Don A. Stevens

High-dose weekly intravenous immunoglobulin to prevent infections in patients undergoing autologous bone marrow transplantation or severe myelosuppressive therapy: A study of the American bone marrow transplant group

Treatment with intense myelosuppressive therapy (including bone marrow transplantation) has improved survival in patients with various malignant neoplasms [1, 2]. Unfortunately, this treatment increases the incidence of infectious complications, primarily during the period of myelosuppression [3]. Various methods have been used to limit infection during myelosuppression [4-7]. Despite these precautions, bacteremia and fungemia continue to occur in at least one third of patients with sustained neutropenia. Intravenous immunoglobulin (IVIG) therapy prevents infections in patients with inborn B-cell deficiencies and hypogammaglobulinemia secondary to hematologic disorders such as chronic lymphocytic leukemia [8-10]. Intravenous immunoglobulin has also been used successfully to treat immune thrombocytopenic purpura, alloimmunity to platelets, and other immune-mediated disorders by a mechanism of immune system modulation [11]. After allogeneic bone marrow transplantation, IVIG is commonly used to prevent graft-versus-host disease [12]. During these bone marrow transplant trials, a reduction in bacterial infection was also observed in patients who were not necessarily hypogammaglobulinemic. This finding was initially reported in small anecdotal series but was later confirmed by large prospective studies [12-17]. This effect of IVIG was observed during the pre-engraftment (neutropenic) and myelosuppression recovery phases. Most patients in these studies were undergoing allogeneic bone marrow transplantation, for which graft-versus-host disease and its treatment contribute to the rate of infection [18]. Intravenous immunoglobulin is not routinely used during autologous bone marrow transplantation or severely myelosuppressive therapy because prevention of graft-versus-host disease is unnecessary. Because IVIG prevents infection after allogeneic bone marrow transplantation, it might also do so in other patients undergoing intense myelosuppression and thus may serve as a general prophylactic agent for infections. Intravenous immunoglobulin is expensive and thus should not be used indiscriminately. We designed a prospective study that randomized patients who were expected to develop severe and sustained myelosuppression to receive IVIG or no treatment. We specifically wished to determine whether IVIG could reduce the incidence of severe infections in patients with neutropenia but without allogeneic cofactors such as graft-versus-host disease. We therefore sought to determine whether the benefits of IVIG after allogeneic bone marrow transplantation occur as a direct effect of the drug or as an indirect result of a reduced incidence of graft-versus-host disease. Methods Study Design We conducted a stratified, randomized comparison of patients who either underwent autologous bone marrow transplantation or received substantial myelosuppressive therapy for acute leukemia or other malignant conditions. The protocol and consent forms were approved by the Institutional Review Boards of the three participating institutions: Baylor University Medical Center, Dallas, Texas; The University of Louisville, Louisville, Kentucky; and Vanderbilt University, Nashville, Tennessee. Patients were stratified for treatment (autologous bone marrow transplantation or myelosuppressive therapy) and were randomized at each study center by a computer-generated scheme to receive IVIG or no treatment. Neither tumor-specific cytoreductive therapy nor state of disease were used as strata. Patients with an ongoing infection, those younger than 17 years, and those with a previous intolerance to IVIG were ineligible for the study. The main end points were the development of proven clinical infection, positive blood cultures for bacteria or fungi, and survival until hospital discharge. Other analyses included the number of platelet transfusions and the development of clinical alloimmunity to platelet transfusion. Patients Between February 1990 and December 1991, 170 patients entered the study. All patients were evaluable for efficacy and were included in the analysis. The distribution of study patients is shown in (Table 1). The duration of neutropenia, the most important determinant for infection, was similar between the two groups (P > 0.2). Patients in the treatment arm and those in the control arm had statistically similar distributions of overall cytotoxic regimens and disease diagnoses (data not shown). Table 1. Patient Characteristics Treatment Protocol The IVIG used (Sandoglobulin, Sandoz Pharmaceuticals, East Hanover, New Jersey) was commercially purchased, reconstituted as a 5% solution, and administered intravenously at an initial rate of 0.02 mL/kg per minute for 30 minutes and, if tolerated, was increased every 30 minutes to a maximum rate of 0.08 mL/kg per minute. Administration of IVIG was not blinded, and controls received no placebo. Immunoglobulin was given at a weekly dose of 500 mg/kg beginning at the start of cytotoxic treatment. It was discontinued when severe side-effects occurred or when neutropenia resolved (as defined by a neutrophil count of more than 500 109/L [500/L] for 1 day). Supportive Care The patients were hospitalized in HEPA-filtered single rooms, observed strict hand-washing rules, and received low-bacterial diets. Prophylactic oral antibacterial agents were allowed, but prophylactic parenteral antibacterial drugs were not. Patients who were seropositive for Herpes simplex virus received prophylactic acyclovir. All administered blood products were leukofiltered, and patients undergoing autologous bone marrow transplantation also received irradiated blood products. During periods of neutropenia, patients with fever greater than 38 C had two blood cultures taken and received empiric broad-spectrum antibacterial therapy as determined by the study center. Patients whose fever persisted were recultured. If fever persisted for 3 days and no bacterial cause was found, amphotericin B was administered at a dose of 0.5 mg/kg per day. Definitions and Evaluation of Infection The duration of neutropenia was defined as the interval from the first day the absolute neutrophil count decreased below 500 109/L (500/L) until the first day the count exceeded 500 109/L (500/L). In patients with neutropenia, the interval was measured from the first day of cytotoxic therapy until recovery from neutropenia. Each platelet transfusion, whether with single-donor platelets or random-donor pooled platelets, was denoted as one episode. Clinical alloimmunity was diagnosed when platelet counts measured 1 hour after transfusion increased by less than 5000 109/L (< 5000/L) per unit of random- or single-donor platelets transfused on two consecutive occasions. The diagnosis of bacteremia and fungemia required one or more positive blood cultures in patients with suspected infection. The diagnosis of clinical infection required evidence of a localized tissue infection with supporting features such as fever, chills, pain, or erythema with or without isolation of a pathogen. Fever without localized evidence of infection or without positive blood cultures was not considered to represent clinical infection. Statistical Analysis Assuming an infection rate of 40%, the study was designed to detect an anticipated decrease to 20% with a power of 0.80 and an -error of 0.05. Results were analyzed according to the intention to treat. For comparisons of patient groups, the Pearson chi-square test or the Mann-Whitney rank-sum test were used. The Pearson chi-square test with confirmation by the confidence interval method of Simon was used to evaluate study end points [19]. Confidence intervals of 95% were used. Binary logistic regression was used to evaluate the influence of various clinical and laboratory parameters on the end points of bacteremia or fungemia. These parameters included age, diagnosis, study center, duration of neutropenia, baseline IgG value, use of prophylactic oral antibacterials, and use of IVIG. To evaluate hypogammaglobulinemia, 5 g/L (500 mg/dL) was chosen as the lower limit of normal. To evaluate the duration of neutropenia, a threshold of 7 days was chosen. The trial ended with the resolution of neutropenia because this patient population rarely experiences serious infections after leukocyte recovery and because survival after hematopoietic recovery is largely determined by the underlying disease. Survival was reported using actual proportions. Results Infections Proven clinical infections were frequent, as shown in Table 2. Of all study patients, 43.5% had documented clinical infections. Bacteremia and fungemia occurred in 35% and 7.6% of patients, respectively. The incidences of proven clinical infection, bacteremia, and fungemia were 43%, 35%, and 6% in the IVIG group and 44%, 34%, and 9% in the control group, respectively. These differences were not statistically significant (P > 0.2). Analysis of bacteremia by organism (gram positive, gram negative, and mixed) showed no statistical difference. The most common infection in the study was bacteremia due to coagulase-negative Staphylococci. This organism was isolated in 58% of all cases of bacteremia and was the sole organism in 38% of all cases of bacteremia. Twenty-eight percent of the documented bloodstream infections were polymicrobial. Table 2. Treatment Results Only 8% of patients in this study had hypogammaglobulinemia. The distribution of these patients was similar in the IVIG (9%) and control (8%) groups. In multiple regression analysis, the pretreatment value of IgG (< 5 g/L [500 mg/dL] compared with > 5 g/L) did not predict the development of bacteremia or fungemia. Bloodstream infections were frequent, but most were controlled by broad-spectrum antibiotics. Death from infection occurred in 3.5% of study patients (4.9% in the IVIG group compared with 2.3% in the control group), yielding a difference of 2.6% (95% CI, 3.0% to 8.2%; P > 0.2). Platelet Transfusion Patients in the IVIG and

Results of Transplanting Bone Marrow from Genetically Identical Twins into Patients with Aplastic Anemia

Considerable data suggest that aplastic anemia is heterogeneous: Some cases are caused by a lack of or a defect in hematopoietic stem cells, whereas others result from immune abnormalities [1-7]. In rare cases, aplastic anemia is caused by an abnormal bone marrow microenvironment [8]. The outcomes of transplanting bone marrow from genetically identical twins into patients with aplastic anemia may provide insight into the causes of bone marrow failure. The infusion of genetically identical bone marrow cells without pretransplantation conditioning should permanently correct bone marrow function in persons whose bone marrow failure has resulted from a lack of or defective hematopoietic stem cells. In contrast, persons whose bone marrow failure is caused by immune abnormalities may only improve when transplantation of genetically identical bone marrow is preceded by conditioning. Finally, persons with abnormal bone marrow microenvironments might never improve [8]. We addressed these issues using data on 40 patients with aplastic anemia who received transplants from their identical twins and were reported to the International Bone Marrow Transplant Registry. Methods Patients Forty patients with severe aplastic anemia who received one or more bone marrow transplants from their genetically identical twins between 1964 and 1992 were reported to the International Bone Marrow Transplant Registry by 31 centers worldwide. Severe aplastic anemia was defined according to published criteria [9]. Nineteen patients have been described in previous reports [4, 10-14]. Genetic identity was established by measuring concordance for HLA-A, -B, -C and -DR antigens (n = 39; HLA testing was not done in 1 patient); ABO blood group (n = 39); erythrocyte antigens (n = 1); and immunoglobulin allotypes (n = 1) and by a history of a single placenta (n = 40). Outcomes Hematologic response, graft-versus-host disease, and survival were the study outcomes. Complete response was defined as normalization of at least two of three hematologic variables (hemoglobin level > 12 g/dL, granulocyte count > 1.5 109/L, and platelet count > 150 109/L) and improvement in the third (hemoglobin level > 8 g/dL, granulocyte count > 0.5 109/L, and platelet count > 20 109/L without transfusion). Partial response was defined as improvement in two or more variables. Lack of response was defined as levels less than those indicated above and continuing dependence on transfusion. Responses were considered to be sustained if they persisted through the date of last contact. Diagnosis and grading of graft-versus-host disease were based on published criteria [15]. Persons at risk included those with complete or partial responses who survived 21 days or longer. Statistical Analysis We compared patient, disease, and transplantation variables using the Mann-Whitney and Fisher exact tests. Probabilities of survival were calculated using the Kaplan-Meier product limit estimator and were expressed as probabilities with 95% CIs. The latter were computed using the arcsine-square root transformation [16]. Survival distributions were compared using the log-rank test. Results Patients We studied 25 male patients and 15 female patients. The median patient age was 19 years (range, 4 to 69 years). Physicians at the transplantation centers ascribed aplastic anemia to drugs or toxins (7 patients), hepatitis (4 patients), or other causes (3 patients). We did not ascertain which criteria were used to make these designations. In 26 cases, no cause of aplastic anemia was identified. Treatments given between diagnosis and transplantation included corticosteroid therapy (9 patients), androgen therapy (1 patient), and both (7 patients). Twenty-three patients received no therapy other than transplantation. Thirty-seven patients received transfusions before transplantation (median number of transfusions, 14 [range, 1 to 263]). Median values for hematologic variables before transplantation were the following: hemoglobin level, 7.5 g/dL (range, 4.8 to 11.3 g/dL); leukocyte count, 1.7 109/L (range, 0.5 to 5.2 109/L); granulocyte count, 0.3 109/L (range, 0 to 1.6 109/L); and platelet count, 17 109/L (range, 1.5 to 101 109/L). Survivors were followed for a median of 7 years (range, 13 months to 29 years); all but one were followed for at least 2 years after transplantation. Transplantation First Transplantation Not Preceded by Conditioning Twenty-three patients received a first transplant without pretransplantation conditioning. Fifteen patients who did not have a sustained complete response received one or more additional transplants after first receiving conditioning with the following regimens: Ten patients received cyclophosphamide alone (150 to 200 mg/kg of body weight); 2 received cyclophosphamide (200 mg/kg) and total-body radiation (3 to 4.5 Gy); 1 received cyclophosphamide (194 mg/kg) and cyclosporine; 1 received nitrogen mustard and antilymphocyte globulin; and 1 received azathioprine. A sixteenth patient who did not have a sustained complete response after the first transplantation received the second transplant without first receiving conditioning. The median dose of nucleated bone marrow cells for the first transplant was 3.6 108/kg (range, 0.4 to 9.8 108/kg). Four of 15 female donors had had transfusion or at least one pregnancy before donating bone marrow. No patients received immunosuppressive therapy after transplantation. First Transplantation Preceded by Conditioning Seventeen patients received conditioning before the first transplantation. Thirteen received cyclophosphamide alone (100 to 200 mg/kg), 1 received cyclophosphamide (152 mg/kg) and cyclosporine, 2 received cyclophosphamide (156 and 219 mg/kg, respectively) and busulfan (12 and 16 mg/kg, respectively), and 1 received cyclophosphamide (200 mg/kg) with total-body radiation (3.0 Gy). The median dose of nucleated bone marrow cells was 3.6 108/kg (range, 1.6 to 4.9 108/kg). After transplantation, 6 patients received immunosuppressive therapy: One received methotrexate, 1 received corticosteroids, 2 received cyclosporine, and 2 received cyclosporine and corticosteroids. We did not ascertain the reasons why immunosuppressive therapy was given after transplantation. The likelihood that the first transplantation would be preceded by conditioning increased during the study years: Only 3 of the initial 20 (15%) patients receiving their first transplant received conditioning compared with 14 (70%) of the subsequent 20 patients receiving their first transplant (P = 0.05). Patients who had conditioning before receiving their first transplants had lower leukocyte, granulocyte, and platelet counts and had had more pretransplantation transfusions than the patients who did not have pretransplantation conditioning (Table 1). Table 1. Variables Correlated with Use of Conditioning before First Transplantation* Outcomes The results of transplantation are summarized in Figure 1. Figure 1. Outcome of transplanting bone marrow from genetically identical twins into 40 patients with aplastic anemia. Hematologic Response: First Transplantation Not Preceded by Pretransplantation Conditioning Seven of the 23 patients (30%) who received a first transplant without first receiving conditioning had a sustained complete response; 16 did not. Five of the 16 had a complete response but had relapse a median of 35 weeks after transplantation (range, 11 to 103 weeks). Seven other patients had a partial response; relapse occurred a median of 10 weeks after transplantation (range, 8 to 16 weeks). Four patients had no response. Granulocyte counts before transplantation were higher in the 12 complete responders than in the 11 patients who did not have a complete response (0.9 109/L [range, 0 to 1.6 109/L] compared with 0.3 109/L [range, 0 to 1.2 109/L]; P = 0.048). Granulocyte and platelet counts and number of transfusions before transplantation did not differ between the 7 patients who had sustained complete response and the 5 patients who had complete response and later had relapse. No correlation was seen between the likelihood of a sustained complete response and age, sex, cause of aplastic anemia, interval from diagnosis to transplantation, previous therapy, infections developing within 1 week before transplantation, previous transfusions, donor pregnancies, or number of cells transplanted. The 16 patients who did not have a sustained complete response after receiving the first transplant without first receiving conditioning had one to four additional transplantations. One patient who did not have conditioning before receiving a second transplant had a sustained complete response. Eleven of 15 patients (73%) who received conditioning before the second transplantation had a sustained complete response. One of the 15 patients died of treatment-related toxicity 1 month after transplantation. Three of the 15 did not have a sustained complete response after receiving a second transplant: Of these, one patient with a partial response and one patient with no response received a third transplant after conditioning. Both had sustained complete responses after the third transplantation. After each of five transplantations, one patient had transient hematologic responses that lasted 11 to 38 months. He died after receiving the fifth transplant. Hematologic Response: First Transplantation Preceded by Conditioning Seventeen patients received their first transplant after first receiving conditioning. Thirteen (76%) had a complete response, and 11 (64%) had a sustained complete response. One patient had relapse 20 months after transplantation; a second transplantation preceded by conditioning resulted in a sustained complete response. Patients who received conditioning before receiving the first transplant had a higher incidence of sustained complete responses than did patients who did not receive conditioning before receiving the first transplant (P = 0.033; Fisher exact tes

Mobilization of Peripheral Blood Stem Cells in High-Risk Breast Cancer Patients Using G-CSF After Standard Dose Docetaxel

Chemotherapy, in addition to recombinant growth factors, has been effective in mobilizing stem cells. Unfortunately, the use of chemotherapy for this purpose has resulted in profound myelosuppression and increased morbidity. Docetaxel, the single most active agent in the treatment of advanced breast cancer, was evaluated for its potential to mobilize stem cells when given at conventional doses followed by granulocyte colony-stimulating factor (G-CSF). Sixteen high-risk breast cancer patients were mobilized with a regimen consisting of docetaxel (100 mg/m2) followed by daily G-CSF (10 microg/kg), beginning 72 h after the docetaxel, and continuing until completion of the apheresis. The median white blood cell count (WBC) nadir was 1,000/microl (range 500 to 4000/microl ) occurring a median of 6 days (range 4 to 9 days) after the docetaxel. No patient experienced a neutropenic febrile episode due to the mobilization regimen. The median time interval for initiating the apheresis was 8 days (range 6 to 11 days) following the docetaxel. The median number of apheresis was 2 (range 1 to 3) in each patient. Stem cell recovery as measured by the CD34 cell count x 10(6)/kg was a median of 5.2 (range 1.4 to 15.1). A significant correlation was found between CFU-GM, BFU-E, and CFU-GEMM/kg and CD34 cells/kg (r = 0.891, 0.945, and 0.749, respectively, p < 0.001). When our results were compared to a matched cohort receiving G-CSF alone, the docetaxel group demonstrated a superior CD34 cells/kg yield (p = <0.001). Following myeloablative chemotherapy consisting of thiotepa and cyclophosphamide with or without carboplatinum, the hematopoetic recovery determined by an absolute neutrophil count (ANC) of greater than 500/microl and an unsupported platelet count of > or =20,000/microl for 48 h, was a median of 10 days (range 9 to 14 days) and 10 days (range 8 to 30 days), respectively. The results demonstrate that conventional dose docetaxel, combined with G-CSF, is an effective mobilization regimen with minimal toxicity in high-risk breast cancer patients.

Protracted results of dose-intensive therapy using cyclophosphamide, carmustine, and continuous infusion etoposide with autologous stem cell support in patients with relapse or refractory Hodgkin's disease: A phase II study from the North American Marrow Transplant Group

To determine the long-term results of high-dose chemotherapy and stem cell support in relapsed or primary refractory Hodgkin disease patients. One hundred and thirty-one patients with relapsed or primary refractory Hodgkins disease were treated with a dose-intensive therapy protocol consisting of etoposide (2400 mg/m2 continuous intravenous infusion) cyclophosphamide (7200 mg/m2 intravenously), and carmustine (300-600 mg/m2 intravenously) CBVi. All patients had previously failed conventional chemoradiotherapy. Severe toxicities were related to infectious, hepatic, and pulmonary complications. Fatal, regimen-related toxicity was 19%; liver and lung dysfunction, as well as infection, were the most frequent problems. Ninety-one (69%) of the patients achieved a complete response (CR) (95% CI = 59% to 75%) after CBVi and autologous stem cell infusion. With a median follow-up of 5.1 years (range 3.0 to 9.5 years), overall and event-free survival are 44% (95% CI = 33% to 47%) and 38% (95% CI = 28% to 46%) respectively. While univariate analysis did not reveal a statistically significant variable to predict a better response, responsiveness to therapy demonstrated a trend. We conclude that CBVi is an effective therapy for relapsed or refractory Hodgkins disease, producing long-term, durable remissions.

Dose-intensive chemotherapy for breast cancer with brain metastases: a case series.

Most clinical trials using dose-intensive chemotherapy exclude patients with brain metastases. This exclusion was based on anecdotal experience reflecting high treatment-related mortality. We analyzed the outcome of 11 patients with metastatic breast cancer who had brain metastases, diagnosed either before or during high-dose chemotherapy. In three patients, the death was attributed to non-central nervous system (CNS) regimen-related toxicity. Five patients died as a results of non-CNS disease progression. One patient died as a result of both CNS and non-CNS disease progression. Two patients are alive without disease progression with follow-up of 13.4 and 7.3 months, respectively. Of the five patients who have survived 1 year, four have hormone receptor expression and continued on antihormone therapy after high-dose therapy. These results are the first to show that breast cancer patients having brain metastases who receive high-dose chemotherapy do not experience more treatment-related complications or treatment failure as a result of the metastatic CNS disease. To this end, exclusion of these patients from high-dose therapy trials, especially those with expression of hormone receptors, needs to be reevaluated.