Topical transforming growth factor-beta3 in the prevention or alleviation of chemotherapy-induced oral mucositis in patients with lymphomas or solid tumors.

Transforming growth factor (TGF)-beta3 has been hypothesized to prevent or alleviate oral mucositis (OM) in cancer patients receiving high-dose chemotherapy (CT). Two double-blind, placebo-controlled, multicenter, phase II studies of TGF-beta3 were initiated in the United States, Europe, and Argentina in patients with lymphomas or solid tumors who were receiving highly stomatotoxic CT regimens. Patients were to apply 10-mL mouthwash applications of TGF-beta3 (25 microg/mL) or placebo four times daily (or twice daily) 1 day before and all days during CT. The patients were subsequently evaluated for OM incidence, severity, and duration using National Institute of Cancer Common Toxicity Criteria (NCI-CTC) criteria and an objective scoring system (1). After the start of the trials, negative results from new preclinical studies suggesting suboptimal formulation and/or dosing led to an interim analysis of the ongoing clinical trials. One hundred fifty-two patients from the combined studies were included in the interim analysis, with 116 patients on the TGF-beta3 four times daily and placebo arms. Most (72%) patients had breast cancer, 22% had lymphomas, and 6% had other solid tumors. Although 98% (149 of 152) of patients experienced adverse events, only 14% (22 of 152) experienced events that were judged as possibly or probably related to the study drug (primarily gastrointestinal symptoms). No clinically relevant differences were seen between the treatment and placebo arms regarding safety, nor was there evidence for systemic absorption of TGF-beta3. Finally, there was no advantage of TGF-beta3 treatment regarding the incidence (TGF-beta3 four times daily versus placebo [46% versus 47%]), onset, or duration of NCI-CTC grade 3 or 4 OM. For this dose, formulation, regimen. and patient population, TGF-beta3 was not effective in the prevention or alleviation of CT-induced OM.

Efficacy and safety of oral granisetron versus i.v. granisetron in patients undergoing peripheral blood progenitor cell and bone marrow transplantation.

This randomized, controlled, double-blind pilot study assessed the efficacy and safety of oral versus i.v. granisetron, both in combination with non-5-HT3 antiemetics, in preventing emesis caused by high-dose chemotherapy. Fifty-one patients who underwent peripheral blood progenitor cell transplantation (PBPCT) or bone marrow transplantation (BMT) were evaluated. Efficacy was assessed by the number of emetic episodes during the worst 24 h period. A complete response (CR) was defined as no vomiting, partial response (PR) as less than three emetic episodes and failure as three or more emetic episodes. Patients who received oral granisetron experienced significantly (p<0.0008) fewer emetic episodes than those who received i.v. granisetron; however, the number of emetic episodes over the worst 24 h was similar between the oral and i.v. granisetron groups (13 and 15, respectively), as were the overall response rates (CR+PR, 54.5 and 41.4%, respectively). Both dosage forms were well tolerated. Based on these findings, further comparative studies of oral granisetron are warranted in patients undergoing PBPCT or BMT.

G-CSF-mobilized donor leukocyte infusions as immunotherapy in acute leukemia relapsing after allogeneic marrow transplantation.

Eight patients who relapsed with acute leukemia within a year after allogeneic BMT were treated with G-CSF-mobilized donor leukocyte infusions (mDLI) to induce GvHD as a form of immunotherapy. Prior to mDLI, 7 who had systemic relapse received one (2 AML, 1 ALL, 1 CML myeloid blast crisis) or two (2 AML, 1 ALL) rounds of conventional dose induction chemotherapy, and 1 patient with isolated central nervous system (CNS) lymphoid blast crisis CML received intrathecal chemotherapy followed by craniospinal irradiation. G-CSF (10 microg/kg/day) was given to original HLA-matched sibling donors for 4-5 days before leukapheresis of at least 6.0 x 10(8) mononuclear cells per kilogram of recipient weight. No GvHD prophylaxis was used when mDLI was given in 6 patients at the nadir of hematologic counts and in 2 who were in hematologic remission. There was no regimen-related mortality, as pancytopenic patients had rapid recovery of neutrophil counts (6-18 days after mDLI). All patients developed moderate to severe GvHD (5 grade III/IV, 3 grade II) at a median of 30 days (range 22-59) after mDLI. Two patients died of complications from refractory GvHD while in remission. The other 6 had short remissions lasting 2.2-9.4 months until leukemic relapse as their GvHD was reversed by corticosteroids with or without cyclosporine. Patients who relapse with acute leukemia within a year after BMT still have a poor prognosis. The success of GvHD as a form of immunotherapy in these patients may depend on the ability to control it to a state that is both safe and continually exerting an antileukemia effect.

Marrow and stem cell transplantation in Oklahoma: fifteen years of experience and results.

From September 1982 to August 1997, 767 bone marrow or peripheral blood stem cell transplants have been performed at the Health Sciences Center in Oklahoma. Five hundred and two (502) autologous transplants (AutoTX) preceded by high-dose myeloablative therapy were performed for breast cancer (BC, 36%), non-Hodgkin's lymphomas (NHL, 24%), Hodgkin's disease (HD, 10%), acute myeloid leukemia (AML, 8%), testicular cancer (TC, 4%), multiple myeloma (MM, 2%) and other malignancies (16%). Two hundred and sixty-five (265) allogeneic marrow transplants (AlloTX) (related, unrelated) were carried out in chronic myeloid leukemia (CML, 30%), AML (23%), acute lymphoid leukemia (ALL, 14%), myelodysplastic syndrome (MDS, 9%), severe aplastic anemia (SAA, 8%), and other diseases (14%). Compared between 1980s to 1990s, 100-day mortality rates have decreased from 28% to 5% for AutoTX and from 40% to 25% for AlloTX. In the AutoTX setting, major changes included the routine use of growth factors post-transplant and the switch from bone marrow to growth factor-mobilized peripheral blood as a source of stem cells over the last five years. In the AlloTX setting, improvements in recognition and control of cytomegalovirus and Candida organisms, the selective use of growth factors and screened blood products, and better selection of unrelated donors using DNA-based techniques of HLA-matching have contributed to reduce early mortality from infection and primary graft failure. The five-year survival outcomes are comparable to those reported in registry data from the International Bone Marrow Transplant Registry (IBMTR) and the National Marrow Donor Program (NMDP).

Long-term results of autologous marrow transplantation for relapsed or refractory male or female germ cell tumors.

Twenty-one patients with relapsed or refractory germ cell tumors were treated with high-dose chemotherapy and marrow transplantation (HDC/BMT) from 1982-1993. Primary sites of disease were testis (17), ovary (three), and pineal gland (one). Pathology included dysgerminoma (one), choriocarcinoma with adenocarcinoma (one), seminoma (four), and nonseminoma or mixed germ cell tumor (15). Nineteen had at least two prior chemotherapy regimens and eight had cisplatin-refractory disease defined as progression within 4 weeks of a cycle of cisplatin-based chemotherapy. HDC regimens were mostly combinations of cyclophosphamide with etoposide and cisplatin or carboplatin. There were only two treatment-related deaths (aspergillosis and interstitial pneumonitis). Times to engraftment of granulocytes (21+/-8.3 days) and platelets (32+/-20.2 days) were reasonable with only the last nine patients receiving growth factors. At a minimum of 4 years follow-up, eight patients have died of disease, six of whom were cisplatin-refractory prior to transplant. Eleven patients (52% overall) are alive and continuously free of disease after 4-10 years including one of three with refractory ovarian germ cell tumor. HDC/BMT provides significant long-term disease-free survival as salvage therapy for both male and female relapsed germ cell tumor patients who are not refractory to cisplatin.

Bullous esophagitis due to chronic graft-versus-host disease.

Vesiculobullous lesions of esophagus in patients post bone marrow transplantation may occur due to infectious agents or acute graft-versus-host disease (GVHD). We report the case of a patient who developed a large bulla in the esophagus as a result of chronic GVHD. Potential etiologies, diagnosis and management of bullous esophagitis are reviewed.

High-dose chemotherapy as salvage treatment in germ cell tumors: a multivariate analysis of prognostic variables.

PURPOSE: To identify prognostic variables for response and survival in male patients with relapsed or refractory germ cell tumors treated with high-dose chemotherapy (HDCT) and hematopoietic progenitor cell support. PATIENTS AND METHODS: Three hundred ten patients treated with HDCT at four centers in the United States and Europe were retrospectively evaluated. Univariate and multivariate analysis of patient, disease, and treatment characteristics were used for comparisons of response rates and failure-free survival (FFS). RESULTS: The actuarial FFS rate was 32% at 1, 30% at 2, and 29% at 3 years. Multivariate analysis identified progressive disease before HDCT, mediastinal nonseminomatous primary tumor, refractory or absolute refractory disease to conventional-dose cisplatin, and human chorionic gonadotropin (HCG) levels greater than 1,000 U/L before HDCT as independent adverse prognostic variables for FFS after HDCT. These variables were used to identify patients with good, intermediate, and poor prognoses. In the good-risk category, the predicted FFS rate at 2 years was 51%, compared with 27% and 5% in the intermediate-risk and poor-risk categories (P < .001). The increased risk for treatment failure was due to both a significantly lower rate of favorable responses and a significantly higher rate of relapses. Within the prognostic categories, the particular HDCT regimen or higher dosages of carboplatin or etoposide did not have a significant influence on treatment outcome. CONCLUSION: Prognostic variables for treatment response after HDCT can be identified. The proposed prognostic model might help to optimize the use of HDCT in germ cell tumors and warrants validation in future trials.

Cytomegalovirus surveillance and prevention in allogeneic bone marrow transplantation: examination of a preemptive plan of ganciclovir therapy.

Forty-two cytomegalovirus (CMV)-seropositive allogeneic marrow transplant patients or recipients of CMV-seropositive marrow allografts were entered into a surveillance program to detect and treat CMV infection during the first 120 days posttransplant. CMV infection was detected at a mean time of day 50 in 21/37 (58%) patients who had surveillance cultures. Twelve of 42 (28%) received preemptive ganciclovir treatment for virus isolated from blood (9 patients) or from bronchoalveolar lavage fluid (3 patients), and all had no CMV-associated sequelae. CMV disease was diagnosed in 5 patients (4 with pneumonia), 1 with gastroenteritis) who did not have positive cultures until the onset of their disease. CMV-related mortality was 4/42 (10%). Patients who earlier manifested lung injury or diffuse alveolar hemorrhage (DAH) were significantly predisposed to subsequent CMV pneumonia (P = 0.0013, Fisher's exact test) at a median onset of day 42. Restricted prophylactic use of ganciclovir in such patients may be indicated. Fifty percent of all patients never required ganciclovir during the surveillance period. When compared to a universal prophylaxis program of ganciclovir for the prevention of CMV disease, the use of ganciclovir in a preemptive strategy could avoid unnecessary therapy for a substantial number of patients and earn significant cost-savings.

Dose escalation study of high-dose carboplatin and etoposide with autologous bone marrow support in patients with recurrent and refractory germ cell tumors.

Thirty-three patients with germ cell cancer (GCT) recurrent after two cisplatin-based regimens or cisplatin refractory (progression within 4 weeks of the last dose of cisplatin) were enrolled in a trial to establish the maximum tolerated doses (MTD) of carboplatin and etoposide given in combination with ABMT for two cycles. BM harvest of > or = 2 x 10(8) nucleated cells/kg preceded two cycles of therapy. Each agent was dose escalated, carboplatin from 1650 mg/m2 to 2100 mg/m2 and etoposide from 1200 mg/m2 to 2250 mg/m2 per cycle in successive cohorts. Twenty patients completed two cycles, 13 underwent only one due to: early death (4), toxicity (2), and progressive disease (6). There were four CR, three of whom achieved NED status with surgery, 14 PR, of whom eight have progressed. Four patients with stable disease and seven PD have died with a median survival of 6 months. There were six treatment-related deaths, four on course 1 and two on course 2. Causes of death on course 1 were: CNS hemorrhage (1), multiorgan failure (3); and on course 2: sepsis (1) and sudden death (1). Severe but reversible mucositis, transaminase and creatinine elevations were observed at the highest dose level. Three of five patients treated at this dose level had severe neurologic toxicity, manifested by both peripheral neuropathy and ototoxicity. The MTD in this patient population was carboplatin 2100 mg/m2 and etoposide 2250 mg/m2 on each of two cycles of therapy. Neurologic and mucosal toxicity were dose limiting.

Autologous bone marrow transplantation for metastatic breast cancer.

UNLABELLED: Metastatic breast cancer accounts for 18% of cancer deaths among women in the U.S. Conventional combination chemotherapy produces responses in 50% to 80% of women with metastatic breast cancer, but is never curative. A major medical center administered high-dose chemotherapy and autologous bone marrow transplantation to 68 women with metastatic breast cancer between 1983 and 1993. Forty-nine of these women had estrogen receptor-negative tumors, a poor prognostic sign. Eighteen women with estrogen receptor-positive tumors had failed prior hormonal manipulation or had metastatic breast cancer at initial diagnosis. Prior to transplantation, 37 women were in first complete or partial remission, 8 were in their second complete or partial remission, 4 had stable disease, 14 had progressive disease, and 5 were in untreated relapse. Bone marrow transplantation preparatory regimens included high doses of single agents or combination chemotherapy. Among women not in remission before transplantation, 71% entered a partial or complete remission following transplantation. Overall, 29 women (43%) were in complete remission after marrow transplantation. Twelve women (18% overall) remain free of disease between 2 and 73+ months post-ABMT. Those in first complete or partial remission prior to transplant (37 patients) had a higher response rate (86%) and higher complete responses (62%), and 10 (27%) are free of disease. There were nine treatment-related deaths (13%). Forty-seven patients (69%) have died from breast cancer following autologous transplantation. Relapses occurred primarily at sites of previous disease. All relapses have occurred within 22 months of ABMT. CONCLUSION: Autologous bone marrow transplantation for metastatic breast cancer in first complete or partial remission has produced a 27% disease-free survival. This therapy should be considered for selected patients with metastatic breast cancer.

Autologous bone marrow transplantation for non-Hodgkin lymphoma.

UNLABELLED: Non-Hodgkin lymphomas (NHLs) are a group of malignant disorders that can be cured with chemotherapy and/or radiotherapy in 30% to 50% of cases. For those who fail initial therapy, cure is rarely achieved with standard dose chemotherapy; therefore higher doses of chemotherapy have been used with autologous bone marrow support. This major medical center has performed 74 autologous bone marrow transplants (ABMT) for patients with non-Hodgkin lymphoma who had failed initial therapy between 1984 and 1993. Preparatory regimens included high doses of chemotherapy with or without radiotherapy. There were 14 patients with low grade, 41 with intermediate grade, and 18 with high grade histologies. Among patients with low grade histologies, 90% responded and 50% are relapse-free between 1 and 33 months post-ABMT. Among patients with intermediate and high grade histologies, 25% are relapse-free between 2 and 80 months post-ABMT. CONCLUSION: Autologous bone marrow transplantation is effective in patients with relapsed non-Hodgkin lymphoma and should be considered an important therapeutic option.

Carboplatin (CBDCA) plus alpha interferon in metastatic non-small cell lung cancer. A Hoosier Oncology Group phase II trial.

Interferons have been shown to increase in vitro cytotoxicity of platinum compounds. The Hoosier Oncology Group has conducted a Phase II clinical trial to determine if interferon alpha-2a (IFN-alpha-2a) given in combination with carboplatin (CBDCA) can increase response rates or survival in patients with metastatic or recurrent inoperable non-small-cell lung cancer. Forty-four patients with no prior chemotherapy and high KPS (80-100) were enrolled. CBDCA 400 mg/m2 was given intravenously on day 1 and IFN-alpha-2a 9 million units was given subcutaneously on days 1, 3, and 5. Treatment was administered every 4 weeks until onset of progressive disease or to a maximum of 4 courses: 37 patients (84%) received at least 2 courses, whereas only 16 (36%) received the full 4 courses. Dose-limiting toxicities were leukopenia (27%) and thrombocytopenia (20%) attributable to CBDCA. Grade 2-3 anemia occurred in 32%. Only 4-7% of patients experienced severe fever, fatigue, or flu-like symptoms attributable to interferon administration. Of 41 patients evaluable for response, there were no complete responses and only 3 (7.3%) partial remissions. The overall median survival was 6 months. The combination of CBDCA and IFN-alpha-2a given in this dose and schedule does not appear to have superior activity compared to CBDCA alone in patients with non-small-cell lung cancer.

Role of p21 RAS in p210 bcr-abl transformation of murine myeloid cells.

The p21 RAS product has been implicated as part of the downstream signaling of certain nonreceptor tyrosine kinase oncogenes and several growth factor receptor-ligand interactions. We have reported that the chronic myelogenous leukemia oncogene p210 bcr-abl transforms a growth-factor-dependent myeloid cell line NFS/N1.H7 to interleukin-3 (IL-3) independence. In these p210 bcr-abl-transformed cells (H7 bcr-abl.A54) and in two other murine myeloid cell lines transformed to IL-3 independence by p210 bcr-abl, endogenous p21 RAS is activated as determined by an elevated ratio of associated guanosine triphosphate (GTP)/guanosine diphosphate (GDP), assayed by thin-layer chromatography of the nucleotides eluted from p21 RAS after immunoprecipitation with the Y13-259 antibody. Treatment of p210 bcr-abl-transformed cells with a specific tyrosine kinase inhibitor herbimycin A resulted in diminished tyrosine phosphorylation of p210 bcr-abl and associated proteins, without major reduction in expression of the p210 bcr-abl protein itself. Inhibition of p210 bcr-abl-dependent tyrosine phosphorylation resulted in a reduction of active p21RAS-GTP complexes in the transformed cells, in diminished expression of the nuclear early response genes c-jun and c-fos, and in lower cellular proliferation rate. To further implicate p21 RAS in these functional events downstream of p210 bcr-abl tyrosine phosphorylation, we targeted G-protein function directly by limiting the availability of GTP with the inosine monophosphate dehydrogenase inhibitor, tiazofurin (TR). In p210 bcr-abl-transformed cells treated for 4 hours with TR, in which the levels of GTP were reduced by 50%, but GDP, guanosine monophosphate, and adenosine triphosphate (ATP) were unaffected, p210 bcr-abl tyrosine phosphorylation was at control levels. However, expression of c-fos and c-jun nuclear proto-oncogenes were strongly inhibited and p21 RAS activity was downregulated. These findings show that p210 bcr-abl transduces proliferative signals, in part, through downstream activation of p21 RAS. Furthermore, p21 RAS activity is linked to pathways that regulate c-jun and c-fos expression.

BCR/ABL confers growth factor independence upon a murine myeloid cell line.

The BCR/ABL oncogene in chronic myelogenous leukemia produces an activated tyrosine kinase fusion protein (p210). Like other tyrosine kinase oncogenes, BCR/ABL can abrogate the interleukin-3 (IL-3) dependence of lymphoid cell lines. To investigate the ability of BCR/ABL to generate growth factor independence in myeloid cells, the IL-3 dependent myeloid cell line NFS/N1.H7 (H7) was transfected with the p210BCR/ABL-containing plasmid, pGD210. Stable clones A54 and A74 were capable of IL-3 independent growth and tumor formation in syngeneic mice. Relief of growth factor dependence was not mediated by autocrine release of IL-3. The baseline proliferation rate of the BCR/ABL transformed cells was greater than that of the parental H7 cells maximally stimulated by IL-3. Abundant constitutive expression of c-myc, c-jun, and c-fos was observed in the p210BCR/ABL transfectants even in low serum conditions. In contrast, c-myc expression in H7 cells was dependent upon IL-3 stimulation, and neither c-jun nor c-fos was highly expressed following IL-3 stimulation in H7 cells. Thus, BCR/ABL transformation and relief of IL-3 dependence involve not only pathways that can substitute for IL-3 induced growth via tyrosine kinase mediated signals, but also pathways that recruit constitutive c-jun and c-fos expression.

Phase II trial of cimetidine in metastatic melanoma. A Hoosier Oncology Group trial.

Fifteen evaluable patients with metastatic malignant melanoma who had received no prior chemotherapy were treated with high-dose cimetidine orally, 600 mg q.i.d. Although three patients had stable disease lasting 2-4 months, there were no objective responses. Median survival was 5.3 months (range 1-18 months). Toxicity was essentially negligible except for severe diarrhea in one patient and worsening liver function abnormalities in another. High-dose cimetidine does not have any significant activity in metastatic melanoma.

The effect of fluid loading, blood transfusion, and catecholamine infusion on oxygen delivery and consumption in patients with sepsis.

Fifty-four patients with systemic sepsis and signs of circulatory shock were prospectively investigated immediately before and after 1 of 3 therapeutic interventions chosen to increase systemic oxygen delivery (DO2): colloidal fluid loading (Group I, n = 20), blood transfusion (Group II, n = 17), or catecholamine infusion (dopamine or dobutamine, Group III, n = 17). Patients in Groups I and II with normal blood lactate concentrations (less than 2.2 mmol/L) exhibited no significant increases in systemic oxygen consumption (VO2) in response to the increases in DO2. However, significant increases in VO2 were noted in patients in Groups I and II with elevated lactate concentrations (greater than 2.2 mmol/L). In contrast to patients in Groups I and II, patients in Group III with and without lactic acidosis exhibited significant increases in VO2 after catecholamine administration. Lactic acidosis, a clinical marker of anaerobic metabolism or oxygen debt, appears to predict increases in VO2 in response to increases in DO2 in septic patients receiving fluid and catecholamines increase VO2 without regard for the presence or absence of anaerobic metabolism. The results of this clinical trial therefore suggest that catecholamines may exert a direct effect on oxidative metabolism.