Resolution of SLE-related soft-tissue calcification following haematopoietic stem cell transplantation.

BACKGROUND: Calciphylaxis and calcinosis can both cause severe morbidity and mortality in patients with systemic lupus erythematosus (SLE). Haematopoietic stem cell transplantation (HSCT) has been successfully used to treat patients with refractory SLE. It was hypothesized that in calciphylaxis and calcinosis, ongoing inflammatory activity contributes to the calcium deposition in the media of small arteries, as well as perivascular and periarticular tissues. We report three patients whose soft-tissue calcification syndromes dramatically resolved after undergoing HSCT. METHODS: Three patients referred for refractory SLE underwent HSCT at a tertiary care medical center. SLE serologies and clinical features before and after HSCT were recorded. RESULTS: Despite receiving >6 months of intravenous cyclophosphamide (CYC), three SLE patients showed signs of persistent lupus activity, including severe soft-tissue calcification. The first patient was on haemodialysis and developed severe calciphylaxis with large ulcers and tissue necrosis. The second patient had calcinosis, with palpable crystals extruding from ulcers. The third patient had calcinosis characterized by subcutaneous nodules and plaques. Because prior conventional therapies had failed, the three were treated with high-dose CYC, anti-thymocyte globulin and HSCT. They have been followed post-HSCT for 26-38 months, with excellent clinical responses, including sustained resolution of skin abnormalities. CONCLUSIONS: The successful treatment of advanced calcium deposition by aggressive immune ablation underscores the contribution of SLE-mediated inflammation to soft-tissue calcification syndromes.

Prevalence and reversibility of pulmonary dysfunction in refractory systemic lupus: improvement correlates with disease remission following hematopoietic stem cell transplantation.

AIM: To report the prevalence and reversibility of pulmonary function test (PFT) abnormalities among systemic lupus erythematosus (SLE) patients, refractory to therapy, undergoing hematopoietic stem cell transplantation (HSCT). METHODS: Thirty-four SLE patients received 200 mg/kg cyclophosphamide and 90 mg/kg equine antithymocyte globulin followed by HSCT. PFTs were performed prior to, at 6 months, and yearly following HSCT. RESULTS: The prevalence of significant PFT abnormalities was high (97%). Low FEV(1) and FVC occurred in 26 of 34 patients (76%). A significant abnormality in diffusion capacity of the lung for carbon monoxide (Dlco) occurred in 26 of 32 individuals able to complete Dlco testing (81%). Dlco 18 months after HSCT. Five of 28 patients had a normal entry FVC; for each, the FVC remains normal. Of the 23 patients with an abnormal baseline FVC, 18 have improved, 15 completely and 3 partially. Eight of these 18 patients also have improved Dlco. The two patients with a diagnosis of SLS and one patient with SLE-related pulmonary hypertension improved in both parameters. Only 5 of 23 patients with an abnormal FVC did not improve. Each of these five patients retained active lupus in spite of HSCT. CONCLUSION: The prevalence of lung impairment among SLE patients requiring long-term immune suppression is high. Following HSCT, pulmonary impairments can improve, which is sustained if disease control is sustained.

Autologous hematopoietic stem cell transplantation in patients with refractory Crohn's disease.

BACKGROUND & AIMS: Crohn's disease (CD) is an immunologically mediated inflammatory disease of the gastrointestinal tract. Due to a high morbidity and/or an increase in mortality in refractory cases, a new treatment approach is needed. In theory, maximum immune ablation by autologous hematopoietic stem cell transplantation (HSCT) can induce a remission. METHODS: We conducted a phase 1 HSCT study in 12 patients with refractory CD. Candidates were younger than 60 years of age with a Crohn's Disease Activity Index (CDAI) of 250-400 despite conventional therapies including infliximab. Peripheral blood stem cells were mobilized with cyclophosphamide and granulocyte colony-stimulating factor and CD34 + enriched. The immune ablative (conditioning) regimen consisted of 200 mg/kg cyclophosphamide and 90 mg/kg equine antithymocyte globulin. RESULTS: The procedure was well tolerated with anticipated cytopenias, neutropenic fever, and disease-related fever, diarrhea, anorexia, nausea, and vomiting. The median days for neutrophil and platelet engraftment were 9.5 (range, 8-11) and 9 (range, 9-18), respectively. The initial median CDAI was 291 (range, 250-358). Symptoms and CDAI improved before hospital discharge, whereas radiographic and colonoscopy findings improved gradually over months to years following HSCT. Eleven of 12 patients entered a sustained remission defined by a CDAI < or =150. After a median follow-up of 18.5 months (range, 7-37 months), only one patient has developed a recurrence of active CD, which occurred 15 months after HSCT. CONCLUSIONS: Autologous HSCT may be performed safely and has a marked salutary effect on CD activity. A randomized study will be needed to confirm the efficacy of this therapy.

Post-transplant plasma cell myeloma and polymorphic lymphoproliferative disorder with monoclonal serum protein occurring in solid organ transplant recipients.

Post-transplant lymphoproliferative disorders are mostly Epstein-Barr virus-related, B-cell tumors that develop as a consequence of immunosuppressive therapy in recipients of solid organ or bone marrow transplants. These disorders range from reactive, polyclonal plasmacytic hyperplasia to those that are morphologically and genotypically indistinguishable from typical non-Hodgkin's lymphomas. Plasma cell myeloma occurring after solid organ transplantation is rare. We report three plasma cell myeloma post-transplant lymphoproliferative disorder cases and one polymorphic, monoclonal post-transplant lymphoproliferative disorder case associated with a monoclonal serum protein. All three plasma cell myeloma post-transplant lymphoproliferative disorder cases had clinical, radiologic, and pathologic features of conventional plasma cell myeloma. The one polymorphic post-transplant lymphoproliferative disorder case was associated with an IgM monoclonal serum protein and was morphologically indistinguishable from a lymphoplasmacytic lymphoma. Three of the four cases, including the one polymorphic post-transplant lymphoproliferative disorder case, were positive for Epstein-Barr virus encoded small RNA by in situ hybridization. One patient died of plasma cell myeloma post-transplant lymphoproliferative disorder. The remaining three patients are alive: two are completely free of post-transplant lymphoproliferative disorder, and one has shown partial response to therapy. We compare the clinicopathologic features of these cases with those in the literature.

SLE - hematopoietic stem cell transplantation for systemic lupus erythematosus.

Hematopoietic stem cell transplantation was first reported for patients with systemic lupus erythematosus in 1997. The procedure has since been performed worldwide including in Europe, in Brazil, and in China. A National Institutes of Health-funded phase III clinical trial of hematopoietic stem cell transplantation for refractory systemic lupus erythematosus is anticipated to begin in 2003. Encouraging responses are raising new hope about the role of adult hematopoietic stem cells in systemic lupus erythematosus.

Hematopoietic stem cell transplantation for severe and refractory lupus. Analysis after five years and fifteen patients.

OBJECTIVE: To determine the safety and long-term efficacy of immune ablation and autologous hematopoietic stem cell transplantation (HSCT) in severe systemic lupus erythematosus (SLE). METHODS: Fifteen patients with persistently active SLE after intravenous (IV) cyclophosphamide (CYC) therapy underwent HSCT. Stem cells were mobilized with CYC (2.0 gm/m(2)) and granulocyte colony-stimulating factor (5 microg/kg/day). Lymphocytes were depleted from the graft by selection of CD34-positive cells. The conditioning regimen used was CYC (200 mg/kg), antithymocyte globulin (90 mg/kg), and methylprednisolone (3 mg/kg). Outcome was evaluated by the SLE Disease Activity Index (SLEDAI), serum complement levels, serologic features, function of diseased organs, and immunosuppressive medication requirements. RESULTS: Fifteen patients with persistent, severe SLE, 7 of whom were critically ill, were treated. No deaths occurred following treatment. The median followup after HSCT has been 36 months (range 12-66 months). All patients demonstrated a gradual, but marked, improvement. The SLEDAI score has declined to 1 year after HSCT, 10 have discontinued immunosuppressive medications, and the prednisone dosage has been tapered to 15 mg/day in 1. Only 2 patients have demonstrated clinical evidence of recurrence of active lupus. One of these patients currently requires no immunosuppressive medication and has a normal performance status. The other patient is currently receiving IV CYC. CONCLUSION: In patients experiencing the persistence of organ-threatening lupus following standard, aggressive therapy, HSCT may be performed safely, with marked improvement and sustained withdrawal of all immunosuppressive medication for most patients. A phase III randomized trial is warranted to determine the relative efficacy and durability of remission of HSCT compared with standard therapies.

Phase 2 trial of infusional cyclophosphamide, doxorubicin, and etoposide in patients with poor-prognosis, intermediate-grade non-Hodgkin lymphoma: an Eastern Cooperative Oncology Group trial (E3493).

Preclinical and clinical evidence suggest a potential advantage for infusional therapy in lymphoma. Sixty-two analyzable patients with predominantly intermediate-grade non-Hodgkin lymphoma received cyclophosphamide (200 mg/m(2) per day), doxorubicin (12.5 mg/m(2) per day), and etoposide (60 mg/m(2) per day) (CDE) by continuous intravenous infusion for 4 days (96 hours) every 3 weeks for a maximum of 8 cycles. By the age-adjusted International Prognostic Index (IPI), 42% were at high risk and 58% were at high-intermediate risk. Complete response (CR) occurred in 30 (48%) patients (95% confidence interval [CI], 35%, 64%), and partial response occurred in 16 (26%) patients, yielding an overall response rate of 74% (95% CI, 62%, 84%). Failure-free survival (FFS) rates at 1 and 2 years were 55% (95% CI, 43%, 67%) and 50% (95% CI, 38%, 62%), respectively. When comparing the outcome for 62 patients receiving infusional CDE with historical data derived from 927 IPI-matched lymphoma patients using a Cox proportional hazards model, there was a nonsignificant trend favoring CDE in FFS (P =.12) and overall survival (P =.09). Severe or life-threatening toxicity included neutropenia (68%), anemia (57%), thrombocytopenia (44%), and infection (24%). Two patients (3%) died of treatment-related infectious complications. The primary end point of improving 1-year FFS from 55% to 70% was not achieved with infusional CDE given as initial therapy in patients with poor-risk intermediate-grade lymphoma. It is unlikely that infusional therapy as used in this study produces a 25% or greater relative improvement in FFS compared with standard therapy.