Expression of the vascular endothelial growth factor receptors 1 and 2 in acute myeloid leukemia: incidence and feasibility of immunohistochemical staining.

Vascular endothelial growth factor (VEGF) and its receptor tyrosine kinases, VEGFR-1 and VEGFR-2, are important therapeutic targets for various cancers including AML. Paraffin-embedded bone marrow samples (PE-BM) are, in most cases, the only tissue accessible to perform retrospective analyses of novel targets such as VEGF and/or its receptors. As a result, it limits our options to immunohistochemistry (IHS), or more expensive and less practical techniques such as enzyme-linked immunosorbent assay (ELISA) or fluorescence in situ hybridization (FISH). We analyzed the feasibility of IHS to measure VEGFR-1 and VEGFR-2 expression in 28 AML samples using monoclonal antibodies (moAbs) against Flt-1 (VEGFR-1) and KDR/Flk-1 (VEGFR-2). Medical records were reviewed for relevant clinical information. Expression of VEGFR-1 (+) and VEGFR-2 (+) were seen in 25% (7/28) and 43% (12/28) respectively. Forty-six percent (13/28) were dual-negatives for VEGFR-1 and VEGFR-2; 14% (4/28) were dual-positives for VEGFR-1 and VEGFR-2. An inferior survival was observed in patients whose myeloblasts express either VEGFR-1 (+) or VEGFR-2 (+), or both. Determination of expression of VEGF receptors (1 and 2) by IHS in PE-BM tissue is feasible. Prospective comparison of IHC to flow cytometry or other molecular techniques, and assessment of the prognostic significance of VEGF receptors in AML patients is warranted.

Successful non-surgical treatment of disseminated polymicrobial fungal infection in a patient with pancytopenia and graft-versus-host disease.

Invasive fungal infections after bone marrow transplantation have an extremely poor prognosis. Surgical excision in combination with antifungal therapy is considered necessary for treatment, especially for central nervous system (CNS) infection. We describe successful medical management with lipid complex amphotericin B (ABLC) and itraconazole, without surgical excision, of disseminated fungal infection involving the lungs and CNS in a patient with pancytopenia and graft-versus-host disease.

Routine chest radiography for the evaluation of febrile neutropenic patients after autologous stem cell transplantation.

Chest radiographs are routinely obtained for diagnostic evaluation of neutropenic febrile patients. We investigated the frequency of chest radiographic abnormalities during febrile episodes after autologous PBSC transplants and assessed the relationship of these abnormalities to past history of pulmonary disease, pre-transplant chest radiographic abnormalities, and pulmonary signs or symptoms at time of fever. We also studied the impact of chest radiographic findings on patient management. Sixty-one consecutive adult autologous PBSC transplant recipients were studied. Fifty-two (85%) developed fever, and 20 (38%) of these showed new chest radiographic abnormalities suggestive of pulmonary infection. Patients with pre-transplant chest radiographic abnormalities were more likely to develop additional abnormalities with fever post-transplant. Pulmonary symptoms or signs had low sensitivity or specificity for predicting radiographic abnormalities. Only 40% of patients with pulmonary symptoms or signs had an abnormal chest radiograph. Twenty-six percent of patients with abnormal chest radiographs had no clinical findings suggestive of pulmonary infection. The identification of chest radiographic abnormality did not change empiric antibiotic treatment in any patient. The role of routine chest radiography for diagnostic evaluation of febrile autologous PBSC transplant patients should be re-evaluated.

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.

Introducing case management to a general medicine ward team of a teaching hospital.

PURPOSE: To introduce case management to a general medicine ward team of a teaching hospital to improve patient care and ensure comprehensive longitudinal care. METHOD: The Department of Veterans Affairs Medical Center is one of four hospitals used by University of Oklahoma School of Medicine residents. There are five medicine teams, each comprising a second- or third-year resident, one or two interns, two medical students, and a faculty physician. The case-management program was initiated in November 1994. No attempt was made to limit the residents assigned to the case-managed team (i.e., many residents who worked with the case-managed team subsequently rotated through the other teams). Patients were assigned to the teams by rotation, and no attempt was made to adjust for the severity of illness among admissions. The teams were separated as follows: pre-case-management teams (all five teams prior to the case-management program), non-case-management teams (the four teams without case managers after the program's initiation), and the case-management team. The study periods were January-July 1994 (pre-case management) and January-July 1995 (after case management). RESULTS: The numbers of patients treated by the three groups were 1,305, 1,139, and 289, respectively. The median length of stay for pre-case-management patients was 5 days (interquartile range, 3-9 days); for non-case-management patients, 5 days (range, 3-8 days); and for case-management patients, 5 days (range, 3-7 days). The cumulative distribution of lengths of stay for case-management patients was significantly different from those of the other study groups by the Kolmogorov-Smirnov test (p = .02). More case-management patients were discharged by day 7. Rates of readmission were not significantly different between the teams. CONCLUSION: In this study a case-management program was effectively implemented in a teaching hospital, resulting in reduced lengths of stay for patients. As academic health centers become more concerned with efficiency and cost, case management should be seriously considered as a way to deal with such issues.

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.

High-dose carboplatin, etoposide and cyclophosphamide with autologous bone marrow transplantation for the treatment of advanced malignancies: a phase I study.

Carboplatin is a platinum-derivative widely used in conditioning regimens with ABMT, particularly in combination with cyclophosphamide and etoposide, drugs which co-express synergism in vitro. The objective of this study was to determine the maximum tolerated dose (MTD) of this combination. Thirty-four patients with refractory lymphoid or solid tumors were treated in a dose-escalation study with continuous infusion carboplatin (1.2-2 g/m2) on days -7 to -4, etoposide (1.2-2.4 g/m2) on days -7 to -5 and cyclophosphamide (120 mg/kg) given in two dose schedules: (1) day -3, -2; (2) day -9, -8. Autologous bone marrow or peripheral blood stem cells were infused on day 0. Mucositis/enterocolitis was dose limiting. In addition, severe cardiac dysfunction occurred in schedule 1 but not in schedule 2. Renal dysfunction occurred in the setting of fungemia, respiratory failure and congestive heart failure, and did not correlate with carboplatin dose. Hepatic and pulmonary dysfunction were minimal. The MTD was etoposide 2.1 g/m2 and carboplatin 2.0 g/m2, in combination with cyclophosphamide (120 mg/kg) on schedule 2. Responses were seen in 16 of 19 patients with measurable disease. Seven patients are disease-free survivors 50-60+ months post-ABMT. This study defines the MTD of carboplatin when combined with etoposide and cyclophosphamide in patients with adequate renal function and suggests significant anti-tumor activity.

Long-term survival after autologous bone marrow transplantation for metastatic breast carcinoma.

A phase II study of doxorubicin (Adriamycin)-based induction chemotherapy followed by cyclophosphamide/BCNU (CyBCNU) intensification and autologous bone marrow transplantation (ABMT) was conducted in 20 consecutive women with hormone-resistant metastatic breast cancer referred to our center. Of these 20 women, aged 24 to 56 (median age, 41), 9 had complete remission and 11 had partial remission after induction chemotherapy. Predominant sites of metastases included liver (5), lung (4), bone/bone marrow (5), and soft tissue (6). The dose of cyclophosphamide was 160 mg/kg and the dose of BCNU, 600 mg/m2, followed by infusion of a mean 2.30 x 10(8) nucleated marrow cells per kilogram of body weight. All patients achieved durable engraftment. Three patients remain disease-free at 62+, 67+, and 73+ months; two of these were in complete remission before ABMT. Actual relapse-free survival at 5 years is 15% and median survival from ABMT is 17 months. Induction chemotherapy followed by CyBCNU intensification in metastatic breast cancer can achieve prolonged relapse-free survival in 15% of patients, some of whom may be cured.

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.

Allogeneic bone marrow transplantation: experience with 92 patients.

Allogeneic bone marrow transplantation (BMT) is potentially curative therapy for leukemia, lymphoma, and marrow failure. Ninety-two patients have received allogeneic BMT at Oklahoma Memorial Hospital in the past 10 years. Patients with acute myelogenous leukemia (AML; N = 30), chronic myelogenous leukemia (CML; N = 27), acute lymphoblastic leukemia (ALL; N = 12), myelodysplastic syndromes (MDS; N = 8), lymphomas (N = 8), and aplastic anemia (N = 7) were treated with a variety of myeloablative preparative regimens. The major causes of mortality were bacterial, viral, and fungal infections, or disease relapse. Standard and high risk (refractory or multiply-relapsed disease) AML, CML, and ALL patients had median survivals of 14.5 months vs. 3 months, > 18 months vs. 9 months, and 10 months vs. 4.5 months (p = 0.01), respectively. At 7.5 years median follow-up, 71% of the aplastic anemia patients are disease-free. Guidelines for the optimal time for BMT have been developed that encourage transplantation earlier in the course of the disease, thus facilitating better outcomes with these otherwise fatal disorders.

High-dose combination alkylating agent therapy with autologous bone marrow rescue for refractory solid tumors.

Twenty-six adults, ages 27 to 60, with refractory metastatic solid tumors were treated with high-dose cyclophosphamide (Cy) + carmustine (BCNU) at one of three escalating dose schedules followed by autologous bone marrow transplantation (ABMT). Toxicity was severe and dose-related, with the maximum tolerated dose for the combination determined to be Cy 160 mg/kg and BCNU 900 mg/m2. Median time to WBC recovery (greater than or equal to 1,000/microL) was 13 days post-ABMT (range, nine to 22 days) and to a platelet count of greater than or equal to 50,000/microL, 22 days (range, 13 to 83 days). Sixteen of 20 evaluable patients (80%) responded to therapy with at least 50% reduction in measurable tumor, and three patients achieved complete remission (CR). Responders included eight of nine evaluable patients with breast carcinoma, two of five with melanoma, two of two with sarcoma, and four of four with colon carcinoma. Response durations were short (median, 4 months), even for complete responders, and relapses generally occurred at sites of previous metastases. In order for this approach to have a more significant impact on overall survival, it may need to be applied earlier in the natural history of the malignancy.