Mortimer M. Bortin

Bone Marrow Transplantation for Chronic Myelogenous Leukemia in Chronic Phase: Increased Risk for Relapse Associated with T-Cell Depletion

Data on 405 patients with chronic myelogenous leukemia who received bone marrow transplants in chronic phase were analyzed for factors predictive of outcome. The 4-year actuarial probability of relapse was 19% (95% confidence interval [CI], 12% to 28%) and of survival, 55%. In multivariate analyses the probability of relapse was higher for recipients of T-cell-depleted bone marrow compared with recipients of non-T-cell-depleted bone marrow (relative risk, 5.4; P less than 0.0001) and for patients who did not develop chronic graft-versus-host disease (95% CI, 50% to 60%) with patients who did (relative risk, 3.1; P less than 0.01). The probability of survival was lower for patients who developed moderate to severe acute graft-versus-host disease than for patients with no or mild acute graft-versus-host disease (relative risk, 3.7; P less than 0.0001), and in patients aged 20 or older than in younger patients (relative risk, 2.6; P less than 0.0002). Duration of disease before transplant was not associated with outcome. Bone marrow transplantation done in the chronic phase of chronic myelogenous leukemia offers some patients prolonged leukemia-free survival. The T-cell-depleted grafts are associated with an increased probability of relapse.

Risk factors for acute graft‐versus‐host disease

Summary. Acute graft‐versus‐host disease (GvHD) is an important complication of bone marrow transplantation in humans. Risk factors are imprecisely defined and controversial. We analysed data from 2036 recipients of HLA‐identical sibling transplants for leukaemia or aplastic anaemia to identify risk factors for GvHD. Analyses indicate that grading of GvHD can be reproducibly divided into absent or mild versus moderate to severe; 2‐year actuarial probability was 54% (95% confidence interval 52–56%) for absent or mild and 46% (44–48%) for moderate to severe. Factors predictive of development of moderate to severe GvHD include donor/recipient sex‐match (female→male greater than others, relative risk 2.0, P<0.001). This risk was markedly increased if female donors for male recipients were previously pregnant or transfused (relative risk 2.9, P<0.0001). Older patients were at increased risk of GvHD (relative risk 1.6, P<0.001), but the age gradient was modest, even the youngest patients had a substantial risk of GvHD and, if parous or transfused female→male transplants were excluded, age was not a significant risk factor. Cyclosporine or methotrexate were equally effective at preventing GvHD and were superior to no prophylaxis (relative risk 2.3, P<0.01). These data should be useful in estimating the risk of acute GvHD in an individual patient and in designing clinical trials to investigate methods to modify or prevent GvHD.

Interstitial Pneumonitis After Bone Marrow Transplantation: Assessment of Risk Factors

Data from 932 patients with leukemia who received bone marrow transplants were analyzed to determine factors associated with an increased risk of developing interstitial pneumonitis. Interstitial pneumonitis developed in 268 patients for a 2-year actuarial incidence of 35 +/- 4% (SD) and with a mortality rate of 24%. Six factors were associated with an increased risk: use of methotrexate rather than cyclosporine after transplantation (relative risk, 2.3; p less than 0.0002); older age (relative risk, 2.1; p less than 0.0001); presence of severe graft-versus-host disease (relative risk, 1.9; p less than 0.003); long interval from diagnosis to transplantation (relative risk, 1.6; p less than 0.002); performance ratings before transplantation of less than 100% (relative risk, 2.1; p less than 0.0001); and high dose-rates of irradiation in patients given methotrexate after transplantation (relative risk, 3.2; p less than 0.03). The risk of developing interstitial pneumonitis ranged from 8% in patients with none of these adverse risk factors to 94% in patients with all six. These findings may help to identify patients at high risk for this complication.

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

Bone marrow transplants from HLA-identical siblings as compared with chemotherapy for children with acute lymphoblastic leukemia in a second remission

BACKGROUND It is unclear how best to treat children with acute lymphoblastic leukemia who are in a second remission after a bone marrow relapse. For those with HLA-identical siblings, the question of whether to perform a bone marrow transplantation or to continue chemotherapy has not been answered. METHODS We compared the results of treatment with marrow transplants from HLA-identical siblings in 376 children, as reported to the International Bone Marrow Transplant Registry, with the results of chemotherapy in 540 children treated by the Pediatric Oncology Group. A preliminary analysis identified variables associated with treatment failure in both groups. We selected cohorts by matching these variables. A possible bias associated with differences in the interval between remission and treatment was controlled for by choosing matched pairs in which the duration of the second remission in the chemotherapy recipient was at least as long as the time between the second remission and transplantation in the transplant recipient. A total of 255 matched pairs were studied. RESULTS The mean (+/- SE) probability of a relapse at five years was significantly lower among the transplant recipients than among the chemotherapy recipients (45 +/- 4 percent vs. 80 +/- 3 percent, P < 0.001). At five years the probability of leukemia-free survival was higher after transplantation than after chemotherapy (40 +/- 3 percent vs. 17 +/- 3 percent, P < 0.001). The relative benefit of transplantation as compared with chemotherapy was similar in children with prognostic factors indicating a high or low risk of relapse (the duration of the first remission, age, leukocyte count at the time of the diagnosis, and phenotype of the leukemic cells). CONCLUSIONS For children with acute lymphoblastic leukemia in a second remission, bone marrow transplants from HLA-identical siblings result in fewer relapses and longer leukemia-free survival than does chemotherapy.

ALLOGENEIC BONE-MARROW TRANSPLANTATION FOR CHRONIC MYELOGENOUS LEUKAEMIA

In 117 patients with chronic myelogenous leukaemia (CML) treatment with a combination of high-dose chemoradiotherapy plus transplantation of allogeneic bone-marrow from HLA-identical, mixed-lymphocyte-culture-identical siblings resulted in an actuarial probability of 3-year survival of 63 +/- 16% (95% confidence interval) for 39 patients transplanted in chronic phases; 36 +/- 14% for 56 transplanted in accelerated phase; and 12 +/- 15% for 22 transplanted during blast crisis. Irrespective of disease status at the time of transplantation, and in contrast to chemotherapy, a plateau-effect was observed in the survival curves starting 14 to 19 months after transplantation. The actuarial probability of recurrent or persistent leukaemia at 3 years was 7 +/- 9% for patients transplanted in chronic phase, 41 +/- 19% for accelerated phase, and 41 +/- 39% for blastic phase. All relapses occurred within 18 months of transplantation. This study demonstrates that long-term disease-free survival in CML can be achieved with bone-marrow transplantation. Best results were obtained in patients transplanted during chronic phase of the disease.

Chemotherapy compared with bone marrow transplantation for adults with acute lymphoblastic leukemia in first remission.

OBJECTIVE To compare efficacy of intensive postremission chemotherapy with allogeneic bone marrow transplantation in adults with acute lymphoblastic leukemia (ALL) in first remission. DESIGN Retrospective comparison of two cohorts of patients. SETTING Chemotherapy recipients were treated in 44 hospitals in West Germany in two cooperative group trials; transplants were done in 98 hospitals worldwide. PATIENTS Patients (484) receiving intensive postremission chemotherapy and 251 recipients of HLA-identical sibling bone marrow transplants for ALL in first remission. Patients ranged from 15 to 45 years of age and were treated between 1980 and 1987. MAIN RESULTS Similar prognostic factors predicted treatment failure (non-T-cell phenotype, high leukocyte count at diagnosis, and 8 or more weeks to achieve first remission) of both therapies. After statistical adjustments were made for differences in disease characteristics and time-to-treatment, survival was similar in the chemotherapy and transplant cohorts: Five-year leukemia-free survival probability was 38% (95% CI, 33% to 43%) with chemotherapy and 44% (CI, 37% to 52%) with transplant. No specific prognostic group had a significantly better outcome with one treatment compared with the other (6% for the difference; CI, -3% to 15%). Causes of treatment failure differed: With chemotherapy, 268 (96%) failures were from relapse and 11 (4%) were treatment-related; with transplants, 43 (32%) failures were from relapse and 92 (68%) were treatment-related. CONCLUSIONS These results suggest that bone marrow transplants currently offer no special advantage over chemotherapy for adults with acute lymphoblastic leukemia in first remission.

Increasing Utilization of Allogeneic Bone Marrow Transplantation: Results of the 1988-1990 Survey

OBJECTIVE To determine the pattern and frequency of allogeneic bone marrow transplantation from related and unrelated donors from 1988 to 1990. DESIGN AND SETTING Survey of 342 institutions in 47 countries. MEASUREMENTS Numbers of patients receiving bone marrow transplantation for specific disease categories at institutions with active allogeneic bone marrow transplant programs. MAIN RESULTS Patients (14,745) received allogeneic bone marrow transplantation between 1988 and 1990; of these, 1153 (8%) were from unrelated donors. Reasons for transplantation were acute leukemia (47%), chronic myelogenous leukemia (27%), lymphoma and other malignancies (10%), severe aplastic anemia (9%), and other nonmalignant diseases (7%). The number of allogeneic bone marrow transplants per million persons differed among countries, averaging 7.7 per million in North America and 5.7 per million in western Europe. CONCLUSIONS The use of allogeneic bone marrow transplantation continued to increase at a rate of more than 600 additional patients and 25 new transplant teams annually. This rise is due in part to increasing use of unrelated volunteers as donors. Resources allocated for transplants vary widely among countries.

Risk factors for interstitial pneumonia following bone marrow transplantation for severe aplastic anaemia

Summary. Data from 547 patients with aplastic anaemia who received bone marrow transplants from HLA‐identical siblings were analysed to determine factors associated with the risk of interstitial pneumonia (IPn). IPn developed in 92 patients (17%). 37% of cases were associated with cytomegalovirus infection and 22% with other organisms: in 41% of cases no organism was identified. The case fatality rate was 64%; the mortality rate due to IPn was 11%. In multivariate analysis, four factors were associated with an increased probability of interstitial pneumonia: use of methotrexate rather than cyclosporine after transplantation (relative risk, 2.8: P<0.0008); occurrence of moderate to severe acute graft‐versus‐host disease (relative risk, 2.2; P<0.002); inclusion of total body radiation in the pretransplant preparative regimen (relative risk 2.2, P<0.004); and patient age >20 (relative risk 1.7, P<0.002). The probability of IPn ranged from 4% for patients with none of these adverse risk factors to 51% (relative risk of 13.4) for patients with all four. The incidence of IPn decreased significantly between 1978 and 1985, paralleling a decrease in the use of total body radiation pretransplant for immune suppression and methotrexate post‐transplant for prophylaxis against graft‐versushost disease.

Increasing utilization of bone marrow transplantation. II: Results of the 1985-1987 survey

The International Bone Marrow Transplant REgistry conducts periodic surveys to determine activity in the field of allogeneic and syngeneic bone marrow transplantation. Data were reported to the IBMTR by 258 institutions in 41 countries regarding their patients who received bone marrow transplants during the period 1985-1987. To the best of our knowledge, the data represent essentially all bone marrow transplants (exclusive of autologous transplants) performed in the past 3 years. A total of 10,887 patients received bone marrow transplants; 73% were for leukemia, 11% for other malignant diseases, 9% for severe aplastic anemia and related disorders, 3% for immune deficiency diseases, 2% for thalassemia major, and 2% for genetic, metabolic, and several other rare diseases. 161 (62%) of the 258 institutions performed fewer than one transplant per month. More than 50% of the patients were transplanted in 37 institutions. 46% of the worlds bone marrow transplants were performed in North America, 42% in Western Europe, 5% in Asia, 3% in Australia and New Zealand, 2% in the Mideast and Africa, 1% in South and Central America, and 1% in Eastern Europe and the USSR. The data reflect continued growth in utilization of allogeneic and syngeneic bone marrow transplantation and quantify the annual increases in the number of patients receiving transplants.