Summary:A 32-year-old female with WHO grade IV, dialysis dependent, lupus nephritis was treated with high-dose immunosuppression and autologous stem cell rescue. Stem cells were mobilized with cyclophosphamide (CY) and G-CSF, and 4.07 × 10 6 CD34 + cells/kg were obtained after CD34 + cell selection using the CellPro column. The preparative regimen consisted of CY, and antithymocyte globulin (ATG), with methylprednisolone. After apparent primary engraftment of neutrophils on day 9, the patient developed recurrent neutropenia on day 19. She showed no evidence of engraftment by day 35, and back-up unmanipulated stem cells were given without effect. Subsequently, she received unmanipulated peripheral stem cells (2 × 10 6 CD34 + cells/kg) from an HLA-identical sibling. The patient remained pancytopenic and expired on day 62 from disseminated fungal infection. An autopsy revealed no evidence of hematopoietic recovery. Progenitor cell assays were performed with the patient's stem cells, which were collected prior to transplantation, and serum collected day 27. Morphologic examination of the patient's cell colonies grown in the presence of her serum revealed abnormal shapes and non-adherent cells. There were significantly fewer BFU-e colonies and a trend toward fewer CFU-GM colonies with the patient's cells and serum compared to normal donor cells. We concluded that a substance present in her serum mediated graft failure and prevented engraftment after additional stem cell infusions. Bone Marrow Transplantation (2001) 27, 221-224.

Conventional preparative regimens for allogeneic stem cell transplantation are associated with excessive regimen-related toxicity (RRT) in some patients because of underlying comorbidities, advanced age, or prior treatment. We studied a preparative regimen designed to reduce RRT, yet allow for adequate engraftment and development of a graft-versus-malignancy effect. Thirty patients (median age, 57 years) were entered on study. Twenty-nine patientsreceived stem cells from HLA-identical siblings and 1 from a sibling mismatched for 1 antigen at the A locus. Sixteen patients had received previous stem cell transplants (6 allogeneic and 10 autologous). The preparative regimen consisted of fludarabine 30 mg/M2 per day IV on day -10 to day -5, busulfan 1 mg/kg per dose PO (n = 6) or 0.8 mg/kg per dose IV (n = 24) for 8 doses every 6 hours on day -6 to day -5, and horse-derived antithymocyte globulin 5 mg/kg per day IV (n = 12) or 15 mg/kg per day IV (n = 18) on day -4 to day -1. GVHD prophylaxis consisted of cyclosporine (CYA) 3 mg/kg BID PO starting on day -3 (n = 13) or CYA and methotrexate 15 mg/m2 IV on day +1 and 10 mg/m2 IV on day +3 and day +6 (n = 17). The median number of CD34 cells transplanted was 3.19 x 10(6)/kg. All patients demonstrated recovery of hematopoietic function. Twenty-six (89%) of 29 evaluable patients achieved greater than 90% donor cell chimerism before day 100. Three patients never achieved greater than 90% donor chimerism, and another 3 patients subsequently lost donor chimerism. All 6 of these patients had autologous reconstitution with progressive disease. RRT was minimal; 7 patients had greater than grade II nonhematologic toxicity and there were no toxic deaths attributable to the conditioning regimen. Transplantation-related mortality was 7% (95% confidence interval [CI], 6%-8%) at 3 months and 28% (95% CI, 23%-34%) at 12 months after transplantation. Non-relapse-related mortality was most often due to infection. Grade II or greater GVHD developed in 56% of evaluable patients, and all patients with disease response developed GVHD. Actuarial estimates of overall and disease-free survival at 12 months were 52% (95% CI, 43%-63%) and 30% (95% CI, 24%-37%), respectively. Although this preparative regimen allowed adequate engraftment with minimal RRT, GVHD and infectious complications caused significant morbidity and mortality. Further study to define appropriate patient populations for this regimen, while limiting GVHD and infection risks, is needed.

Summary:Multifocal extramedullary plasmacytomas (EMP) are an uncommon manifestation of plasma cell malignancies. We report two patients with multiple EMP who developed rapidly progressive and ultimately fatal disease shortly after undergoing nonmyeloablative, matched-related donor allogeneic peripheral blood stem cell transplantation (PBSCT). We have not observed a similar course in patients transplanted for multiple myeloma without extramedullary manifestations and hypothesize that the intense immunosuppression associated with the fludarabine, busulfan and anti-thymocyte globulin conditioning regimen may have contributed to rapid disease progression in the two EMP patients. Our observations support the assertion that extramedullary disease is a marker for an aggressive, refractory plasma cell malignancy and suggest that patients should be treated intensively from the time of diagnosis. The utility of a graft-versus-tumor effect and the role of nonmyeloablative allogeneic PBSCT is yet to be defined in patients with extramedullary plasma cell malignancies, but it is logical to consider using it at the time of minimal residual disease rather than at disease relapse or progression. Nevertheless, we recommend circumspection in the administration of highly immunosuppressive conditioning regimens to patients with refractory EMP and encourage further clinical research in this area. related mortality has limited its usefulness in this patient population. A promising new approach to reducing the toxicity of conventional allogeneic PBSCT in these patients is the use of nonmyeloablative conditioning regimens. Although still experimental, early reports of the safety and efficacy of nonmyeloablative transplantation in patients with multiple myeloma are encouraging.