RESUMEN
PURPOSE: In this first-in-human, phase I, GVHD prevention trial (NCT02891603), we combine pacritinib (PAC), a JAK2 inhibitor, with sirolimus to concurrently reduce T-cell costimulation via mTOR and IL6 activity. We evaluate the safety of pacritinib when administered with sirolimus plus low-dose tacrolimus (PAC/SIR/TAC) after allogeneic hematopoietic cell transplantation. PATIENTS AND METHODS: The preclinical efficacy and immune modulation of PAC/SIR were investigated in xenogeneic GVHD. Our phase I trial followed a 3+3 dose-escalation design, including dose level 1 (pacritinib 100 mg daily), level 2 (pacritinib 100 mg twice daily), and level 3 (pacritinib 200 mg twice daily). The primary endpoint was to identify the lowest biologically active and safe dose of pacritinib with SIR/TAC (n = 12). Acute GVHD was scored through day +100. Allografts included 8/8 HLA-matched related or unrelated donor peripheral blood stem cells. RESULTS: In mice, we show that dual JAK2/mTOR inhibition significantly reduces xenogeneic GVHD and increases peripheral regulatory T cell (Treg) potency as well as Treg induction from conventional CD4+ T cells. Pacritinib 100 mg twice a day was identified as the minimum biologically active and safe dose for further study. JAK2/mTOR inhibition suppresses pathogenic Th1 and Th17 cells, spares Tregs and antileukemia effector cells, and exhibits preliminary activity in preventing GVHD. PAC/SIR/TAC preserves donor cytomegalovirus (CMV) immunity and permits timely engraftment without cytopenias. CONCLUSIONS: We demonstrate that PAC/SIR/TAC is safe and preliminarily limits acute GVHD, preserves donor CMV immunity, and permits timely engraftment. The efficacy of PAC/SIR/TAC will be tested in our ongoing phase II GVHD prevention trial.
Asunto(s)
Hidrocarburos Aromáticos con Puentes/administración & dosificación , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Inmunosupresores/administración & dosificación , Inhibidores de las Cinasas Janus/administración & dosificación , Pirimidinas/administración & dosificación , Tacrolimus/administración & dosificación , Animales , Aurora Quinasa A/metabolismo , Ensayos Clínicos como Asunto , Manejo de la Enfermedad , Evaluación Preclínica de Medicamentos , Enfermedad Injerto contra Huésped/diagnóstico , Trasplante de Células Madre Hematopoyéticas/métodos , Prueba de Histocompatibilidad , Humanos , Inmunofenotipificación , Janus Quinasa 2/metabolismo , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Ratones , Factor de Transcripción STAT3/metabolismo , Índice de Severidad de la Enfermedad , Transducción de Señal , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Donantes de Tejidos , Trasplante HomólogoRESUMEN
During the past decade, the demand for hematopoietic stem cell transplantation has grown dramatically, and there are expectations that this will continue or even accelerate over the next decade. This prompts a variety of questions about the ability of the health care system to accommodate the increased demands on transplantation centers; for example, what is the current patient capacity of transplantation programs, and how much elasticity do they have to accept a larger volume of patients? An informal survey of a sample of medical directors of transplantation programs found that existing facilities might be able to increase their patient volume by about 7%. Expanding much beyond that limit will require an infusion of resources to enlarge current programs and/or establish new programs.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Bancos de Tejidos/organización & administración , Recolección de Datos , Fuerza Laboral en Salud , Humanos , Programas Nacionales de Salud , Bancos de Tejidos/normas , Bancos de Tejidos/tendenciasRESUMEN
Health-related quality of life (QOL) is a vital concern in the pre-treatment consent process and post-treatment care of recipients of haematopoietic cell transplantation (HCT). We propose that comprehensive care of such patients requires an integration of knowledge of the impact of HCT on QOL, assessment of QOL, as well as resources available for intervention. This knowledge may significantly improve patient care when incorporated into daily clinical practice in the transplant setting. As a framework for this approach, this article reviews the literature on QOL after allogeneic and autologous HCT for adults with haematological malignancies. We then discuss evidence in support of the beneficial impact of clinical QOL assessment, and finally evaluate behavioural interventions that show promise to maintain or improve QOL after HCT.
Asunto(s)
Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas/psicología , Educación del Paciente como Asunto/métodos , Calidad de Vida , Adulto , Neoplasias Hematológicas/rehabilitación , HumanosRESUMEN
Peripheral blood stem cells (PBSCs) and bone marrow (BM) hematopoietic stem cells represent therapeutic alternatives in allogeneic hematopoietic cell transplantation. Randomized controlled trials and an individual patient data meta-analysis (IPDMA) have demonstrated a decreased risk of disease relapse and an increased risk of acute and chronic graft-versus-host disease (aGVHD, cGVHD) in patients receiving PBSCs compared with those receiving BM stem cells. Decision modeling provides quantitative integration of the risks and benefits associated with these alternative treatments, incorporates survival discounts for lower quality of life in patients with aGVHD or cGVHD and post-transplantation relapse, and allows sensitivity analyses for all model assumptions. We have constructed an externally validated Markov model to represent and analyze the decision to use PBSC or BM, estimating post-transplantation state transition probabilities (eg, GVHD and relapse) and quality-of-life discounts from the IPDMA and relevant literature; importantly, this IPDMA synthesized data from primarily adult patients treated with myeloablative (MA) conditioning regimens with T cell-replete matched sibling donors. In this setting, the model demonstrates the superiority of PBSC over BM in both overall and quality-adjusted life expectancy, with a 7-month advantage for PBSC. Sensitivity analyses support this conclusion through a range of values for each variable supported by the IPDMA and quality-of-life discounts, as supported by the literature. However, BM is the optimal strategy in conditions in which the 1-year relapse probability is < 5%. PBSC is the optimal stem cell source in terms of both overall and quality-adjusted life expectancy, except in conditions with a very low relapse probability, in which BM provides optimal outcomes.
Asunto(s)
Trasplante de Médula Ósea/estadística & datos numéricos , Técnicas de Apoyo para la Decisión , Cadenas de Markov , Trasplante de Células Madre de Sangre Periférica/estadística & datos numéricos , Enfermedad Aguda , Adolescente , Adulto , Anciano , Trasplante de Médula Ósea/efectos adversos , Enfermedad Crónica , Ensayos Clínicos como Asunto/estadística & datos numéricos , Enfermedad Injerto contra Huésped/epidemiología , Enfermedad Injerto contra Huésped/etiología , Humanos , Donadores Vivos , Metaanálisis como Asunto , Persona de Mediana Edad , Agonistas Mieloablativos/administración & dosificación , Trasplante de Células Madre de Sangre Periférica/efectos adversos , Años de Vida Ajustados por Calidad de Vida , Recurrencia , Hermanos , Acondicionamiento Pretrasplante/estadística & datos numéricos , Trasplante Homólogo/efectos adversos , Trasplante Homólogo/estadística & datos numéricos , Resultado del Tratamiento , Adulto JovenRESUMEN
Psoralen plus ultraviolet A irradiation (PUVA) has immunomodulatory effects and is used to treat a variety of immune-mediated dermatologic diseases. We administered PUVA to 103 patients for treatment of steroid-resistant acute graft-versus-host disease (GVHD) of the skin. Twenty-nine patients had related donors (12 HLA-mismatched) and 74 had unrelated donors (23 HLA-mismatched). The median onset of GVHD was day 13 after transplantation, and the median onset of PUVA treatment was day 46. PUVA was administered as secondary therapy for 86 patients and tertiary therapy or greater for 17 patients. The median number of treatments was 16, and the mean cumulative exposure was 41 J/cm2. PUVA was generally well tolerated with 8 patients discontinuing therapy because of toxicity. At the start of PUVA treatment, 48 patients had rash affecting >50% of their body surface area (BSA), and 91 had rash involving >25% BSA. Of 65 patients who were evaluated after 6 weeks of PUVA treatment, 11 still had rash involving >50% BSA, 24 had rash involving >25% BSA, and 24 had no rash. The mean daily dose of prednisone at the start of PUVA therapy was 1.6 mg/kg compared to 0.7 mg/kg after 6 weeks of therapy. Fifty-nine patients (57%) did not require additional therapy for skin GVHD after starting PUVA. Ninety-two percent of patients developed chronic GVHD. Fifty-three patients (51%) remain alive at 129-1883 days after transplantation. These results suggest that PUVA can be an effective therapy for steroid-resistant acute GVHD of the skin.