Geoffrey P. Herzig

High-dose cytosine arabinoside therapy with and without anthracycline antibiotics for remission reinduction of acute nonlymphoblastic leukemia

Seventy-eight patients with acute nonlymphoblastic leukemia in relapse were treated with high-dose cytosine arabinoside (3 g/m2 intravenously (IV) every 12 hours for 12 doses) alone, or with three days of anthracycline antibiotics (doxorubicin 20 mg/m2 or daunorubicin 30 mg/m2 IV daily) after completing the course of cytosine arabinoside. Consolidation and maintenance therapy was not given. When anthracyclines were added there was no increase in frequency or severity of nonhematologic toxicity including conjunctivitis, photophobia, dermatitis, cerebellar dysfunction, and gastrointestinal disturbance. All 78 patients achieved aplasia of the bone marrow. Five patients in each group died before bone marrow recovery. The use of anthracyclines did not prolong bone marrow recovery, with both groups demonstrating adequate granulocyte and platelet counts about four weeks after beginning treatment. Forty-one (53%) of the total 78 patients achieved a complete remission. In patients not clinically resistant to conventional-dose cytosine arabinoside, both regimens were equally effective inducing a complete remission (high-dose cytosine arabinoside alone, 12/19 [63%]; with anthracycline, 11/17 [65%], P = .270); in patients clinically resistant, the regimen including anthracycline was superior (15/27 [56%] v 3/15 [20%], P = .022). The duration of unmaintained response was similar (median, five months), but the longest remissions occurred when anthracyclines were used. Thus, high-dose cytosine arabinoside is effective in producing remissions in relapsed patients with acute nonlymphoblastic leukemia, and the addition of an anthracycline enhances this effect.

Treatment of resistant malignant lymphoma with cyclophosphamide, total body irradiation, and transplantation of cryopreserved autologous marrow.

Twenty-seven patients with malignant lymphoma in whom primary chemotherapy had failed and the prognosis was poor were treated with cyclophosphamide, total body irradiation, and transplantation of cryopreserved autologous marrow. The median time to recovery of more than 500 neutrophils per microliter and more than 10,000 platelets per microliter was 18 and 24 days, respectively. Complete remission was achieved in 15 patients (56 per cent), five of whom were in continuous remission at this writing 19 to 71 months after transplantation without further therapy and one of whom was alive in a subsequent remission at 20 months. Fifteen patients died of lymphoma, three of interstitial pneumonitis, two of sepsis, and one of congestive heart failure. This experience shows that intensive therapy and autologous-marrow transplantation can produce prolonged remissions in patients with malignant lymphoma in whom conventional chemotherapy has failed.

A controlled trial of prophylactic granulocyte transfusions during initial induction chemotherapy for acute myelogenous leukemia.

To evaluate the role of prophylactic granulocyte transfusions during remission-induction chemotherapy for acute myelogenous leukemia (AML) we randomized 102 infected patients either to receive daily granulocyte transfusions when blood granulocytes fell below 0.5 x 10(9) per liter (54 patients) or not to receive them (48). Although the percentage of patients acquiring any infection was similar in the transfusion and control groups (46 and 42 per cent, respectively), granulocyte transfusions decreased the proportion of patients with bacterial septicemia (9 per cent of those with transfusions vs. 27 per cent of the controls; P = 0.01). Granulocyte transfusions did not reduce the incidence of other infections or improve bone-marrow recovery, remission rate and duration, or survival. Seventy-two per cent of the patients given transfusions had transfusion reactions. Pulmonary infiltrates were more common in the transfusion group than in the control group (57 per cent vs. 27 per cent; P = 0.002). Thirty-five per cent of the patients with pulmonary filtrates died, as compared with 5 per cent of those without filtrates. We conclude that prophylactic granulocyte transfusions should not be used during remission-induction chemotherapy in AML because the risks outweigh the benefits.

Veno-Occlusive Disease of the Liver After Allogeneic Bone Marrow Transplantation: Possible Association with Graft-Versus-Host Disease

Acute veno-occlusive disease of the liver developed in seven of 29 patients undergoing bone marrow transplantation for treatment of leukemia, aplastic anemia, or disseminated carcinomatosis. All seven died despite successful marrow engraftment. Hepatic failure was the principal cause of death in four and contributory in three. The veno-occlusive disease did not relate to the nature of the pretransplant immunosuppressive regimen, since it occurred in patients receiving irradiation alone, chemotherapy alone, or both. Twenty-two of the patients were autopsied. Among these, the lesion was found in seven of 11 in whom a graft-versus-host reaction developed but in none of the 11 without such a reaction who had received similar pretransplant immunosuppression (P less than 0.025). Hence, acute veno-occlusive disease of the liver appears to be a complication of allogeneic bone marrow transplantation related to the development of a graft-versus-host reaction.

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

Allogeneic marrow transplantation for refractory Hodgkin's disease.

Eight patients with refractory Hodgkins disease received intensive combination chemotherapy conditioning with cyclophosphamide, carmustine (BCNU), and etoposide (VP 16-213), and allogeneic marrow transplants. All patients achieved complete responses. Three patients relapsed; two died of Hodgkins disease and one of chronic graft-v-host disease (GVHD) and infection. In all, four patients died due to transplant-related toxicity. One patient developed a fatal B-cell lymphoproliferative disorder soon after transplantation, and died without evidence of Hodgkins disease. One patient is alive and free of progression 29 months after transplantation. These data indicate that allogeneic marrow transplantation may be considered as therapy for selected patients with advanced Hodgkins disease and, despite substantial toxicity, will occasionally result in long-term responses. Better patient selection would likely improve results.

Expression of c-mpl mRNA, the receptor for thrombopoietin, in acute myeloid leukemia blasts identifies a group of patients with poor response to intensive chemotherapy.

PURPOSE c-mpl, the human homolog of v-mpl, is the receptor for thrombopoietin. Given that c-mpl expression carries an adverse prognosis in myelodysplastic syndrome and given the prognostic significance of expression of other growth factor receptors in other diseases, we attempted to determine whether c-mp/mRNA expression is a prognostic factor in acute myeloid leukemia (AML). PATIENTS AND METHODS We analyzed bone marrow samples from 45 newly diagnosed AML patients by reverse-transcription polymerase chain reaction. RESULTS Samples from 27 patients (60%) expressed c-mpl mRNA (c-mpl+); their clinical and laboratory features were compared with those of the 18 patients without detectable levels of c-mpl(c-mpl-). No significant differences in age, sex, leukocyte count, French-American-British subtype, or karyotype group were found. c-mpl+ patients more commonly had secondary AML (41% v 11%; P = .046) and more commonly expressed CD34 (67% v 12%; P = .0004). There was no significant difference in complete remission (CR) rate. However, c-mpl+ patients had shorter CR durations (P = .008; median, 6.0 v > 17.0 months). This was true when only de novo AML patients were considered and when controlling for age, cytogenetics, or CD34 expression. There was a trend toward shorter survival in c-mpl+ patients (P = .058; median, 7.8 v 9.0 months). CONCLUSION These data suggest that c-mpl expression is an adverse prognostic factor for treatment outcome in adult AML that must be considered in the analysis of clinical studies using thrombopoietin in AML.

Combined modality treatment of American Burkittapos;s lymphoma

Fifteen American patients with Burkittapos;s lymphoma were treated in a clinical trial employing chemotherapy, radiotherapy, and immunotherapy. Two patients died during induction, and 13 achieved complete responses. Eight patients relapsed at a median of 11 weeks from initial treatment, and seven of these have died. The remaining patient has enjoyed a prolonged third remission following intensive chemotherapy and bone marrow autograft. Five patients remain in their first remission in excess of 1 year. The major therapeutic goal in the management of Burkittapos;s lymphoma is the prevention of relapse; the identification of risk factors and various strategies to achieve this goal are discussed.

Tissue plasminogen activator (tPA) as therapy for hepatotoxicity following bone marrow transplantation

The treatment of established veno-occlusive disease (VOD) of the liver with tissue plasminogen activator (tPA) has been disappointing. In attempts to improve upon these results we identified a subgroup of patients with consistently elevated bilirubin levels who did not meet conventional criteria for VOD (Susp VOD) but who had a significant risk of later developing clinical VOD. In January 1994 we began to treat patients who developed Susp VOD with tPA rather than waiting until they developed clinical VOD. We now report on the results of the first 37 patients who ultimately developed clinical VOD and received tPA therapy prior to Susp VOD, or at the time they had established VOD. Significant bleeding complications occurred in 13 (35%) patients but resolved with discontinuation of therapy in all but one. We found that patients treated early in the course of hepatotoxicity prior to the development of overt VOD had a significantly higher response rate and 100 day survival than patients treated at the time of established VOD. Given the poor results seen in treating late VOD, we suggest that early treatment with tPA may improve the outcome in patients who develop signs of hepatotoxicity following marrow transplantation.

Delphi-panel analysis of appropriateness of high-dose therapy and bone marrow transplants in adults with acute lymphoblastic leukemia in first remission

BACKGROUND There is controversy over whether high-dose therapy and a bone marrow transplant is better than conventional-dose chemotherapy in adults with acute lymphoblastic leukemia (ALL) in first remission. This decision may depend on which type of donor is available: an HLA-identical sibling, an alternative donor transplant (HLA-matched related or unrelated people other than HLA-identical siblings), or autotransplant. OBJECTIVE To determine the appropriate use of high-dose therapy and bone marrow transplants in ALL in first remission. Develop a treatment algorithm. PANELISTS: Nine leukemia experts from diverse geographic sites and practice settings. EVIDENCE Boolean MEDLINE searches of acute lymphoblastic leukemia and chemotherapy and/or transplants. CONSENSUS PROCESS We used a modified Delphi-panel group judgment process. Age, white blood cell (WBC) count, cytogenetics and immune type were permuted to define 48 clinical settings. Each panelist rated appropriateness of high-dose therapy and a transplant versus conventional-dose chemotherapy on a 9-point ordinal scale (1, most inappropriate; 9, most appropriate) considering three types of donors: (1) HLA-identical siblings; (2) alternative donors; and (3) autotransplants. An appropriateness index was developed based on median rating and amount of disagreement. Relationship of appropriateness indices to the permuted clinical variables was considered by analysis of variance and recursive partitioning. Preference between donor types was analyzed by comparing mean appropriateness indices of comparable settings and a treatment algorithm was developed. CONCLUSIONS In people with an HLA-identical sibling donor, transplants were rated appropriate in those with unfavorable cytogenetics and uncertain in all other settings. An HLA-identical sibling donor was always preferred to an alternative donor or autotransplant. In people without an HLA-identical sibling but with an alternative donor, this type of transplant was rated appropriate in those with unfavorable cytogenetics. However, an autotransplant was preferred over an alternative donor transplant in all other settings where a transplant was rated uncertain. In people without an HLA-identical sibling or alternative donor, autotransplants were rated uncertain in all settings except in those with not unfavorable cytogenetics, WBC < 100 x 10(9) l(-1) and T- or pre-B-cell type where they were rated inappropriate.