Tratamiento de la enfermedad de injerto contra huésped crónica esclerodermiforme con imatinib: una perspectiva dermatológica / Sclerodermatous Chronic Graft-versus-Host Disease Treated With Imatinib: A Dermatological Perspective

INTRODUCCIÓN: La enfermedad de injerto contra huésped crónica (EICHc) es la causa más importante de mortalidad tardía no relacionada con la recidiva del trasplante alogénico de células progenitoras hematopoyéticas. La EICHc esclerodermiforme suele ser refractaria a los corticosteroides y supone todo un reto terapéutico. Se han descrito anticuerpos activadores contra el RFCDP en pacientes con EICHc esclerodermiforme. Estos anticuerpos inducen la fosforilación del RFCDP, produciendo fibrosis. Hay cada vez más evidencias de la efectividad de imatinib, un inhibidor de la tirosina cinasa, en el tratamiento de la EICHc esclerodermiforme. OBJETIVO: Evaluar la respuesta de la EICHc esclerodermiforme al imatinib. MATERIALES Y MÉTODOS: Estudio retrospectivo de 18 pacientes con EICHc cutánea esclerodermiforme refractaria a inmunosupresores tratada con imatinib en un único centro. La evaluación de la respuesta al tratamiento se realizó mediante valoración clínica del dermatólogo y percepción subjetiva del paciente tras uno, 3, 6, 9, 12 y 18 meses de iniciar el tratamiento con imatinib. La respuesta fue valorada como completa, parcial, significativa, sin cambios o progresión. El descenso de la dosis de esteroides se catalogó como completo, parcial o no posible. RESULTADOS: En nuestra serie, 4 (22%) pacientes lograron una respuesta completa, 9 (50%) alcanzaron una respuesta parcial, 2 (11%) tuvieron un grado significativo de respuesta, 2 (11%) no presentaron ningún cambio y uno (6%) experimentó avance de la enfermedad en el último seguimiento que se llevó a cabo. El tiempo medio transcurrido desde el inicio del imatinib hasta mostrar algún grado de respuesta fue de 2,75 meses (rango 1-9 meses). CONCLUSIONES: Este estudio apoya la evidencia de la utilidad del imatinib en el tratamiento de la EICHc esclerodermiforme

INTRODUCTION: Chronic graft-versus-host disease (cGVHD) is the most important cause of late non-relapse mortality after allogeneic hematopoietic stem cell transplantation. Sclerodermatous cGVHD is usually steroid refractory and remains a therapeutic challenge. Activating antibodies against the PDGFR have been reported in patients with sclerodermatous cGVHD. These antibodies induce PDGFR phosphorylation and lead to fibrosis. There is increasing evidence of successful treatment of sclerodermatous cGVHD with imatinib, a tyrosine kinase inhibitor. OBJECTIVE: To evaluate the response of cutaneous sclerodermatous cGVHD to imatinib. MATERIALS AND METHODS: Retrospective study of 18 patients with sclerodermatous cGVHD refractory to immunosuppressants treated with imatinib in a single center. Evaluation of treatment response was performed by clinicians' assessment and patients' subjective response at one, 3, 6, 9, 12 and 18 months after initiation of imatinib. Response was assessed as complete, partial, significant, no change or progression. Tapper off steroids was complete, partial or not possible. RESULTS: In our series, 4 (22%) patients achieved complete response, 9 (50%) patients partial response, 2 (11%) patients significant response, 2 (11%) patients had no change and one (6%) patient progressive disease at last follow-up. Mean time from initiation of imatinib to any degree of response was 2,75 months (range 1-9 months). CONCLUSIONS: This study provides further evidence of the role of imatinib for the treatment of steroid refractory sclerodermatous cGVHD

Fludarabine/Busulfan versus Fludarabine/Melphalan Conditioning in Patients Undergoing Reduced-Intensity Conditioning Hematopoietic Stem Cell Transplantation for Lymphoma.

There is at present little data to guide the choice of conditioning for patients with lymphoma undergoing reduced-intensity conditioning (RIC) allogeneic stem cell transplantation (SCT). In this study, we compared the outcomes of patients undergoing RIC SCT who received fludarabine and melphalan (FluMel), the standard RIC regimen used by the Spanish Group of Transplantation, and fludarabine and busulfan (FluBu), the standard RIC regimen used by the Dana-Farber Cancer Institute/Brigham and Women's Hospital. We analyzed 136 patients undergoing RIC SCT for lymphoma with either FluBu (n = 61) or FluMel (n = 75) conditioning between 2007 and 2014. Median follow-up was 36 months. The cumulative incidence of grades II to IV acute graft-versus-host disease (GVHD) was 13% with FluBu and 36% with FluMel (P = .002). The cumulative incidence of nonrelapse mortality (NRM) at 1 year was 3.3% with FluBu and 31% with FluMel (P < .0001). The cumulative incidence of relapse at 1 year was 29% with FluBu and 10% with FluMel (P = .08). The 3-year disease-free survival rate was 47% with FluBu and 36% with FluMel (P = .24), and the 3-year overall survival rate was 62% with FluBu and 48% with FluMel (P = .01). In multivariable analysis, FluMel was associated with a higher risk of acute grades II to IV GVHD (HR, 7.45; 95% CI, 2.30 to 24.17; P = .001) and higher risk of NRM (HR, 4.87; 95% CI, 1.36 to 17.44; P = .015). The type of conditioning was not significantly associated with relapse or disease-free survival in multivariable models. However, conditioning regimen was the only factor significantly associated with overall survival: FluMel conditioning was associated with a hazard ratio for death of 2.78 (95% CI, 1.23 to 6.27; P = .014) compared with FluBu. In conclusion, the use of FluBu as conditioning for patients undergoing SCT for lymphoma was associated with a lower risk of acute GVHD and NRM and improved overall survival when compared with FluMel in our retrospective study. These results confirm the differences between these RIC regimens in terms of toxicity and efficacy and support the need for comparative prospective studies.

Reduced-intensity conditioning allogeneic hematopoietic cell transplantation using oral fludarabine as part of the conditioning regimen.

BACKGROUND: In 2003, oral fludarabine was introduced for the treatment of patients with hematologic malignancies as an alternative to its intravenous (i.v.) formulation. In an attempt to simplify the management of patients undergoing reduced intensity allogeneic hematopoietic transplantation, we have incorporated oral fludarabine in the conditioning regimen. METHODS: We present a non-randomized retrospective analysis of 37 patients conditioned with oral fludarabine compared with 144 patients conditioned with the i.v. formulation. In addition to fludarabine, the conditioning regimens also included melphalan or busulfan depending on the underlying disease. Donors were HLA-matched siblings in 75% of cases and unrelated donors in the remaining 25%. RESULTS: Eight patients (22%) receiving oral fludarabine were switched to the i.v. route because of gastrointestinal toxicity (three patients), patient preference (two patients) and physician preference (three patients). There were no statistical differences in terms of hospital admission (P=0.16), time to neutrophil engraftment (P=0.35), time to platelet engraftment (P=0.38), acute graft versus host disease rate (P=0.71) and non-relapse mortality at days +30 (P=1.0) and +100 (P=0.43). DISCUSSION: This preliminary analysis confirms that oral fludarabine can replace its i.v. formulation as part of reduced-intensity conditioning regimens with no deleterious effect on any of the early transplantation outcomes. In addition, oral fludarabine can be more convenient for patients and caregivers, facilitating its implementation.