Norma K.C. Ramsay

Successful bone-marrow transplantation for infantile malignant osteopetrosis

A five-month-old girl with autosomal-recessive osteopetrosis received a bone-marrow transplant from her five-year-old HLA-MLC-identical brother after preparation with cyclophosphamide and modified total-body irradiation. Engraftment was documented by chromosomal analysis. Anemia, thrombocytopenia, and leukoerythroblastosis corrected within 12 weeks of transplantation. Low serum calcium and elevated serum alkaline and acid phosphatase levels became normal. Serial x-ray studies revealed bony remodeling and new nonsclerotic bone formation. A pretransplantation bone biopsy revealed small marrow spaces, rare marrow elements, increased osteoclasts, and no bony resorption. After transplantation, osteoclasts were actively resorbing bone, and medullary cavities contained normal bone marrow. Fluorescent Y-body analysis after transplantation revealed donor (male) osteoclasts and recipient (female) osteoblasts. Monocyte bactericidal activity, markedly decreased before transplantation, became normal. Vision, hearing, growth, and development were progressively improving 16 months after transplantation. Allogeneic bone-marrow transplantation appears to be the treatment of choice in this fatal disorder.

Risk Factors For Acute Graft-versus-host Disease In Histocompatible Donor Bone Marrow Transplantation

We have analyzed factors associated with acute graft-versus-host disease following allogeneic bone marrow transplantation in 469 patients with histocompatible sibling donors between 1979 and 1987. Overall, 46±5% (95% confidence interval) developed clinical grade II-IV acute GVHD following transplantation. In univariate analysis, patient or donor age ≥18 years was significantly associated with increased GVHD risks (≥18, 63± 6% grade II-IV GVHD vs. <18,27±6%, P<.0001), without incremental risk in older adults. Univariate analysis showed that donor:recipient sex match and female: female transplants were associated with less-frequent GVHD. More frequent GVHD was associated with chronic myelogenous leukemia, cytomegalovirus seropositivity, and prior donor alloimmunity (pregnancy or transfusion). Additionally, the allele HLA-A26 was associated with increased risk of GVHD (72%, P=.005) while HLA-DR3 was associated with less GVHD (31%, P=.03). Stepwise multivariate analysis confirmed the increased GVHD risks associated with older recipient age, HLA-A26 and donor:recipient gender (not female: female) and the protective effect of HLA-DR3. Similar results were found using the different analytic technique of recursive partition analysis, which identified within the adult population the lowest GVHD risk in female recipients with nonalloimmunized female donors (20%), while other gender combinations had 68% acute GVHD, regardless of donor alloimmunity. In children (<18 years), lower GVHD risk accompanied donor:recipient sex-matched (18%) versus mismatched (33%) BMT. Clinical trials undertaken to lessen the hazards of GVHD must be designed with appropriate attention to these reproducibly identified clinical variables associated with different GVHD risks.

New Malignancies After Blood or Marrow Stem-Cell Transplantation in Children and Adults: Incidence and Risk Factors

PURPOSE To determine the incidence and risk factors for the development of new malignancies occurring after stem-cell transplantation (SCT). PATIENTS Between January 1, 1974, and March 31, 2001, 3,372 patients underwent SCT at the University of Minnesota. From these transplants, 147 posttransplant malignancies (PTMs) were identified in 137 patients. RESULTS Excluding nonmelanoma skin cancers (n = 19) and carcinoma-in-situ (n = 5), the remaining 123 cases represented an 8.1-fold (95% confidence interval [CI], 6.7 to 9.6) increased risk of a PTM, an excess risk of 102.7 cases/10,000 persons/yr (age and sex adjusted). This includes a significantly elevated risk for developing myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML; standardized incidence ratio [SIR] = 300; 95% CI, 210 to 406), non-Hodgkins lymphoma including posttransplant lymphoproliferative disorder (PTLD; SIR = 54.3; 95% CI, 39.5 to 41.1), Hodgkins disease (SIR = 14.8; 95% CI, 3.9 to 32.9), or solid tumors overall (SIR = 2.8; CI, 2.0 to 3.7) and in specific for melanoma, brain, and oral cavity tumors. The cumulative incidence for the development of any PTM was 6.9% (95% CI, 5.2 to 8.6) at 20 years post-SCT. For PTLD (n = 43), the cumulative incidence plateaued at 1.4% (95% CI, 1.0 to 1.8) by 10 years post-SCT. For MDS or AML, the cumulative incidence plateaued at 1.4% (95% CI, 0.9 to 1.9) by 10 years post-SCT. The cumulative incidence of developing a solid tumor did not plateau and was 3.8% (95% CI, 2.2 to 5.4) at 20 years post-SCT. CONCLUSION These data reveal that the risk of PTMs, especially solid tumors, continues to increase even 20 years after transplant, necessitating long-term close follow-up for these patients.

Positive effect of prophylactic total parenteral nutrition on long-term outcome of bone marrow transplantation.

In a randomized trial we studied the impact of providing total parenteral nutrition (TPN) to bone marrow transplant (BMT) patients during their cytoreductive therapy, and for 4 weeks following BMT, on 8 parameters of outcome. A total of 137 patients over 1 year of age and with normal nutritional status were randomized either to receive TPN starting one week prior to transplant or to receive hydration with a 5% dextrose solution containing electrolytes, minerals, trace elements, and vitamins. TPN was ultimately required by 40 of the 66 control patients when nutritional depletion was documented. Average total calorie and protein intake was significantly higher for the TPN group than for the control group. Minimum follow-up was 1 year and median was 2 years. Overall survival, time to relapse, and disease-free survival were significantly improved in the TPN group. Engraftment, duration of hospitalization, and incidences of acute and chronic graft-vs.-host disease and bacteremia were not different. Thus TPN during BMT had a positive effect on long-term outcome. Prophylactic nutritional therapy appears to be indicated even for well-nourished individuals during cytoreduction and BMT.

Bone marrow transplantation for Fanconi anemia

Fanconi anemia is a genetic disorder associated with diverse congenital abnormalities, progressive bone marrow failure, and increased risk of leukemia and other cancers. Affected persons often die before 30 years of age. Bone marrow transplantation is an effective treatment, but there are few data regarding factors associated with transplant outcome. We analyzed outcomes of HLA-identical sibling (N = 151) or alternative related or unrelated donor (N = 48) bone marrow transplants for Fanconi anemia performed between 1978 and 1994 and reported to the International Bone Marrow Transplant Registry. Fanconi anemia was documented by cytogenetic studies in all cases. Patient, disease, and treatment factors associated with survival were determined using Cox proportional hazards regression. Two-year probabilities (95% confidence interval) of survival were 66% (58% to 73%) after HLA-identical siblings transplants and 29% (18% to 43%) after alternative donor transplants. Younger patient age (P .0001), higher pretransplant platelet counts (P = .04), use of antithymocyte globulin (P = .005), and use of low-dose (15 to 25 mg/kg) cyclophosphamide plus limited field irradiation (P = .009) for pretransplant conditioning and cyclosporine for graft-versus-host disease prophylaxis (P = .002) were associated with increased survival. Bone marrow transplants are effective therapy for Fanconi anemia. The adverse impact of increasing age and lower pretransplant platelet count on transplant outcome favors earlier intervention, especially when there is an HLA-identical sibling donor.

A Randomized Study of the Prevention of Acute Graft-versus-Host Disease

Acute graft-versus-host disease is a major problem in allogeneic bone-marrow transplantation. We performed a randomized study to compare the effectiveness of two regimens in the prevention of acute graft-versus-host disease. Thirty-five patients received methotrexate alone, and 32 received methotrexate, antithymocyte globulin, and prednisone. Of the patients who received methotrexate alone, 48 per cent had acute graft-versus-host disease, as compared with 21 per cent of those who received methotrexate, antithymocyte globulin, and prednisone (P = 0.01). The age of the recipient was a significant factor in the development of acute graft-versus-host disease: Older patients had a higher incidence of the disease (P = 0.001). We conclude that the combination of methotrexate, antithymocyte globulin, and prednisone significantly decreased the incidence of acute graft-versus-host disease and should be used to prevent this disorder in patients receiving allogeneic marrow transplants.

Comparison of Preparative Regimens in Transplants for Children With Acute Lymphoblastic Leukemia

PURPOSE Preparative regimens involving total-body irradiation (TBI) produce significant late toxicities in some children who receive bone marrow transplants, including impaired growth and intellectual development. Busulfan is often used as an alternative to TBI, but there are few data regarding its relative efficacy. PATIENTS AND METHODS We compared outcomes of HLA-identical sibling transplants for acute lymphoblastic leukemia (ALL) in children (< 20 years of age) who received cyclophosphamide plus TBI (CY/TBI) (n = 451) versus those who received busulfan plus cyclophosphamide (Bu/CY) (n = 176) for pretransplant conditioning. Patients received transplants between 1988 and 1995 and their results were reported to the International Bone Marrow Transplant Registry by 144 participating institutions. The CY/TBI and Bu/CY groups did not differ in gender, immune phenotype, leukocyte count at the time of diagnosis, chromosome abnormalities, remission status, or length of initial remission. T-cell depletion was used more frequently in the CY/TBI group; the Bu/CY group included a higher proportion of children who were less than 5 years of age. The median follow-up period was 37 months. RESULTS The 3-year probabilities of survival were 55% (95% confidence interval [CI], 50% to 60%) with TBI/CY and 40% (95% CI, 32% to 48%) with Bu/CY (univariate P =.003). The 3-year probabilities of leukemia-free survival were 50% (95% CI, 45% to 55%) and 35% (95% CI, 28% to 43%), respectively (univariate P =.005). In a multivariate analysis, the risks of relapse were similar in the two groups (relative risk [RR], 1.30 for Bu/CY v CY/TBI; P =.1). Treatment-related mortality was higher in the Bu/CY group (RR, 1.68; P =.012). Death and treatment failure (relapse or death, inverse of leukemia-free survival) were more frequent in the Bu/CY group (RR, 1. 39; P =.017 for death; RR, 1.42; P =.006 for treatment failure). CONCLUSION These data indicate superior survival with CY/TBI conditioning, compared with Bu/CY conditioning, for HLA-identical sibling bone marrow transplants in children with ALL.

Adverse reactions in patients transfused with cryopreserved marrow

Marrow is cryopreserved for use in autologous bone marrow transplants, but little is known of the incidence of reactions in patients transfused with these cryopreserved marrows. Reactions in patients transfused during a 4‐year period with 134 autologous marrows cryopreserved in dimethyl sulfoxide (DMSO) were compared with those in patients transfused with marrow that had been collected from HLA‐ compatible donors and that had not been cryopreserved. Patients transfused with cryopreserved marrow had significantly more nausea (44.8 vs. 14.1%; p less than 0.0005), vomiting (23.9 vs. 8.5%; p less than 0.01), chills (31.3 vs. 1.4%; p less than 0.0005), and fever (17.9 vs. 0%; p less than 0.005) than patients transfused with fresh allogeneic marrow. The incidence of emesis correlated with the dose of DMSO received, but that of nausea did not. All cryopreserved marrows were cultured for bacteria at the time of transfusion and 17 (12.7%) were found to be positive. Only 1 of the 17 patients transfused with culture‐positive marrow developed sepsis during the transplant course with the same organism that was present in the transfused marrow. Although the reactions in donors transfused with cryopreserved marrow were readily treated, this study suggests that the incidence of some reactions might be decreased by reducing the dose of DMSO transfused. Bacterial contamination of transfused marrow was a worrisome complication, and efforts should be made to improve marrow collection and processing techniques to minimize that risk.

A syndrome of thrombosis and hemorrhage complicating l-asparaginase therapy for childhood acute lymphoblastic leukemia**

L-Asparaginase therapy for childhood acute lymphoblastic leukemia causes deficiencies of plasma hemostatic proteins, especially antithrombin, plasminogen, and fibrinogen. Severe thromboses and hemorrhages occurred in 18 children receiving vincristine, prednisone, and asparaginase therapy for ALL. Thirteen children had intracranial thrombosis or hemorrhage, four had extremity thrombosis, and one had both an intracranial hemorrhage and an extremity thrombosis. These events occur characteristically in the third and fourth weeks of therapy during or just after a three-week course of L-asparaginase. Symptoms of headache, obtundation, hemiparesis, and seizure were common for the intracranial events: local pain, swelling, and discoloration were common for the extremity thromboses. These complications have been recognized in 1 to 2% of children undergoing induction therapy which includes asparaginase.

Effect of low-dose oral glutamine on painful stomatitis during bone marrow transplantation

Painful oral mucositis is a common complication after bone marrow transplantation (BMT). Glutamine is a nutrient for rapidly dividing cells and the major energy source for intestinal epithelium. This study tested whether an oral glutamine preparation could decrease the severity of oral mucositis in patients undergoing BMT. Glutamine or a placebo (glycine) were administered from admission until day +28 in 193 BMT patients in a randomized, double-blind, placebo-controlled study at a dose of 1.0 g amino acid/m2/dose swish and swallow four times a day. In autologous BMT patients (n = 87) glutamine was associated with significantly less mouth pain by self report and by opiate use (5.0 ± 6.2 days of morphine for glutamine vs 10.3 ± 9.8 days for placebo; P = 0.005). Matched sibling BMT patients had no effect by self report and an increased duration of opiate use (23.2 ± 5.7 days for glutamine vs 16.3 ± 8.3 days for placebo) (P = 0.002). However, day 28 survival of allogeneic patients was improved by glutamine. No significant differences in TPN use, rate of relapse or progression of malignancy, parenteral antibiotic use, acute or chronic GVHD, or days of hospitalization were observed in either autologous or allogeneic recipients. No toxicity of glutamine was observed. We conclude that oral glutamine can decrease the severity and duration of oropharyngeal mucositis in autologous BMT patients but not in allogeneic BMT patients, possibly due to interaction with methotrexate.