Beate Steiner

Treatment of steroid-resistant acute graft-versus-host disease with daclizumab and etanercept

Summary:Steroid-resistant acute GVHD (aGVHD) following allogeneic hematopoietic stem cell transplantation (alloHSCT) continues to be associated with a high mortality. We report the results of a phase II study of treatment of steroid-resistant aGVHD with the IL-2 receptor antibody daclizumab combined with the TNF-receptor fusion protein etanercept. Treatment consisted of daclizumab 1 mg/kg given i.v. on days 1, 4, 8, 15, 22 and etanercept 16 mg/m2 s.c. on days 1, 5, 9, 13, 17. A total of 21 patients (age 15–61 years) with steroid-resistant aGVHD after alloHSCT were included in the study. Donor types were HLA-matched related (n=6), HLA-matched unrelated (n=14), and HLA-mismatched unrelated (n=1). Eight patients achieved complete, and six showed partial remission of aGVHD. Seven patients did not respond. Four of 21 patients are currently alive with a median follow-up of 586 (185–1155) days. Three patients died due to relapsed malignancy. Treatment-related mortality was due to infectious complications (n=11) or organ failure due to aGVHD (n=3). In total, 12 patients developed subsequent chronic GVHD. In conclusion, the data demonstrate an acceptable response rate of the combination of daclizumab and etanercept in the treatment of steroid-resistant aGVHD. Nevertheless, long-term mortality due to infectious complications and chronic GVHD remains high.

Replacement of calcineurin inhibitors with daclizumab in patients with transplantation-associated microangiopathy or renal insufficiency associated with graft-versus-host disease

Transplantation-associated microangiopathy (TAM) or renal insufficiency (RI) after allogeneic hematopoietic stem cell transplantation is associated with a high mortality. As calcineurin inhibitors (CI) may contribute to TAM or RI, we evaluated the efficacy of replacing CI by daclizumab in patients with graft-versus-host disease (GVHD). Thirteen patients with GVHD-associated TAM and five patients with RI were treated with daclizumab 1 mg/kg intravenous (i.v.)/week, discontinuation of the CI and continuation of the remaining GVHD treatment. All patients had acute GVHD (steroid-sensitive (n=4), steroid-refractory (n=10)) or chronic GVHD (n=4) and were treated with CI before the start of daclizumab. Nine of 13 patients with TAM treated with daclizumab and discontinuation of CI achieved complete remission of TAM, two had stable disease, and one patient did not respond. Patients receiving daclizumab for RI without TAM showed stabilization (2/5) or improvement (3/5) of renal function. Four of 14 patients with acute GVHD achieved CR, two partial remission, eight patients did not respond and 11/14 died at a median of 39 days after start of the daclizumab. Our data demonstrate that replacement of CI by daclizumab can improve TAM and RI. However, mortality remains high in patients with acute GVHD.

Progressive interstitial fibrosis of the lung in sclerodermoid chronic graft-versus-host disease

Sclerodermoid chronic graft-versus-host disease (sGVHD) is a well-known complication in patients with a long history of chronic GVHD. Pulmonary involvement in chronic GVHD presents typically as bronchiolitis obliterans (BO). Pulmonary fibrosis after allogeneic hematopoietic stem cell transplantation (HSCT) is presumed to be caused by the long-term toxicity of the conditioning regimen or the result of lung injury elicited predominantly by viral infections or GVHD. We present two patients with late onset pulmonary fibrosis associated with moderate sGVHD of the skin after HSCT. At the initial diagnosis of chronic GVHD both patients presented with symptoms of interstitial pneumonia. Years later both patients developed moderate to severe interstitial pulmonary fibrosis in association with sGVHD. One patient showed additional clinical and histological signs of BO. While one patient responded to increased immunosuppression including total nodal irradiation (1 Gy), the other patient died due to complications related to pulmonary fibrosis.Bone Marrow Transplantation (2002) 29, 357–360. doi:10.1038/sj.bmt.1703386

Severe hypophosphatemia during hematopoietic reconstitution after allogeneic peripheral blood stem cell transplantation.

A patient suffering from acute myeloid leukemia (FAB M5a) received a PBSC allograft from a matched, related donor. On day 13 after transplantation severe hypophosphatemia (0.21 mmol/l) was first noted which persisted irrespective of intravenous phosphate administration, and within 2 days reached concentrations below 0.13 mmol/l. After repeated phosphate substitution serum phosphate returned to 1.40 mmol/l on day 17. Phosphate in urine, and calcium in serum were recorded as unchanged throughout. Clinical signs and symptoms due to severe hypophosphatemia were not observed except for paresthesia in the lower extremities. The precipitous fall in serum phosphate coincided with hematopoietic reconstitution as reflected by a steep rise in leukocyte count from 0.08 × 109/l on day 10 to 5.94 × 109/l on day 15 after transplantation. Thus, isolated hypophosphatemia was likely the result of excessive cellular phosphate uptake during hematopoietic reconstitution. Electrolyte monitoring after PBSCT should include serum phosphate to identify the hypophosphatemia associated with hematopoietic recovery. Bone Marrow Transplantation (2000) 25, 1015–1016.

Neurological complications after intrathecal liposomal cytarabine application in patients after allogeneic haematopoietic stem cell transplantation

Liposomal cytarabine has been proven to be useful for the prevention and intrathecal treatment of neoplastic meningitis. It has no demonstrable myelosuppressive effects and may therefore be an attractive alternative for prophylaxis and treatment of the central nervous system (CNS) relapse after allogeneic haematopoietic stem cell transplantation (HSCT). The use of liposomal cytarabine had not been reported in HSCT recipients. We retrospectively reviewed the feasibility of liposomal cytarabine in the prophylaxis (n = 2) and treatment (n = 4) of neoplastic meningitis in a cohort of patients after allogeneic HSCT. This report focusses on neurological complications after intrathecal application of liposomal cytarabine. Mild headache was the most commonly reported adverse event. Two patients experienced sacral radiculopathy with irreversible cauda equina syndrome in one patient. Another patient progressed with pre-existing leukencephalopathy. Intrathecal liposomal cytarabine should be used very cautiously in allogeneic HSCT recipients with a history of CNS complications potentially involving cerebral-spinal fluid circulation, since significant neurotoxicity was observed in patients with extensive CNS-directed pre-treatment. The feasibility and safety of liposomal cytarabine in HSCT recipients has to be evaluated in a prospective study.

Enteral budesonide in treatment for mild and moderate gastrointestinal chronic GVHD

Budesonide (BUD) is a steroid with a low bioavailability, which has been used for the treatment of oral manifestations of chronic GVHD (cGVHD). We retrospectively evaluated the efficacy of BUD in the treatment of gastrointestinal cGVHD. Thirteen patients (median age 47 years) receiving BUD for the treatment of cGVHD after allogeneic hematopoietic SCT for hematological malignancies were evaluated for response. Five patients had isolated gastrointestinal cGVHD and 8 patients had mild multiorgan involvement including gastrointestinal manifestations. Six patients received CYA at the time of onset of cGVHD, which was continued during treatment with BUD. Treatment consisted of BUD, with an initial daily dose of 3 × 3 mg orally. Complete resolution of cGVHD was achieved in seven patients, and one patient achieved partial remission of cGVHD. One patient achieved complete resolution of gastrointestinal cGVHD, while systemic manifestations of cGVHD remained stable. Four patients progressed on BUD. Owing to the predominantly local effect, relapse of symptoms of cGVHD after withdrawal of immunosuppression (n=3) as well as progression of GVHD at other sites (n=3) has been observed. BUD represents a treatment option in mild-to-moderate cGVHD, which is well tolerated and associated with a high response rate in gastrointestinal cGVHD.

Methotrexate-albumin and aminopterin-albumin effectively prevent experimental acute graft-versus-host disease.

Background. During the last several years, major progress has been made in developing targeted chemotherapy using cytotoxic drugs covalently bound to human serum albumin (HSA). We explored the activity of two antifolates methotrexate (MTX) and aminopterin (AMPT) bound to HSA in prophylaxis and treatment of experimental acute graft-versus-host disease (aGVHD). Methods. In all, 113 female F1 hybrid BN/Lew-rats were irradiated with 8.2 Gy (n=103) or 9.9 Gy (n=10). One day after irradiation each rat received 4×107 bone marrow cells and 1.5×107 spleen T-cells from female Lew-rats. GVHD prophylaxis consisted of MTX-HSA 2 mg/kg (n=25), MTX-HSA 0.5 mg/kg (n=8), AMPT-HSA 0.65 mg/kg (n=8), MTX 0.5 mg/kg (n=17), or native HSA (n=39) given intraperitoneally (IP) on days 0, 4, 8, and 12. Treatment of aGVHD consisted of MTX-HSA 2 mg/kg (n=8) or AMPT-HSA 0.5 mg/kg (n=8) given intraperitoneally at the time of onset of aGVHD and subsequently every fourth day (a total of four doses). Results. All animals receiving native HSA developed lethal aGVHD. Prophylactic treatment with MTX-HSA 2 mg/kg prevented aGVHD in 18 of 25 animals and in 6 of 8 receiving AMPT-HSA. In contrast, five out of nine rats receiving free MTX died due to aGVHD. The survival rates in the prophylactic MTX-HSA 2 mg/kg and AMPT-HSA groups were significantly higher compared to the MTX and control groups (P<0.05), while non hematologic toxicity of MTX-HSA was not detectable. AMPT-HSA at a dose of 0.65 mg/kg as well as MTX at a dose of 0.5 mg/kg were associated with temporary weight loss and lethargy. Conclusions. The albumin conjugates MTX-HSA and AMPT-HSA effectively prevent experimental aGVHD.

Loss of the GVL effect by loss of the Y-chromosome as putative mechanism of immune escape in ALL

Loss of the GVL effect by loss of the Y-chromosome as putative mechanism of immune escape in ALL

T-cell-depleted stem cell boost for the treatment of autoimmune haemolytic anaemia after T-cell-depleted allogeneic bone marrow transplantation complicated by adenovirus infection.

Delayed and poor engraftment is a well-known complication after T-cell-depleted allogeneic BMT and may favour a transient immune system imbalance with delayed reconstitution of T-cell immunity.1, 2

Accidental intrathecal administration of bleomycin: favorable outcome after pneumo-encephalus and cerebrospinal fluid exchange: a case report

Bleomycin is generally used as an antineoplastic drug for the intravenous treatment of germ cell tumors or lymphomas. Due to its toxic effect on epithelial cells bleomycin is also used for the treatment of malignant pleural or pericardial effusions. Inadvertent intrathecal administration of cytotoxic drugs may occur due to increasingly complex therapeutic protocols, even when control mechanisms are applied. We report the case of a 39-year-old man with chronic myeloid leukemia. During the treatment of a lymphoblast crisis 30 mg of bleomycin were inadvertently injected intrathecally. Prompt cerebrospinal fluid exchange, dilution with normal saline, and corticosteroid treatment resulted in a positive outcome without major side effects.