Philip A. Rowlings

Solid Cancers after Bone Marrow Transplantation

BACKGROUND The late effects of bone marrow transplantation, including cancer, need to be determined in a large population at risk. METHODS We studied 19,229 patients who received allogeneic transplants (97.2 percent) or syngeneic transplants (2.8 percent) between 1964 and 1992 at 235 centers to evaluate the risk of the development of a new solid cancer. Risk factors relating to the patient, the transplant, and the course after transplantation were evaluated. RESULTS The transplant recipients were at significantly higher risk of new solid cancers than the general population (observed cases, 80; ratio of observed to expected cases, 2.7; P<0.001). The risk was 8.3 times higher than expected among those who survived 10 or more years after transplantation. The cumulative incidence rate was 2.2 percent (95 percent confidence interval, 1.5 to 3.0 percent) at 10 years and 6.7 percent (95 percent confidence interval, 3.7 to 9.6 percent) at 15 years. The risk was significantly elevated (P<0.05) for malignant melanoma (ratio of observed to expected cases, 5.0) and cancers of the buccal cavity (11.1), liver (7.5), brain or other parts of the central nervous system (7.6), thyroid (6.6), bone (13.4), and connective tissue (8.0). The risk was higher for recipients who were younger at the time of transplantation than for those who were older (P for trend <0.001). In multivariate analyses, higher doses of total-body irradiation were associated with a higher risk of solid cancers. Chronic graft-versus-host disease and male sex were strongly linked with an excess risk of squamous-cell cancers of the buccal cavity and skin. CONCLUSIONS Patients undergoing bone marrow transplantation have an increased risk of new solid cancers later in life. The trend toward an increased risk over time after transplantation and the greater risk among younger patients indicate the need for life-long surveillance.

Long-term survival and late deaths after allogeneic bone marrow transplantation

Background and Methods It is uncertain whether mortality rates among patients who have undergone bone marrow transplantation return to the level of the mortality rates of the general population. We analyzed the characteristics of 6691 patients listed in the International Bone Marrow Transplant Registry. All the patients were free of their original disease two years after allogeneic bone marrow transplantation. Mortality rates in this cohort were compared with those of an age-, sex-, and nationality-matched general population. Cox proportional-hazards regression was used to identify risk factors for death more than two years after transplantation (late death). Results Among patients who were free of disease two years after transplantation, the probability of living for five more years was 89 percent (95 percent confidence interval, 88 to 90 percent). Among patients who underwent transplantation for aplastic anemia, the risk of death by the sixth year after transplantation did not differ significantly from ...

IBMTR Severity Index for grading acute graft-versus-host disease: retrospective comparison with Glucksberg grade.

Acute graft‐versus‐host disease (GVHD) severity is graded by pattern of organ involvement and clinical performance status using a system introduced by Glucksberg and colleagues 21 years ago. We examined how well Glucksberg grade predicted transplant outcome and constructed a Severity Index not requiring subjective assessment of performance in 2881 adults receiving an HLA‐identical sibling T‐cell‐depleted (n = 752) or non‐T‐cell‐depleted (n = 2129) bone marrow transplant for leukaemia between 1986 and 1992. Relative risks (RR) of relapse, treatment‐related mortality (TRM) and treatment failure (TF) (relapse or death) were calculated for patients with Glucksberg Grade I, II or III/IV acute GVHD versus those without acute GVHD and for patients with distinct patterns of organ involvement regardless of Glucksberg grade. Using data for non‐T‐cell‐depleted transplants, a Severity Index was developed grouping patients with patterns of organ involvement associated with similar risks of TRM and TF. Higher Glucksberg grade predicted poorer outcome; however, patients with the same grade but different patterns of skin, liver or gut involvement often had significantly different outcomes. The revised Severity Index groups patients in four categories, A–D. Compared to patients without acute GVHD, RRs (95% confidence interval) of TF were 0.85 (0.69, 1.05) for patients with Index A, 1.21 (1.02, 1.43) with B, 2.19 (1.78, 2.71) with C, and 5.69 (4.57, 7.08) with D. Prognostic utility of the Index was tested in patients receiving T‐cell‐depleted transplants; similar RRs of TF were observed. An acute GVHD Severity Index is proposed to enhance design and interpretation of clinical trials in the current era of allogeneic blood and bone marrow transplantation.

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.

High-dose chemotherapy with autologous hematopoietic stem-cell support for breast cancer in North America.

PURPOSE To identify trends in high-dose therapy with autologous hematopoietic stem-cell support (autotransplants) for breast cancer (1989 to 1995). PATIENTS AND METHODS Analysis of patients who received autotransplants and were reported to the Autologous Blood and Marrow Transplant Registry. Between January 1, 1989 and June 30, 1995, 19,291 autotransplants were reviewed; 5,886 were for breast cancer. Main outcomes were progression-free survival (PFS) and survival. RESULTS Between 1989 and 1995, autotransplants for breast cancer increased sixfold. After 1992, breast cancer was the most common indication for autotransplant. Significant trends included increasing use for locally advanced rather than metastatic disease (P < .00001) and use of blood-derived rather than marrow-derived stem cells (P < .00001). One-hundred-day mortality decreased from 22% to 5% (P < .0001). Three-year PFS probabilities were 65% (95% confidence intervals [Cls], 59 to 71) for stage 2 disease, and 60% (95% Cl, 53 to 67) for stage 3 disease. In metastatic breast cancer, 3-year probabilities of PFS were 7% (95% Cl, 4 to 10) for women with no response to conventional dose chemotherapy; 13% (95% Cl, 9 to 17) for those with partial response; and 32% (95% Cl, 27 to 37) for those with complete response. Eleven percent of women with stage 2/3 disease and less than 1% of those with stage 4 disease participated in national cooperative group randomized trials. CONCLUSION Autotransplants increasingly are used to treat breast cancer. One-hundred-day mortality has decreased substantially. Three-year survival is better in women with earlier stage disease and in those who respond to pretransplant chemotherapy.

New Malignant Diseases After Allogeneic Marrow Transplantation for Childhood Acute Leukemia

PURPOSE To determine the incidence of and risk factors for second malignancies after allogeneic bone marrow transplantation (BMT) for childhood leukemia. PATIENTS AND METHODS We studied a cohort of 3, 182 children diagnosed with acute leukemia before the age of 17 years who received allogeneic BMT between 1964 and 1992 at 235 centers. Observed second cancers were compared with expected cancers in an age- and sex-matched general population. Risks factors were evaluated using Poisson regression. RESULTS Twenty-five solid tumors and 20 posttransplant lymphoproliferative disorders (PTLDs) were observed compared with 1.0 case expected (P <.001). Cumulative risk of solid cancers increased sharply to 11.0% (95% confidence interval, 2.3% to 19.8%) at 15 years and was highest among children at ages younger than 5 years at transplantation. Thyroid and brain cancers (n = 14) accounted for most of the strong age trend; many of these patients received cranial irradiation before BMT. Multivariate analyses showed increased solid tumor risks associated with high-dose total-body irradiation (relative risk [RR] = 3.1) and younger age at transplantation (RR = 3.7), whereas chronic graft-versus-host disease was associated with a decreased risk (RR = 0.2). Risk factors for PTLD included chronic graft-versus-host disease (RR = 6.5), unrelated or HLA-disparate related donor (RR = 7. 5), T-cell-depleted graft (RR = 4.8), and antithymocyte globulin therapy (RR = 3.1). CONCLUSION Long-term survivors of BMT for childhood leukemia have an increased risk of solid cancers and PTLDs, related to both transplant therapy and treatment given before BMT. Transplant recipients, especially those given radiation, should be monitored closely for second cancers.

HLA-Identical Sibling Bone Marrow Transplantation in Younger Patients with Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) is considered a disease of the elderly, but it is being increasingly diagnosed in younger people. About 40% of patients with CLL are less than 60 years old [1]. The median survival is about 3 years for patients with Rai stage 3 or 4 disease [1]. Prognostic variables associated with reduced survival include high blood lymphocyte levels, short lymphocyte doubling time, chromosome abnormalities, and a diffuse pattern of bone marrow infiltration with leukemia cells [1-7]. The short median survival of patients with Rai stage 3 or 4 CLL and of those with additional adverse prognostic features has led to studies of intensive treatments [8-10]. Bone marrow transplants from HLA-identical siblings reportedly result in long-term survival in some patients [11]. We analyzed results of HLA-identical sibling bone marrow transplantation for CLL in 54 patients who were younger than 60 years old; these transplantations were done between 1984 and 1992 and reported to either the European Group for Blood and Marrow Transplantation or the International Bone Marrow Transplant Registry. We estimate that this analysis includes more than half of all HLA-identical sibling donor transplants for CLL done before 1993 [12]. Methods Patients Data on 54 patients receiving HLA-identical sibling bone marrow transplants for CLL were reported to the European Group for Blood and Marrow Transplantation or the International Bone Marrow Transplant Registry or both between 1984 and 1992. Patient and disease characteristics are described in Table 1. The median age of the 54 patients was 41 years (range, 21 to 58 years). The median interval from diagnosis to transplantation was 37 months (range, 5 to 130 months). Seventeen patients have been previously described [11]. Six transplantations were done in the first year after diagnosis; 17 were done 1 to 3 years after diagnosis; 19 were done 3 to 5 years after diagnosis; and 12 were done more than 5 years after diagnosis. Forty-seven patients had B-cell CLL, and the immunotype was unknown in 7 patients. Table 1. Characteristics and Transplant Outcomes for 54 Patients Receiving HLA-Identical Sibling Transplants for Chronic Lymphocytic Leukemia* The therapy administered before transplantation varied. Four patients received no treatment; 19 received chlorambucil alone or with prednisone; 5 received cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP); and 21 received cyclophosphamide, vincristine, doxorubicin, bleomycin, and interferon, alone or in combination. No data on previous treatment were available in 5 patients. Two patients received local irradiation and 3 received total lymphoid irradiation and chemotherapy. Ten patients had a splenectomy. Of 47 evaluable patients, 7 were considered to have disease responsive to chemotherapy at the time of transplantation, 19 had stable disease, and 21 had progressive disease according to previously published criteria [13]. Patients were selected for transplantation according to criteria set at each transplantation center. Most received transplants for advanced (Rai stage 3 or 4) or longstanding disease. In patients with Rai stage 0 to 2 CLL whose disease had been diagnosed less than 3 years previously, indications varied from consolidation of a good response to chemotherapy, poor response to conventional-dose therapy, or young age. Donors Donors were HLA-identical siblings; 39 were men and 15 were women. The median age was 41 years (range, 21 to 55 years). Pretransplant Conditioning All patients received cyclophosphamide (median dose, 120 mg/kg body weight; range, 90 to 150 mg/kg). Fifty-one also received total body irradiation (median dose, 12 Gy [range, 8 to 14 Gy]; median fractions, 5 [range, 1 to 9 fractions]). Three patients received cyclophosphamide and busulfan (16 mg/kg) without irradiation. Nineteen patients received one or more additional drugs including etoposide (n = 13), cytarabine (n = 5), chlorambucil (n = 1), melphalan (n = 1), and daunorubicin (n = 1). Prophylaxis for Graft-versus-Host Disease All patients received prophylactic therapy for graft-versus-host disease. Two received methotrexate, 8 received cyclosporine, and 35 received both methotrexate and cyclosporine. Eight patients received a T-cell-depleted graft; 7 of these patients also received cyclosporine. One patient received a monoclonal anti-interleukin-2 receptor antibody and cyclosporine. Four patients had prednisone added to these regimens. Outcome Measures Patients were considered evaluable for engraftment if they survived more than 30 days after transplantation. Those with engraftment who survived more than 21 days were considered at risk for acute graft-versus-host disease, and those with engraftment who survived more than 100 days were considered at risk for chronic graft-versus-host disease. Hematologic remission was defined as normalization of leukocyte counts, hemoglobin level, and platelet counts and absence of lymphadenopathy and hepatosplenomegaly. There was no requirement for bone marrow normalization. The focus of the study was hematologic remission and survival; we did not study leukemia-free survival because bone marrow examinations were not routinely done after transplantation and because leukemia-free survival is poorly defined in CLL. Data from immunologic and molecular tests were not used to define remission; tests for assessing clonality, such as immunoglobulin gene rearrangement and dual antibody-labeling flow cytometry, are not commonly done and are of unproven clinical significance. However, these data are reported when available. Kaplan-Meier survival estimates and CIs were calculated using BMDP software (BMDP Statistical Software, Los Angeles, California). Results Patient outcomes are shown in Table 1. Forty-five of 49 evaluable patients (92%) had stable engraftment, and 4 (8%) had graft failure. Acute (grade II-IV) graft-versus-host disease developed in 17 of 46 patients at risk (37%); 9 of these patients (53%) died. Chronic graft-versus-host disease developed in 17 of 35 patients at risk (49%) and was extensive in 6. Thirty-eight patients (70%) achieved hematologic remission. Twenty-four were alive at a median of 27 months (range, 5 to 80 months) after transplantation. Three-year survival probability was 46% (95% CI, 32% to 60%) (Figure 1). The 3 patients receiving transplants at Rai stage 0 were alive 21, 32, and 45 months after transplantation. Three-year survival probabilities were 68% (CI, 38% to 98%) in the 10 patients receiving transplants at Rai stage 1, 30% (CI, 2% to 58%) in the 10 patients receiving transplants at Rai stage 2, 57% (CI, 21% to 93%) in the 7 patients receiving transplants at Rai stage 3, and 34% (CI, 12% to 56%) in the 22 patients receiving transplants at Rai stage 4. Three-year survival probability was 86% (CI, 62% to 100%) in patients with disease responsive to pretransplant chemotherapy; 61% (CI, 38% to 84%) in those with stable disease; and 23% (CI, 2% to 44%) in those with progressive disease. Figure 1. Probability of survival among 54 patients after HLA-identical sibling bone marrow transplantation for chronic lymphocytic leukemia. Of the 24 transplant recipients who are alive, 23 (96%) are in hematologic remission. Ten of these 23 patients had immune phenotyping of the peripheral blood: Seven had a normal profile (patients 7, 10, 12, 21, 23, 27, and 42), whereas 3 (patients 3, 24, and 30) had an excess of cluster differentiation antigen 5 (CD5) expression, which is known to be associated with CLL. Four patients had molecular studies after transplantation; these studies did not show gene rearrangement that would suggest persistent leukemia (patients 12, 21, 27, and 49). Of the 30 patients who died, 5 died of disease and 25 died of treatment-related causes. Ten treatment-related deaths were from acute or chronic graft-versus-host disease; 4 from hepatic veno-occlusive disease; 2 each from graft failure, adult respiratory distress syndrome, interstitial pneumonitis, and bacterial infection; and 1 each from hemorrhage, fungal infection, and viral infection. Discussion The 54 patients we evaluated all had CLL, were less than 60 years of age, and received HLA-identical sibling transplants. About half of this patient group achieved hematologic remission. Although we studied data from more than half the transplant recipients for CLL worldwide, the small number of patients precluded adjustment for potential prognostic variables like interval from diagnosis to transplantation and response to conventional chemotherapy. Treatment-related mortality in this study was highnearly 50%a figure similar to that observed after allografts for adults with acute lymphoblastic leukemia in first remission, acute myelogenous leukemia in second remission, and Hodgkin disease [14-16]. It may result, in part, from effects of extensive previous treatment. The focus of this study was on hematologic remission and survival after transplantation. We did not consider leukemia-free survival, because this is poorly defined in CLL. We also did not use data from immunologic or molecular tests because these are not uniformly performed and are of unproven clinical import. Our study was not designed to evaluate the role of HLA-identical sibling bone marrow transplantation in the treatment of CLL. However, we believe that the results in 54 patients treated at different centers suggest that allogeneic transplantation is feasible in patients less than 60 years of age. These results must be compared with those for other therapies, such as traditional chemotherapy, fludarabine, 2-chlorodeoxyadenosine, and autotransplantation [17-20]. Appendix Other contributors to this manuscript were Mary M. Horowitz, MD, MS, John P. Klein, PhD, and Mortimer M. Bortin, MD (deceased), of the International Bone Marrow Transplant Registry, Health Policy Institute, Medical College of Wisconsin, Milwaukee, Wisconsin; Kerry Atkinson, MD, of the Depar

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.

Impact of early dose intensity on cytogenetic and molecular responses in chronic- phase CML patients receiving 600 mg/day of imatinib as initial therapy

We conducted a trial in 103 patients with newly diagnosed chronic phase chronic myeloid leukemia (CP-CML) using imatinib 600 mg/day, with dose escalation to 800 mg/day for suboptimal response. The estimated cumulative incidences of complete cytogenetic response (CCR) by 12 and 24 months were 88% and 90%, and major molecular responses (MMRs) were 47% and 73%. In patients who maintained a daily average of 600 mg of imatinib for the first 6 months (n = 60), MMR rates by 12 and 24 months were 55% and 77% compared with 32% and 53% in patients averaging less than 600 mg (P = .037 and .016, respectively). Dose escalation was indicated for 17 patients before 12 months for failure to achieve, or maintain, major cytogenetic response at 6 months or CCR at 9 months but was only possible in 8 patients (47%). Dose escalation was indicated for 73 patients after 12 months because their BCR-ABL level remained more than 0.01% (international scale) and was possible in 45 of 73 (62%). Superior responses achieved in patients able to tolerate imatinib at 600 mg suggests that early dose intensity may be critical to optimize response in CP-CML. The trial was registered at www.ANZCTR.org.au as #ACTRN12607000614493.

Graft-versus-leukemia effects in T lineage and B lineage acute lymphoblastic leukemia

T and B lineage ALL cells express different levels of HLA-class II antigens, which may serve as targets for graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL). The object of this study was to determine whether GVL effects after HLA-identical sibling bone marrow transplantation differed in T and B lineage ALL. We studied 1132 patients with ALL of T lineage (n = 416) or of B lineage (cALLa+) (n = 716) transplanted in first (n = 605) or second (n = 527) remission with bone marrow from an HLA-identical sibling donor, between 1982 and 1992, and reported to the IBMTR by 165 teams. Cox proportional hazards regression models were used to determine the relative risk (RR) of relapse in patients with acute (grades II–IV) or chronic GVHD vs patients without GVHD. Acute and chronic GVHD were considered as time-dependent covariates. Patients transplanted in first and second remission were analyzed separately. GVHD decreased relapse risks to a similar extent in T and B lineage ALL. For first remission transplants, relative risks of relapse for patients with vs those without GVHD was 0.34 for T lineage ALL and 0.44 for B lineage ALL. Corresponding relative risks in second remission transplants were 0.54 and 0.61. This study confirms earlier findings of an antileukemia effect of GVHD in ALL. This effect was similar in T lineage and B lineage ALL, despite probable differences in HLA-class II antigen expression.