PubMed · 10100013
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S von Eckardstein, J Gromoll, N Terwort, A Schmidt, E Nieschlag. 1999. Deception by chimerism.. https://doi.org/10.1093/humrep%2F14.2.572
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BACKGROUND: Two patients with end-stage renal disease secondary to multiple myelomas were treated with combined kidney and bone marrow transplantation in an effort to achieve donor-specific allotolerance through the induction of mixed lymphohematopoietic chimerism. METHODS: Two female patients (55 and 50 years of age) with end-stage renal disease secondary to kappa light-chain multiple myelomas received a nonmyeloablative conditioning regimen that consisted of 60 mg/kg cyclophosphamide intravenously (IV) on days -5 and -4; 15 mg/kg equine anti-thymocyte globulin (ATGAM) IV on days -1, +1, and +3; and thymic irradiation (700 cGy) on day -1. On day 0, the recipients underwent kidney transplantation, followed by IV infusion of donor bone marrow (2.7x10(8) and 3.8x10(8) /kg nucleated cells, respectively) obtained from a human leukocyte antigen (HLA)-matched sibling. Cyclosporine A was administered IV at a dose of 5 mg/kg on day -1, then continued orally at 8 to 12 mg/kg per day until days +73 and +77, respectively, after which no further immunosuppression was given. Donor leukocyte infusions (1x10(7) /kg CD3+ T cells) were administered in an attempt to enhance the graft-versus-myeloma effect (days +66 and +112 in the first patient and day +78 in the second patient). Hematopoietic chimerism was monitored weekly by microsatellite assays. RESULTS: Multilineage lymphohematopoietic chimerism (5%-80% donor CD3+ or CD3- cells, or both) was first detected during the second posttransplant week and was maintained for approximately 12 weeks, after which there was a gradual decline to undetectable levels (<1% donor cells) after day 105 in the first patient and after day 123 in the second patient. In both recipients, the blood urea nitrogen and creatinine levels returned to normal within 3 days. No rejection episodes have occurred. Quantification of urinary kappa light chains revealed a decline from 28 mg/dL to undetectable levels (<2.5 mg/dL) within 29 days in the first case and from 99.8 mg/dL to <10 mg/dL within 50 days in the second case. Both patients continue with normal kidney function and sustained anti-tumor responses, while receiving no immunosuppression for nearly 4 years and 2 years, respectively. CONCLUSIONS: This nonmyeloablative regimen followed by combined HLA-matched donor bone marrow and renal allotransplantation is the first example of an intentional and clinically applicable approach to inducing renal allograft tolerance and achieving potent and sustained antitumor effects in patients with multiple myeloma.
T-cell depletion (TCD) and immunosuppressive medications (ISTs) are 2 methods used for graft-versus-host disease (GVHD) prophylaxis in unrelated donor (URD) transplantation. However, comparisons of the clinical outcomes including quality of life and direct medical costs associated with each type of procedure have not been reported. We reviewed 48 TCD and 98 IST procedures performed from 1/1/97 to 12/31/99 at the Dana-Farber Cancer Institute, Boston, MA. With a median follow-up of 1.5 years for survivors, no differences were seen in relapse, acute GVHD, and overall survival between TCD and IST patients. Multivariable Cox modeling showed that age of 50 years or less (P =.002) and low-risk disease (P =.001) predicted survival, but method of GVHD prophylaxis (P =.6) and degree of human leukocyte antigen (HLA) matching (P =.8) did not. A subset of patients (53%) completed quality of life surveys prior to and at 6 and 12 months after transplantation; participation in the quality of life study was not associated with clinical characteristics and outcomes. No differences were seen in quality of life scores prior to transplantation, and changes over time were similar between groups. Costs ($113 000 vs $155 000, P <.0001) and total hospital days (34 vs 46, P =.0006) were significantly lower for patients undergoing TCD procedures. As prospective, randomized studies comparing methods of GVHD prophylaxis are performed, assessment of quality of life and costs should be included to fully understand the overall impact of each intervention.
Juan A. del Regato, 1909-1999, was a superb clinician-educator who recognized the radiocurability of Hodgkin's disease but questioned treatment without late effects, particularly in children. The remarkable progress in pediatric Hodgkin's disease today is a tribute to this influential pioneer, who served as a role model to many. Combined modality therapy using low-dose, involved-field radiation and multiagent chemotherapy today results in a 5-year relative survival rate of 94% among American children with Hodgkin's disease. However, several areas hold promise for future advances, including a new pathology classification and biology studies that distinguish classic Hodgkin's disease from other lymphomas; new noninvasive staging techniques, including 18F-fluorodeoxyglucose-positron emission tomography; the definition of risk groups to segregate low-, intermediate-, and high-risk groups on the basis of a prognostic index, facilitating risk-adapted therapy; and myeloablative therapy followed by hematopoietic stem cell transplantation. Currently used for children with relapse, it is associated with a 5-year survival of 65% and should be considered as the initial therapy for high-risk groups. Idiopathic diffuse pulmonary toxicity after autologous transplantation is high among children with an atopic history; thus, atopy should be considered when selecting children appropriate for transplantation. Finally, novel therapies, such as the anti-CD20 antibody, rituximab, may be useful for children with CD20+, lymphocyte-predominant Hodgkin's disease. The universal goal of cure without late effects is realistic for almost all children with Hodgkin's disease today.