Robert Peter Gale

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.

Report of the National Cancer Institute-sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia.

The National Cancer Institute (NCI) sponsored a workshop to develop a set of standardized diagnostic and response criteria for acute myeloid leukemia (AML) clinical trials. The French-American-British (FAB) classification was retained for diagnosing AML, with the addition of patients with bone marrow morphologic features of a myelodysplastic syndrome and less than 30% bone marrow blasts, but with greater than or equal to 30% blasts in the peripheral blood. In this report, there are four important subgroups of AML not defined in the FAB classification that are discussed: undifferentiated acute leukemia, MO (AML lacking definitive myeloid differentiation by morphology or conventional cytochemistry but with ultrastructural or immunophenotypic evidence for AML), mixed lineage leukemia, and hypocellular AML. Definitions of response for clinical trials are presented to facilitate comparisons among different studies. Complete remission is considered the only response worth reporting in phase III trials, since lesser responses do not improve survival. Partial remissions may be of interest to identify active new agents in phase I and II studies. Monoclonal antibodies and cytogenetic studies are not part of the routine assessment of remission or reassessment at relapse, and their role in the evaluation of patients with AML is currently being evaluated in clinical trials. Although we recognize that some of the definitions in this report are arbitrary, generalized use of these guidelines will make results of clinical trials more comparable and interpretable.

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.

Infectious complications of human bone marrow transplantation.

Infections are an almost inevitable complication of human bone marrow transplantation and account for the majority of deaths in transplant recipients. Even prior to the initiation of the transplantation procedure, patients may present with infections complicating previously unsuccessful chemotherapy for hematological malignancy or aplastic anemia. Nevertheless, these pre-transplantation infections should not exclude the possibility of bone marrow transplantation if they can be successfully controlled with specific antimicrobial therapy and necessary adjunctive measures. The immediate post-transplantation period prior to engraftment is characterized by severe marrow aplasia that results from high-dose chemotherapy and total-body irradiation. Infections are primarily septicemias and localized processes caused by bacteria and fungi and their incidence increases as the intensity of immunosuppression is escalated. The high mortality associated with bacterial septicemia makes early, empirical antibacterial therapy mandatory. However, the reduction in mortality from bacterial infection resulting from such an aggressive approach may be offset by a higher mortality from invasive fungal infection, especially in patients with prior fungal colonization and undergoing prolonged conditioning therapy. Thus, until more specific and sensitive tests for the diagnosis of invasive fungal infection become available, empirical intravenous amphotericin should be considered in patients who are persistently febrile and deteriorate clinically in the face of appropriate antibacterial therapy. Interstitial pneumonia associated with severe GVHD is the major infectious complication after successful marrow engraftment and is the most significant barrier to long-term survival. Trimethoprim-sulfamethoxazole is effective prophylaxis against interstitial pneumonia due to Pneumocystis carinii, but one half of the patients still develop a pneumonitis either associated with CMV or of unknown etiology. Mortality from interstitial pneumonia is related to prior radiation therapy while survival is associated with a four-fold rise in CMV CF antibody titer. The latter observation supports the need to investigate passive immunization with CMV antibody as a means of preventing some interstitial pneumonias. Despite the progress made in many areas of human bone marrow transplantation, the majority of graft recipients still die of infectious complications. Thus, new approaches to the management of infections in transplant recipients are urgently needed. Better-tolerated oral nonabsorbable antibiotics, laminar-air-flow rooms, granulocyte transfusions, and chemotherapy and immunotherapy for CMV are among the prophylactic and therapeutic measures that must be critically evaluated in well-controlled, prospective studies. Continued assessment of the infectious complications of bone marrow transplantation is a critical aspect of any ongoing transplant program, not just a research goal...

Effect of Age on Outcome of Reduced-Intensity Hematopoietic Cell Transplantation for Older Patients With Acute Myeloid Leukemia in First Complete Remission or With Myelodysplastic Syndrome

PURPOSE Acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) primarily afflict older individuals. Hematopoietic cell transplantation (HCT) is generally not offered because of concerns of excess morbidity and mortality. Reduced-intensity conditioning (RIC) regimens allow increased use of allogeneic HCT for older patients. To define prognostic factors impacting long-term outcomes of RIC regimens in patients older than age 40 years with AML in first complete remission or MDS and to determine the impact of age, we analyzed data from the Center for International Blood and Marrow Transplant Research (CIBMTR). PATIENTS AND METHODS We reviewed data reported to the CIBMTR (1995 to 2005) on 1,080 patients undergoing RIC HCT. Outcomes analyzed included neutrophil recovery, incidence of acute or chronic graft-versus-host disease (GVHD), nonrelapse mortality (NRM), relapse, disease-free survival (DFS), and overall survival (OS). RESULTS Univariate analyses demonstrated no age group differences in NRM, grade 2 to 4 acute GVHD, chronic GVHD, or relapse. Patients age 40 to 54, 55 to 59, 60 to 64, and > or = 65 years had 2-year survival rates as follows: 44% (95% CI, 37% to 52%), 50% (95% CI, 41% to 59%), 34% (95% CI, 25% to 43%), and 36% (95% CI, 24% to 49%), respectively, for patients with AML (P = .06); and 42% (95% CI, 35% to 49%), 35% (95% CI, 27% to 43%), 45% (95% CI, 36% to 54%), and 38% (95% CI, 25% to 51%), respectively, for patients with MDS (P = .37). Multivariate analysis revealed no significant impact of age on NRM, relapse, DFS, or OS (all P > .3). Greater HLA disparity adversely affected 2-year NRM, DFS, and OS. Unfavorable cytogenetics adversely impacted relapse, DFS, and OS. Better pre-HCT performance status predicted improved 2-year OS. CONCLUSION With these similar outcomes observed in older patients, we conclude that older age alone should not be considered a contraindication to HCT.

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

Intravenous immune globulin for prevention of cytomegalovirus infection and interstitial pneumonia after bone marrow transplantation.

The effects of high doses of polyvalent intravenous immune globulin given for prophylaxis of cytomegalovirus infection and interstitial pneumonia in recipients of allogeneic marrow transplants were evaluated in a randomized controlled trial. Both symptomatic cytomegalovirus infection (21% compared with 46%, p = 0.03) and interstitial pneumonia (18% compared with 46%, p = 0.02) occurred less frequently in the recipients of intravenous immune globulin than in control patients. Prophylactic intravenous immune globulin was also associated with a lower incidence of graft-versus-host disease (34% in recipients compared with 65% in controls, p = 0.01), but its reduction in rates of interstitial pneumonia was independent of graft-versus-host disease and occurred in both patients with and without graft-versus-host disease. The high doses of immune globulin were well tolerated. Prophylactic intravenous immune globulin can modify the severity of cytomegalovirus infection and prevent interstitial pneumonia and possibly graft-versus-host disease in patients having allogeneic marrow transplantation.

Chronic Lymphocytic Leukemia: New Insights into Biology and Therapy

PURPOSE To review the recent advances in the biologic and clinical research of chronic lymphocytic leukemia. DATA IDENTIFICATION English-language literature search using MEDLINE (1980 to 1990) and CANCERLIT (1980 to 1990), review of meeting abstracts and reports, and an extensive manual search of bibliographies of identified articles. STUDY SELECTION Approximately 800 articles, abstracts, and book chapters were selected for analysis. DATA EXTRACTION The literature was reviewed and 227 articles were selected as representative of the important advances in chronic lymphocytic leukemia. RESULTS OF DATA SYNTHESIS Chronic lymphocytic leukemia is a disease of lymphocytes that appear to be mature but are biologically immature. These B lymphocytes arise from a subset of CD5-B cells that appear to have a role in autoimmunity. The pathogenesis of chronic lymphocytic leukemia is likely a multistep process, initially involving a polyclonal expansion of CD5-B cells followed by transformation of a single cell. Chromosome studies indicate that trisomy 12 is the most common abnormality, followed by 14q+, 13q, and 11q. These abnormalities portend a poor prognosis. Recent progress in the treatment of chronic lymphocytic leukemia involves three new drugs: fludarabine, pentostatin, and 2-chlorodeoxyadenosine. Recent preliminary results of allogeneic bone marrow transplantation present insights into the potential curability of chronic lymphocytic leukemia. Therapy with intravenous immunoglobulin can prevent or delay moderate bacterial infections in persons with chronic lymphocytic leukemia. CONCLUSION Major advances in the biologic research of chronic lymphocytic leukemia have resulted in new understanding of this complex disease. New therapies, such as those with intravenous immunoglobulin and fludarabine, may lead to improved outcome.

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

Risk factors for acute GVHD and survival after hematopoietic cell transplantation

Risk factors for acute GVHD (AGVHD), overall survival, and transplant-related mortality were evaluated in adults receiving allogeneic hematopoietic cell transplants (1999-2005) from HLA-identical sibling donors (SDs; n = 3191) or unrelated donors (URDs; n = 2370) and reported to the Center for International Blood and Marrow Transplant Research, Minneapolis, MN. To understand the impact of transplant regimen on AGVHD risk, 6 treatment categories were evaluated: (1) myeloablative conditioning (MA) with total body irradiation (TBI) + PBSCs, (2) MA + TBI + BM, (3) MA + nonTBI + PBSCs, (4) MA + nonTBI + BM, (5) reduced intensity conditioning (RIC) + PBSCs, and (6) RIC + BM. The cumulative incidences of grades B-D AGVHD were 39% (95% confidence interval [CI], 37%-41%) in the SD cohort and 59% (95% CI, 57%-61%) in the URD cohort. Patients receiving SD transplants with MA + nonTBI + BM and RIC + PBSCs had significantly lower risks of grades B-D AGVHD than patients in other treatment categories. Those receiving URD transplants with MA + TBI + BM, MA + nonTBI + BM, RIC + BM, or RIC + PBSCs had lower risks of grades B-D AGVHD than those in other treatment categories. The 5-year probabilities of survival were 46% (95% CI, 44%-49%) with SD transplants and 33% (95% CI, 31%-35%) with URD transplants. Conditioning intensity, TBI and graft source have a combined effect on risk of AGVHD that must be considered in deciding on a treatment strategy for individual patients.