RESUMEN
Chronic graft-versus-host disease (cGVHD) is major cause of morbidity and mortality following allogeneic hematopoietic cell transplantation (HCT). Ixazomib is an oral, second-generation, proteasome inhibitor that has been shown in preclinical models to prevent GVHD. We conducted a phase I/II trial in 57 patients to evaluate the safety and efficacy of ixazomib administration for cGVHD prophylaxis in patients undergoing allogeneic HCT. Oral ixazomib was administered on a weekly basis for a total of 4 doses, beginning days +60 through +90, to recipients of matched related donor (MRD, n = 25) or matched unrelated donor (MUD, n = 26) allogeneic HCT in phase II portion of the study, once the recommended phase II dose of 4 mg was identified in phase I (n = 6). All patients received peripheral blood graft and standard GVHD prophylaxis of tacrolimus and methotrexate. Ixazomib administration was safe and well tolerated, with thrombocytopenia, leukopenia, gastrointestinal complaints, and fatigue the most common adverse events (>10%). In phase II (n = 51), the cumulative incidence of cGVHD at 1 year was 36% (95% confidence interval [CI], 19% to 54%) in the MRD cohort and 39% (95% CI, 21% to 56%) in the MUD cohort. One-year cumulative incidence of nonrelapse mortality (NRM) and relapse was 0% and 20% (95% CI, 8% to 36%) in the MRD cohort, respectively. In the MUD cohort, the respective NRM and relapse rates were 4% (0% to 16%) and 34% (17% to 52%). The outcomes on the study were compared post hoc with contemporaneous matched Center for International Blood and Marrow Transplant Research (CIBMTR) controls. This post hoc analysis showed no significant improvement in cGVHD rates in both the MRD (hazard ratio [HR] = 0.85, P = .64) or MUD cohorts (HR = 0.68, P = .26) on the study compared with CIBMTR controls. B cell activating factor plasma levels were significantly higher after ixazomib dosing in those who remained cGVHD free compared with those developed cGVHD. This study shows that the novel strategy of short-course oral ixazomib following allogeneic HCT is safe but did not demonstrate significant improvement in cGVHD incidence in recipients of MRD and MUD transplantation compared with matched CIBMTR controls. This study is registered at www.clinicaltrials.gov as NCT02250300.
Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Compuestos de Boro , Enfermedad Crónica , Glicina/análogos & derivados , Glicina/uso terapéutico , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Tacrolimus , Acondicionamiento PretrasplanteRESUMEN
Allogeneic hematopoietic cell transplantation (alloHCT) is a highly specialized procedure. We surveyed adult transplant centers in the United States (US) and then used data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) (2008-2010) to evaluate associations of center volume, infrastructure, and care delivery models with survival post alloHCT. Based on their 2010 alloHCT volume, centers were categorized as low-volume (≤40 alloHCTs; N = 42 centers, 1900 recipients) or high-volume (>40 alloHCTs; N = 41 centers, 9637 recipients). 100-day survival was 86% (95% CI, 85-87%) in high-volume compared with 83% (95% CI, 81-85%) in low-volume centers (difference 3%; P < 0.001). One-year survival was 62% (95% CI, 61-63%) and 56% (95% CI, 54-58%), respectively (difference 6%; P < 0.001). Logistic regression analyses adjusted for patient and center characteristics; alloHCT at high-volume centers (odds ratio [OR] 1.32; P < 0.001) and presence of a survivorship program dedicated to HCT recipients (OR 1.23; P = 0.009) were associated with favorable 1-year survival compared to low-volume centers. Similar findings were observed in a CIBMTR validation cohort (2012-2014); high-volume centers had better 1-year survival (OR 1.24, P < 0.001). Among US adult transplant centers, alloHCT at high-volume centers and at centers with survivorship programs is associated with higher 1-year survival.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Trasplantes , Adulto , Estudios de Cohortes , Humanos , Acondicionamiento Pretrasplante , Trasplante Homólogo , Estados UnidosRESUMEN
Corticosteroid refractory graft-versus-host disease (GVHD) is one of the major challenges in the management of allogeneic stem cell transplant recipients. Although numerous agents have been employed to treat this patient population, no standardized second-line therapy exists. In this study, we report our experience with the administration of tocilizumab, an anti-interleukin 6 receptor antibody, in the treatment of steroid refractory GVHD. Tocilizumab was administered to 8 patients with refractory acute (n = 6) or chronic GVHD (cGVHD) (n = 2) once every 3 to 4 weeks. The majority of patients with acute GVHD (aGVHD) had grade IV organ involvement of the skin or gastrointestinal tract, whereas both patients with cGVHD had long-standing severe skin sclerosis at the time of treatment. There were no allergic or infusion-related adverse events. Treatment was discontinued in one patient over concerns that tocilizumab may have worsened preexisting hyperbilirubinemia. Several patients also had transient elevations in serum transaminase values. Infections were the primary adverse events associated with tocilizumab administration. Four patients (67%) with aGVHD had either partial or complete responses apparent within the first 56 days of therapy. One patient with cGVHD had a significant response to therapy, whereas the second had stabilization of disease that allowed for a modest reduction in immune suppressive medications. These results indicate that tocilizumab has activity in the treatment of steroid refractory GVHD and warrants further investigation as a therapeutic option for this disorder.
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Corticoesteroides/farmacología , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/efectos adversos , Estudios de Cohortes , Resistencia a Medicamentos , Femenino , Enfermedad Injerto contra Huésped/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Most acute myeloid leukaemia (AML) patients lack human leucocyte antigen-identical sibling donors for transplantation. Autotransplants and unrelated donor (URD) transplants are therapeutic options. To compare autologous versus URD transplantation for AML in first (CR1) or second complete remission (CR2), we studied the outcomes of 668 autotransplants were compared with 476 URD transplants reported to the Center for International Blood and Marrow Transplant Research. Proportional hazards regression adjusted for differences in prognostic variables. In multivariate analyses transplant-related mortality (TRM) was significantly higher and relapse lower with URD transplantation. Adjusted 3-year survival probabilities were: in CR1 57 (53-61)% with autotransplants and 44 (37-51)% URD (P = 0.002), in CR2 46 (39-53)% and 33 (28-38)% respectively (P = 0.006). Adjusted 3-year leukaemia-free survival (LFS) probabilities were: CR1 53 (48-57)% with autotransplants and 43 (36-50)% with URD (P = 0.021), CR2 39 (32-46)% and 33 (27-38)% respectively (P = 0.169). Both autologous and URD transplantation produced prolonged LFS. High TRM offsets the superior antileukaemia effect of URD transplantation. This retrospective, observational database study showed that autotransplantation, in general, offered higher 3-year survival for AML patients in CR1 and CR2. Cytogenetics, however, were known in only two-thirds of patients and treatment bias cannot be eliminated.