Analysis of prognostic factors for the outcome of marrow transplantation or further chemotherapy for patients with acute nonlymphocytic leukemia in first remission.

To test whether variables at diagnosis can identify patients with acute nonlymphoblastic leukemia (ANL) for whom bone marrow transplantation (BMT) is more likely to be of benefit and those for whom continued chemotherapy is a better approach, the association of 15 clinical and laboratory factors with outcome was investigated among 220 patients (ages 1 to 53 years) treated with cyclophosphamide and total body irradiation (TBI) followed by allogeneic BMT, and among 392 patients (ages 13 to 50) administered intensive chemotherapy. In the BMT group, female sex, younger age, the absence of hepatitis during induction, a larger percentage of circulating blasts, and a shorter duration of symptoms were associated with longer survival, whereas only female sex and younger age favorably influenced disease-free survival (DFS). In the chemotherapy group, younger age, lower WBC at diagnosis, a single successful induction course, and the absence of circulating promyelocytes were associated with longer survival, whereas only a lower WBC and a lower percentage of peripheral neutrophils were associated with longer DFS. Estimated regression coefficients for treatment-by-prognostic-factor interactions were used to characterize subgroups of patients in which one treatment or the other produced better outcomes. BMT and chemotherapy produced similar durations of survival in a subset of patients characterized by many or all of the following: older age, male sex, achievement of complete remission (CR) after one induction, and absence of circulating blast cells at presentation. These data suggest that, using pretreatment variables, subgroups of patients can be identified for whom either BMT or continued chemotherapy is most likely to be beneficial.

High rate of long-term survival in adult acute leukemia following ten-day chemotherapy (OAP) induction. Maintenance with chemotherapy or chemotherapy plus BCG vaccine.

In this Southwest Oncology Group (SWOG) study, 216 adults with acute leukemia were treated with ten-day chemotherapy consisting of vincristine sulfate (Oncovin), cytarabine (ara-C) (100 mg per square meter of body area per day by 24-hour infusion), and prednisone (ten-day OAP). The results were compared with those of a previous SWOG study in which cytarabine (200 mg per square meter of body area per day) was given for five days (five-day OAP). Patients entering complete remission (CR) were given three consolidation courses of five-day OAP and randomized to maintenance chemotherapy alone (32 patients) or combined with BCG vaccine (24 patients). For 160 previously untreated patients with acute myelogenous leukemia, there was no difference in remission rates (53% vs 43%) or median survival times (48 vs 47 weeks) between ten-day and five-day OAP. The difference in duration of CR (74 vs 54 weeks, respectively) between the two maintenance arms was not statistically significant. However, 14% of evaluable patients with acute myelogenous leukemia and 26% of those achieving CR were alive and in remission more than five years.

Chemotherapy of acute leukemia: a comparison of vincristine, cytarabine, and prednisone alone and in combination with cyclophosphamide or daunorubicin.

Adults (274) with acute leukemia (AML) were randomly assigned to one of three treatment regimens: vincristine, prednisone, cytarabine--(1) 100 mg/sq m/day with cyclophosphamide (COAP); (2) 100 mg/sq m/day with daunorubicin (DOAP); and 200 mg/sq m/day (OAP). Cytarabine was infused continuously for five days. Patients entering complete remission randomly received maintenance treatment with COAP or OAP. For 197 previously untreated AML patients given COAP, DOAP, or OAP, remission rates were 37%, 35%, and 43%, respectively; median lengths, 40, 45, and 90 weeks; median survival, 7, 11, and 8 weeks. No statistically significant difference was found among treatments. Therefore, adding cyclophosphamide or daunorubicin, or using the COAP regimen with continuously infused cytarabine, produced no significant improvement over previously reported regimens. There was no significant difference in remission lengths in previously untreated AML patients maintained on OAP (median 81 weeks) or COAP (median 65 weeks).

Treatment of severe aplastic anemia with antithymocyte globulin.

Eleven patients with acute-onset (less than 2 months), severe aplastic anemia were treated with antithymocyte globulin (ATG) at a total dose between 50 and 420 mg/kg. Median age was 27 (5-74) years. Two additional patients with chronic severe aplastic anemia received ATG but were excluded from analysis after development of bone marrow morphologic and cytogenetic abnormalities suggestive of acute leukemia. Of the 11 analyzed patients, 5 died within 6 months after initial ATG treatment. Six patients, or 54 percent, survived with a minimum follow-up of 24 months and the longest 48 months. Median survival is 42 months. All patients are transfusion-independent although none are completely normal, due to mild thrombocytopenia. The in vitro effect of ATG on pretreatment marrow CFUE was determined in 8 patients and concordance with clinical outcome was observed for only 3 patients. Three patients had no in vitro response and survived, and 2 patients had a positive in vitro response and died. Survival after ATG correlated with maximum percent decrease in absolute lymphocyte count during treatment. No significant correlation was determined for any other parameter. The mechanism of ATG action remains unknown but the clinical response suggests that immune dysfunction may play an important role in the development or prolongation of aplastic anemia, and that this abnormality may be reversible by ATG in some patients.

SPLEEN/PATHOL.

Lymphocyte subpopulations were studied in the peripheral blood, lymph nodes, and spleens in a group of 17 patients with untreated Hodgkin's disease. In 12 of 15 cases, diminished absolute levels of T-lymphocytes in the peripheral blood were found; however, this was correlated with total lymphopenia. No direct relationship between "T-lymphopenia" and diminished cellular immunity, as measured by phytohemagglutinin and pokeweed mitogen blast transformation, and delayed cutaneous hypersensitivity was demonstrated. In eight lymph nodes involved histologically by Hodgkin's disease, a preponderance of T-lymphocytes was found when compared with a group of seven hyperplastic nodes (78.2 +/- 8.9% versus 54.5 +/- 11.0%, P is less than 0.01). These latter data appear to be consistent with the hypothesis that the pathogenesis of Hodgkin's disease involves a cell-mediated immune response to a neoplastic (antigenic) element.

VP16-213, cisplatinum, and adriamycin salvage therapy of refractory and/or recurrent nonseminomatous germ cell neoplasms.

Eleven patients with recurrent and/or resistant nonseminomatous germinal cell neoplasms refractory to conventional chemotherapy were treated with the combination. VP16-213, cis-diamminedichloroplatinum, and adriamycin. One complete response, four partial responses which at surgery were benign teratomas, and six partial responses have been observed. Four patients are prolonged survivors (greater than 18 months). The possibility that this regimen may offer true salvage for refractory patients exists. Incorporation of VP16-213 into initial treatment regimens for germinal cell neoplasms is warranted.

Intermittent regional infusion of chemotherapy for pancreatic adenocarcinoma. Phase I and II pilot study.

Nineteen patients with unresectable and metastatic adenocarcinoma of the pancreas and ampulla of Vater were treated with intermittent regional infusion of the celiac axis (CAI) with the combination of 5-fluorouracil, adriamycin, mitomycin-C, and streptozotocin (FAM-S). Three schedules with escalating doses were investigated. The arterial infusion was repeated at 4 weeks, and in responding and stable patients, I.V. FAM-S was continued at monthly intervals. Twelve patients had measurable disease, and in this group one complete response and seven partial responses occurred. Median duration of response was 6+ months and median survival for all patients was 5.2 months. Four patients had catheter-related complications (emboli, three, sepsis, one). Hematologic and gastrointestinal toxicity was minimal. Celiac artery infusion with FAM-S in locally extensive and metastatic adenocarcinoma of the pancreas and ampulla of Vater is a relatively simple procedure associated with low incidence of serious complications and toxicity but a higher response rate than previously reported. Induction of response with CAI and subsequent maintenance therapy with intravenous chemotherapy is under investigation.

Phase II trial of dianhydrogalactitol in metastatic malignant melanoma: a Southwest Oncology Group study.

Dianhydrogalactitol given iv in a schedule of 30 mg/m2/day for 5 consecutive days every 4 weeks was administered to 27 patients with metastatic malignant melanoma. All patients had received extensive prior therapy including chemotherapy and had progressive disease at the start of the study. Of 24 patients evaluable for response, 21 demonstrated progressive disease and three had stable disease for periods of from 4 to 11 months. No objective responses were observed. Two of the remaining three patients died 6 and 10 days after entry in the study, while the third refused to return after one drug course. Adverse effects included myelosuppression in eight patients, nausea and vomiting in five patients, and alopecia in one patient. Dianhydrogalactitol is considered to be insignificantly active in the secondary treatment of metastatic malignant melanoma at the dose and schedule studied.

Plasmapheresis in the treatment of thrombotic thrombocytopenic purpura.

Two patients with thrombotic thrombocytopenic purpura (TTP) have recovered completely after intensive plasmapheresis. The mechanisms responsible for the improvement in these instances are most likely related to the removal of an inciting or damaging agent. The possibility that this agent may be an immune complex is discussed. Plasmapheresis appears to be useful therapy for some patients with this syndrome.

T and B lymphocytes in non-Hodgkin's lymphoma: a comparison of tumor-derived cells and peripheral blood lymphocytes.

T- and B-cell markers of lymphocytes in peripheral blood, involved node and spleen, PHA response of peripheral blood lymphocytes, serum immunoglobulin levels, and skin test reactivity to six common antigens were studied in 16 cases of untreated non-Hodgkin's lymphoma. Impaired response of peripheral lymphocytes to PHA was observed in 13 of 16 cases, regardless of the proportion of T lymphocytes. Of 12 cases in which skin tests were done, two were positive and had a normal PHA response, seven cases were positive in spite of low PHA response, and three were negative with low PHA response. In the lymph nodes from involved areas two cases showed monoclonal increase of B-cells, five showed "null" cell increase, and the remaining nine showed no increase or decrease of subpopulation of lymphocytes. No correlation with surface marker of lymphocytes to histologic classification was seen. From the above observations it was concluded: 1) a low PHA response in non-Hodgkin's lymphoma was not due to the decreased population of T-cells; 2) a low PHA response may not necessarily indicate impaired delayed hypersensitivity; and 3) non-Hodgkin's lymphoma can be classified in the following ways--B-cell proliferative type, "null" cell increase type, and normal T/B proportion type.

High dose BCNU with autologous bone marrow rescue in the treatment of recurrent malignant gliomas.

Eleven patients with malignant gliomas recurring after surgery and radiation therapy, were treated with high dose BCNU 1 050-1 200 mg/M2 with autologous bone marrow rescue. Four patients also received concomitant 5-fluorouracil 1 000 mg/M2/24 hr daily for three days. Eight of ten evaluable patients demonstrated improvement on CAT scan as well as a decrease in steroid requirement. All patients surviving longer than two weeks after BCNU administration experienced full hematologic recovery. No delayed myelosuppression was seen after a single course of high dose therapy. Two patients died as a result of therapy, one following a second induction of BCNU for a total cumulative BCNU dose of 2 400 mg/M2 and one of infection while cytopenic. Additional toxicity includes one steroid-responsive interstitial pneumonitis, one centrilobular necrosis of the liver which spontaneously resolved and one episode of deep vein thrombosis. With limitation on the maximum BCNU dose and distribution of the total dose over three days, high dose BCNU can be administered with acceptable toxicity. This approach may offer a higher response rate than that expected for standard dose BCNU.

Fluctuation of serum phenytoin concentrations during autologous bone marrow transplant for primary central nervous system tumors.

We reviewed our experience for adult patients receiving oral anticonvulsant therapy during high-dose chemotherapy and autologous bone marrow re-infusion for primary malignant tumors of the central nervous system. Nineteen patients received either iv carmustine (BCNU) 900-1050 mg/m2 and 6120 cGy cranial irradiation (N = 10), iv carmustine 900-1050 mg/m2 and iv cisplatin 200 mg/m2 (N = 8), or iv carmustine 600 mg/m2, iv cisplatin 200 mg/m2, and iv etoposide 2400 mg/m2 (N = 1). Anticonvulsant therapy consisted of phenytoin alone (N = 8), phenobarbital alone (N = 4), carbamazepine alone (N = 2), phenytoin and carbamazepine (N = 2), carbamazepine and phenobarbital (N = 1), and no anticonvulsant therapy (N = 2). Serum anticonvulsant concentrations were monitored frequently and doses adjusted to keep values in the therapeutic range. While phenobarbital and carbamazepine doses remained relatively stable, all patients required increased doses of phenytoin anticonvulsant therapy after beginning chemotherapy (mean onset 3.7 days after initiation of chemotherapy). The increase in phenytoin dose ranged from 50% to 300% above baseline (mean 134%). By the time of discharge from the hospital (approximately 3-4 weeks after the start of chemotherapy) anticonvulsant dose was decreased to near pre-therapy levels. These swings coincided with the initiation of dexamethasone therapy for antiemetic effect and were more pronounced in patients also receiving cisplatin therapy. Due to close monitoring of serum phenytoin concentrations, no instances of toxicity due to excessive drug concentration, or seizures due to subtherapeutic doses, were noted in patients with primary CNS malignancies. Serum phenytoin concentrations fluctuate markedly during high-dose chemotherapy and must be analyzed frequently during the course of therapy.