Clinical utility of oral valacyclovir compared with oral acyclovir for the prevention of herpes simplex virus mucositis following autologous bone marrow transplantation or stem cell rescue therapy.

Oral acyclovir has been demonstrated to prevent reactivation of herpes simplex virus (HSV) infections when administered prophylactically to autologous bone marrow transplant (BMT) recipients or patients undergoing stem cell rescue therapy. Oral valacyclovir, which is converted in the body to acyclovir, has greater oral bioavailability than oral acyclovir and compared with oral acyclovir yields similar acyclovir plasma concentrations with less frequent (twice-daily) dosing. This study compared the efficacy of oral valacyclovir with that of oral acyclovir at preventing HSV mucositis in BMT recipients. A total of 60 HSV-1-positive patients scheduled for BMT or stem cell rescue therapy were treated prophylactically with valacyclovir 500 mg twice daily until resolution of neutropenia. Data from these patients were compared with those of a historical control group of 60 patients who had received acyclovir 600 mg every 6 h until resolution of neutropenia or acyclovir 125 mg/m(2) intravenously every 6 h. The results show that none of the patients developed oral or oropharyngeal HSV infection while receiving either treatment. Of the 60 patients receiving valacyclovir, 38 (63%) completed treatment without the need for intravenous acyclovir compared with 12 of 60 (20%) patients in the acyclovir group. Additionally, the total number of doses of drug administered to the valacyclovir group was significantly less than the number received by patients in the acyclovir group. No serious adverse events occurred in either group of patients. This study demonstrates that oral valacyclovir and acyclovir are comparably effective and safe in preventing reactivation of HSV infections in autologous BMT and stem cell recipients. The less frequent dosing schedule with valacyclovir compared with acyclovir offers a potential advantage for patients undergoing BMT who frequently suffer with severe mucositis and have difficulty taking oral medications.

Double dose-intensive chemotherapy with autologous stem cell support for relapsed and refractory testicular cancer: the University of Michigan experience and literature review.

Testicular cancer patients refractory or in relapse after primary chemotherapy have < or =25% 5-year progression-free survival with salvage. To improve prognosis, patients entered a phase I/II tandem dose-escalation trial of carboplatin (1500-2100 mg/m(2)) and etoposide (1200-2250 mg/m(2)) with ABMT. Patients were eligible for a second cycle if disease progression was absent and performance status allowed. From August 1990 to June 1998, 29 males (25 NSGCT) were treated. At the time of ABMT, 10 were chemosensitive, four were chemoresistant, and 10 were absolutely refractory to platinum. Disease status (no. patients) at transplant: primary refractory disease (six), first relapse (10), second relapse (eight), third relapse (five). Fifteen (52%) received both transplants. Treatment-related mortality was 10%. Best response after ABMT included: two CR, one CR surgically NED, five PR, three PR surgically NED, seven SD, and eight PD. Eight (28%) patients are continuously progression-free a median 60 months (range, 31-93) from first ABMT. Three seminoma patients remain progression-free. Of five long-term NSGCT survivors, four were treated in first relapse with platinum-sensitive disease. Eighteen relapses occurred a median of 4 months after ABMT I (two late relapses at 28 and 44 months). The median PFS and OS for the whole group are 4 and 14 months, respectively. Patients with relapsed/ refractory testicular cancer benefit most from ABMT if they have platinum-sensitive disease in first relapse. Patients who do poorly despite ABMT have a mediastinal primary site, true cisplatin-refractory disease, disease progression prior to ABMT, and/or markedly elevated betaHCG at ABMT. New treatment modalities are needed for the latter group.

Interim analysis of the use of the anti-idiotype breast cancer vaccine 11D10 (TriAb) in conjunction with autologous stem cell transplantation in patients with metastatic breast cancer.

The anti-idiotype monoclonal antibody breast cancer vaccine 11D10 (TriAb) was administered before and after autologous stem cell transplantation (ASCT) in 45 patients with metastatic breast cancer whose disease was responsive to conventional chemotherapy. Evidence of a positive anti-anti-idiotype antibody (Ab3) humoral response was noted at a median of 1.76 months post-ASCT (range, before ASCT-6 months) with this strategy. Maximal Ab3 levels and idiotype-specific T-cell proliferative responses were observed at a median of 3 and 4 months, respectively, after ASCT. The achievement of rapid immune responses after ASCT, during a known period of decreased immunoresponsiveness, opens the possibility of an additional antitumor effect at a time when the tumor burden is relatively small. Moreover, in this interim analysis, patients with the most vigorous humoral and cellular immune responses had a significant improvement in progression-free survival. Further follow-up and evaluation of this approach is warranted.

Longitudinal study of adaptation to the stress of bone marrow transplantation.

PURPOSE: This prospective longitudinal study of adaptation to bone marrow transplantation (BMT) addressed three questions: (1) When during BMT do individuals experience the greatest distress? (2) What factors are associated with this distress? (3) Are there variables that could be potential clinical indicators of persons in greatest need of preventive intervention? PATIENTS AND METHODS: One hundred one participants undergoing either an autologous or allogeneic BMT completed questionnaires before hospitalization, before bone marrow infusion, 7 days and 14 days after transplantation, and then 1 month, 3 months, and 12 months after hospitalization. Adaptation was indicated by the degree of emotional distress. Independent variables were personal control, social support from specific sources, cognitive response, self-perception, and coping strategies, controlling for symptomatology. RESULTS: The greatest emotional distress occurred after admission to the hospital and before the bone marrow infusion. Anxiety and depression decreased 1 week after the transplant, although symptomatology increased during this time. The periods of least emotional distress were 3 months and 1 year after transplantation. Factors that accounted for the greatest variance in emotional distress/adaptation were the degree of emotional distress at baseline, personal control, cognitive response, and symptomatology. CONCLUSION: According to this longitudinal study, which includes pretransplant data, data from in-hospital transplantation, and posttransplant data, (1) psychosocial vulnerability of these BMT recipients was greatest during hospitalization before the transplant, (2) perceived personal control may be a potential indicator of vulnerability to secondary psychosocial morbidity, and (3) the demonstrated significance of psychosocial well-being before BMT indicates the importance of obtaining prospective data for both research and clinical purposes.

Rapid engraftment after allogeneic transplantation using CD34-enriched marrow cells.

Bone marrow cells expressing the surface antigen CD34 comprise approximately 1% of harvested marrow and are highly enriched for marrow progenitor cells, including the cells believed to be responsible for long-term engraftment following bone marrow transplantation (BMT). Selection of CD34-expressing cells was applied in allogeneic BMT (alloBMT) to decrease the number of T lymphocytes in the infused marrow in an attempt to prevent severe graft-versus-host disease (GVHD). We report 14 patients who underwent HLA-identical sibling-matched alloBMT with marrow-enriched for CD34 cells using the Isolex 300 SA device. Patients received total body irradiation, thiotepa, cyclophosphamide, antithymocyte globulin and methylprednisolone prior to marrow infusion. No post-transplantation immunosuppressive therapy was given except for a 5-week course of steroids. The purity of the infused marrow was 64.9+/-6.0% (mean +/- s.e.m.) CD34-positive cells and patients received a mean of 1.24+/-0.21 x 10(6) CD34 cells/kg. A mean of 9.4+/-1.7 x 10(4) CD3 T cells/kg were present in the CD34-enriched product, representing a 2.7+/-0.1 log depletion. There were no graft rejections and patients achieved a sustained absolute granulocyte count of >500 in a median of 10.5 days and a sustained platelet engraftment of >20000 untransfused in a median of 27 days. Patients were discharged a median of 21.5 days after marrow infusion. There were no instances of grade III or IV graft-versus-host disease (GVHD) and no unexpected adverse events during the transplant hospitalization. With a median follow-up of 12 months, the estimated 100 day survival is 86+/-9%. CD34 selection in alloBMT permits rapid engraftment without unanticipated toxicities.

Recombinant methionyl human stem cell factor and filgrastim for peripheral blood progenitor cell mobilization and transplantation in non-Hodgkin's lymphoma patients--results of a phase I/II trial.

To examine the safety and efficacy of recombinant-methionyl human stem cell factor (r-metHuSCF), 38 patients with intermediate-grade or immunoblastic high-grade non-Hodgkin's lymphoma who were eligible for autologous transplantation were randomized to receive r-metHuSCF (5, 10, 15, or 20 microg/kg/d) plus Filgrastim (10 microg/kg/d) or Filgrastim (10 microg/kg/d) alone to mobilize peripheral blood progenitor cells. Subcutaneous administration of r-metHuSCF was well tolerated in conjunction with a multi-agent pre-medication regimen; local injection site reactions were the most commonly seen adverse event. The total mononuclear cell count, CD34+ cell content, granulocyte-macrophage colony-forming cells (GM-CFC), and burst-forming units-erythroid (BFU-E) per kilogram in the apheresis product was similar when all patients were analyzed by treatment cohort and mobilization regimen (Filgrastim or r-metHuSCF in combination with Filgrastim); however, when prior chemotherapy was taken into account in a supplementary analysis, clinically important differences were observed. Extensive prior therapy was defined as the amount of exposure to specific stem cell toxic chemotherapeutic agents that patients received. These agents include procarbazine, nitrogen mustard, melphalan, nitrosoureas (> or = 2 cycles of any of these drugs) or greater than 7.5 g of cytosine arabinoside. In these patients, there was an increased number of CD34+ cells (1.76 v 0.28 x 10(6)/kg), GM-CFC (20.5 v 5.0 x 10(4)/kg), and BFU-E (36.9 v 8.9 x 10(4)/kg) in patients receiving r-metHuSCF and Filgrastim (N = 18) compared with Filgrastim alone (N = 5). These patients also had a decreased time to an untransfused platelet count of 20 x 10(9)/L that was 10.5 days shorter in the patients who received r-metHuSCF and Filgrastim (12.5 v 23 days). These differences were not found to be statistically significant, possibly because of small size, but are clinically important.

Tandem high dose chemotherapy with autologous bone marrow transplantation for initial relapse of testicular germ cell cancer.

BACKGROUND: The purpose of this study was to evaluate the use of two cycles of high dose chemotherapy with autologous bone marrow transplantation (ABMT) in the treatment of patients having a first relapse of testicular germ cell cancer. METHODS: Twenty-five patients whose disease had relapsed after 1 platinum-based regimen received 1-2 cycles of conventional dose salvage therapy, followed by a planned 2 consecutive cycles of carboplatin 2100 mg/m2 and etoposide 2250 mg/m2 with ABMT. Patients were required to have testicular germ cell cancer, adequate organ function, and performance status. The median patient age was 32 years; 3 cisplatin refractory. RESULTS: Conventional dose salvage therapy consisted of vinblastine, ifosfamide, and cisplatin (for 16 patients); etoposide, cisplatin, and ifosfamide (for 3 patients); cisplatin, vinblastine, and bleomycin (for 2 patients); or none (for 4 patients). Twenty-five patients received high dose therapy; of these, 19 (76%) received two cycles. The median time to an absolute neutrophil count of 500 was 12 days (range, 8-20 days) for the first cycle and and 11 days (range, 8-18 days) for the second. The median time to a platelet count of 20,000/microL, independent of transfusions, was 15 days (range, 8-60 days) for the first cycle and 14 days (range, 8-22 days) for the second. Extramyeloid toxicities were as follows: Grade 3-4 stomatitis in 17 of 25 patients, Grade 3-4 nausea/emesis in 12 of 25 patients, and Grade 3 ototoxicity in 3 of 25 patients. At the completion of therapy, nine patients were in complete remission, six had only teratoma found at resection, one had carcinoma resected, six were in partial remission, two had stable disease, and one had progressive disease. With a median follow-up period of 26 months (range, 14-36 months), 13 of 25 patients (52%) had been continuously progression free at last follow-up, 11 of 25 (44%) progressed, and 1 patient died in treatment. CONCLUSIONS: Salvage treatment incorporating brief conventional dose therapy followed by two cycles of high dose therapy resulted in prolonged disease free survival in a proportion of patients with relapsed testicular germ cell cancer.

A phase II trial of edatrexate in previously treated squamous cell cervical cancer: a Gynecologic Oncology Group study.

A Phase II trial of edatrexate in patients with recurrent cervical carcinoma was conducted by the Gynecologic Oncology Group (GOG). Twenty patients were treated with edatrexate at a dose of 80 mg/m2 i.v. weekly for 5 consecutive weeks per cycle. Four patients received an inadequate trial and were inevaluable for response. Among the 16 patients evaluable for response, there were no objective responses: 50% had stable disease, 50% had progressive disease. All 20 patients were evaluable for toxicity, predominantly stomatitis and bone marrow suppression were substantial. Grades 3-4 bone marrow toxicity were observed in eight of 20 (40%) patients, and there were two deaths due to neutropenic sepsis. Fanconi's syndrome, possibly treatment related, was seen in two patients. Edatrexate administered in this dose and schedule has no demonstrated activity and has severe toxicity in patients with previously-treated advanced cervical cancer.

Oral cavity complications of bone marrow transplantation.

Bone marrow transplantation, once regarded as experimental, has evolved into a standard treatment for a variety of malignancies. Considerable advances have been made in histocompatibility typing, pretransplantation chemotherapy, and posttransplantation immunosuppressive therapy as well as prophylaxis and treatment of infections. Oral complications develop in almost all patients, and their early recognition may result in the institution of prompt treatment and prolonged survival. Mucositis, often severe and extremely painful, develops in more than three quarters of bone marrow transplant recipients, and its prevention, unfortunately, remains unsatisfactory. Herpes simplex virus and Candida albicans account for most oral infections, although their incidence has been dramatically reduced by the institution of prophylactic agents. Graft versus host disease continues to be a significant complication of marrow transplantation, and the detection of commonly occurring oral changes may support its diagnosis.

Minimizing graft rejection in allogeneic T cell-depleted bone marrow transplantation.

Between October 1991 and May 1994, 42 patients were treated with cyclophosphamide, thiotepa, and total body irradiation followed by an allogeneic transplantation of marrow depleted of T cells with soybean agglutinin and E-rosetting. Patients included in this study had acute myelogenous leukemia (13), chronic myelogenous leukemia (12), acute lymphocytic leukemia (nine), Hodgkin's disease or non-Hodgkin's lymphoma (four), multiple myeloma (three), or myelodysplastic syndrome (one). The mean age was 34 (range 8 to 51 years). Nineteen patients had a matched sibling donor and 18 received marrow from 6/6 matched unrelated donors while five received transplants from unrelated donors disparate at one DR locus (5/6 match). Time to granulocyte engraftment (AGC > or = 500/mm3) occurred at a mean of 16.5 days for related and 11.4 days for unrelated transplant recipients, and was related to the increased use of G-CSF in the unrelated population. There was no correlation with number of mononuclear cells, T cells, or CD34-positive cells infused, the rate of engraftment or the incidence of transplant complications. Multivariate analysis determined that G-CSF administration and a diagnosis other than ALL were the only factors associated with a faster rate of engraftment. Patients receiving unrelated donor transplants, those with ALL, or those who had a low T cell number infused (< or = 8.0 x 10(3) cells/kg) experienced delayed hospital discharge. The regimen resulted in excellent rates of engraftment (95.2%) with only one failure to engraft and one graft rejection. The incidence of grade III-IV acute graft-versus-host disease was 0% with sibling and 26.1% with unrelated donors. There were no cases of veno-occlusive disease. Fifty percent of patients are alive with a mean follow-up of 26.4 months. We conclude that this regimen is well tolerated and results in excellent engraftment with a low incidence of severe graft-versus-host disease and few therapy-related toxicities.

Retroviral gene transfer in autologous bone marrow transplantation for adult acute leukemia.

To evaluate whether marrow contributes to relapse after autologous bone marrow transplantation (AuBMT) for acute leukemia, transplanted marrow was marked with the G1N retroviral vector (Genetic Therapy Inc.) containing the neomycin phosphotransferase gene (neo). Between April 1992 and August 1993, 4 patients were transplanted for acute myeloid leukemia (AML) in second complete remission (CR) and 1 patient for acute lymphoid leukemia in first CR. An average of 12.4% (range 5-19%) of transplanted marrow mononuclear cells were exposed to G1N vector for 4 hr. In the vector-treated portion of the marrow, 4.9% of GM-CFU and 3.6% of erythroid burst-forming units (BFU-E) were resistant to G418 in vitro. In the 5 patients, the polymerase chain reaction (PCR) detected the neo sequence on only two occasions after AuBMT. Of 4 patients surviving 1 year after transplantation, only 1 had evidence of gene marked cells by PCR. Two AML patients have relapsed, one of whom had evidence of neo sequences in the bone marrow at day 100 but not at relapse 11 months after AuBMT. The second patient relapsed 18 months after AuBMT but never had PCR evidence of neo sequences before or after relapse. Our results indicate vector-transduced autologous bone marrow from heavily pretreated adults with acute leukemia mark with low efficiency, although vector sequences have been detected in bone marrow and peripheral blood up to 1 year after transplant. Of the 2 relapsed patients, no evidence of vector-marked leukemic blasts have been detected.

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.

Tandem autotransplantation for the treatment of metastatic breast cancer.

PURPOSE: To investigate the tolerability and impact on progression-free and overall survival of two consecutive cycles of high-dose chemotherapy (HDC) with autologous bone marrow transplantation (ABMT) in patients with previously untreated metastatic breast cancer. PATIENTS AND METHODS: Twenty-eight patients received conventional-dose induction therapy (ITx) followed by a planned two cycles of HDC with ABMT. Median age was 45 years (range, 34 to 60 years). Sites of disease were bone (seven patients), visceral (three), soft tissue (11), multiple (six), and CNS (one). The ITx regimens of cyclophosphamide, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), methotrexate, fluorouracil, prednisone, and tamoxifen (CAMFTP) (three patients); fluorouracil, doxorubicin, and cyclophosphamide (FAC; 11 patients); cyclophosphamide, methotrexate, and fluorouracil (CMF; four patients); or doxorubicin or mitoxantrone/cyclophosphamide (10 patients) were given to maximum response (three to five cycles). HDC was cyclophosphamide 6 g/m2, carboplatin 2 g/m2, and etoposide 625 mg/m2 with ABMT. RESULTS: Of 28 patients, 24 received two (86%) cycles of HDC. Four received only one cycle due to persistent toxicity from course 1 (one patient), no response to course 1 (two), and death on course 1 (one). Grade 3 to 4 nonhematologic toxicities included mucositis (in one or both cycles in 21 of 28 patients; 75%), diarrhea, nausea, and vomiting. Reversible peripheral neuropathy was seen in 15 of 28 patients and was severe in one. Documented infections were seen in 19 of 52 cycles. There was one transplant-related death. Six patients were converted from partial remission (PR) to complete remission (CR) with HDC; two of 24 patients (8%) were converted from PR to CR with the second cycle of HDC. Progression-free survival rate is nine of 28 patients (32%) with median follow-up of 23 months (range, 13 to 36+ months). Eighteen of 28 patients (64%) have progressed at 1 to 17 months from ABMT. CONCLUSION: Two cycles of HDC with ABMT was well tolerated with a high response rate in patients with metastatic breast cancer. The importance of the second cycle of HDC in this population is unclear.

A phase II trial of edatrexate in previously treated ovarian cancer. A Gynecologic Oncology Group study.

Twenty-two patients with recurrent ovarian cancer were entered into a Phase II trial of edatrexate at a dose of 80 mg/m2 i.v. weekly for five consecutive weeks. One patient received an inadequate trial, and six did not complete one cycle due to adverse effects. There were 21 patients evaluable for toxicity and 15 for response. There were no objective responses, 10/15 (67%) had stable disease, 5/15 (33%) increasing disease. Toxicity was predominantly stomatitis and hematologic. Two patients developed skin rashes, and one experienced pulmonary toxicity felt to be related to the drug. Edatrexate administered in this dose and schedule has no demonstrated activity, but moderately severe toxicity in patients with previously treated advanced ovarian cancer.

Autologous bone marrow transplantation.

Autologous bone marrow transplantation has become a very popular and successful treatment for many patients with lymphomas and other malignancies. The current indications, pretreatment regimes, and laboratory manipulations are discussed as well as the application of gene transfer to eliminate selected genetic diseases and detect disease relapse.

Salvage therapy for recurrent and refractory ovarian cancer with high-dose chemotherapy and autologous bone marrow support: a Gynecologic Oncology Group pilot study.

Nine patients with recurrent or refractory epithelial ovarian carcinoma following previous chemotherapy were treated with high-dose carboplatin (300 mg/m2) and ifosfamide according to a dose escalation schedule (1.50, 1.75, 2.00 g/m2), each given intravenously daily for 5 days with autologous bone marrow support. Eight of the nine patients were evaluable for response. Five achieved complete response (CR), all of whom relapsed at 4, 5, 6, 8, and 23 months following treatment. Two partial responses persisted for 6 months, and one patient with stable disease progressed after 2 months and has since died of disease. The median duration of remission was 6 months. The treatment was well tolerated across the doses of ifosfamide with the exception of one treatment-related death which was due to acute renal failure and central nervous system toxicity from ifosfamide. It appears that the use of high-dose chemotherapy with autologous bone marrow support in the treatment of ovarian cancer produced a high rate of response of short duration in this small group of heavily pretreated women.

Early salvage therapy for germ cell cancer using high dose chemotherapy with autologous bone marrow support.

BACKGROUND: Patients with relapsed germ cell cancer (GCT) have a poor prognosis when treated solely with conventional chemotherapy; high dose chemotherapy with autologous bone marrow rescue (ABMR) has shown curative potential in patients with relapsed and refractory GCT. This protocol was designed to incorporate high dose therapy with initial salvage therapy. METHODS: Twenty-three patients in the first relapse of GCT received two cycles of conventional dose cisplatin-based therapy (either vinblastine, ifosfamide and cisplatin [VeIP] or cisplatin, vinblastine, and bleomycin) followed by carboplatin (1500-2100 mg/m2) and etoposide (1200-2250 mg/m2) given in divided doses with ABMR. RESULTS: Eighteen of 23 patients completed protocol therapy including high dose therapy. Five of 23 did not undergo high dose therapy due to: insurance refusal (1); patient refusal (1); active infection (1); central nervous system metastasis (1); death on induction therapy (1). Response to two courses of conventional dose induction therapy (N = 23) was complete response (CR), 8; partial response (PR), 12; stable disease (SD), 2; and toxic death, 1. Two of five individuals who did not continue with high dose therapy are alive and progression free after conventional salvage therapy and surgery with at least 24 months of follow-up. Outcome after high dose therapy (N = 18) was CR, 9, PR, 6, SD, 1, and PD, 2. Two patients who were in PR after receiving two cycles of conventional dose therapy were converted to CR using high dose therapy. There was only one treatment-related death in this cohort, a septic death during VeIP induction therapy. There were no transplant related deaths. Of those patients completing high dose therapy, 7 of 18 (39%) survived, progression free with a median follow-up of 26 months, 2 of 18 are alive with active disease, and 9 of 18 died of recurrent disease. CONCLUSIONS: Conventional dose induction therapy followed by consolidation with high dose therapy and ABMR is well tolerated and provides prolonged disease-free survival in some patients with chemosensitive relapsed germ cell cancer.