Robert C. Ash

Analysis of 462 Transplantations from Unrelated Donors Facilitated by the National Marrow Donor Program

BACKGROUND AND METHODS Allogeneic bone marrow transplantation is curative in a substantial number of patients with hematologic cancers, marrow-failure disorders, immunodeficiency syndromes, and certain metabolic diseases. Unfortunately, only 25 to 30 percent of potential recipients have HLA-identical siblings who can act as donors. In 1986 the National Marrow Donor Program was created in the United States to facilitate the finding and procurement of suitable marrow from unrelated donors for patients lacking related donors. RESULTS During the first four years of the program, 462 patients with acquired and congenital lymphohematopoietic disorders or metabolic diseases received marrow transplants from unrelated donors. The probability of engraftment by 100 days after transplantation was 94 percent, although 8 percent of patients later had secondary graft failure. The probability of grade II, III, or IV acute graft-versus-host disease was 64 percent, and the probability of chronic graft-versus-host disease at one year was 55 percent. The rate of disease-free survival at two years among patients with leukemia and good prognostic factors was 40 percent and among patients at higher risk, 19 percent. Twenty-nine percent of the patients with aplastic anemia were alive at two years, and the rate of two-year disease-free survival among patients with myelodysplasia was 18 percent. For patients with congenital immunologic or nonimmunologic disorders, the probability of survival was 52 percent. CONCLUSIONS The National Marrow Donor Program has benefited a substantial number of patients in need of marrow transplants from closely HLA-matched unrelated donors and has facilitated the recruitment of unrelated donors into the donor pool and the access to suitable marrow.

Results of allogeneic bone marrow transplants for leukemia using donors other than HLA-identical siblings.

PURPOSE To compare outcomes of bone marrow transplants for leukemia from HLA-identical siblings, haploidentical HLA-mismatched relatives, and HLA-matched and mismatched unrelated donors. PATIENTS A total of 2,055 recipients of allogeneic bone marrow transplants for chronic myelogenous leukemia (CML), acute myelogenous leukemia (AML), and acute lymphoblastic leukemia (ALL) were entered onto the study. Transplants were performed between 1985 and 1991 and reported to the International Bone Marrow Transplant Registry (IBMTR). Donors were HLA-identical siblings (n = 1,224); haploidentical relatives mismatched for one (n = 238) or two (n = 102) HLA-A, -B, or -DR antigens; or unrelated persons who were HLA-matched (n = 383) or mismatched for one HLA-A, -B, or -DR antigen (n = 108). HLA typing was performed using serologic techniques. RESULTS Transplant-related mortality was significantly higher after alternative donor transplants than after HLA-identical sibling transplants. Among patients with early leukemia (CML in chronic phase or acute leukemia in first remission), 3-year transplant-related mortality (+/-SE) was 21% +/- 2% after HLA-identical sibling transplants and greater than 50% after all types of alternative donor transplants studied. Among patients with early leukemia, relative risks of treatment failure (inverse of leukemia-free survival), using HLA-identical sibling transplants as the reference group, were 2.43 (P < .0001) with 1-HLA-antigen-mismatched related donors, 3.79 (P < .0001) with 2-HLA-antigen-mismatched related donors, 2.11 (P < .0001) with HLA-matched unrelated donors, and 3.33 (P < .0001) with 1-HLA-antigen-mismatched unrelated donors. For patients with more advanced leukemia, differences in treatment failure were less striking: 1-HLA-antigen-mismatched relatives, 1.22 (P = not significant [NS]); 2-HLA-antigen-mismatched relatives, 1.81 (P < .0001); HLA-matched unrelated donors, 1.39 (P = .002); and 1-HLA-antigen-mismatched unrelated donors, 1.63 (P = .002). CONCLUSION Although transplants from alternative donors are effective in some patients with leukemia, treatment failure is higher than after HLA-identical sibling transplants. Outcome depends on leukemia state, donor-recipient relationship, and degree of HLA matching. In early leukemia, alternative donor transplants have a more than twofold increased risk of treatment failure compared with HLA-identical sibling transplants. This difference is less in advanced leukemia.

Identical-twin bone marrow transplants for leukemia

Bone marrow transplants are increasingly used to treat leukemias including acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), and chronic myelogenous leukemia (CML). Approximately 4000 allogeneic transplants are done annually worldwide [1]. Most transplants are from HLA-identical siblings; few persons with leukemia receive transplants from identical twins. Consequently, analyses of results of twin transplants are limited by the small number of participants and diverse remission states. We analyzed the results of identical-twin transplants for leukemia in 103 persons reported to the International Bone Marrow Transplant Registry between 1978 and 1990. Transplant outcomes were compared with those of concurrent HLA-identical sibling transplants for leukemia. Methods The study population included 103 patients with ALL or AML in first remission or CML in first chronic phase receiving bone marrow transplants from identical twins between 1978 and 1990 and reported to the International Bone Marrow Transplant Registry by 66 centers. During the same period, 3214 recipients of non-T-cell-depleted HLA-identical sibling transplants for these indications were reported to the International Bone Marrow Transplant Registry by 163 centers: 581 for ALL in first remission, 1394 for AML in first remission, and 1240 for CML in first chronic phase. Assessing Comparability of Twin and HLA-identical Sibling Transplant Recipients For each disease, prognostic factors for transplant outcome were compared between twin and HLA-identical sibling transplant recipients using chi-square for categorical variables and the Mann-Whitney test [2] for continuous variables. Factors considered were those associated with HLA-identical sibling transplant outcome in previous International Bone Marrow Transplant Registry studies [3-7]. These included the following: for ALL, age, leukocytes at diagnosis, immune phenotype, and time to achieve first remission [3, 4]; for AML, age, leukocytes at diagnosis, FAB type, and Karnofsky performance score [5]; and for CML, age, previous splenectomy, interval between diagnosis and transplant, and previous treatment with busulfan [6, 7]. Conditioning regimens were also compared. For each twin transplant, 10 controls were selected from among 3214 HLA-identical sibling transplants matched for disease and any prognostic factors differing between the two cohorts with P < 0.1. For ALL, pairs were matched for age within 5 years; for AML, pairs were matched for FAB type and Karnofsky score; for CML, pairs were matched for age, interval between diagnosis and transplant, and use of busulfan before transplantation. Statistical Methods Actuarial probabilities of relapse, treatment-related mortality [8], and leukemia-free survival were calculated in the twins and matched HLA-identical sibling controls using life-table methods. Relapse was defined as hematologic recurrence in any site; patients in continuous complete remission were censored at death or, for survivors, at last contact. Treatment-related mortality was defined as death in continuous complete remission; patients were censored at time of relapse or at last follow-up. Leukemia-free survival was defined as survival in continuous complete remission. Relapse and death from causes other than leukemia were considered failures; patients alive and in remission were censored at time of last follow-up. Univariate comparisons of survival distributions were done using the matched log-rank test [9]. To compare relapse risks after adjusting for the effect of graft-versus-host disease, we used Cox proportional-hazards regression with acute and chronic graft-versus-host disease entered as time-dependent covariates [10, 11]. The International Bone Marrow Transplant Registry The Registry is a voluntary working group of more than 200 transplant teams worldwide that contribute detailed data on their allogeneic and identical-twin bone marrow transplants to a statistical center [12, 13]. The program is primarily funded by a program project grant from the U.S. National Institutes of Health. Participants are required to report all consecutive transplants; compliance is monitored by on-site audits. Approximately two thirds of all active allogeneic transplant centers report their data to the Registry. The Registry database includes 40% to 45% of all allogeneic transplant recipients since 1970. Patients are followed longitudinally. Computerized error checks, physician review of submitted data, and on-site audits of participating centers ensure data quality. Transplant outcomes estimated using Registry data are similar to those reported by large nonparticipating centers for comparable patients. Results Differences were found in patient-, disease- and treatment-related variables between the 103 recipients of identical-twin transplants and the 3214 recipients of HLA-identical sibling transplants reported to the International Bone Marrow Transplant Registry during the same interval. Some were intrinsic to the study design. For example, identical-twin donors and recipients were always of the same sex compared with only about one half of HLA-identical sibling donor-recipient pairs. Also, only eight (8%) twin recipients received immune suppression after transplantation compared with 100% of HLA-identical sibling transplant recipients. It was not possible to match or otherwise control for potential effects of these differences. Other differences were as follows: for ALL, younger median age in twins compared with HLA-identical siblings (17 compared with 22 years; P = 0.003); for AML, higher proportion of twins older than 40 years of age (22% compared with 8%; P = 0.002) and with Karnofsky performance scores at transplantation of less than 90% (15% compared with 10%; P < 0.001); and for CML in first chronic phase, shorter median interval from diagnosis to transplant in twins (6 compared with 13 months; P < 0.001) and fewer twins treated with busulfan before transplant (12% compared with 32%, P = 0.04). Ten HLA-identical sibling transplant controls were selected for each twin transplant, matching for diagnosis and for these variables. The resulting matched cohort was similar to the twin cohort for all variables considered, other than those intrinsic to twin transplants as indicated (Appendix Table 1). The median follow-up times of 6.3 years (range, 0.4 to 13.6 years) and 5.0 years (range, 0.3 to 14.8 years) were similar for twin and HLA-identical sibling transplant cohorts, respectively (P = 0.2). Appendix Table 1. Matched-Twin Compared with HLA-identical Sibling Cohorts* Transplant Outcome The two matched cohorts, twins and HLA-identical siblings, were compared for three transplant outcomes: relapse, treatment-related mortality, and leukemia-free survival. Cox regression analysis was used to compare relapse risk between the cohorts after adjusting for acute and chronic graft-versus-host disease. Acute Lymphoblastic Leukemia Ten of 24 twins had a relapse. The 3-year probability of relapse was 36% (CI, 17% to 55%) compared with 26% (CI, 20% to 32%) after 240 HLA-identical sibling transplants (P = 0.1; Figure 1). The 95% CI for the difference in relapse rates between twin and HLA-identical sibling transplants at 3 years was 10% to 30%. Regression analysis with adjustment for acute and chronic graft-versus-host disease showed no difference between identical-twin and HLA-identical sibling transplants in relapse risk (relative risk for twins compared with HLA-identical siblings, 1.4; CI, 0.6 to 2.8, P > 0.2). Figure 1. Outcome of transplants for acute lymphoblastic leukemia. top bottom Two recipients of twin transplants died in remission. The 3-year probability of treatment-related mortality in twins was 10% (CI, 3% to 30%) compared with 21% (CI, 16% to 26%) in HLA-identical sibling transplant recipients (P = 0.1). Twelve of 24 twins were alive in continuous complete remission between 1.2 and 9.5 years (median, 5.4 years) after transplantation. The 3-year probability of leukemia-free survival was 57% (CI, 37% to 77%) compared with 58% (CI, 52% to 64%) after HLA-identical sibling transplants (P > 0.2; Figure 1). Acute Myelogenous Leukemia Twenty-three of 45 twins had a relapse. The 3-year probability of relapse was 52% (CI, 37% to 67%) compared with 16% (CI, 12% to 20%) after 450 HLA-identical sibling transplants (P < 0.001; Figure 2). The 95% CI for the difference in relapse rates at 3 years was 20% to 52%. Regression analysis after adjustment for acute and chronic graft-versus-host disease also showed an increased relapse risk in twins (relative risk, 3.8; CI, 2.3 to 6.2, P < 0.001). Figure 2. Outcome of transplants for acute myelogenous leukemia. top bottom Five twins died of treatment-related causes. The 3-year probability of treatment-related mortality was 12% (CI, 1% to 23%) compared with 34% (CI, 29% to 39%) after HLA-identical sibling transplants (P = 0.004). Seventeen recipients of twin transplants were alive in continuous complete remission 5 months to 13.6 years (median, 6.3 years) after transplantation. The 3-year probability of leukemia-free survival was 42% (CI, 27% to 57%) compared with 55% (CI, 50% to 60%) after HLA-identical sibling transplants (P = 0.2; Figure 2). Chronic Myelogenous Leukemia Seventeen of 34 twins had a relapse. The 3-year probability of relapse was 40% (CI, 23% to 57%) compared with 7% (CI, 4% to 10%) after 340 HLA-identical sibling transplants (P < 0.001; Figure 3). The 95% CI for the difference in relapse rates at 3 years was 16% to 50%. Regression analysis after adjustment for acute and chronic graft-versus-host disease also showed increased relapse risk in twins (relative risk, 5.5; CI, 2.8 to 11.0, P < 0.001). Figure 3. Outcome of transplants for chronic myelogenous leukemia. top bottom One twin died of treatment-related causes. The 3-year probability of treatment-related mortality was 3% (CI, 0% to 16%) compared with 34% (CI, 29% to 39%) after HLA-ident

Interstitial pneumonitis associated with human herpesvirus-6 infection after marrow transplantation

Severe interstitial pneumonitis in 2 marrow-transplant recipients was associated with human herpesvirus-6 (HHV-6) infection. The virus was repeatedly detected in respiratory specimens from 1 patient, and HHV-6-infected cells were shown in lung tissue from both patients by immunohistochemical staining. The infected cells were primarily intra-alveolar macrophages, although infected lymphocytes were seen. HHV-6 should be considered as a cause of unexplained lung disease in marrow-transplant recipients and other immunocompromised patients.

Successful Allogeneic Transplantation of T-Cell–Depleted Bone Marrow from Closely HLA-Matched Unrelated Donors

We describe a four-year experience with bone marrow transplantation involving closely HLA-matched unrelated donors and 55 consecutive patients with hematologic disease who were seven months to 48.6 years old (median, 18 years). An intensive pretransplantation conditioning regimen and graft-versus-host disease (GVHD) prophylaxis with CD3-directed T-cell depletion and cyclosporine were employed. Durable engraftment was achieved in 50 of 53 patients who could be evaluated (94 percent; 95 percent confidence interval, 83 to 98 percent). Acute GVHD of Grade II to IV developed in 46 percent of the patients (confidence interval, 27 to 66 percent). The incidence and severity of acute GVHD were increased in recipients of HLA-mismatched marrow as compared with recipients of phenotypically matched marrow (incidence of 53 percent [confidence interval, 37 to 68 percent] vs. 17 percent [confidence interval, 5 to 45 percent]; P less than 0.05). Extensive chronic GVHD and deaths not due to relapse also tended to be more frequent when HLA-mismatched marrow was used, but not significantly so. With a median follow-up of more than 19 months (range, greater than 9 to greater than 39), the actuarial disease-free survival of transplant recipients with leukemia and a relatively good prognosis (acute leukemia in first remission and chronic myelogenous leukemia in chronic phase) was 48 percent (confidence interval, 24 to 73 percent), and that of recipients with more aggressive leukemia was 32 percent (confidence interval, 18 to 51 percent); the actuarial survival of recipients with non-neoplastic disease was 63 percent (confidence interval, 31 to 86 percent). We conclude that marrow transplantation with closely HLA-matched unrelated donors can be effective treatment for neoplastic and non-neoplastic diseases. Although transplants from phenotypically HLA-matched unrelated donors appear to be most effective, transplants with limited HLA disparity can also be successful in some patients.

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.

Chlorhexidine prophylaxis for chemotherapy-and radiotherapy-induced stomatitis: A randomized double-blind trial

Patients receiving cytotoxic antineoplastic therapy often have treatment-associated stomatitis. A 0.12% chlorhexidine digluconate mouthrinse was evaluated (15 ml, three times a day) in a prospective, double-blind randomized trial as prophylaxis against cytotoxic therapy-induced damage to oral soft tissues. Seventy subjects, forty inpatients receiving high-dose chemotherapy and thirty outpatients receiving high-dose head and neck radiation therapy, were evaluated. Chlorhexidine mouthrinse significantly reduced the incidence of oral mucositis in the chemotherapy group on day 14 (p less than 0.02) and at 1 week follow-up on day 28 (p less than 0.002). Mucositis in the patients undergoing chemotherapy who received chlorhexidine also resolved more rapidly. Mucositis severity was significantly less compared to the control chemotherapy group on day 14 (p less than 0.03), day 21 (p less than 0.04), and on 1 week follow-up (p less than 0.02). Concomitant trends in the reduction in oral streptococci and yeast were noted in the chemotherapy group receiving chlorhexidine mouthrinse. Although no differences were observed in oral mucositis between the control and chlorhexidine groups of patients undergoing high-dose radiotherapy, similar reductions of oral microflora to those seen in the chemotherapy population were also noted for patients undergoing radiation therapy who received chlorhexidine. Although generally not significant, some increase in gram-negative bacilli was noted in the chlorhexidine-treated patients in both the chemotherapy and radiotherapy groups, but there was no correlation with increased systemic infection. Prophylactic chlorhexidine mouthrinse reduces oral mucositis and microbial burden in patients with cancer undergoing intensive chemotherapy.

Studies on the Liver to Kidney Switch of Erythropoietin Production

Although the liver is the major site of erythropoietin (Ep) production in the fetus, this function is assumed by kidneys in the adult. The mechanisms underlying the liver to kidney switch of Ep formation are not understood. We studied the natural progression of this transition in sheep by measuring Ep production in response to anemia in normal and bilaterally nephrectomized fetal and newborn sheep beginning at about 80 d gestation (normal gestation: 140 d). Removal of both kidneys before induction of anemia did not affect Ep formation up to about 120 d of gestation. A significant reduction (29%, P < 0.02) in Ep synthesis was first noted at about 130 d of gestation (initiation of switch). This level of nephrectomy-induced reduction of Ep formation persisted until about 15 d after birth. Thereafter, bilateral nephrectomy caused further significant decreases (P < 0.05) in Ep production, gradually resulting in near total absence of Ep production at about day 40 postpartum (completion of switch). Chronic administration of testosterone (12 mg/wk) or estradiole benzoate (1.5 mg/d, 5 d/wk) to the fetus/newborn beginning at 85-90 d of gestation enhanced or suppressed erythropoiesis, respectively, but failed to affect the time at which the liver to kidney switch was initiated and/or completed. By contrast, a significant delay (P < 0.001) in the onset, but not completion of the switch occurred in animals that were either thyroidectomized or rendered chronically anemic beginning in the second third of the gestation period. Administration of thyroxin (1.2 mg/d, 5 d/wk) to thyroidectomized fetus/newborns not only prevented the delay in the initiation of the switch, but also accelerated the rate at which the switch was completed. These results demonstrate that in sheep (a) the liver to kidney switch of Ep production is initiated in utero during the last third of the gestation period, but is completed after birth, (b) this transition occurs gradually; the assumption of Ep producing capacity by the kidney is not preceded by an abrupt loss of hepatic Ep formation; and (c) the switch is not affected by changes in sex hormone levels during the prenatal-postnatal growth periods, but is profoundly influenced by alterations in thyroid hormone and oxygen supply-demand levels.

Low-dose amphotericin B prophylaxis against invasive Aspergillus infections in allogeneic marrow transplantation

PURPOSE Invasive Aspergillus infections cause significant morbidity and mortality in marrow transplant patients. In this study, we examined whether administration of intravenous low-dose prophylactic amphotericin B could reduce the incidence and mortality associate with invasive aspergillosis in patients undergoing allogenic marrow transplantation. PATIENTS AND METHODS The subjects of this analysis were 186 consecutive patients undergoing allogeneic marrow transplantation in an adult bone marrow transplant unit between July 1, 1985, and September 30, 1990, utilizing consistent disease-specific chemoirradiation and graft-versus-host disease protocols. The incidence, morbidity, and case fatality of invasive aspergillosis in the study group receiving amphotericin chemoprophylaxis were compared with that in two historic cohorts managed without prophylactic amphotericin B. Univariate and multivariate statistical analyses were performed to examine whether an apparent protective effect could be attributed to differences in patient and treatment variables among the cohorts and to determine potential toxicities of the chemoprophylaxis regimen. RESULTS There was a significant reduction in both the incidence (p = 0.003) and mortality (p = 0.03) of invasive aspergillosis in patients receiving amphotericin B chemoprophylaxis as compared with those not receiving chemoprophylaxis. The prophylactic amphotericin B schedule, as employed here, was not associated with increased renal or hepatic toxicity as compared with that in historically managed patients. CONCLUSION These data suggest that the risks of invasive aspergillosis in allogeneic marrow transplant recipients can be reduced by administration of prophylactic amphotericin B during the pretransplant and peritransplant periods.

Late renal dysfunction in adult survivors of bone marrow transplantation.

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.