RESUMEN
Patients with systemic light chain (AL) amyloidosis undergoing treatment with high-dose melphalan and autologous stem cell transplantation (HDM/SCT) may develop renal and cardiac toxicities potentially exacerbated by the co-solvent propylene glycol in conventional melphalan formulations. We investigated the safety and efficacy of propylene glycol-free melphalan (PGF-Mel) during HDM/SCT in patients with AL amyloidosis (ClinicalTrials.gov identifier NCT02994784). The primary objective of this phase II, open-label study was evaluation for renal dysfunction, new cardiac arrhythmias, and postural hypotension related to autonomic dysfunction. Secondary objectives included time to neutrophil and platelet engraftment, treatment-related mortality (TRM), overall hematologic response, organ response, and number of peritransplantation hospitalizations. Twenty-eight patients with AL amyloidosis enrolled, of whom 27 underwent HDM/SCT. PGF-Mel at 140 to 200 mg/m2 was administered i.v. in 2 equally divided doses. Patients were monitored for up to 30 days after the last administration of PGF-Mel to assess for treatment-related toxicity. Patients were followed for 12 months from the time of treatment with HDM/SCT for evaluation of hematologic and organ responses. Kaplan-Meier analysis was used to estimate progression-free survival. Two patients (7%) developed renal dysfunction, 5 (19%) experienced new cardiac arrhythmias, and 3 (11%) developed orthostatic hypotension. All patients achieved neutrophil and platelet engraftment, at a median of 10 days and 17 days post-HDM/SCT, respectively. TRM on day +100 was 0%. Peritransplantation hospitalization was required for 23 patients (85%). The most common nonhematologic adverse events were diarrhea (93%), fatigue (82%), and nausea (74%). At 6 months post-HDM/SCT, hematologic complete response or very good partial response occurred in 66% of the patients. At 12 months post-HDM/SCT, renal response occurred in 12 of 23 (52%) patients with renal involvement, and cardiac response occurred in 3 of 11 (27%) patients with evaluable cardiac involvement. Our data indicate that PGF-Mel is safe and efficacious as a high-dose conditioning regimen for autologous SCT in patients with AL amyloidosis.
Asunto(s)
Amiloidosis , Trasplante de Células Madre Hematopoyéticas , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas , Enfermedades Renales , Humanos , Melfalán/efectos adversos , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/terapia , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/tratamiento farmacológico , Trasplante de Células Madre Hematopoyéticas/métodos , Amiloidosis/terapia , Trasplante Autólogo , Enfermedades Renales/complicaciones , Enfermedades Renales/tratamiento farmacológico , Arritmias Cardíacas/complicaciones , Arritmias Cardíacas/tratamiento farmacológicoRESUMEN
BACKGROUND: Primary systemic light-chain (AL) amyloidosis is a rare clonal plasma cell disorder characterized by the production of abnormal immunoglobulin fragments, which form insoluble fibrils that aggregate as amyloid deposits in organs and tissues, leading to organ dysfunction and death. OBJECTIVES: The aim of this literature review is to increase awareness of AL amyloidosis and educate nurses on the care of this patient population. METHODS: This overview is based on a literature search of AL amyloidosis, including its pathogenesis, prognosis, and presentation. Guidance for nursing assessment, intervention, and patient education throughout the disease trajectory is presented. FINDINGS: AL amyloidosis is a rare disease resulting in organ impairment and death if untreated. Nursing management includes knowledge of key assessment, monitoring, intervention, and education strategies with goals to preserve organ function and improve survival and quality of life in patients with AL amyloidosis.
Asunto(s)
Amiloidosis , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas , Amiloidosis/tratamiento farmacológico , Amiloidosis/patología , Humanos , Pronóstico , Calidad de VidaRESUMEN
INTRODUCTION: Symptomology of AL amyloidosis can be vague, with a broad range of manifestations and potential etiologies. We sought to determine whether time from initial patient-reported symptom onset to diagnosis was associated with survival. METHODS: The Boston University Amyloidosis Patient Database was queried for patients with AL amyloidosis who presented to the Center for initial evaluation from 2010 to 2015. RESULTS: A total of 324 patients with AL amyloidosis were evaluated for initial evaluation. The median time to diagnosis from initial symptom onset was 7.1 months (range, 0-61). At data cutoff, 60.2% (n = 195) of patients were alive; of those, the majority were diagnosed <6 months from initial symptoms (52.3%, n = 102). In contrast, time to diagnosis from symptom onset was >6 months in 63.6% (n = 82) of patients who did not survive at the time of data cutoff (P = .0005). Survival analysis of time from diagnosis to death or data cutoff stratified by time from patient-reported symptom onset to diagnosis (<6, 6-12, and >12 months) showed significant differences among groups (P = .001). Additionally, multivariable regression demonstrated that an increase in time from self-reported symptom onset to diagnosis was significantly associated with an increased risk of death (HR = 1.02, 95% CI = 1.01-1.04, P = .002). CONCLUSION: These results support the importance of early diagnosis for patients with AL amyloidosis.
Asunto(s)
Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/epidemiología , Bases de Datos Factuales , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Diagnóstico Precoz , Encuestas de Atención de la Salud , Humanos , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/diagnóstico , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/etiología , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/terapia , Evaluación del Resultado de la Atención al Paciente , PronósticoRESUMEN
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 TratamientoAsunto(s)
Infecciones por HTLV-I/complicaciones , Infecciones por HTLV-II/complicaciones , Trasplante de Células Madre Hematopoyéticas , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/terapia , Linfoma de Células B Grandes Difuso/terapia , Mieloma Múltiple/terapia , Enfermedades Asintomáticas , Femenino , Humanos , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/complicaciones , Linfoma de Células B Grandes Difuso/complicaciones , Masculino , Persona de Mediana Edad , Mieloma Múltiple/complicaciones , Estudios Retrospectivos , Trasplante Autólogo , Activación ViralAsunto(s)
Bortezomib/administración & dosificación , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas , Factores Inmunológicos/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Femenino , Humanos , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/sangre , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/tratamiento farmacológico , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/mortalidad , Masculino , Persona de Mediana Edad , Tasa de SupervivenciaRESUMEN
In immunoglobulin light-chain (AL) amyloidosis, the depth of hematologic response to treatment is associated with improved survival and organ responses. We conducted a clinical trial using bortezomib in induction and in conditioning with melphalan before stem cell transplantation (SCT) for AL amyloidosis. The results of this clinical trial with a median follow-up of 36 months have been reported previously. Here we report the long-term results of this clinical trial with a median follow-up of 77 months. We describe survival, durability of hematologic and organ responses, and relapse rates. Thirty-five patients were enrolled between 2010 and 2013. Hematologic complete response and very good partial response (VGPR) were noted in 100% (27 of 27) of the evaluable patients at 6 months post-SCT. Four patients (15%) had hematologic relapse at a median of 42 months, and 1 patient (3.7%) had organ progression despite maintaining a VGPR at 37 months. The median overall survival and progression-free survival have not yet been reached at the time of this report. Renal and cardiac responses occurred in 65% and 88%, respectively, at 5 years post-SCT. The median time to renal and cardiac response was 12 months and 6 months, respectively. In conclusion, incorporating bortezomib into induction and conditioning yielded durable hematologic responses of AL amyloidosis, with corresponding organ responses and prolonged survival.
Asunto(s)
Bortezomib/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/métodos , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/terapia , Inducción de Remisión/métodos , Acondicionamiento Pretrasplante/métodos , Adulto , Anciano , Antineoplásicos/uso terapéutico , Dexametasona/uso terapéutico , Femenino , Estudios de Seguimiento , Humanos , Masculino , Melfalán/uso terapéutico , Persona de Mediana Edad , Agonistas Mieloablativos/uso terapéutico , Trasplante Autólogo , Resultado del TratamientoRESUMEN
High-dose melphalan and autologous stem cell transplantation (HDM/SCT) have been used in patients with immunoglobulin light chain (AL) amyloidosis for over 2 decades now with durable responses, prolonged survival, and decreasing treatment-related mortality. Historically, patients with poorer baseline functional status, advanced age, renal compromise, and cardiac involvement have been treated with a risk-adapted modified conditioning dose of melphalan (mHDM) of 100 to 140 mg/m2 before SCT. In part because of these baseline characteristics, patients receiving mHDM/SCT have had poorer outcomes compared with patients receiving full-dose melphalan at 200 mg/m2. With the advent of novel therapeutic agents such as proteasome inhibitors, immunomodulatory agents, and monoclonal antibodies for the treatment of AL amyloidosis, it is imperative to understand the long-term effects of mHDM/SCT. Here we report the long-term outcomes of 334 patients with AL amyloidosis treated with mHDM/SCT. Median overall survival was 6.1 years and median event-free survival 4.3 years, with median overall survival reaching 13.4 years for patients who had achieved a hematologic complete response (CR). Overall hematologic response rate was 69%, and treatment-related mortality was 3% after 2010. Thus, mHDM/SCT leads to prolonged survival and favorable outcomes, especially if a hematologic CR is achieved.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/tratamiento farmacológico , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/terapia , Melfalán/uso terapéutico , Acondicionamiento Pretrasplante/métodos , Trasplante Autólogo/métodos , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/mortalidad , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/patología , Masculino , Melfalán/farmacología , Persona de Mediana Edad , Análisis de SupervivenciaRESUMEN
Nephrogenic diabetes insipidus is a condition characterized by polyuria with dilute urine due to the inability of the principal cells of the renal collecting ducts to respond to antidiuretic hormone and concentrate urine. Nephrogenic diabetes insipidus can be drug induced, and several chemotherapeutic agents have been reported to cause it. Bendamustine is a traditional chemotherapeutic agent being studied for treatment for relapsed systemic AL amyloidosis. We report a case of a 59-year-old man with AL amyloidosis who developed partial nephrogenic diabetes insipidus after receiving bendamustine for treatment of AL amyloidosis. The nephrogenic diabetes insipidus responded well to sodium restriction, hydrochlorothiazide, and desmopressin treatment, allowing the patient to receive subsequent bendamustine cycles without polyuria. Nephrogenic diabetes insipidus resolved shortly after completion of bendamustine therapy.
Asunto(s)
Amiloidosis/tratamiento farmacológico , Antineoplásicos Alquilantes/efectos adversos , Clorhidrato de Bendamustina/efectos adversos , Diabetes Insípida Nefrogénica/inducido químicamente , Amiloidosis/inmunología , Antineoplásicos Alquilantes/uso terapéutico , Clorhidrato de Bendamustina/uso terapéutico , Humanos , Cadenas Ligeras de Inmunoglobulina , Masculino , Persona de Mediana EdadRESUMEN
The objectives of a phase 1/2 trial of pomalidomide with dexamethasone for the treatment of light chain (AL) amyloidosis were to determine the safety, tolerability, maximum tolerated dose (MTD), recommended phase 2 dose, and hematologic and clinical response. A 3+3 dose-escalation phase (15 patients) was followed by an expansion cohort (12 patients) enrolled at the MTD. Pomalidomide was administered at 2 and 3 mg on days 1 to 28 (cohorts 1 and 2) and 4 mg on days 1 to 21 (cohort 3) every 28 days, with weekly dexamethasone at a dose of 20 mg. Twenty-seven patients with previously treated AL were enrolled, 15 during dose escalation (6 at 2 mg, 3 at 3 mg, and 6 at 4 mg) and 12 during dose expansion (all at 4 mg). One patient experienced dose-limiting toxicity at 4 mg; the MTD was determined as 4 mg. The most common grade ≥3 drug-related adverse events included myelosuppression and fatigue. Overall, hematologic response (HR) was 50% in 24 evaluable patients. The median time to best HR was 3 cycles, and median duration of HR was 15 months. Median overall survival has not yet been reached, with a median follow-up of 17.1 months and median event-free survival of 17.8 months. This trial was registered at www.clinicaltrials.gov as #NCT01570387.
Asunto(s)
Amiloidosis/tratamiento farmacológico , Dexametasona/uso terapéutico , Talidomida/análogos & derivados , Adulto , Anciano , Dexametasona/efectos adversos , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Análisis de Supervivencia , Talidomida/efectos adversos , Talidomida/uso terapéutico , Resultado del TratamientoRESUMEN
The depth of hematologic response has been shown to correlate with survival and organ responses for patients with light chain (AL) amyloidosis. We conducted a prospective trial of 2 cycles of induction with bortezomib and dexamethasone on a twice a week schedule followed by conditioning with bortezomib and high-dose melphalan (HDM) and autologous stem cell transplantation (SCT). The objectives were hematologic responses, tolerability, and survival. Thirty-five patients were enrolled from 2010 to 2013. Of these, 30 proceeded with SCT, whereas 5 did not because of clinical deterioration during induction (n = 3) or complications after stem cell collection (n = 2). Two patients developed features of an autologous graft-versus-host disease-like syndrome post-SCT, which responded to steroids; no other unusual complications were seen. Treatment-related mortality occurred in 8.5% (3/35). Hematologic responses were achieved by 100% of the 27 assessable patients (63% complete response, 37% very good partial response [VGPR]) who completed the planned treatment. By intention-to-treat, hematologic responses occurred in 77% of patients (49% complete response, 29% VGPR). With a median follow-up of 36 months, the median overall survival and progression-free survival were not reached. In conclusion, incorporating bortezomib into induction and conditioning yielded a high rate of hematologic responses after HDM/SCT in patients with AL amyloidosis.
Asunto(s)
Amiloidosis/tratamiento farmacológico , Amiloidosis/terapia , Antineoplásicos/uso terapéutico , Bortezomib/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/métodos , Quimioterapia de Inducción/métodos , Melfalán/uso terapéutico , Acondicionamiento Pretrasplante/métodos , Adulto , Anciano , Amiloidosis/mortalidad , Antineoplásicos/administración & dosificación , Bortezomib/administración & dosificación , Femenino , Humanos , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas , Masculino , Melfalán/administración & dosificación , Persona de Mediana Edad , Estudios Prospectivos , Análisis de SupervivenciaAsunto(s)
Amiloidosis , Inhibidores de la Angiogénesis/efectos adversos , Neoplasias Primarias Secundarias , Talidomida/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Amiloidosis/tratamiento farmacológico , Amiloidosis/mortalidad , Amiloidosis/patología , Inhibidores de la Angiogénesis/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Lenalidomida , Masculino , Persona de Mediana Edad , Neoplasias Primarias Secundarias/inducido químicamente , Neoplasias Primarias Secundarias/mortalidad , Neoplasias Primarias Secundarias/patología , Estudios Retrospectivos , Factores de Riesgo , Talidomida/administración & dosificación , Talidomida/efectos adversosRESUMEN
We report results of a phase II trial of combination of melphalan, lenalidomide, and dexamethasone for the treatment of immunoglobulin light chain (AL) amyloidosis. The primary objectives were tolerability and hematologic response rate; secondary objectives were organ responses and survival. Treatment protocol consisted of melphalan 5 mg/m(2)/day for four days, lenalidomide 10 mg/day for 21 days and dexamethasone 20-40 mg once a week every 28 days for a total of 12 cycles. Sixteen subjects were enrolled of whom 14 completed at least 3 cycles and were evaluable for response. Grade 3/4 toxicities were experienced by 88% (n=14), the most common being myelosuppression (n=7). Dose reductions occurred in 85% (n=12 of 14) of subjects. Hematologic partial and complete responses were achieved by 43% (n=6 of 14) and 7% (n=1 of 14), respectively. The median overall survival has not been reached and median progression-free survival is 24 months. In conclusion, this combination is associated with significant myelosuppression leading to dose modifications and producing minor hematologic responses in AL amyloidosis. http://clinicaltrials.gov/ct2/show/NCT00679367.