Summary:own is late or long-term renal toxicity. [2][3][4][5][6][7][8][9][10][11] The renal toxicity described consists of a group of clinical signs including hypertension, anemia, and decreased glomerular filThe purpose of this study was to evaluate the effect of partial renal shielding used in conjunction with total tration rate (GFR) with occasional proteinuria and microscopic hematuria, and edema. Biopsies of the affected body irradiation (TBI) on the incidence of bone marrow transplantation nephropathy (BMT Np) seen as a late kidneys have a unifying aspect in that there is extreme subendothelial widening of the basement membranes, with sequelae after transplantation. Of 402 patients who have undergone bone marrow transplantation (BMT) at the endothelial cell dropout, glomerular arteriolar intimal thickening and atrophic tubules. Whether all the changes seen Medical College of Wisconsin (MCW) 157 were greater than 18 years of age, received 14 Gy TBI and survived on biopsy relate to the 'BMT nephropathy' (BMT Np) previously described has yet to be determined. What is unquesat least 100 days post-transplant. The incidence of BMT nephropathy was evaluated in these patients by dose to tionably true of the data to date is that the use of TBI appears to play a significant role in the development of the the kidneys. In the 72 patients who received 14 Gy TBI with no renal shielding, the actuarial risk of developing syndrome. 5,7-11 Previously, our institution described the use of selective BMT Np at 2. years (30 months) post-BMT was 29 ± 7%. Sixty-eight patients received 14 Gy TBI with partial renal shielding in an effort to reduce the incidence of this late renal toxicity. 7 Here, we found an incidence of partial renal shielding of 15% (renal dose = 11.9 Gy), the actuarial risk of developing BMT Np was 14 ± 5%BMT nephropathy of 26% in the unshielded patients at 18 months vs 6% in the shielded patients (P Ͻ 0.05). Shielding at 2. years. Seventeen patients received 14 Gy TBI with renal shielding of 30% (renal dose = 9.8 Gy); none of utilized at that time was a 70% transmission posterior/ anterior (PA)-only shield that decreased the total renal dose this group have developed BMT Np despite a median follow-up of over 2. years (985 days). The trend of from 14 Gy to 11.9 Gy. Since the partial shielding appeared effective but we were still experiencing some level of late decreasing BMT Np with increasing shielding is statistically significant (P = 0.012). Prognostic factors such as renal toxicity we doubled the shielding to a 40% transmission PA-only block to decrease the dose to the kidneys age, type of transplant and good-risk vs poor-risk disease status were evaluated and were similar in each to 9.8 Gy. Results of this change as well as long-term follow-up of the initial cohort of patients both renally blocked cohort of patients described above. We conclude that given the statistically significant benefit seen here in the and unblocked are the focus of this manuscript. reduced incidence of BMT Np by the use of selectiv...

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Allogeneic bone marrow transplantation is the treatment of choice for many childhood leukemias. The donor of choice-an HLA matched sibling-is only available about 30% of the time. Unrelated donors are an alternative choice. In this report, we describe the results of unrelated donor bone marrow transplants (BMT) in 50 children with leukemia (25 acute lymphoblastic leukemia [ALL], 3 acute myeloid leukemia [AML], 3 juvenile chronic myelogenous leukemia [JCML], 10 chronic myeloid leukemia [CML]) or myelodysplastic syndrome (MDS; 9). The median age of the 31 male and 19 female patients was 9 years (range 2 to 18). Only 13 patients were serologically matched at HLA-A, B, DR, and DQ with their donors; 6 of these were reactive in mixed lymphocyte culture. The other 37 patients were mismatched for one (36 patients) or more (1 patient) HLA antigens. Pretransplant conditioning included cytosine arabinoside, cyclophosphamide, fractionated total body irradiation (TBI) (with lung, liver, and more recently, kidney shielding), and methylprednisolone. High-risk patients also received busulfan. Graft-versus-host disease (GVHD) prophylaxis consisted of T- cell depletion with IgM monoclonal antibody T10B9 plus complement and posttransplant cyclosporine-A. Forty-nine patients (98%) engrafted. Median times to greater than 500 polymorphonuclear leukocytes (PMN)/microL and greater than 25,000 platelets/microL were 18 and 20 days, respectively. Acute GVHD > or = grade II occurred in 16 patients (33%); 13 (81%) of these died. Chronic GVHD developed in 30 of 40 patients at risk, but was extensive in only 5. Event-free survival (EFS) for all patients was 44% +/- 7% (median follow-up was 49 months), and overall survival was 50 +/- 7%. Patients with low-risk disease (ALL or AML in first or second remission and CML in chronic phase) had a better EFS than children with high-risk disease (60% v 34%, P = .07). There was no significant difference in EFS between patients who were serologically matched with their donors (46%) and those who were partially mismatched (43%) (P = .97). These data compare favorably with published reports for children transplanted with HLA-matched sibling donors and should encourage earlier consideration of unrelated donor BMT in children with leukemia or myelodysplasia.

Until recently long-term renal toxicity has not been considered a major late complication of bone marrow transplantation (BMT). Late renal dysfunction has been described in a pediatric population status post-BMT which was attributable to the radiation in the preparatory regimen. A thorough review of adults with this type of late renal dysfunction has not previously been described. Fourteen of 103 evaluable adult patients undergoing allogeneic (96) or autologous (7) bone marrow transplantation, predominantly for leukemia and lymphomas, at the Medical College of Wisconsin (Milwaukee, WI) have had a syndrome of renal insufficiency characterized by increased serum creatinine, decreased glomerular filtration rate, anemia, and hypertension. This syndrome developed at a median of 9 months (range, 4.5 to 26 months) posttransplantation in the absence of specific identifiable causes. The cumulative probability of having this renal dysfunction is 20% at 1 year. Renal biopsies performed on seven of these cases showed the endothelium widely separated from the basement membrane, extreme thickening of the glomerular basement membrane, and microthrombi. Previous chemotherapy, antibiotics, and antifungals as well as cyclosporin may add to and possibly potentiate a primary chemoradiation marrow transplant renal injury, but this clinical syndrome is most analogous to clinical and experimental models of radiation nephritis. This late marrow transplant-associated nephritis should be recognized as a potentially limiting factor in the use of some intensive chemoradiation conditioning regimens used for BMT. Some selective attenuation of the radiation to the kidneys may decrease the incidence of this renal dysfunction.

Between January 1988 and March 1993, 48 patients received T-cell- depleted marrow grafts from unrelated donors as treatment for chronic myelogenous leukemia (CML). The median age of the population was 31.7 years (range 5.4 to 53) with 17 of 48 patients greater than 40 years of age. Twenty-seven patients were transplanted in chronic phase, 17 in accelerated phase, and 4 in blast crisis. All patients received a standardized preparative regimen of cyclophosphamide, high-dose cytosine arabinoside, methylprednisolone, and total body irradiation. Marrow grafts were depleted of mature T cells with the alpha beta T- cell receptor antibody T10B9 as graft-versus-host disease (GVHD) prophylaxis. All patients also received posttransplant cyclosporine therapy. Twenty-eight of 48 patients were mismatched with their donors for one or more HLA-A, B, DR, or DQ loci by either serology or high- resolution oligonucleotide genotyping. Nine of 28 were mismatched at multiple HLA loci. Durable engraftment was achieved in 94% (45/48) of patients. The actuarial probability of developing grades II to IV and grades III to IV acute GVHD were 39.6% (95% confidence interval (CI) 26.9 to 53.0) and 8.3% (95% CI 6.1 to 10.9) for the entire cohort. There was no difference in the incidence of grades II to IV acute GVHD between patients receiving matched (36.8%) or mismatched (41.4%) marrow grafts (P = .77). The actuarial probability of relapse at 2 years was 8.8% (95% CI 2.1 to 21.6) for the entire cohort and 18% (95% CI 4 to 41) for patients transplanted in either the accelerated or blast crisis phase (advanced disease). One cytogenetic relapse has occurred among patients transplanted in the chronic phase. The probability of disease- free survival at 2 years was 52% (95% CI 24 to 70) for patients transplanted in chronic phase and 46% (95% CI 25 to 73) for patients transplanted with advanced disease. No difference in disease-free survival was observed between patients receiving matched (49%) or mismatched (51%) marrow grafts (P = .90). This study shows that patients receiving unrelated T-cell-depleted marrow grafts for CML can achieve durable engraftment with a low incidence of severe GVHD and apparent preservation of graft-versus-leukemia reactivity. These data also suggest that T-cell depletion may allow patients who might otherwise experience unacceptable toxicity from GVHD-related complications caused by older age or increased HLA disparity to benefit from unrelated marrow grafts.