Mycophenolate mofetil (MMF) as therapy for refractory chronic GVHD (cGVHD) in children receiving bone marrow transplantation.

Mycophenolate mofetil (MMF) is an alternative immunosuppressant which inhibits the proliferation of T and B lymphocytes. The purpose of the present study was to evaluate the safety and efficacy of MMF as salvage therapy for chronic GVHD (cGVHD) in children receiving allogeneic bone marrow transplantation. Fifteen children, 3-16 years of age, who had received grafts from HLA-compatible siblings (n = 8), partially matched related donors (n= 2) or matched unrelated donors (n = 5), developed extensive cGVHD which had proved unresponsive to standard immunosuppressive therapy. Patients were treated with MMF at the dose of 15-40 mg/kg/day in combination with other immunosuppressive therapy for a median of 4 months (range 1-15 months). The overall response rate (complete or partial response) was 60%. Thirteen percent had only minor responses, whereas 27% of patients had progressive disease. Best responses were seen in patients with GI tract (60% of complete responses) or mouth (33% of complete responses) cGVHD and skin involvement (43% of complete responses) that did not include sclerodermatous manifestations. Once MMF was started, improvements in the clinical manifestations of cGVHD allowed a significant reduction of steroids in 45% of patients and discontinuation in 27% of cases. Six patients (40%) experienced adverse events, with gastrointestinal symptoms predominating. Five patients experienced opportunistic infections. MMF was discontinued after 35-180 days in six patients for the following reasons: parents choice (n = 2), liver toxicity (n = 1), poor compliance (n = 2), and no response (n = 1). In conclusion, these preliminary results suggest that MMF in combination with other immunosuppressive agents may have a role to play in patients with cGVHD. Prospective clinical trials are needed to establish exact indications for therapy and dosage scheduling. Bone Marrow Transplantation (2000).

Analysis of early infectious complications in pediatric patients undergoing bone marrow transplantation.

The purpose of the present study was to analyze the characteristics of infectious complications occurring during the first 100 days after bone marrow transplantation (BMT) in a cohort of 123 pediatric patients with hematological malignancies (n = 73), solid tumors (n = 32) and nonmalignant disorders (n = 18). Fifty-eight patients received allogeneic grafts, and 65 patients an autologous transplant. Fever developed in 107 (87%) children; 82% of infectious complications occurred during the neutropenic period. Documented infection developed in 33 (31%) patients, while 74 (69%) patients had possible infection (i.e. fever of unknown origin). The incidence of bacteremia was 21%, and gram-positive cocci were the predominant pathogens; non-bacteremic microbiologically documented infection developed in 6% of patients; clinically evident infection developed in 4% of subjects. The incidence of primary febrile episodes was not significantly different between autologous and allogeneic BMT (86% vs 88%); nor did the median number of days to the onset of fever (5 days in both groups) or the median duration of fever (5 days in both groups) differ. In contrast, the frequency of secondary febrile episodes was significantly higher (P = 0.0001) in allogeneic BMT recipients (40%) than in autologous recipients (15%). The mortality rate due to infections was 2/36 (5%) for matched sibling donor BMT, and 1/13 (8%) for matched unrelated donor BMT. No deaths occurred in the 65 patients who were autografted. Invasive fungal infections accounted for 2 of the 3 infectious deaths. In conclusion, the majority of children undergoing BMT experienced at least one infectious episode; allogeneic BMT recipients were at high risk of developing secondary febrile episodes, but the overall mortality rate due to infection in the first 100 days after transplantation was low.

[Use of cyclosporin and verapamil in association with chemotherapy in the treatment of pediatric patients with advanced-stage neoplasms. A pilot study]. / Impiego della ciclosporina e del verapamile in associazione a chemioterapici nel trattamento di pazienti pediatrici con neoplasia in fase avanzata. Studio pilota.

Multidrug resistance represents one of the most important factors that may lead to a therapeutic failure in some patients affected by malignancies. One of the best known mechanisms is linked to the genic amplification or the overproduction of a membrane glycoprotein, GP170, that is the product of the gene MDR1. The existence of drugs (calcium blockers, cyclosporine, tamoxifen, reserpine, quinidine) able to bind themselves to gp170 and to paralyze its activity in vitro is well known. We studied 20 pediatric patients (median age 9 years) affected by acute lymphoblastic leukemia (ALL), osteosarcoma, neuroblastoma and medulloblastoma, in advanced stage of disease. We employed in all cases the association of cytostatics with verapamil (50-70 mg/m2 i.v.) and cyclosporine (5-8 mg/kg i.v.) with different infusion schedules. In leukemias we administered vincristine (1.5 mg/m2), and daunomycin (40 mg/m2), in solid tumors VP16 (150 mg/m2) and adriamycin (60 mg/m2). Seventy-two therapeutic courses were performed: 39 in ALL, 16 in osteosarcoma, 16 in neuroblastoma and 1 in medulloblastoma. On the whole 5 complete remissions were achieved in ALL patients and 1 in an osteosarcoma patient. We did not observe a significant myelosuppression during treatment, therefore few infectious complications occurred; furthermore electrocardiographic changes have been mild and promptly resolved after temporary discontinuation of verapamil infusion. Our data suggest a synergy of verapamil and cyclosporine in the inhibition of multidrug resistance induced by gp170, without the occurrence of heavy toxicity. The results obtained in ALL patients are encouraging., especially in view of a possible subsequent bone marrow transplantation, while in solid tumors they are not as satisfying.