Long-term survival in adult acute lymphoblastic leukemia: follow-up of a Southeastern Cancer Study Group trial.

Current observation was obtained for adults treated on a protocol for acute lymphoblastic leukemia, which was open from 1972 to 1978, in order to determine the long-term outcome and to evaluate potential prognostic factors. Long-term survival (five + years) was seen in 32% (25/79) of patients who achieved complete remission; 16/79 remain in first remission and 2/79 are currently in second remission. Young age (less than 40) and female sex were significant prognostic factors for long-term survival, but the basis for this advantage is unclear. Further improvements in chemotherapy are needed.

Randomized phase III comparison of three doxorubicin-based chemotherapy regimens in advanced non-small cell lung cancer: a Southeastern Cancer Study Group trial.

From 1978 to 1981, 537 patients with advanced non-small cell lung cancer were randomly assigned to three regimens containing cyclophosphamide and doxorubicin alone or in combination with methotrexate or cisplatin. Eligible patients had measurable disease and had no prior exposure to chemotherapy. Of the patients entered on the study, 505 were evaluable for toxicity and 488 were evaluable for response. The overall response rate (complete and partial responses) was only 9%. Response rates did not vary significantly with respect to treatment regimen, histologic subtypes, extent of disease, or performance status. There was no survival advantage for any regimen. The major toxicities were myelosuppression and nausea-vomiting. These doxorubicin-based chemotherapy regimens produced disappointing results in patients with advanced non-small cell lung cancer. A search for more active antitumor agents in lung cancer is necessary.

Randomized trial of cyclophosphamide plus cisplatin with or without doxorubicin in ovarian carcinoma: a Gynecologic Oncology Group Study.

A randomized clinical trial was conducted in women with stage III ovarian carcinoma (less than or equal to 1 cm residual lesions), using cyclophosphamide plus cisplatin (CP) with or without doxorubicin. There were 349 evaluable patients, of whom 176 received CP while 173 patients received CP plus doxorubicin (CAP). Hematologic toxicity was almost identical. There was no significant difference in progression-free interval (PFI) (median, 22.7 months and 24.6 months), frequency of negative second-look laparotomy (30.2% and 32.8%), or survival (median, 31.2 months and 38.9 months) between CP and CAP, respectively. Thus, doxorubicin in the dose schedule employed does not improve combination chemotherapy of optimal stage III ovarian carcinoma. Several other findings, independent of treatment arm, were of interest. There was a significant difference in PFI and survival by residual disease category (yes v no) and by grade of differentiation (1 v 2 + 3). In multivariate analysis, age, residual disease at entry, cell type (clear cell carcinoma), and time from surgery to initiation of chemotherapy were significant predictors of survival. There was no difference in outcome comparing those who refused second-look with those who had a second-look.

Long-term follow-up and prognostic factor analysis in advanced ovarian carcinoma: the Gynecologic Oncology Group experience.

Long-term follow-up was obtained on 726 women with advanced ovarian carcinoma (suboptimal stage III and stage IV) who had received primary chemotherapy on two Gynecologic Oncology Group (GOG) protocols between 1976 and 1982. The first study compared melphalan alone versus melphalan plus hexamethylmelamine versus cyclophosphamide plus doxorubicin (CA). The second study evaluated the same CA regimen with or without cisplatin. Eligibility for the two studies was the same. At last contact, 76 patients were alive. In a multivariate analysis, cell type other than clear cell or mucinous, cisplatin-based treatment, good performance status, younger age, lower stage, clinically nonmeasurable disease, smaller residual tumor volume, and absence of ascites were favorable characteristics for overall survival (P less than .05). Second-look laparotomy was negative significantly more often among those with endometrioid tumors; there were no negative second-look laparotomies among those with mucinous or clear cell tumors. There were 30 patients with suboptimal stage III disease who had a negative second-look laparotomy; 18 (60%) have experienced recurrence, and 13 (43%) have died. Although cisplatin treatment was beneficial, new treatments are clearly needed.

Combination chemotherapy with or without thoracic radiotherapy in limited-stage small-cell lung cancer: a randomized trial of the Southeastern Cancer Study Group.

PURPOSE: The primary objective of this randomized prospective study was to compare the survival of limited-stage small-cell lung cancer (SCLC) patients treated with chemotherapy alone or chemotherapy plus thoracic radiotherapy (TRT). A secondary objective was to determine the effect of consolidation chemotherapy on survival. PATIENTS AND METHODS: This multiinstitutional phase III study included 386 patients with limited-stage SCLC. All patients received cyclophosphamide 1,000 mg/m2, doxorubicin 40 mg/m2, and vincristine 1 mg/m2 (CAV) every 3 weeks for six cycles. Irradiated patients received 30 Gy in 10 fractions during weeks 1 and 2 of chemotherapy. Fifteen Gy in five fractions was administered during week 7 (total dose, 45 Gy). Following CAV, responding patients were randomized to receive two cycles of consolidation chemotherapy (cisplatin 20 mg/m2/d for 4 days plus etoposide 100 mg/m2/d for 4 days) or observation. RESULTS: Complete (46% and 38%; P = .14) and overall response rates (67% and 64%; P = .58) were not statistically significantly different. Although not significantly different, median (14.4 v 12.8 months) and 2-year survival (33% v 23.5%) rates favored the irradiated patients. Grade 4 hematologic toxicity was greater in irradiated patients (60% and 39%; P < .001). Patients given consolidation chemotherapy experienced superior median (21.1 v 13.2 months; P = .028) and 2-year survival (44% v 26%; P = .028) rates. CONCLUSION: The concurrent use of TRT and CAV chemotherapy as administered in this study failed to improve the survival of limited-stage SCLC patients compared with CAV alone. Life-threatening hematologic toxicities were more frequent with combined-modality therapy. The survival of limited-stage patients treated with CAV (with or without TRT) was improved with two cycles of cisplatin and etoposide consolidation therapy. Whether similar survival results could be achieved with cisplatin and etoposide alone requires additional study.

Preliminary analysis of the behavior of stage I ovarian serous tumors of low malignant potential: a Gynecologic Oncology Group study.

PURPOSE: From December 1983 through February 1992, a prospective study designed to determine the clinical course of patients with ovarian tumors of low malignant potential (LMP) was conducted by the Gynecologic Oncology Group (GOG). MATERIALS AND METHODS: This protocol was developed to evaluate the following (1) the biologic behavior of ovarian LMP tumors, (2) the effectiveness of melphalan chemotherapy in patients with clinically detectable residual disease after surgical staging and in patients whose tumors progress or recur after surgical therapy, and (3) the response rate to cisplatin in those who failed to respond to melphalan therapy. The study group consisted of 146 assessable patients with stage I serous LMP tumors. All of these women had the affected ovary (or ovaries) removed, and a complete staging operation was performed in each case. While 123 patients had a total abdominal hysterectomy (TAH) and bilateral salpingo-oophorectomy (BSO), 21 retained the uterus and one normal-appearing ovary and fallopian tube. No adjuvant chemotherapy or radiation therapy was administered to any patients in the stage I study group. RESULTS: The median follow-up time was 42.4 months (range, 1.6 to 108). Thus far, no patient with a stage I ovarian serous LMP tumor has developed recurrent disease. CONCLUSION: Stage I ovarian serous LMP tumors rarely, if ever, recur. Limited resection, after meticulous surgical exploration, is adequate therapy for women of reproductive age.

A phase III trial comparing idarubicin and daunorubicin in combination with cytarabine in acute myelogenous leukemia: a Southeastern Cancer Study Group Study.

PURPOSE: A randomized clinical trial was undertaken to compare the therapeutic effectiveness of idarubicin (IDR) to daunorubicin (DNR), and both were given in combination with cytarabine (CA) in acute myelogenous leukemic (AML) patients. PATIENTS AND METHODS: Newly diagnosed patients were given a daily infusion of CA (100 mg/m2) for 7 days and were assigned randomly to receive DNR (45 mg/m2) or IDR (12 mg/m2) daily for the first 3 days. Those patients who achieved a complete remission (CR) were given three consolidation courses that consisted of CA (100 mg/m2 intravenously [IV]) and thioguanine (TG; 100 mg/m2 orally) every 12 hours for 5 days and either DNR (50 mg/m2) or IDR (15 mg/m2) on the first day of each cycle. After consolidation, patients received late intensification, which consisted of the same drugs used for induction except that the CA was given for 5 days and the anthracycline for 2 days. Four courses were planned at 13-week intervals. RESULTS: The CR rates were 75 of 105 (71%) on the IDR arm and 65 of 113 (58%) on the DNR arm (P = .03). The median survival and median remission durations were 297 and 433 days, respectively, on the IDR arm. The median survival and median remission durations were 277 and 328 days, respectively, on the DNR arm. Six deaths occurred during late intensification, five on IDR and one on DNR; this approach was abandoned after 47 patients were entered. The median survival was significantly longer for patients who received late intensification. CONCLUSION: This trial demonstrated that IDR was more effective than DNR in remission induction in AML.

Randomized trial of cisplatin versus cisplatin plus mitolactol versus cisplatin plus ifosfamide in advanced squamous carcinoma of the cervix: a Gynecologic Oncology Group study.

PURPOSE: Cisplatin, mitolactol (dibromodulcitol), and ifosfamide have been the most active single agents in squamous carcinoma of the cervix identified so far by the Gynecologic Oncology Group (GOG). Combinations of cisplatin plus ifosfamide and cisplatin plus mitolactol are prospectively compared with cisplatin alone. PATIENTS AND METHODS: Patients were randomized to receive cisplatin 50 mg/m2 or the same dose of cisplatin plus mitolactol (C + M) 180 mg/m2 orally on days 2 to 6, or cisplatin plus ifosfamide (CIFX) 5 g/m2 given as a 24-hour infusion plus mesna 6 g/m2 during and for 12 hours after the ifosfamide infusion, every 3 weeks for up to six courses. Of 454 patients entered, 438 were eligible and analyzed for response and survival. RESULTS: CIFX had a higher response rate (31.1% v 17.8%, p = .004) and longer progression-free survival (PFS) time (P = .003) compared with cisplatin alone. The median times to progression or death were 4.6 and 3.2 months, respectively. C + M showed no significant improvement in these parameters compared with cisplatin alone. Survival was associated with initial performance score (PS; 0 was more favorable; P < .001) and with age (younger was unfavorable, P = .025). There was no significant difference in overall survival between cisplatin and either of the combinations. Leukopenia, renal toxicity, peripheral neurotoxicity, and CNS toxicity were more frequent with CIFX (P < .05). CONCLUSION: CIFX improved the response rate and PFS duration in advanced cervix cancer compared with cisplatin alone, but at the cost of greater toxicity and with no improvement in survival.

Randomized comparison of two combination regimens versus minimal chemotherapy in nonsmall-cell lung cancer: a Southeastern Cancer Study Group Trial.

Patients with advanced nonsmall-cell lung cancer (NSCLC), good performance status, and no prior chemotherapy were randomized to receive one of three regimens: intravenous vindesine (V) 3 mg/m2 every 2 weeks; V 3 mg/m2 weekly for 5 weeks, followed by a dose every 2 weeks plus mitomycin (VM) 20 mg/m2 day 1 and then 15 mg/m2 every 6 weeks; or V at the more intensive dose rate plus cisplatin (VC) 120 mg/m2 with forced diuresis on days 1 and 29 and then every 6 weeks. A total of 435 patients were enrolled in the trial, with 410 (94%) assessable for prognostic characteristics and survival. Among the 375 patients assessable for response, only 58 (15%) achieved objective response. Single-agent V every 2 weeks was inactive (response rate less than 1%), effectively acting as a no-treatment arm. Among assessable patients receiving VM, 33 (27%) responded; among patients receiving VC, 24 (19%) responded. There was no statistically significant survival difference among the treatment arms, with median survival among those treated with V 14.8 weeks, VM 20.4 weeks, and VC 24.7 weeks; VC achieved borderline significance (P = .06) compared with V. In a prognostic factor analysis, treatment was not a significant factor (P = .447) for survival. Thus, in this large multicenter trial, neither a high-dose cisplatin combination nor a noncisplatin regimen (VM) with a comparable response rate had a significant survival advantage over minimal chemotherapy. New approaches are needed in advanced NSCLC.

A randomized clinical trial of adjuvant adriamycin in uterine sarcomas: a Gynecologic Oncology Group Study.

After hysterectomy, 156 evaluable patients with stage I (limited to the corpus) or stage II (limited to the corpus and cervix) uterine sarcomas were randomly assigned to adjuvant chemotherapy with Adriamycin (Adria Laboratories, Columbus, Ohio) for six months or to no further treatment. Pelvic irradiation (external or intracavitary) was optional before randomization. Of 75 patients receiving Adriamycin, 31 have suffered recurrences compared with 43 of 81 receiving no adjuvant chemotherapy. This difference is not statistically significant. Moreover, there is no difference in progression-free interval or survival. The optional radiotherapy did not influence the outcome although there was a suggestion that vaginal recurrence was decreased by pelvic radiotherapy. The recurrence rates in specific cell types (leiomyosarcoma, homologous mixed mesodermal sarcoma, or heterologous mixed mesodermal sarcoma) were not significantly different although the pattern of recurrence differed, with pulmonary metastases being more common in leiomyosarcoma and extrapulmonary recurrence being more common in mixed mesodermal sarcoma. The outcome with respect to chemotherapy was not altered even after adjusting for maldistribution of cases. Thus, we could not show a benefit for this dose schedule of Adriamycin as adjuvant treatment for uterine sarcomas.

Long-term follow-up of a randomized post-induction therapy trial in acute myelogenous leukemia (a Southeastern Cancer Study Group trial).

A phase III clinical trial was designed to determine if more intensive induction and consolidation therapy for acute myeloblastic leukemia increases the remission rate and prolongs survival. A minor objective was to determine if the use of non-cross resistant drugs was more effective than the same drugs used for induction. Patients with untreated leukemia between the ages of 15 and 50 were given daunorubicin 45 mg/m2 for the first 3 days of a 10-day continuous infusion of cytosine arabinoside, initially at a dose of 2000 mg/m2 but reduced to 100 mg/m2 because of toxicity. Those under 36 achieving a complete remission and with an histocompatible donor were assigned to a transplant arm. The rest were randomized to receive one of three consolidation arms: A, cytosine arabinoside, 200 mg/m2 daily for 7 days and daunorubicin 45 mg/m2 daily for 3 days for three courses; B, one course as in Arm A followed by amsacrine, 120 mg/m2 daily for 5 days followed by a 5-day continuous infusion of azacytidine, 150 mg/m2/day; C, thioguanine and cytosine arabinoside, 100 mg/m2 every 12 h and daunorubicin 10 mg/m2 daily for 5 days for three courses followed by four maintenance courses of cytosine arabinoside, 100 mg/m2 daily for 5 days and daunorubicin, 45 mg/m2 for 2 days every 13 weeks. From 1981 to 1986, 398 eligible patients were enrolled and 219 achieved a complete remission. The initial induction dose of cytosine arabinoside was reduced after five of 29 patients exhibited fatal gastrointestinal toxicity. Only 11 patients were assigned to the transplant arm. There were no significant differences in the consolidation arms. The 5 year disease-free survivals were 38, 31 and 27% in arms A, B, and C respectively. Intensive consolidation therapy with the same or different drugs used in induction was as effective as lower dose consolidation followed by maintenance therapy.

A phase III trial of high-dose cytosine arabinoside with or without etoposide in relapsed and refractory acute myelogenous leukemia. A Southeastern Cancer Study Group trial.

A phase III clinical trial was developed to test whether the addition of etoposide to a high-dose cytosine arabinoside regimen would improve the remission rate, duration of remission, and survival in relapsed and refractory patients with acute myelogenous leukemia. One hundred and thirty-one patients stratified by age, performance status, percentage of marrow blasts, platelet count, bilirubin and presence or absence of clinical infection, refractory or relapsed (+/- 9 months) were randomized to receive high-dose cytosine arabinoside, 3 g/m2 every 12 h for 6 days with or without three doses of etoposide, 100 mg/m2 days 7-9. Of 67 patients randomized to cytosine arabinoside alone, 31% obtained a complete remission with a median remission duration of 11.9 months. Of 66 patients randomized to the combination regimen, 38% obtained a complete remission with a median duration of 25 months. None of these differences were statistically significant. Significantly (p = 0.036) longer survival was seen in patients on the combination regimen under the age of 50. There was no difference in overall survival. Six and 8%, respectively, of patients were free of disease at 5 years. The addition of etoposide to a high-dose cytosine arabinoside regimen had at best a marginal effect at the expense of some increase in toxicity.

Chemotherapy for stage IVB or recurrent cancer of the uterine cervix.

Numerous drugs and drug combinations have been evaluated, largely in phase II trials, for the treatment of carcinoma of the uterine cervix. There clearly is a need for effective chemotherapy for this disease, but the results to date have unfortunately not met that need. Cisplatin is active but overrated. Drug combinations have not shown a consistent advantage and require careful study, with the initial focus on maximizing the complete response rate in women with no or minimal prior chemotherapy and with adequate sample size to have confidence about the results. The patient populations under treatment need to be carefully defined with respect to potential prognostic factors for response and survival, so that results will be more reproducible. The few large, randomized trials completed so far have failed to show a survival benefit with combination chemotherapy; in fact, there does not appear to have been a comparison of chemotherapy with best supportive care. Systemic therapy of cervical cancer remains experimental.

Inhibitors of the enzyme purine nucleoside phosphorylase as potential therapy for psoriasis.

Purine nucleoside phosphorylase (PNP) is one of the enzymes comprising the purine salvage pathway , and is responsible for the catalysis of the reversible phosphorolytic cleavage of purine ribonucleosides and 2'-deoxyribonucleosides. The pivotal role of PNP in T-cell proliferation has been demonstrated in patients with inherited PNP deficiency, where T-cell levels may be 1-3% of normal. This observation helped establish the critical role of PNP in T-cells and provided a rationale for developing inhibitors of PNP. Inhibitors of PNP may be useful for treating a variety of T-cell related autoimmune diseases including psoriasis, rheumatoid arthritis and Crohn s disease and T-cell cancers. In this manuscript, the x-ray crystal structure of the PNP enzyme is described. Results of a structure-based drug design program aimed at designing small-molecule inhibitors of PNP are also described. Of the many classes of compounds synthesized, studied and reviewed, only one, the 3-pyridinylmethyl-9-deazaguanine (BCX-34, 39) analog has been used in clinical trials. Both topical and oral formulations of BCX-34 were studied in psoriatic patients and the results of these clinical trials are described.

Pharmacokinetics and pharmacodynamics of peldesine (BCX-34), a purine nucleoside phosphorylase inhibitor, following single and multiple oral doses in healthy volunteers.

The pharmacokinetic parameters of peldesine (BCX-34) were investigated after single and multiple oral doses in two groups of healthy adult volunteers. The pharmacodynamic elevation of endogenous inosine and 2'-deoxyguanosine was simultaneously monitored. The first group of 8 subjects received an intravenous dose (18 mg/m2) and five oral doses (30, 63, 108, 144, and 192 mg/m2) of drug. A second group of 12 subjects received 160 mg/m2 in four and in six divided doses orally. Serial blood samples and total urine outputs were collected during dosing and for at least 24 hours after the last dose was administered. One set of samples was analyzed using high-pressure liquid chromatography/ultraviolet (LC/UV) methods, validated for intact drug in human plasma and urine samples. Another set of samples was analyzed for the biomarkers, inosine and 2'-deoxyguanosine, using high-pressure LC with either mass spectrometry (MS) or electrochemical detection (EC) methods. The pharmacokinetic parameters of inosine and 2'-deoxyguanosine were calculated using noncompartmental methods and correlated against the pharmacokinetic parameters of BCX-34. For the single-dose study, the results exhibited linear pharmacokinetics over the dose range from 30 to 144 mg/m2. The calculated terminal half-life was 3.5 +/- 1.0 h, and the absolute bioavailability of the oral formulation was approximately 51%. Analysis of urine in the first 24 hours of collection accounted for approximately 82% of the absorbed intact drug. Evaluation of the multiple-dose pharmacokinetics indicated that steady-state blood concentrations were achieved by 24 hours when the drug was administered four or six times a day. A drug dose-related elevation of plasma 2'-deoxyguanosine was observed. This phenomenon was not seen with plasma inosine levels. However, analysis of urine samples showed an increase in inosine output with an increase in the drug dose. The calculated terminal half-life of inosine and 2'-deoxyguanosine was 15.3 +/- 1.8 h and 1.3 +/- 0.1 h, respectively.

Clinical pharmacology of oral intermediate-dose methotrexate with or without probenecid.

Serum methotrexate (MTX) levels were measured in 20 patients who received an oral, intermediate-dose MTX regimen preceded by an IV loading dose, with or without probenecid. Plateau serum MTX levels were relatively modest (less than or equal to 2 X 10(-6)M) during the 24 h of treatment. Pretreatment with probenecid (PBC) led to a doubling of the serum MTX level and a significant increase in the area under the concentration-time curve. Nevertheless, oral therapy is not a suitable means of producing sustained, high (10(-5) molar) MTX levels, even with the addition of PBC.

Clinical pharmacology of intermediate-dose oral methotrexate.

The clinical pharmacology of intermediate-dose oral methotrexate (MTX) was studied in nine patients receiving 18 courses of treatment. Serum and urine MTX concentrations were measured by means of a competitive protein binding assay after oral aqueous solution (3 courses), 50-mg tablets (13 courses) or IV drug (2 courses) had been administered in four doses of 100 mg/m2 at 6-h intervals or in four doses of 200 mg/m2 at 6-h intervals and followed by citrovorum factor rescue. Levels above 150 ng/ml (3.3 x 10(-7) M) were maintained throughout all treatment cycles, with rapid disappearance of drug after the last dose. A 100% increase in administered dose resulted in only a 42% increase in the concentration-time level. Methotrexate was absorbed well from both aqueous solutions and 50-mg tablets, but serum levels after 50-mg tablets were only 20% of those achieved after IV administration. We conclude that significant serum MTX concentrations can be achieved for prolonged periods of time after oral administration of intermediate doses, but that the proportion of drug absorbed is much less than is seen with lower doses.

A randomized, double-blind comparison of single-dose and divided multiple-dose dolasetron for cisplatin-induced emesis.

PURPOSE: Intravenous dolasetron has been shown to be an effective antiemetic agent in patients receiving high-dose cisplatin-containing chemotherapy. Previous studies have suggested that 1.8 mg/kg is an optimal dose for achieving control of emesis and nausea. The objective of this study was to compare the efficacy and safety of a single intravenous (IV) dose of dolasetron with an equal divided multiple dose. METHODS: In this randomized, double-blind, parallel-group, multicenter study, the efficacy and safety of a single 1.8-mg/kg dose of dolasetron given 30 min prior to high-dose cisplatin ( > or = 80 mg/m2) chemotherapy was compared with the same total amount of dolasetron administered in three separate doses (0.6 mg/kg each) over a 12-h interval commencing 30 min prior to beginning chemotherapy and ending 11.5 h later. Antiemetic efficacy, safety, and tolerability were compared in 55 patients with various malignancies during the 24 h following the initiation of chemotherapy. The number of emetic episodes was the primary efficacy parameter. RESULTS: A single IV dose of dolasetron was generally more effective than a multiple-dose regimen in all measures of efficacy. There was a larger proportion of complete responders in the single-dose group compared with the multiple-dose group (48% vs 23%), although this difference did not reach statistical significance. Compared with the multiple-dose group, patients who received a single dose of dolasetron had a significantly (P = 0.034) longer median time to the first emetic episode (10.1 h vs > 24 h, respectively). Overall, 53% of patients had either a complete response or a major response to dolasetron, and only 40% of the total patient population received escape antiemetic medication in the 24 h after cisplatin administration. Except for headache, adverse events were similar with both regimens and were generally of mild or moderate intensity; no serious adverse events occurred. Neither dolasetron treatment regimen was associated with any clinically important events, trends in laboratory variables, or differences in safety profile. CONCLUSIONS: single-dose dolasetron was well tolerated and effectively controlled emesis and nausea in patients who received highly emetogenic, high-dose cisplatin chemotherapy. The greater antiemetic efficacy of a single prophylactic dose of dolasetron offers both convenience and potential cost savings, compared with a multiple-dose schedule of administration.

Clinical pharmacology of cytarabine in patients with acute myeloid leukemia: a cancer and leukemia group B study.

The pharmacokinetics of cytarabine (ara-C) were determined in 265 patients with acute myeloid leukemia (AML) receiving ara-C (200 mg/m2 per day for 7 days as a continuous infusion) and daunorubicin during induction therapy. The mean (standard deviation) ara-C concentration at steady-state (Css) and systemic clearance (Cl) were 0.30 (0.13) microM and 134 (71) l/h per m2 respectively. Males had a significantly faster ara-C Cl (139 vs 131 l/h per m2, P = 0.025) than females. Significant correlations were noted between ara-C Cl and the pretreatment, peripheral white blood cell count (P = 0.005) and pretreatment blast count (P = 0.020). No significant differences in ara-C Css or Cl were noted in patients achieving complete remission compared with those failing therapy (P = 0.315, P = 0.344, respectively). No significant correlations were observed between ara-C pharmacokinetic parameters and several indices of patient toxicity. Our findings indicate that variability in ara-C disposition in plasma at this dosage level does not correlate with remission status or toxicity in patients with AML receiving initial induction therapy with ara-C and daunorubicin.

Late intensification therapy in adult acute lymphoid leukemia: long-term follow-up of the Southeastern Cancer Study Group experience.

One hundred and ninety-two evaluable patients were treated on a multicenter protocol for adult acute lymphoid leukemia to determine in a prospective randomized fashion if late intensification chemotherapy beginning after about six months of treatment would improve remission duration and survival. The complete remission rate was 60%. The median remission duration from beginning of maintenance was 18.7 versus 25.9 months (P = 0.36) for standard maintenance therapy and late intensification, respectively, and the median survival from randomization was 25.8 versus 28.5 months (P = 0.94) respectively. There was a suggestion that the late intensification strategy was helpful with respect to remission duration, and this trend was sustained in long-term follow-up. However, relapse proved to be common during the earlier phases of treatment; thus, insufficient numbers of patients were available at the randomization point to conclusively address the possible value of late intensification. Intensive therapy earlier in the course of treatment should be evaluated, including transplantation in selected patients.