Pharmacokinetics of high-dose etoposide (VP-16-213) administered to cancer patients.

Plasma urine, and cerebrospinal fluid etoposide concentrations have been measured in 12 adult patients after administration of high-dose (400 to 800 mg/sq m) etoposide in order to determine the pharmacokinetics of this drug at these elevated dosages. Increasing the drug dosage produced proportionally higher peak plasma etoposide concentrations (27 to 114 micrograms/ml) and total areas under the concentration-time curve (9,200 to 48,000 micrograms/ml X min). The etoposide mean (+/- S.D.) terminal half-life of 8.05 +/- 4.3 hr and plasma clearance of 28.0 +/- 9.7 ml/min/sq m, however, were independent of the dosage given. The mean etoposide renal clearance in 5 patients was 10.0 +/- 4.3 ml/min/sq m, representing from 35 to 40% of the total clearance of this drug from plasma. Cerebrospinal fluid etoposide concentrations ranged from 0.1 to 1.4 micrograms/ml, as measured in 6 patients at 1 to 8 hr after high-dose etoposide therapy, and were 1.8 +/- 1.7% of the simultaneously measured plasma levels. Pleural fluid removed from one patient at 18 hr posttherapy contained etoposide at 1.8 micrograms/ml. Our data, combined with data published previously, indicate that the pharmacokinetics of high-dose etoposide is linear within the dosage range tested and similar to that seen with lower drug doses. They also suggest that etoposide penetrates poorly into the cerebrospinal fluid.

High-dose VP-16-213 monotherapy for refractory germinal malignancies: a phase II study.

VP-16-213 at standard dose is one of the more active agents for the treatment of germ cell tumors. In previous phase I studies, VP-16-213 has been investigated in suprastandard dose when hematopoietic reconstitution was assured by autologous bone marrow transplantation (ABMT). This phase II study was performed to explore the possibility that an augmented dose of VP-16-213 may be more active than standard dose against germ cell tumors. Eleven patients with progressive refractory germ cell tumors were treated with high-dose VP-16-213: 2,400 mg/m2 with ABMT every three to four weeks followed by 1,200 mg/m2 without ABMT. Seven patients had received VP-16-213 at standard dose prior to high-dose VP-16-213. Toxicity to high-dose VP-16-213 included severe myelosuppression, nausea, vomiting, alopecia, mucositis, and hepatitis. Of 10 evaluable patients, two complete responses and four partial responses, all of short duration, were obtained. However, some patients unresponsive to standard-dose VP-16-213 exhibited responses to the augmented-dose VP-16-213. Therefore, although more myelosuppressive, VP-16-213 may have increased activity against germ cell tumors when administered at augmented dose. High-dose VP-16-213 may be considered in designing new approaches for initial management of patients with germ cell tumors not expected to be cured with standard chemotherapy.

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

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

Etoposide kinetics in patients with obstructive jaundice.

The kinetics and urinary excretion of etoposide and etoposide glucuronide were determined in 11 patients with obstructive jaundice (bilirubin greater than 2.0 mg/dL) and in 23 patients with normal renal and hepatic function. Mean (+/- SE) measurements of clearance (24.5 +/- 2.06 v 26.5 +/- 2.05 mL/min/m2), half-life (5.7 +/- 0.5 v 6.4 +/- 0.5 hours), and volume of distribution (12.4 +/- 1.1 v 13.7 +/- 1.6 L/m2) were not significantly different in patients with jaundice when compared with controls. Similarly, etoposide kinetics in three patients determined during a period of hyperbilirubinemia were not different from measurements made in the same patients following resolution of their obstructive jaundice. In patients with jaundice, 46% of an administered etoposide dose was excreted in the urine as etoposide compared with 35% in controls (P = .15). Urinary excretion of etoposide glucuronide accounted for 29% of an administered etoposide dose in control patients and 15% in those with hepatic obstruction (P = .03). Biliary etoposide excretion measured in four patients with T-tubes was insignificant (less than 2.0% of an administered dose). The calculated renal clearance of etoposide was 11.5 mL/min/m2 in patients with jaundice and 10.4 mL/min/m2 in controls (P = .53). Respective metabolic clearance was 4.9 and 6.9 mL/min/m2 in these two study groups (P = .13). Although hepatic metabolism of etoposide may be slightly decreased in patients with obstructive jaundice, a modest increase in renal etoposide excretion appears to compensate for this change, so that total clearance is similar in the patients with jaundice when compared with controls. No etoposide dose reductions appear to be needed in treating patients with obstructive jaundice who have normal renal function.

Effective treatment of small-noncleaved-cell lymphoma with high-intensity, brief-duration chemotherapy.

Small-noncleaved-cell (SNC) lymphoma is a high-grade, biologically aggressive neoplasm notable for poor response to therapy, high relapse rate, and less than a 20% long-term survival. We treated 20 patients with SNC lymphoma with a novel chemotherapeutic regimen using intensive doses of chemotherapy at frequent intervals in the inpatient setting. All patients were previously untreated. Sixteen patients (80%) had stage IV disease. Most patients (95%) had at least one other characteristic associated with poor prognosis (bulky [greater than 10 cm] disease, multiple extranodal sites, poor performance status), and 85% had two or more characteristics associated with poor prognosis. Seventeen patients (85%) achieved a complete response (CR) to therapy, including all three patients with human immunodeficiency virus (HIV)-associated disease. There have been three relapses, all occurring less than 18 months after treatment, and two of three relapses occurred in patients who were unable to complete therapy. At a median follow-up of 29 months, 13 patients (65%) remain disease-free; the calculated 5-year actuarial disease-free survival is 60%. Toxicity, chiefly myelosuppression, was severe but manageable. There were two treatment-related deaths, both in elderly patients with poor performance status and advanced-stage disease. These data suggest that such a dose-intensive approach improves the response and survival of patients with SNC lymphoma.

Intensive 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) monochemotherapy and autologous marrow transplantation for malignant glioma.

Intensive monochemotherapy with carmustine (BCNU) (either 1,050, 1,200, or 1,350 mg/m2) and cryopreserved autologous marrow transplantation was administered to 36 patients with malignant glioma: 27 with progressive disease and nine without progression (adjuvant therapy group). Twelve (44%) of the patients with progressive disease responded; two remain disease free 84 and 60 months after BCNU treatment. In the adjuvant therapy group, three patients remain progression free at 70, 48, and 27 months after BCNU therapy. Tumor progression posttransplantation occurred in 25 patients; six others died of therapy-induced complications. In addition, late neurologic deterioration of unknown cause has developed in two surviving patients. Results from this and other series using intensive BCNU monochemotherapy and autologous marrow transplantation for progressive malignant glioma indicate that prolonged progression-free survival can be produced in an occasional patient, an extremely unusual result with conventional chemotherapy. Although intensive BCNU and autologous marrow transplant regimens are toxic, these results are encouraging. The treatment of patients in an adjuvant fashion with BCNU and other active agents may produce improved results.

Effective therapy for poor-prognosis non-Hodgkin's lymphoma with 8 weeks of high-dose-intensity combination chemotherapy.

PURPOSE: Despite substantial advances in the treatment of aggressive non-Hodgkin's lymphoma, therapeutic results with conventional regimens remain poor in some subsets of patients. In an attempt to improve the prognosis of such patients we used an 8-week, multidrug chemotherapy regimen of high dose-intensity. PATIENTS AND METHODS: Between April 1986 and April 1991, 70 patients with advanced intermediate- or high-grade non-Hodgkin's lymphoma were treated. The median age was 41 years (range, 18 to 69). Fifty-one patients (73%) had stage IV disease; 37 (53%) were Shipp's category 3; 17 (24%) had small noncleaved-cell lymphoma; 35 (50%) had Eastern Cooperative Oncology Group (ECOG) performance status > or = 2; 24 (34%) had two or more extranodal sites involved; and 17 (24%) had bone marrow involvement. The 8-week regimen included cyclophosphamide, etoposide, doxorubicin, vincristine, bleomycin, methotrexate with leucovorin rescue, and prednisone. RESULTS: Sixty-two of 70 patients completed the regimen as planned. Fifty-seven patients (81%) obtained a complete response (CR) and the actuarial 5-year failure-free survival rate is 52%. Thirty-seven patients remain alive and disease-free a median of 35 months (range, 7 to 68) after therapy. Adverse prognostic factors included age more than 50 years, bone marrow involvement, and serum lactic dehydrogenase (LDH) more than 500 IU/L (normal range, 125 to 250). Myelosuppression was responsible for most of the treatment-related toxicity. Severe leukopenia (< 1,000/microL) occurred in all patients and lasted a median of 9 days. Seven patients (10%) died of myelosuppression-related complications; five of these patients were older than 60 years. CONCLUSION: This brief but intensive therapy was effective in treating poor-prognosis patients with non-Hodgkin's lymphoma. With this therapy, patients with small noncleaved-cell lymphoma or Shipp's category 3 disease had treatment outcome similar to the group as a whole. This therapy was not well tolerated by patients older than 60 years, and should not be given to this subgroup. Verification of these results in a randomized trial setting is indicated.

Clinical features of 31 patients with Ki-1 anaplastic large-cell lymphoma.

Thirty-one patients were diagnosed by morphologic and immunophenotypic features as having primary Ki-1 anaplastic large-cell lymphoma (Ki-1 ALCL). the median age was 35 years (range, 4 months to 78 years); the male:female ratio was 18:13. B symptoms were observed in 13 patients. Peripheral adenopathy was present in 26 patients, while mediastinal adenopathy occurred in five. There was extranodal disease in 13 patients; the most common extranodal site was skin with seven affected. Seventeen patients had stage III/IV disease. Immunophenotypes were T cell in 24 patients and B cell in four patients; immunophenotype could not be determined in three patients. Cytogenetic abnormalities in chromosomes 2, 5, and 7 were detected in three patients. Although therapy was heterogeneous, the actuarial 2-year survival was 73%. Two-year disease-free survival was 39% for all patients; for stages I and II, it was 62% compared with 20% for stages III and IV (P = .001). Complete remission (CR) occurred in 21 of 23 patients receiving combination chemotherapy; however, nine relapses, including six of seven stage IV patients, occurred within 21 months of diagnosis. Preliminary observations suggest that Ki-1 ALCL may have a quiescent phase in the rare patient with only localized skin disease. However, the disease generally behaves as an intermediate- to high-grade lymphoma, and patients with Ki-1 ALCL should receive curative-intent combination chemotherapy.

High-dose induction chemotherapy with cyclophosphamide, etoposide, and cisplatin for extensive-stage small-cell lung cancer.

To exploit possible dose-response and combination drug synergism, 20 previously untreated patients with extensive-stage small-cell lung cancer (SCLC) received one or two courses of high-dose induction chemotherapy consisting of cyclophosphamide (100 mg/kg), etoposide (1,200 mg/m2), and cisplatin (120 mg/m2) (HDCEP). HDCEP was followed by four cycles of standard-dose cyclophosphamide (1,000 mg/m2), doxorubicin (40 mg/m2), and vincristine (1.4 mg/m2) (CAV). Response was determined after HDCEP and following CAV. Reevaluation included repeat bronchoscopy and chest computerized tomography (CT), as well as repetition of all initially abnormal studies. All patients were evaluable for response and toxicity. Overall response to HDCEP was 90%, with a complete response (CR) rate of 65% (95% confidence limits, 44% to 86%) and a partial response (PR) rate of 25% (95% confidence limits, 6% to 44%). All patients either maintained or improved their initial response while receiving CAV. Median duration of response was 6 months (range, 2 to 12 months) and median survival was 9.5 + months (range, 2 to 21 + months). All 37 courses of HDCEP were associated with leukopenia (less than 1,000/microL), 92% with thrombocytopenia (less than 20,000/microL), and 84% with fever of greater than 38.5 degrees C. Additional toxicities included bacteremia (24%), nausea and emesis (59%), mucositis (57%), diarrhea (38%), and hemorrhagic cystitis (5%). There were two treatment-related deaths due to infection. A third patient died 4 months after completing HDCEP with pulmonary fibrosis. Although response duration and median survival were not improved, HDCEP produced a high CR rate in ambulatory patients with extensive-stage SCLC.

High-dose thiotepa with autologous bone marrow transplantation for metastatic malignant melanoma: results of phase I and II studies of the North American Bone Marrow Transplantation Group.

We evaluated thiotepa in escalating dose in a broad phase I and II study using cryopreserved autologous bone marrow transplantation to assure hematopoietic recovery. Thiotepa was administered intravenously (IV) over two hours daily for three consecutive days followed in three to four days by marrow transplantation. The daily dose ranged from 60 to 525 mg/m2 (total dose, 180 to 1,575 mg/m2). A total of 71 patients with malignant melanoma were treated. Forty-three patients (61%) had received prior cytotoxic therapy and 28 were untreated. Sixty-two patients (87%) had melanoma disseminated to at least one visceral site, nine patients had skin and/or lymphatic metastases only. As of January 1, 1988 one patient was too early to be evaluated, 15 patients were inevaluable for tumor response, four patients had a complete response (CR), and 25 patients had a partial response (PR) to treatment. The response rates (95% confidence interval) for the 55 evaluable patients and for all 71 treated patients were 53% (40% to 65%) and 41% (30% to 53%), respectively. The median duration of response was 3 months, with a range of 1 to 31 + months. Three patients were alive and well without evidence of tumor more than 1 year after treatment. Analysis of patient subsets indicated that neither total dose, previous cytotoxic therapy, or sites of metastases influenced response rate. In this study, high-dose thiotepa has demonstrated a high response rate in patients with metastatic malignant melanoma with both PRs and CRs noted. Although most of the responses were not durable, 10% of the responses lasted more than 1 year. Future studies will evaluate additional methods for increasing the response rate and improving the duration of response.

Dose-intensive chemotherapy in refractory germ cell cancer--a phase I/II trial of high-dose carboplatin and etoposide with autologous bone marrow transplantation.

Between September 1986 and March 1988, 33 patients with refractory germ cell cancer were entered on a phase I/II trial of two courses of high-dose carboplatin plus etoposide with autologous bone marrow support. All patients had extensive prior treatment and had either cisplatin-refractory disease (67%) defined as progression within 4 weeks of the last cisplatin dose or failed at least two cisplatin-based regimens (35%) including a cisplatin-ifosfamide salvage regimen. Patients received a fixed total dose of etoposide of 1,200 mg/m2 with each cycle. The carboplatin dose ranged from 900 mg/m2 to 2,000 mg/m2. Twenty of the 33 patients received the second cycle of therapy. Despite extensive prior therapy with cisplatin, neurotoxicity, nephrotoxicity, or hearing impairment with high-dose carboplatin and etoposide was unusual. The most common nonhematologic toxicity was moderate enterocolitis. The hematologic toxicity of this regimen was substantial at each dose level. All 53 courses were accompanied by granulocytopenic fevers. Seven of the 33 patients (21%) died from treatment. All of these deaths occurred during the granulocyte nadir, and five were related to documented sepsis. Overall, 14 of 32 patients (44%) evaluable for response obtained an objective response, including eight complete remissions. Four patients remain in complete remission, with three patients being continuously free of disease in excess of 1 year. Eight responders (including four complete remissions) had progressed while receiving cisplatin. We conclude that carboplatin and etoposide can be administered in combination at high dosages and this regimen may have curative potential for patients with germ cell tumors resistant to conventional-dose cisplatin-based therapies.

T-cell-rich B-cell lymphomas: diagnosis and response to therapy of 44 patients.

PURPOSE: Clinicopathologic features of 44 patients with well-documented T-cell-rich B-cell lymphomas (TCRBCLs) were reviewed to determine if there were distinguishing clinical characteristics and to evaluate the responsiveness to therapy. PATIENTS AND METHODS: Forty-one patients had de novo TCRBCL, while three patients had a prior diagnosis of diffuse large B-cell lymphoma. Seventeen TCRBCLs were identified from a retrospective analysis of 176 lymphomas diagnosed before 1988 as peripheral T-cell lymphoma (PTCLs). The initial pathologic diagnosis was incorrect in 36 of 44 cases (82%), usually due to the absence of adequate immunophenotypic and/or genotypic studies at the initial study. RESULTS: The median age of patients was 53 years (range, 17 to 92), and the male-to-female ratio was 1.4:1. B symptoms were present in 22 of 41 patients (54%); splenomegaly was detected in 11 patients (25%). Clinical stage at diagnosis was as follows: I (n = 8), II (n = 6), III (n = 15), IV (n = 14), and unstaged (n = 1). Although therapy was heterogeneous, the disease-free survival (DFS) and overall survival (OS) rates at 3 years for patients with de novo TCRBCL were 29% and 46%, respectively. A complete response (CR) to combination chemotherapy for intermediate-grade lymphomas was observed in 16 of 26 patients (62%); 11 of these patients (42%) had a continuous CR, compared with one of 14 patients (7%) who received radiation therapy or therapy for low-grade lymphoma or Hodgkin's disease (HD) (P < .05). However, there was no difference in OS between patients who received chemotherapy for intermediate-grade lymphoma versus other therapies (49% v 48%) due to a high response rate to salvage therapies, including seven patients without disease after marrow transplantation. CONCLUSION: TCRBCLs are difficult to recognize without immunoperoxidase studies. Patients with TCRBCL have clinical features similar to patients with other large B-cell lymphomas, except they may have more splenomegaly and advanced-stage disease; they should receive combination chemotherapy directed at large-cell lymphomas.

Extensive-stage small-cell bronchogenic carcinoma: intensive induction chemotherapy with high-dose cyclophosphamide plus high-dose etoposide.

Seventeen ambulatory patients with extensive-stage small-cell lung cancer received one or two courses of high-dose induction chemotherapy consisting of cyclophosphamide (100 mg/kg) plus etopside (1,200 mg/m2) followed by four or five cycles of conventional-dose cyclophosphamide (1,000 mg/m2), doxorubicin (40 mg/m2), and vincristine (1.4 mg/m2) (CAV) given every 21 days. No additional chemotherapy was given until relapse or progression was documented. Response was assessed initially after high-dose induction therapy and again after completion of all chemotherapy. After induction therapy, 16/17 (94%) patients had achieved an objective response, including five (29%) complete responses and 11 (65%) partial responses. Two partially responding patients improved to a complete response after CAV, while one partial responder progressed and one patient died of an intercurrent illness while receiving CAV. Thus, the overall response after completing all chemotherapy was 15/16 (94%), including seven (44%) complete responses and eight (50%) partial responses. Median response duration was six months (range, 3 to 11 months), and overall median survival was ten months (range, 2 to 17 months). All 31 courses of induction therapy were associated with leukopenia (less than 1,000/microL), 81% with thrombocytopenia (less than 20,000/microL), and 77% with fever (greater than 38.5 degrees C). Seven episodes of bacteremia and one axillary abscess were documented, and there was one treatment-related death (6%). These toxicities are similar to that produced by high-dose etoposide alone. High-dose cyclophosphamide combined with high-dose etoposide can be administered to ambulatory patients with extensive-stage small-cell lung cancer without requiring bone marrow transplantation to reestablish hematopoiesis. Complete response and median survival rates, however, are similar to those obtained with less intensive therapy.

High-dose VP-16-213 and autologous bone marrow transplantation for refractory malignancies: a phase I study.

VP-16-213, a congener of epipodophyllotoxin, is a useful chemotherapeutic agent especially against small-cell carcinoma of the lung, germ cell carcinoma, and lymphoma. The standard dose of this drug is limited by myelosuppression. Autologous transplantation of cryopreserved bone marrow assures the restoration of hematopoiesis after marrow ablative cytotoxic therapy. By using this technique, VP-16-213 was dose-escalated using a Fibonacci scheme from the previous highest dose administered to humans (1,500 mg/m2) to 2,700 mg/m2 (900 mg/m2 per day for three consecutive days). At 2,700 mg/m2, severe extramedullary toxicity of the mucous membranes was observed in three of three courses. At the next highest dose (2,400 mg/m2), two of 18 courses (11%, p less than 0.01) resulted in severe mucositis, thus defining this dose as the maximally tolerated dose based on extramedullary toxicities. As anticipated, myelotoxicity was severe but based on the kinetics of marrow recovery, VP-16-213 in these doses appeared not to be marrow ablative. Based on responses observed in this study, high-dose VP-16-213 should be explored in phase II studies or used in combination chemotherapy.

Intensive melphalan chemotherapy and cryopreserved autologous bone marrow transplantation for the treatment of refractory cancer.

Thirty-three adult and pediatric patients with refractory malignancies were treated with escalating doses of melphalan (120-225 mg/m2 IV over 3 days) followed by reinfusion of previously harvested and cryopreserved autologous marrow. The hematological and nonhematological toxicities and the therapeutic effects of this regimen were evaluated. Increasing doses of melphalan did not alter the rate of decline nor the recovery of peripheral blood counts. Granulocyte (greater than 500/microL) and platelet count (greater than 20,000/microL) recovery occurred in a median of 19 (range 12-54) and 24 (range: 12-54) days after bone marrow transplantation, respectively. Five patients experienced severe infection, three of which were fatal, and one patient died due to thrombocytopenic hemorrhage. Toxicity to the gastrointestinal system was dose limiting. The maximum tolerated dose of melphalan was 180 mg/m2; only three of 24 patients experienced severe stomatitis, esophagitis, and diarrhea at this level or less, while eight of nine patients at 225 mg/m2 were affected (p less than 0.005). Administration of cyclophosphamide (300 mg/m2 IV) 1 week before melphalan therapy did not reduce the incidence of severe gastrointestinal toxicity. Plasma melphalan concentration peaked 30-60 min after infusion (4.8-11.5 micrograms/mL) but declined rapidly. Cerebrospinal fluid concentration was 10% of the corresponding plasma concentration and was undetectable at 3 hours. Antitumor responses occurred in nine of 13 patients with malignant melanoma (five complete and four partial remissions), and ranged 2-12+ months with a median of 5 months. Four of six neuroblastomas demonstrated responses (three complete and one partial remission( lasting a median of 7.5 (range: 5-10) months. Other tumors in which this regimen had activity included breast cancer and Ewing's sarcoma. The overall response rate for the 33 patients was 30% complete remissions (10 patients) and 21% partial remissions (seven patients). High dose melphalan and autologous bone marrow transplantation is a promising therapy for patients with malignancies for which no effective treatment is known or for patients whose cancer is refractory to conventional therapeutic agents.

Cerebellar toxicity with high-dose cytosine arabinoside.

CNS dysfunction, especially impaired cerebellar function, is the dose-limiting toxicity associated with high-dose cytosine arabinoside, which precludes doses of greater than 48 g/m2. Four hundred eighteen patients between the ages of 2 and 74 years with leukemia or lymphoma received 36 to 48 g/m2 cytosine arabinoside either alone or with anthracycline antibiotics, 4'-(9-acridinylamino) methane sulfon-m-anisidine (m-AMSA), or total body irradiation. In only 35 of 418 patients (8%) did severe cerebellar toxicity develop; it was irreversible or fatal in four (1%) patients. The age of the patient was a critical factor in the incidence of severe cerebellar toxicity. Patients greater than 50 years old had a statistically significant greater incidence of cerebellar toxicity compared with younger patients (26/137, 19%, v 9/281, 3%; P less than .0005, chi 2). Neither the diagnosis, disease status, sex, nor the regimen altered the incidence of severe cerebellar toxicity (when corrected for age). A second course of high-dose cytosine arabinoside, administered to 62 patients, did not increase the incidence of severe cerebellar toxicity, which occurred in five (8%) of these patients. Two of the five patients had severe toxicity with the initial course. Of the 60 patients with no antecedent cerebellar dysfunction, three (5%) had severe toxicity with the second course: one of 41 patients were less than 50 years old; two of 19 patients were greater than or equal to 50 years. Since the occurrence of severe cerebellar dysfunction is greatly affected by age, reduced doses of high-dose cytosine arabinoside should be given to patients greater than 50 years old, and methods for reducing the cerebellar toxicity should be investigated in these patients.

Allogeneic marrow transplantation for refractory Hodgkin's disease.

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

High-dose cytarabine and daunorubicin as consolidation therapy for acute myeloid leukemia in first remission: long-term follow-up and results.

In an effort to increase the proportion of patients with acute myeloid leukemia (AML) remaining in continued complete remission (CCR), we administered intensive postremission consolidation therapy with high-dose cytarabine (Ara-C) and daunorubicin. Eighty-seven patients, with a median age of 38 years (range, 7 to 71), received consolidation therapy after first complete remission was obtained with standard induction chemotherapy that included conventional doses of Ara-C. Consolidation therapy consisted of from one to three cycles of high-dose Ara-C (3 g/m2 intravenously [IV] over 1 hour every 12 hours for 12 doses) followed by daunorubicin (30 mg/m2/d IV bolus for 3 days). After completion of the high-dose Ara-C and daunorubicin, no further therapy was administered. Myelosuppression encountered with consolidation resulted in a median duration of neutropenia and thrombocytopenia of 3 weeks. Four patients (5%) died during consolidation due to infection and/or hemorrhage; 59% of patients experienced severe but nonfatal infectious or extramedullary organ toxicity. With a median follow-up of more than 3.5 years from diagnosis, the proportion of patients, by Kaplan-Meier product-limit estimate, remaining in CCR is 49% (95% confidence limits, 37% to 61%). In a Cox multivariate analysis, only age significantly (P less than .001) influenced the probability of remaining in CCR. The probability of remaining in CCR was 83%, 50%, and 23% for age groups of 25 or less, 26 to 45, and more than 45 years, respectively. These survival curves all have stable long-term plateaus, suggesting cure. In this study, the administration of brief, intensive nonmarrow ablative chemotherapy resulted in a large proportion of patients with AML remaining in CCR, results similar to those reported with allogeneic bone marrow transplantation. Relapse of acute leukemia was still the major reason for therapy failure, suggesting that more effective or additional postremission therapy will be required to further improve the likelihood of cure especially for older patients.

Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation.

PURPOSE: Recipients of allogeneic bone marrow transplants (BMTs) who have relapsed may attain complete remissions when treated with transfusions of leukocytes obtained from the original bone marrow donor. We performed a retrospective study to characterize better this new treatment modality. PATIENTS AND METHODS: We surveyed 25 North American BMT programs regarding their use of donor leukocyte infusions (DLI). Detailed forms were used to gather data regarding the original BMT, relapse, DLI, response to DLI, complications of DLI, and long-term follow-up evaluation. Reports of 140 patients were thus available for analysis. RESULTS: Complete responses were observed in 60% (95% confidence interval [CI], 51.9% to 68.1%) of chronic myelogenous leukemia (CML) patients who received DLI and did not receive pre-DLI chemotherapy; response rates were higher in patients with cytogenetic and chronic-phase relapse (75.7%; 95% CI, 68.2% to 83.2%) than in patients with accelerated-phase (33.3%; 95% CI, 19.7% to 46.9%) or blastic-phase (16.7%; 95% CI, 1.9% to 31.9%) relapse. The actuarial probability of remaining in complete remission at 2 years was 89.6%. Complete remission rates in acute myelogenous leukemia (AML) (n = 39) and acute lymphocytic leukemia (ALL) (n = 11) patients who had not received pre-DLI chemotherapy were 15.4% (95% CI, 9.6% to 21.2%) and 18.2% (95% CI, 6.6% to 29.8%), respectively. Complete remissions were also observed in two of four assessable myeloma patients and two of five assessable myelodysplasia patients. Complications of DLI included acute graft-versus-host disease (GVHD) (60%; 95% CI, 51.4% to 68.6%), chronic GVHD (60.7%; 95% CI, 50.3% to 71.1%), and pancytopenia (18.6%; 95% CI, 12.2% to 25.0%). Pre-DLI characteristics predictive of complete response in CML patients were post-BMT chronic GVHD, pre-DLI disease status of chronic phase, and time interval between BMT to DLI less than 2 years. Acute and chronic GVHD post-DLI were highly correlated with disease response (P < .00001). CONCLUSION: DLI results in complete remissions in a high percentage of patients with relapsed chronic-phase CML. Complete remissions are observed less frequently in patients with advanced CML and acute leukemia. GVHD and pancytopenia occur commonly; GVHD is highly correlated with response.

Intensive 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) autologous bone marrow transplantation therapy of refractory cancer: a preliminary report.

Eighteen patients with refractory malignancies were treated with escalating doses of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and autologous bone marrow transplants (BMTX). Hematopoietic recovery was similar with doses of 300mg/m2qd X 3 and 500mg/m2qd X 3 providing suggestive evidence of a myeloprotective effect of the BMTX. Extramedullary toxicity was sporadic but occasionally severe; pulmonary fibrosis and severe cholestatic jaundice were seen in one case each. Antitumor responses were noted in patients with brain tumors, melanoma, hematological neoplasms and lung cancer.