Imunoglobulina/análise , Amiloidose de Cadeia Leve de Imunoglobulina/tratamento farmacológico , Pandemias , Paraproteinemias/tratamento farmacológico , SARS-CoV-2 , Idoso , Alberta/epidemiologia , Anticorpos Monoclonais/uso terapêutico , Membrana Basal/imunologia , Membrana Basal/patologia , Bortezomib/uso terapêutico , COVID-19/diagnóstico , COVID-19/epidemiologia , Teste para COVID-19/estatística & dados numéricos , Ciclofosfamida/uso terapêutico , Dexametasona/uso terapêutico , Gerenciamento Clínico , Suscetibilidade a Doenças , Quimioterapia Combinada , Feminino , Humanos , Amiloidose de Cadeia Leve de Imunoglobulina/mortalidade , Estimativa de Kaplan-Meier , Lenalidomida/uso terapêutico , Masculino , Metilprednisolona/uso terapêutico , Pessoa de Meia-Idade , Neoplasia Residual , Paraproteinemias/mortalidade , Medicina de Precisão , Estudos Retrospectivos , TelemedicinaRESUMO
Lenalidomide is an important component of initial therapy in newly diagnosed multiple myeloma, either as maintenance therapy post-autologous stem cell transplantation (ASCT) or as first-line therapy with dexamethasone for patients' ineligible for ASCT (non-ASCT). This retrospective study investigated treatment patterns and outcomes for ASCT-eligible and -ineligible patients who relapsed after lenalidomide as part of first-line therapy, based on data from the Canadian Myeloma Research Group Database for patients treated between January 2007 and April 2019. Among 256 patients who progressed on lenalidomide maintenance therapy, 28.5% received further immunomodulatory derivative-based (IMiD-based) therapy (lenalidomide/pomalidomide) without a proteasome inhibitor (PI) (bortezomib/carfilzomib/ixazomib), 26.2% received PI-based therapy without an IMiD, 19.5% received both an IMiD plus PI, 13.5% received daratumumab-based regimens, and 12.1% underwent salvage ASCT. Median progression-free survival (PFS) was longest for daratumumab-based therapy (22.7 months) and salvage ASCT (23.4 months) and ranged from 6.6 to 7.3 months for the other treatments (P < .0001). Median overall survival (OS) was also longest for daratumumab and salvage ASCT. A total of 87 non-ASCT patients received subsequent therapy, with 66.7% receiving bortezomib-based therapy and 13.8% receiving other PI-based therapy. Median PFS was 15.4 and 24.8 months for bortezomib-based and other PI-based therapy, respectively (P = .404). During most of the study period, daratumumab was not funded; in this setting, switching to a different therapeutic class following relapse on lenalidomide produced the longest remissions for non-ASCT patients. Further prospective studies are warranted to determine optimum treatment following relapse on lenalidomide, especially in the light of increased access to daratumumab.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Lenalidomida/uso terapêutico , Mieloma Múltiplo/terapia , Adulto , Idoso , Anticorpos Monoclonais/uso terapêutico , Compostos de Boro/uso terapêutico , Bortezomib/uso terapêutico , Canadá , Dexametasona/uso terapêutico , Feminino , Glicina/análogos & derivados , Glicina/uso terapêutico , Humanos , Quimioterapia de Manutenção , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Oligopeptídeos/uso terapêutico , Recidiva , Estudos Retrospectivos , Terapia de Salvação , Análise de Sobrevida , Talidomida/análogos & derivados , Talidomida/uso terapêutico , Transplante AutólogoRESUMO
OBJECTIVES: To understand the impact of therapy sequencing on progression-free (PFS) and overall survival (OS) for the treatment of multiple myeloma (MM). The use of daily, low-dose, lenalidomide maintenance (LM) has raised concern for fostering resistance, preventing its use in the relapsed setting. METHODS: We conducted a retrospective analysis of survival outcomes from the Canadian Myeloma Research Group Database. Patients were grouped based on receipt of LM after autologous stem cell transplant and receipt of lenalidomide in second-line therapy, 575 patients were included. RESULTS: Patients treated with LM had statistically similar 2nd PFS when re-exposed to lenalidomide in second-line therapy compared to those receiving non-lenalidomide-containing regimens (10.2 vs 14.0 months, P =.53). This cohort also had the longest 2nd OS, 18 months longer than patients treated with LM who did not receive lenalidomide at relapse (55.3 vs 37 months, P =.004). Patients treated with LM also demonstrated deeper responses to second-line therapy than their non-LM counterparts. CONCLUSION: Our data suggest that patients progressing on LM who receive lenalidomide-containing therapy at first relapse have comparable 2nd PFS and better 2nd OS compared to non-lenalidomide-containing second-line regimens. Identification of patients mostly likely to benefit from further lenalidomide-containing therapy is paramount.
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Lenalidomida/uso terapêutico , Mieloma Múltiplo/terapia , Cuidados Pré-Operatórios , Canadá , Gerenciamento Clínico , Transplante de Células-Tronco Hematopoéticas , Humanos , Lenalidomida/administração & dosagem , Quimioterapia de Manutenção , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/mortalidade , Prognóstico , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Patients with monoclonal gammopathy of undetermined significance (MGUS) have clinical features including older age, presence of medical comorbidities, susceptibility to infections, and thrombotic tendencies which are relevant when assessing their risk during the coronavirus disease (COVID-19) pandemic. OBJECTIVE: To study the vulnerability of patients with MGUS during the COVID-19 pandemic, we assessed the local management of MGUS patients and their clinical outcomes. METHODS: Retrospective chart reviews were performed for all patients with MGUS seen at a university medical center clinic (2014-2020). RESULTS: A total of 228 MGUS patients were included; 211 patients are alive, 7 patients died before the pandemic, and 10 patients died since the pandemic declaration. The mean age and the overall survival (OS) of the patients who died before versus during the pandemic were 83.0 versus 75.2 years, p = 0.4, and OS 40.6 versus 53.2 months, p = 0.3, respectively. One patient died of COVID-19. Nine patients had venous thromboembolisms (VTE), all of which occurred before the pandemic onset. CONCLUSIONS: There were no significant differences found in the mean age or OS of the MGUS patients who died before versus after the pandemic onset. An increase in VTE rates was not seen. Study results are limited by small patient numbers.
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COVID-19 , Gamopatia Monoclonal de Significância Indeterminada/terapia , Tromboembolia Venosa/epidemiologia , Centros Médicos Acadêmicos , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Gamopatia Monoclonal de Significância Indeterminada/epidemiologia , Gamopatia Monoclonal de Significância Indeterminada/mortalidade , Estudos Retrospectivos , Taxa de Sobrevida , Tromboembolia Venosa/etiologia , Populações VulneráveisRESUMO
BACKGROUND: International guidelines for Pneumocystis jirovecii pneumonia (PJP) prevention recommend prophylaxis for ≥6 months following allogeneic hematopoietic cell transplantation, and longer in patients with graft-versus-host disease (GVHD) or on immunosuppressive therapy (IST). These recommendations are based on cohorts of patients who did not routinely receive anti-thymocyte globulin (ATG) for GVHD prophylaxis. METHODS: We performed a retrospective chart review of 649 patients, all of whom received ATG as part of GVHD prophylaxis. RESULTS: The cumulative incidence of definite PJP was 3.52% at both 3 and 5 years (median follow up, 1648 days for survivors). PJP occurred in 13 non-GVHD patients between days 207 and 508, due in part to low CD4 T-cell counts (<200 CD4 T cells/µL). PJP occurred in eight GVHD patients between days 389 and 792, due in part to non-adherence to PJP prophylaxis guidelines (discontinuation of PJP prophylaxis at <3 months after discontinuation of IST). Breakthrough PJP infection was not observed in patients receiving prophylaxis with cotrimoxazole, dapsone or atovaquone, whereas three cases were observed with inhaled pentamidine. DISCUSSION: In conclusion, for non-GVHD patients receiving ATG-containing GVHD prophylaxis, 6 months of PJP prophylaxis is inadequate, particularly if the CD4 T-cell count is <200 cells/µL or if there is a high incidence of PJP in the community. For patients with GVHD receiving ATG-containing GVHD prophylaxis, continuing PJP prophylaxis until ≥3 months post-discontinuation of IST is important. Cotrimoxazole, dapsone and atovaquone are preferred over inhaled pentamidine.
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Antibacterianos/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Terapia de Imunossupressão/efeitos adversos , Pneumocystis carinii/isolamento & purificação , Pneumonia por Pneumocystis/epidemiologia , Adolescente , Adulto , Idoso , Soro Antilinfocitário/efeitos adversos , Soro Antilinfocitário/uso terapêutico , Atovaquona/uso terapêutico , Contagem de Linfócito CD4 , Dapsona/uso terapêutico , Feminino , Doença Enxerto-Hospedeiro/tratamento farmacológico , Humanos , Hospedeiro Imunocomprometido/imunologia , Incidência , Linfopenia/induzido quimicamente , Linfopenia/imunologia , Masculino , Pessoa de Meia-Idade , Pentamidina/efeitos adversos , Pentamidina/uso terapêutico , Pneumonia por Pneumocystis/tratamento farmacológico , Pneumonia por Pneumocystis/prevenção & controle , Estudos Retrospectivos , Combinação Trimetoprima e Sulfametoxazol/uso terapêutico , Adulto JovemRESUMO
Optimal conditioning and graft-vs-host disease (GVHD) prophylaxis for hematopoietic cell transplantation (HCT) are unknown. Here, we report on outcomes after low toxicity, myeloablative conditioning consisting of fludarabine, busulfan, and 4 Gy total body irradiation, in combination with thymoglobulin and post-transplant methotrexate and cyclosporine. We retrospectively studied 700 patients with hematologic malignancies who received blood stem cells from 7 to 8/8 HLA-matched unrelated or related donors. Median follow-up of surviving patients was 5 years. At 5 years, overall survival (OS), relapse-free survival (RFS), and chronic GVHD/relapse-free survival (cGRFS) were 58%, 55%, and 40%. Risk factors for poor OS, RFS, and cGRFS were (1). high to very high disease risk index (DRI), (2). high recipient age, and (3). cytomegalovirus (CMV)-seropositive recipient with seronegative donor (D-R+). The latter risk factor applied particularly to patients with lymphoid malignancies. Neither donor other than HLA-matched sibling (7-8/8 unrelated) nor one HLA allele mismatch was risk factors for poor OS, RFS, or cGRFS. In conclusion, the above regimen results in excellent long-term outcomes. The outcomes are negatively impacted by older age, high or very high DRI, and CMV D-R+ serostatus, but not by donor unrelatedness or one HLA allele mismatch.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Idoso , Soro Antilinfocitário/uso terapêutico , Bussulfano/uso terapêutico , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Agonistas Mieloablativos/uso terapêutico , Recidiva Local de Neoplasia , Estudos Retrospectivos , Condicionamento Pré-Transplante , Resultado do Tratamento , Vidarabina/análogos & derivados , Vidarabina/uso terapêutico , Irradiação Corporal TotalRESUMO
BACKGROUND: The tolerability and utility of combination doxycycline and ursodeoxycholic acid (ursodiol) amyloid fibril disruption therapy for transthyretin cardiac amyloidosis (ATTR CA) in clinical practice is poorly described. METHODS AND RESULTS: We report the clinical experience of 53 ATTR CA patients treated with doxycycline and ursodiol. Six patients (11%) did not tolerate the therapy owing to dermatologic and gastrointestinal effects. Of those remaining, the median follow-up was 22 months (range 8-30), mean age was 71 ± 11years, 41 (87%) were male, and 42 (89%) had wild-type and 5 (11%) mutant ATTR. Five patients (11%) died during follow-up. There was no significant change in New York Heart Association (NYHA) functional class, cardiac biomarkers, or echocardiographic parameters during follow-up. Left ventricular (LV) global longitudinal systolic strain (GLS) improved in 16 patients (38%) (-12 ± 4% to -17 ± 4%; P < .01). Patients whose LV GLS improved were significantly younger and had lower NYHA functional class, troponin-T, N-terminal pro-B-type natriuretic peptide (BNP), and baseline LV GLS levels compared with those whose LV GLS did not improve. Troponin-T improved in follow-up for patients whose LV GLS improved (35 ± 21 to 20 ± 14 ng/L; Pâ¯=â¯.06). CONCLUSIONS: Doxycycline and ursodiol therapy for treatment of ATTR CA was tolerable and was associated with stabilized markers of disease progression. LV GLS improved in patients with less advanced disease.
Assuntos
Amiloidose/tratamento farmacológico , Doxiciclina/administração & dosagem , Cardiopatias/tratamento farmacológico , Pré-Albumina , Ácido Ursodesoxicólico/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Amiloide/antagonistas & inibidores , Amiloide/metabolismo , Amiloidose/metabolismo , Antibacterianos/administração & dosagem , Colagogos e Coleréticos/administração & dosagem , Estudos de Coortes , Quimioterapia Combinada , Feminino , Seguimentos , Cardiopatias/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Pré-Albumina/metabolismo , Resultado do TratamentoRESUMO
BACKGROUND: Post-transplant lymphoproliferative disorder (PTLD) is a potentially fatal complication of allogeneic hematopoietic cell transplantation (HCT). Epstein-Barr virus (EBV) reactivation (detectable DNAemia) predisposes to the development of PTLD. METHODS: We retrospectively studied 306 patients monitored for EBV DNAemia after Thymoglobulin-conditioned HCT to determine the utility of the monitoring in the management of PTLD. DNAemia was monitored weekly for ≥12 weeks post-transplantation. RESULTS: Reactivation was detected in 82% of patients. PTLD occurred in 14% of the total patients (17% of patients with reactivation). PTLD was treated with rituximab only when and if the diagnosis was established. This allowed us to evaluate potential DNAemia thresholds for pre-emptive therapy. We suggest 100,000-500,000 IU per mL whole blood as this would result in unnecessary rituximab administration to only 4-20% of patients and near zero mortality due to PTLD. After starting rituximab (for diagnosed PTLD), sustained regression of PTLD occurred in 25/25 (100%) patients in whom DNAemia became undetectable. PTLD progressed or relapsed in 12/17 (71%) patients in whom DNAemia was persistently detectable. DISCUSSION: In conclusion, for pre-emptive therapy of PTLD, we suggest threshold DNAemia of 100,000-500,000 IU/mL. Persistently detectable DNAemia after PTLD treatment with rituximab appears to have 71% positive predictive value and 100% negative predictive value for PTLD progression/relapse.
Assuntos
DNA Viral/sangue , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Herpesvirus Humano 4/genética , Transtornos Linfoproliferativos/etiologia , Transtornos Linfoproliferativos/virologia , Adolescente , Adulto , Idoso , Infecções por Vírus Epstein-Barr/sangue , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/virologia , Feminino , Herpesvirus Humano 4/imunologia , Humanos , Transtornos Linfoproliferativos/sangue , Transtornos Linfoproliferativos/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Rituximab/uso terapêutico , Ativação Viral , Adulto JovemRESUMO
Epstein-Barr virus (EBV)-induced post-transplant lymphoproliferative disorder (PTLD) occurs frequently when rabbit antithymocyte globulin (ATG) is used in hematopoietic cell transplant (HCT) conditioning. We retrospectively studied 554 patients undergoing ATG-conditioned myeloablative HCT. Strategies used to minimize mortality due to PTLD were either therapy of biopsy-diagnosed PTLD in the absence of EBV DNAemia monitoring (n = 266) or prompt therapy of presumed PTLD (based on clinical/radiologic signs and high EBV DNAemia, in the setting of weekly EBV DNAemia monitoring) (n = 199). Both strategies resulted in similar mortality due to PTLD (0.7% vs 1% at 2 years, P = .43) and similar overall survival (63% vs 67% at 2 years, P = .23) even though there was a trend toward higher PTLD incidence with the prompt therapy. Donor positive with recipient negative EBV (D+R-) serostatus was a risk factor for developing PTLD. Older patient age, HLA-mismatched donor, and graft-versus-host disease were not associated with increased risk of PTLD. In summary, in ATG-conditioned HCT, D+R- serostatus, but not older age, mismatched donor or GVHD is a risk factor for developing PTLD. EBV DNAemia monitoring may be a weak risk factor for developing/diagnosing PTLD; the monitoring coupled with prompt therapy does not improve survival.
Assuntos
Soro Antilinfocitário/administração & dosagem , Infecções por Vírus Epstein-Barr/complicações , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Herpesvirus Humano 4/patogenicidade , Transtornos Linfoproliferativos/etiologia , Condicionamento Pré-Transplante/efeitos adversos , Adolescente , Adulto , Idoso , Criança , Infecções por Vírus Epstein-Barr/virologia , Feminino , Seguimentos , Herpesvirus Humano 4/isolamento & purificação , Humanos , Imunossupressores/administração & dosagem , Transtornos Linfoproliferativos/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Carga Viral , Adulto JovemRESUMO
In multiple myeloma (MM) patients ineligible for transplant, the selection of up-front therapy needs to balance efficacy and toxicity. Recently, regimens with bortezomib, a proteasome inhibitor with anti-myeloma effects, have been reported. We aimed to evaluate the impact of different bortezomib-containing regimens (BCR) for the treatment of transplant-ineligible MM. All- consecutive patients treated with BCR at our institution from 01/05 to 02/16 were evaluated. With a median of 6 cycles, an overall response rate of 95.2, 80.9, and 76.3% was observed for patients treated with cyclophosphamide-bortezomib-dexamethasone (CyBorD), bortezomib-melphalan-prednisone (VMP), and bortezomib-dexamethasone (VD), respectively (p = 0.03). The median overall survival was similar between the three different BCR, but a trend for better progression-free survival was noted in favor of CyBorD. BCR are efficacious in the treatment of transplant-ineligible MM. Patients receiving continuous therapy (CT) exhibited better outcomes, suggesting that strategies to prevent toxicity and increase the cumulative dose are warranted.