High-dose chemotherapy and autologous stem-cell transplantation for ovarian cancer: an autologous blood and marrow transplant registry report.

BACKGROUND: Autologous transplantation is increasingly used to treat epithelial ovarian cancer. However, it is not clear which patients may benefit. OBJECTIVE: To determine overall and progression-free survival and factors associated with favorable outcome after autotransplantation for ovarian cancer. DESIGN: Observational cohort study. SETTING: 57 centers reporting to the Autologous Blood and Marrow Transplant Registry (ABMTR). PATIENTS: 421 women who received transplants between 1989 and 1996. INTERVENTIONS: High-dose chemotherapy using diverse regimens with hematopoietic stem-cell rescue. MEASUREMENTS: Primary outcomes were progression-free survival and overall survival. Multivariate analyses using Cox proportional hazards regression considered the following factors: age, Karnofsky performance score, initial stage, histologic characteristics, previous therapy, remission status, extent of disease, graft source, transplant regimen, and year of transplantation. RESULTS: Most patients had extensive previous chemotherapy. Forty-one percent had platinum-resistant tumors, and 38% had tumors at least 1 cm in diameter. Only 34 patients (8%) received transplants as part of initial therapy. The probability of death within 100 days was 11% (95% CI, 8% to 14%). Two-year progression-free survival was 12% (CI, 9% to 16%), and 2-year overall survival was 35% (CI, 30% to 41%). Younger age, Karnofsky performance score of at least 90%, non-clear-cell disease, remission at transplantation, and platinum sensitivity were associated with better outcomes. Progression-free and overall survival were 22% (CI, 12% to 33%) and 55% (CI, 42% to 66%), respectively, for women with a high Karnofsky performance score and non-clear-cell, platinum-sensitive tumors. CONCLUSIONS: Some subgroups of patients with ovarian cancer seem to have good outcomes after autotransplantation, although several biases may have affected these observations. Phase III trials are needed to compare such outcomes with outcomes of conventional chemotherapy.

A comparison of prestorage WBC-reduced whole-blood-derived platelets and bedside-filtered whole-blood-derived platelets in autologous progenitor cell transplant.

BACKGROUND: Prestorage WBC-reduced platelet concentrates (PCs) can be manufactured from platelet-rich plasma (PRP) by in-line filtration of PRP. There are few published data on the clinical use of these products, as compared to bedside-filtered pools of standard PCs (S-PCs) manufactured from PRP. STUDY DESIGN AND METHODS: A prospective, randomized trial was conducted in autologous progenitor cell transplant patients requiring platelet transfusions with each patient as his or her own control who was given a pool of 5 units of WBC-reduced PCs and a pool of 6 units of S-PCs within a 3-hour period. The pools were characterized before transfusion for platelet and WBC content, P-selectin expression, and IL-8. The patients were monitored with platelet counts and vital signs and observed for reactions. Data were analyzed using Mann-Whitney U tests. RESULTS: Thirty-three transfusions were administered to 13 patients. Median platelet content in the WBC-reduced PC pools was lower than that in the S-PC pools (3.3 vs. 4.0 x 10(11), p<0.01). Median WBC content was 4 to 5 log less in the WBC-reduced PC pools (2.5 x 10(4) vs. 4.6 x 10(8), p<0.01). Median IL-8 levels (pg/mL) were lower in the WBC-reduced PC pools (2 vs. 36, p<0.01). No differences were observed in CCI, but the median absolute increase after transfusion of the S-PC pools was higher (25 vs. 19 x 10(9)/L, p<0.01), which reflected the larger size of the S-PC pools. No overall differences in vital signs were recorded. Two reactions were observed, both in temporal association with the transfusion of pools of S-PCs. CONCLUSIONS: A pool consisting of 5 units of WBC-reduced PCs gave a median platelet increment of 19 x 10(9) per L in these thrombocytopenic patients and has a median WBC content 1 to 2 log below the accepted threshold for primary alloimmunization or CMV transmission.

Allogeneic transplantation after a conditioning regimen with ifosfamide, carboplatin and etoposide (ICE).

Successful allogeneic hematopoietic transplants require conditioning regimens with sufficient immunosuppression to allow acceptance of the allograft. Cyclophosphamide, in combination either with TBI or with chemotherapeutic drugs, is the keystone of commonly used regimens. The toxicities of TBI and tumor resistance to cyclophosphamide create a niche for alternative, chemotherapy-based conditioning regimens. We report successful allogeneic stem cell transplantation after an ifosfamide-based regimen with ifosfamide 20 g/m2, carboplatin 1.8 g/m2 and etoposide 3 g/m2 (ICE) in divided doses over 6 days. Engraftment was prompt with neutrophils > or = 20 x 10(9)/l on day +10 and platelets > 20 x 10(9)/l on day +18. Engraftment of donor cells was documented by chromosome analysis and by VNTR analysis. An ifosfamide-based regimen provides sufficient immunosuppression for hematopoietic allograft acceptance in the absence of cyclophosphamide or of TBI.

Propantheline protects the oral mucosa after high-dose ifosfamide, carboplatin, etoposide and autologous stem cell transplantation.

Oral mucositis is a dose-limiting toxicity of high-dose etoposide regimens. Since etoposide is excreted in saliva, we tested the hypothesis that the induction of xerostomia would reduce the severity of the mucositis. We designed a phase II trial of propantheline in patients receiving high-dose ICE (ifosfamide 20 mg/m2, carboplatin 1.8 g/m2, etoposide 3 g/m2 in divided doses over 6 days) chemotherapy plus autologous hematopoietic stem cell support. We treated 31 consecutive patients and graded the oral mucositis according to WHO criteria. Mild (WHO grade 0, I, II) mucositis occurred in 28 of 31 (90%) (95% CI 74-98%) patients; severe (WHO grade III, IV) mucositis occurred in three of 31 patients (10%) (95% CI 2-25%) patients. In contrast, a published reference group treated with the same doses and schedule of ICE reported mild mucositis in 10 of 46 (22%) (95% CI 11-36%) patients and severe mucositis in 36 of 46 (78%) (95% CI 64-89%). Propantheline therapy had no protective effect on esophagitis and enteritis associated with high-dose ICE. Minor toxicities were constipation and asymptomatic tachycardia; major toxicities were palpitations in one patient and urinary retention in one patient. We conclude that anticholinergic therapy dramatically reduced the oral mucositis associated with high-dose etoposide and should be considered as a supportive care measure for patients receiving etoposide-containing regimens.

Use of messenger RNA differential display to identify interleukin-11-responsive genes in human umbilical cord blood mononuclear cells: IL-11 upregulates the expression of the hMAL gene.

Human umbilical cord blood (HUCB) mononuclear cells represent a source of hematopoietic stem and progenitor cells, including cells responsive to interleukin-11 (IL-11). To investigate the molecular mechanisms associated with IL-11 action, we have used HUCB mononuclear cells as a model system to identify genes that are transcriptional targets of IL-11. Using the technique of messenger RNA differential display, we have identified 17 candidate cDNA differentially expressed in mononuclear cells incubated without and with IL-11. Fifteen of these cDNA were recovered, and 11 were sequenced. DNA sequence analysis has identified one of these cDNA as being the human MAL gene, originally identified as a marker for intermediate stages of T cell differentiation. Northern analysis using a MAL-specific probe confirms the upregulation of MAL by IL-11 in HUCB cells.

Clinical experience with single agent and combination regimens in the management of infection in the febrile neutropenic patient.

Choice of antibiotic therapy for the management of infection in the neutropenic patient continues to challenge the clinician. The shift toward gram-positive organisms and the continuing need to provide gram-negative coverage demands the use of an agent or agents that provide coverage for the spectrum of potential infecting organisms. Cefepime is an extended-spectrum fourth-generation cephalosporin that has good activity against gram-positive and gram-negative organisms; in addition, it resists degradation by Bush group 1 beta-lactamases. These properties make this agent a promising candidate for empiric therapy with febrile neutropenic patients. Data presented in this article are from febrile neutropenic cancer patients enrolled into two randomized, prospective, nonblinded comparative U.S. clinical trials. Patients were randomized to receive cefepime (2 g thrice daily) or a comparator regimen of either ceftazidime (2 g thrice daily) or piperacillin + gentamicin (3 g every 4 hours + 1.5 mg/kg every 8 hours). When indicated, vancomycin was added to the regimen. A total of 109 febrile episodes were treated with cefepime and 107 episodes were treated with the comparator regimens. Neutropenia (< or = 500 PMNs/mm3) persisted for > or = 10 days in >40% of episodes and severe neutropenia (< or = 100 PMNs/mm3) in >25%. More than 40% of the total number of episodes were documented bacterial infections. These characteristics did not differ among treatment groups. Duration of therapy was similar in both groups (median: cefepime, 9 days; comparators, 11 days). In >40% of episodes, patients received study therapy without addition of other antibacterials (cefepime, 46%; comparators, 41%). Vancomycin was added in almost half of all the episodes (cefepime, 45%; comparators, 53%). Patients became afebrile by the fourth day of study therapy in approximately 60% of episodes (cefepime, 58%; comparators, 60%). In approximately 75% of the episodes, patients had a satisfactory response at the end of therapy (cefepime, 74%; comparators, 76%); and following approximately 90% of episodes, patients survived for >30 days (cefepime, 90%; comparators, 92%). Eradication rates were similar for all pathogens for cefepime and comparator agents. There were similar numbers of superinfecting organisms in each treatment arm; most involved gram-positive organisms. These multiple measures of efficacy suggest that initial empiric cefepime monotherapy is comparable to the pooled experience with standard therapies and that antibacterial modifications occur with similar frequency for cefepime compared with standard empiric regimens.

Improved survival of patients with chronic myelogenous leukemia undergoing allogeneic bone marrow transplantation.

A total of 28 patients with chronic myelogenous leukemia (CML) in chronic phase (CP) received bone marrow allografts from HLA-matched siblings at the University of Florida between August 1984-July 1992. The present study compares the disease-free survival (DFS) for those patients who were transplanted before or after August 1988 using the same conditioning regimen. The analysis shows significant difference in 3-year DFS for those patients transplanted post- vs. pre-August 1988 (69.6% vs. 20%, respectively; P = 0.006). A decrease in pneumonitis due to different etiologies from pre-August 1988 (6/13, 46%) to post-August 1988 (1/15, 7%) was statistically significant (P = 0.029). A decrease, although statistically insignificant, in the overall incidence and severity of acute and chronic graft vs. host disease (GVHD) after August 1988 was also noticed. This study indicates significantly improved outcome for patients with CML in CP who have been treated in the University of Florida after August 1988. Better supportive care and prophylaxis for GVHD most likely contributed to such improvement.

Bladder preservation and durable complete remission of small cell carcinoma of the bladder with systemic chemotherapy and adjuvant radiation therapy.

BACKGROUND: Small cell (oat cell) carcinoma of the bladder is a rare entity characterized clinically by an aggressive behavior with a high incidence of systemic metastases. Radical cystectomy has been the therapeutic focal point for this disease, but systemic relapse is almost universal. RESULTS: The authors report that combination chemotherapy with cisplatin, methotrexate, and vinblastine, followed by external beam irradiation to the bladder, gave a durable continuous complete remission (more than 4.5 years). In addition, this bladder-sparing approach has preserved normal bladder function and an excellent quality of life. CONCLUSION: This experience shows that radical cystectomy may not be necessary for small cell carcinoma of the bladder and that early intervention with systemic chemotherapy offers greater potential for cure.

Outcome of clinical congestive heart failure induced by anthracycline chemotherapy.

BACKGROUND: Anthracycline-induced congestive heart failure (A-CHF) is associated with a high reported incidence of morbidity and mortality. The long-term clinical outcome of patients with clinical A-CHF is less well defined. METHODS: A retrospective chart review was done of 19 patients with a clinical diagnosis of A-CHF. RESULTS: In 19 patients, the mean anthracycline dose was 379 +/- 141 mg/m2 (range, 120-570 mg/m2). The median time from the last dose of the drug to the onset of A-CHF was 4 weeks (range, 1-17 weeks). Seven patients (Group I) died of A-CHF within a median of 6 weeks (range, 1-15 weeks) from onset of disease to death. Twelve patients (Group II) had clinical recovery, three with a complete response, eight had partial improvement, and one had stable disease. Most importantly, four patients who had an intercurrent illness (two patients with infections and two with progression of their malignant lesions) had a relapse of clinical congestive heart failure that was fatal. CONCLUSIONS: Many (63%) patients recover from clinical A-CHF. However, the cardiac reserve of these patients is limited, and they may require careful medical management during other illnesses or surgical procedures.

High-dose methylprednisolone therapy for acute graft-versus-host disease associated with matched unrelated donor bone marrow transplantation.

Acute graft-versus-host disease (aGVHD) is a major barrier to successful bone marrow transplantation (BMT) with matched unrelated donors. Eight of eight recipients of matched unrelated donor BMT developed aGVHD. We used a regimen of high-dose methylprednisolone (5 mg/kg/day for 4 days with responders continuing on treatment, and dose escalation to 10 mg/kg/day for non-responders) as initial therapy of aGVHD. One patient died on the second day of steroid administration. Each of the seven remaining patients responded to methylprednisolone, five at the 5 mg/kg/day dose and two at the 10 mg/kg/day dose. Three of five patients developed flare of aGVHD during reduction of the corticosteroid dosage and died with aGVHD and infection. Two patients have undergone reduction of methylprednisolone at a modified rate without a flare. Infectious complications during methylprednisolone treatment were very common and contributed to the death of the three patients with flare of aGVHD. Four patients in whom aGVHD was in remission survived serious systemic infections. High-dose methylprednisolone is effective initial therapy for aGVHD associated with matched unrelated BMT, but is associated with a high risk of serious infections.

Vancomycin is not an essential component of the initial empiric treatment regimen for febrile neutropenic patients receiving ceftazidime: a randomized prospective study.

The use of vancomycin as part of the initial antibiotic therapy of febrile neutropenic patients has become a controversial issue. Some studies support its incorporation in the initial regimen, and others suggest that vancomycin can be added later. We examined this issue in a prospective, randomized trial. We randomized 127 febrile neutropenic patients to receive either ceftazidime alone or ceftazidime plus vancomycin as the initial empiric antibiotic treatment. We added vancomycin to the ceftazidime arm of the study when fever persisted after 96 h of monotherapy, when new fever occurred after this time, or when a moderately ceftazidime-resistant gram-positive bacterium was isolated. Each of these regimens had similar initial response rates, similar durations of initial fever, similar frequencies of new fever during therapy, similar microbiological cure rates, similar superinfection rates, and similar survival rates. We observed more renal and cutaneous toxicities in patients receiving vancomycin and ceftazidime as initial therapy. We conclude that ceftazidime is appropriate as initial therapy for febrile neutropenic patients and that the addition of vancomycin is appropriate when fever persists after 4 days of monotherapy or when fever recurs following an initial response.

A single-blind comparison of intravenous ondansetron, a selective serotonin antagonist, with intravenous metoclopramide in the prevention of nausea and vomiting associated with high-dose cisplatin chemotherapy.

Ondansetron (GR 38032F), a selective antagonist of serotonin subtype 3 receptors, is effective in the prevention of emesis associated with cisplatin as well as other chemotherapeutic agents. In this randomized, single-blind, multicenter, parallel group study, we compared the efficacy and safety of intravenous (IV) ondansetron with IV metoclopramide in the prevention of nausea and vomiting associated with high-dose (greater than or equal to 100 mg/m2) cisplatin chemotherapy. Three hundred seven patients receiving their first dose of cisplatin, either alone or in combination with other antineoplastic agents, were randomized to receive ondansetron 0.15 mg/kg IV every 4 hours for three doses or metoclopramide 2 mg/kg IV every 2 hours for three doses, then every 3 hours for three additional doses. The study prohibited the concurrent administration of other antiemetics or dexamethasone. Patients receiving ondansetron had a higher rate of complete protection from emesis (40% v 30%, P = .07), a higher complete plus major response rate (65% v 51%, P = .016), a lower rate of failure (21% v 36%, P = .007), and a lower median number of emetic episodes (one v two, P = .005) than did those receiving metoclopramide. The median time to the first emetic episode was longer on ondansetron (20.5 v 4.3 hours, P less than .001). Adverse events occurred in 48% of patients receiving ondansetron and 69% of those receiving metoclopramide (P less than .001). Akathisia and acute dystonic reactions occurred only on metoclopramide; headache (controlled with acetaminophen) was significantly more frequent with ondansetron. Ondansetron is more effective, produces fewer adverse events, and is easier to administer than metoclopramide for the prevention of emesis associated with high-dose cisplatin chemotherapy.

Myelodysplastic syndromes presenting in pregnancy. A report of five cases and the clinical outcome.

Five female patients, ranging in age between 22 and 36 years, presented with myelodysplastic syndromes during pregnancy between June 1982 and March 1987. Three of these five cases evolved into acute leukemia. A bone marrow transplant was attempted in the fourth. It is suggested that the association of myelodysplastic syndromes during pregnancy is more than coincidental and that acute leukemia evolves in a majority of these cases. Furthermore, refractory macrocytic anemias in pregnancy need to be carefully evaluated for a primary myelodysplastic state.

Immunophenotypic characterization of an unusual T-cell lymphoma presenting as anterior uveitis. A clinicopathologic case report.

A 54-year-old woman presented with a unilateral, anterior uveitis that progressed to hypopyon over 4 months despite treatment with steroids. One hundred percent of the cells collected from aspirates of the anterior chamber of the affected eye were morphologically large granular lymphocytes. The aspirated cells were demonstrated by flow cytometry to be a uniform population of T lymphocytes with a diploid genome and an S fraction of 2.3%. On further investigation, the patient was found to have an extensive abdominal malignant lymphoma with the same immunophenotype but different morphologic features than the anterior chamber lymphoid infiltrate. In contrast to the cells in the anterior chamber, the abdominal tumor was highly aggressive as indicated by the cellular morphologic features and the S fraction of 43%. DNA hybridization studies of the abdominal lymphoma demonstrated a T beta 2 T-cell receptor gene rearrangement. The use of these modern diagnostic methods should facilitate the diagnosis of intraocular lymphomas and may have important therapeutic and prognostic implications in the future.

Interleukin 1 stimulates fibroblasts to produce granulocyte-macrophage colony-stimulating activity and prostaglandin E2.

Granulocyte-macrophage colony-stimulating activity (GM-CSA) can be produced by a variety of normal cell types including mononuclear phagocytes, activated T lymphocytes, endothelial cells, and fibroblasts. Recent evidence shows that a major role of the monocyte-macrophage is the recruitment of environmental cells, i.e., fibroblasts, to produce GM-CSA. In this study we have identified interleukin 1 (IL-1) as a monokine that stimulates fibroblasts to produce and release GM-CSA and prostaglandin E2 (PGE2). Both purified human monocyte-derived IL-1 and human recombinant IL-1 (10(-10) M) can be substituted for monocyte-conditioned medium in stimulating fibroblast GM-CSA and PGE2 production. Both forms of IL-1 stimulate fibroblasts to produce GM-CSA and PGE2 in a dose-dependent fashion. The fibroblast-stimulating activity found in monocyte-conditioned medium was completely blocked by anti-IL-1. We conclude that monocytes produce IL-1, and that monocyte-derived IL-1 induces fibroblasts to produce GM-CSA and PGE2.

Recurrent varicella-zoster infection after acyclovir therapy in immunocompromised patients.

Varicella-zoster virus (VZV) infection is a late complication of bone marrow transplantation in almost half of the long-term survivors. We have reported the clinical relapse of VZV infection in two marrow transplant recipients treated with standard regimens of acyclovir, a new antiviral agent with activity against VZV. Since most VZV infections occur after discharge from a transplant center, primary care physicians must be alert to the possibility of relapse of VZV infection after acyclovir therapy.

Intensive short-term chemotherapy for patients with acute myelogenous leukemia: long-term follow-up.

Our pilot study addresses the problem of early relapse from complete remission in young adults with acute myelogenous leukemia (AML). Twelve patients with AML, 16-58 years of age, were entered in a study of four intense courses of cytotoxic chemotherapy using the following drugs: cytarabine, daunorubicin, 5-azacitidine, and 6-thioguanine. They received no maintenance therapy. Nine of 12 patients achieved complete response. With a minimum follow-up of 35 months, the observed disease-free survival at 2 years was 67% (14 +/- SE) and the actuarial disease-free survival at 4 years was 38% (17 +/- SE). It appears that brief intensive chemotherapy early in the management of AML can produce prolonged remission without the need for maintenance therapy.

Etoposide, carmustine, bleomycin, and methotrexate with leucovorin rescue as re-treatment for unfavorable non-Hodgkin's lymphoma.

Fifteen patients with unfavorable, non-Hodgkin's lymphoma refractory to front-line chemotherapy were treated with etoposide, carmustine, bleomycin, and methotrexate with leucovorin rescue. Four patients achieved complete response and two achieved partial response. The durations of the complete responses were 4, 12, 24, and 32 months, respectively. Three of the four complete responses occurred in five patients who failed to respond to initial combination chemotherapy. The major toxic effects were severe myelosuppression in eight of 52 courses and pulmonary fibrosis in two patients. This regimen is useful in inducing durable remissions in patients with refractory, unfavorable, non-Hodgkin's lymphomas.