Pathogenesis of preeclampsia: a comprehensive model

PROBLEM: Therapy of children with relapsed acute lymphoblastic leukemia (ALL) not achieving a second remission (CR2) after an initial reinduction attempt is problematic. METHODS: 52 children with ALL in first relapse received high-dose cytosine arabinoside and L-asparaginase (HDAraC/L-Asp) after failed attempts to achieve CR2. AraC was given at a dose of 3 gm/m2 q12 h x 4 on days 0-1 and 7-8. L-asparaginase was given IM 6,000 IU/m2 3 hours after completion of each 2-day cycle of AraC. RESULTS: Of the 42 surviving to day 28, 22 (42% of all patients) achieved CR2. Ten died before day 28 (19%); four from leukemia and six from infections or toxicity (12% regimen-related mortality), There were 17 bacterial infections (three fatal), 17 invasive fungal infections (12 fatal), one fatal adenoviral infection, and one-non-fatal Pneumocystis pneumonia. One patient was surviving when lost to follow-up at four months and one patient survives over 5 years after transplant. Sixteen of the 22 patients who entered CR2 subsequently relapsed, five died of non-leukemic causes, and one was lost to follow-up. The median duration of second remission was 3 months (range 0.7 to 19 months). CONCLUSIONS: HDAraC/L-Asp rescue reinduction for relapsed childhood ALL achieves CR2 in approximately 40% of patients who fail reinduction, but remissions are short for most patients and maintenance of CR2 remains unsatisfactory.     

Results of the CCLSG high risk ALL 874 protocol in childhood acute lymphoblastic leukemia. Children's Cancer and Leukemia Study Group

One hundred and eighty eight children with acute lymphoblastic leukemia (ALL) were treated in a Children's Cancer and Leukemia Study Group high-risk ALL 874 study from April, 1987 to September, 1991. These patients received a four-drug induction regimen followed by the early consolidation regimen, cranial irradiation at 6 months of remission and three years of continuation therapy with rotational administration of four drugs. The patients were randomized into two regimens. In regimen A, the consolidation chemotherapy consisted of the intermediate dose cytosine arabinoside (Ara-C), cyclophosphamide (CPM) plus 6MP, and in regimen B, it consisted of high-dose Ara-C plus CPM. Regimen A was given to 106 patients and 82 patients received regimen B. The complete remission induction rate for regimen A and B was 89.4% (93/104) and 98.7% (78/79), respectively. The 3-year event-free-survival (EFS) rate was 70.6% for regimen A, which was higher than the 56.7% for regimen B. The 3-year EFS rate was 44.4% for the 53 patients with an initial leukocyte count > or = 10 x 10(4)/microliters and 72.2% for 132 patients with a leukocyte count < 10 x 10(4)/microliter. We considered that Ara-C plus L-asp, added to the conventional high-risk ALL 811 protocol, improved the prognosis of the high risk ALL patients. However, further intensive chemotherapy was required for improvement of the outcome of the patients with hyperleukocytosis (> or = 10 x 10(4)/microliters).     

Autologous bone marrow transplantation with monoclonal antibody purged marrow for children with acute lymphoblastic leukemia in second remission. Spanish Working Party for BMT in Children

The purpose of this study was to evaluate the outcome of children with acute lymphoid leukemia (ALL) in second remission who have undergone high-dose chemotherapy and radiotherapy and autologous bone marrow transplantation (ABMT) with monoclonal antibody purged marrow, and to determine the main prognostic factors. From 1987 to 1992, 55 children with ALL in second remission underwent ABMT. The conditioning regimen consisted of total body irradiation (TBI) plus cyclophosphamide in 21 patients and TBI plus cyclophosphamide plus cytarabine or VP-16 in 28 patients; the remaining six patients were treated with chemotherapy alone (cyclophosphamide and busulfan, and/or VP-16). The marrow was purged using monoclonal antibodies and complement or magnetic microspheres in all cases. All patients engrafted. Three patients (5%) died early post transplant from infections. Twenty-six patients (47%) relapsed (median 150 days); 26 patients (47%) are alive and in complete remission (CR) at a median of 36 months. The Kaplan-Meier estimation showed a probability of event-free survival (EFS) of 46 +/- 0.007%. In the univariate analysis, first CR length and conditioning with TBI plus two or more cytotoxic drugs were found to be the most significant predictors of EFS. ABMT with purged marrow is a treatment modality which offers a chance of cure in children with ALL after relapse, including children who relapse early.     

Treatment of relapsed adult acute lymphoblastic leukemia with fludarabine and cytosine arabinoside followed by granulocyte colony-stimulating factor (FLAG-GCSF)

The aim of the present study was to evaluate the efficacy of the combination of fludarabine 30/mg/m2 + cytarabine 2g/m2 followed by the administration of G-CSF to achieve a complete remission (CR) in patients with relapsed acute lymphoblastic leukemia (ALL). We treated twelve patients in first relapse, overall 10 patients achieved a second CR, one patient showed resistant disease and one patient died during remission induction. The regimen was well tolerated and we observed a short period of neutropenia with a low incidence of myelosuppression-associated problems. Eight patients in second CR received the same chemotherapeutic regimen as consolidation used for the reinduction. In six patients the chemotherapeutic regimen was well tolerated, two patients died, (cerebral hemorrhage in one patient and sepsis in the other). In conclusion the combination of fludarabine, cytarabine and G-CSF has significant antileukemic activity and non hematological toxicities were acceptable. The addition of G-CSF reduced the period of neutropenia obtaining a low incidence of myelosuppression-associated problems.     

High-dose busulfan, melphalan and thiotepa followed by autologous peripheral blood stem cell (PBSC) rescue in patients with advanced stage III/IV ovarian cancer

The purpose of this study was to evaluate the efficacy of high-dose chemotherapy (HDC) with busulfan, melphalan and thiotepa (BUMELTT) followed by autologous PBSC infusion in treating patients with advanced ovarian cancer. Thirty-one patients, 18 with stage III/IIIc and 13 with stage IV ovarian cancer, were treated with BU (12 mg/kg), MEL (100 mg/m2) and TT (500 mg/m2) and autologous PBSC rescue. Fifteen patients were in clinical complete remission (CR) at treatment; 11 had platinum-sensitive disease. Sixteen patients were not in CR; two had platinum-sensitive disease. The probabilities of overall survival (OS), event-free survival (EFS) and relapse (R) for all patients at 18 months were 0.57, 0.30 and 0.63; for patients in CR, the rates were 0.87, 0.44 and 0.49 and for patients not in CR, 0.38, 0.13 and 0.81. Two patients (6.5%) died of treatment-related causes. Among the 13 patients with platinum-sensitive disease, all are still alive, with seven having relapsed 129-1021 days after PBSC infusion. OS, EFS and R were 1.00, 0.52 and 0.48. Of the 18 patients with platinum-resistant disease, four remain alive (two in remission). Six patients did not respond and eight relapsed from days 104-429. The OS, EFS and R were 0.33, 0.11 and 0.78. We conclude that BUMELTT is well tolerated in patients with advanced ovarian cancer and results are equivalent to other published HDC regimens.     

MRI of hyperpolarized 3He gas in human paranasal sinuses

Relapsed or refractory adult acute lymphoblastic leukemia (ALL) carries a grave prognosis. The most promising strategy for curing these patients is through re-induction chemotherapy followed by successful allogeneic transplant. We studied a new high-dose induction regimen in order to improve the outcome for these patients. Eighteen adult patients with relapsed/refractory ALL were treated on a phase I study of high-dose cytarabine combined with a single escalating dose of idarubicin. Five patients had primary refractory disease and 13 were treated in refractory relapse. Nine patients (50%) had Ph+ ALL. The induction regimen was cytarabine 3 g/m2/day intravenously days 1-5 and idarubicin as a single intravenous dose on day 3. G-CSF 5 microg/kg subcutaneously every 12 h was started on day 7. The initial idarubicin dose was 20 mg/m2 with dose escalations of 10 mg m2. Cohorts of three patients were treated at each idarubicin dose level. Unacceptable toxicity was encountered at 50 mg/m2 with one death from infection and one death from cardiotoxicity in a patient with significant prior anthracycline exposure. There were no instances of grade 4 non-hematologic toxicity encountered at idarubicin doses of 20 mg/m2, 30 mg/m2, or 40 mg/m2. The data suggest a dose-response relationship for increasing doses of idarubicin with 0/3 complete responses (CR) at 20 mg/m2, 1/3 CR at 30 mg/m2, and 7/12 (58%) CR at idarubicin doses > or = 40 mg/m2. We conclude that concomitant administration of cytarabine 3 g/m2/day x 5 and high-dose idarubicin at 40 mg/m2 as a single dose on day 3 can be administered safely to patients with refractory and relapsed ALL.     

Use of the microculture kinetic assay of apoptosis to determine chemosensitivities of leukemias

Chemotherapeutic agents exert their antitumor effects by inducing apoptosis. The microculture kinetic (MiCK) assay provides an automated, continuous means of monitoring apoptosis in a cell population. We used the MiCK assay to determine the chemosensitivities of the human promyelocytic HL-60 and lymphoblastic CEM cell lines and leukemia cells freshly isolated from patients with acute nonlymphocytic (ANLL) or acute lymphocytic (ALL) leukemias. Continuous monitoring of apoptosis in the MiCK assay permits determination of the time to the maximum apoptosis (Tm) and its two components which are initiation time (Ti) and development time (Td). Duration of the three timing components of apoptosis varies from hours to days depending on the drug, drug concentration, and type of target cells. In the MiCK assay, the extent of apoptosis is reported in kinetic units of apoptosis. Kinetic units are determined by the slope of the curve created when optical density caused by cell blebbing is plotted as a function of time. Using the leukemia cell lines, we define the relationship between kinetic units determined by the MiCK assay and the percentage of morphologically apoptotic cells in the culture. Flow cytometry analysis of apoptosis in Annexin-V-fluorescein isothiocyanate-labeled preparations of HL-60 and CEM cells was also used to compare with data obtained by the MiCK assay. The feasibility of the MiCK assay of apoptosis as a chemosensitivity test was confirmed by its comparison with a 3H-thymidine incorporation assay. We show that samples from 10 ANLL and ALL patients patients tested for sensitivity to various doses of idarubicin (IDR), daunorubicin (DNR), or mitoxantrone (MTA) gave the same percentages of apoptotic cells when calculated by the MiCK assay as when determined by morphological analysis. The MiCK assay was used for dose-response analyses of the sensitivities to IDR, DNR, and MTA of leukemia cells from 4 other patients (2 ANLL and 2 ALL). The results from both cell lines and patient samples indicate that ANLL cells are more sensitive than ALL cells to all three of these chemotherapeutic agents. However, for individual patients the chemosensitivities varied significantly among the three chemotherapeutic agents. These varying responses to IDR, DNR, and MTA indicate that the MiCK assay results can be of potential use in designing a treatment regimen for a specific patient with acute leukemia. Among several drugs of presumed similar efficacy, the MiCK assay can permit the selection of the specific chemotherapeutic agent that causes the most apoptosis in the patient's leukemic cells.     

Stage IV neuroblastoma in patients over 1 year of age at diagnosis: consolidation of poor responders with combined busulfan, cyclophosphamide and melphalan followed by in vitro mafosfamide-purged autologous bone marrow transplantation

In an attempt to improve the poor prognosis of poor responders with stage IV neuroblastoma, a new combined high-dose chemotherapy conditioning regimen was tested. Event-free and overall survival, as well as the incidence of complications, were analysed. Twenty-five children aged 12-146 months at diagnosis entered this study. All were in complete remission (CR) at the time of high-dose chemotherapy. Two or three different protocols had been necessary for them to achieve a CR. High-dose chemotherapy consisted of a combination of busulfan (600 mg/m2), cyclophosphamide (4400 mg/m2) and melphalan (140 mg/m2). It was followed by autologous bone marrow transplantation (ABMT). The bone marrow graft was purged in vitro with mafosfamide. The probability of event-free survival (EFS) at 5 years post-ABMT was 34%, compared to < 8% in a historical series. Toxicity was severe but manageable and 2 complication-related deaths were observed. Veno-occlusive disease was the most frequent extrahaematopoietic complication encountered, but its outcome was always favourable. By using a very intensive conditioning regimen consisting of a combination of three alkylating agents, the EFS of poor responders with metastatic neuroblastoma was improved and similar to that of good responders. When compared with a previously published similar series of patients, the improvement in survival appears probably related to intensification of the conditioning regimen.     

Phase I trial of high-dose tamoxifen as a modulator of drug resistance in combination with daunorubicin in patients with relapsed or refractory acute leukemia

Tamoxifen and its main metabolite N-desmethyltamoxifen (NDMTmx) have been shown to increase intracellular daunorubicin (DNR) levels in human leukemia cell lines that display the multidrug resistant (MDR) phenotype. We designed a phase I dose escalation study of Tmx (200-700 mg/day p.o. for 7 days) in combination with a fixed dose of DNR (50 mg/m2 intravenously on days 5, 6 and 7) in patients with advanced leukemia to determine whether this combination could be given safely and whether plasma levels of 10 microM, the effective in vitro MDR modulator concentration, could be achieved. Pharmacologic studies of Tmx, NDMTmx and DNR, and its main metabolite daunorubicin-ol (DNR-ol) were performed as was determination of P-glycoprotein (Pgp) using a monoclonal antibody that recognizes an external epitope of the molecule. A total of 14 patients (median age 50, range 22-67) were treated at the following dose levels: 200 mg/day: three patients; 400 mg/day: four patients; 550 mg/day: three patients; and 700 mg/day: four patients. Two patients with relapsed AML achieved remission. Toxicity of the combination was similar to that seen with DNR alone and no severe hepatic, cardiac or retinal toxicity was noted. Plasma Tmx levels approached 7 microM at the two highest dose levels studied; plasma levels of NDMTmx were slightly less. The area under the curve for DNR and its main metabolite daunorubicin-ol (DNR-ol) did not show significant changes with escalation of Tmx dose. This phase I study suggests that concentrations of Tmx high enough to reverse the MDR phenotype can be approached and that the combination of high-dose Tmx with a standard dose of DNR has an acceptable toxicity profile. More evaluation in phase II studies is necessary to define further its role as an MDR modulator.     

ALL R-87 protocol in the treatment of children with acute lymphoblastic leukaemia in early bone marrow relapse

Seventy-three children with acute lymphoblastic leukaemia (ALL) in first bone marrow (BM) relapse, occurring within 30 months from complete remission (CR), were enrolled in an Italian cooperative study (ALL R-87 protocol). This treatment programme consisted of an induction phase with intermediate-dose cytarabine (IDARA-C) plus idarubicin (IDA) and prednisone (PDN), followed by a multidrug consolidation therapy and bone marrow transplant (BMT). 55/73 children achieved CR (75.3%); 15 (20.5%) failed to respond and three (4.2%) died during induction. The response rate was significantly higher for children with a first CR duration > or = 12 months (P=0.0005) and for those with a white blood cell (WBC) count at relapse < 20 x 10(9)/l (P=0.004). The estimated disease-free survival (DFS +/- SE) at 82 months was 0.18 +/- 0.05 for all responders, and 0.70 +/- 0.14 for allotransplanted patients versus 0.05 +/- 0.05 for those autografted (P=0.001). The estimated probabilities of survival +/- SE and event-free survival (EFS +/- SE) at 83 months were 0.16 +/- 0.07 and 0.13 +/- 0.04, respectively. for all enrolled children. Univariate analysis showed that age < 10 years at initial diagnosis and B-lineage immunophenotype favourably influenced both DFS (P=0.001) and EFS probabilities (P=0.0014 and P=0.012, respectively), whereas a first CR duration > or = 12 months and a WBC count at relapse < 20 x 10(9)/l were associated only with a better EFS rate (P=0.026 and P=0.004, respectively). Our results show the efficacy of the IDA plus IDARA-C schedule used in the ALL R-87 protocol in high-risk relapsed ALL children. Allogeneic BMT proved effective for patients with an HLA sibling donor. In a multivariate analysis, age > or = 10 years at initial diagnosis (P=0.016) and WBC count at relapse > or = 20 x 10(9)/l (P=0.048) were independently associated with a worse disease outcome.     

Augmented Berlin-Frankfurt-Munster therapy abrogates the adverse prognostic significance of slow early response to induction chemotherapy for children and adolescents with acute lymphoblastic leukemia and unfavorable presenting features: a report from the Children's Cancer Group

PURPOSE: Compared with previous Children's Cancer Group (CCG) acute lymphoblastic leukemia (ALL) trials, therapy based on the Berlin-Frankfurt-Munster (BFM) 76 trial has effected an improvement in event-free survival (EFS). In an attempt to improve EFS further, CCG investigators formulated an augmented BFM (A-BFM) regimen that provides prolonged, intensified postinduction chemotherapy relative to the CCG-modified BFM regimen. PATIENTS AND METHODS: We tested A-BFM in 101 patients with ALL and unfavorable presenting features that showed slow early response (SER) to induction therapy who attained remission on day 28. Their outcome was compared with that of 251 concurrent patients with unfavorable presenting features, a rapid early response to therapy (RER), and remission by day 28, treated with CCG-BFM with or without cranial radiation (CRT). RESULTS: The 4-year EFS rate from the end of induction for SER patients treated with A-BFM was 70.8% +/- 4.6%. Seventeen patients remain in continuous remission beyond 5 years. Vincristine (VCR) neurotoxicity developed in 50% of patients, but was rarely debilitating. Allergies to Escherichia coli L-asparaginase (L-ASP) occurred in 35% of patients. Avascular necrosis of bone (AVN) developed in 9% of patients. In comparison, a concurrent RER group treated with standard BFM +/- CRT had a 4-year EFS rate of 73.1% +/- 4.6%. CONCLUSION: The toxicity of A-BFM is significant, but acceptable. Compared with historical control SER patients treated with CCG-modified BFM, A-BFM therapy appears to produce a significant improvement in EFS. This is the first study to show that intensive chemotherapy, as given in the A-BFM regimen, can abrogate the adverse prognostic significance of SER.     

In vitro evaluation of dissolution properties and degradation products of omeprazole in enteric-coated pellets

Between 1985 and 1990, 133 patients with advanced multiple myeloma (MM) (74% resistance; 41% resistant relapse, RR) were treated with five high-dose therapy (HDT) regimens including: melphalan < or =100 mg/m2 (MEL 100) (46 patients); MEL 100 plus GM-CSF (24 patients); MEL 140 plus autologous bone marrow transplantation (ABMT) (eight patients); MEL 140 plus TBI 850 cGy plus ABMT (37 patients); and thiotepa 750 mg/m2 (THIO 750) + TBI 850 cGy plus ABMT (18 patients). The median follow-up of alive patients as of December 1997 was 9 years. Overall, 17% experienced treatment-related mortality within 60 days (TRM) and 12% achieved stringently defined complete remission (CR) with a median duration of 16 months; four of 16 patients (25%) remain in CR at 10 years. The median durations of event-free survival (EFS)/overall survival (OS) were 6/15 months. Superior EFS/OS were noted with MEL 100 plus GM-CSF and the two TBI-containing regimens (9/24 months among 79 patients) compared to the remaining 54 patients receiving MEL < or =100 or MEL 140 plus ABMT (3/5 months) (P = 0.0001/0.0001, respectively). Multivariate regression analyses (MVA) were performed so that, despite patient heterogeneity among the five treatment groups, potentially relevant disease, host, treatment, and supportive care variables could be identified that were associated with TRM, CR, EFS and OS. TRM was higher with creatinine >2.0 mg/dl, absence of ABMT/GM-CSF support and age >50 years; CR was superior with TBI-containing regimens and < or =12 months of prior therapy; EFS and OS both were longer with B2M < or =2.5 mg/l, age < or =50 years, absence of RR and with ABMT/GM-CSF support. In the presence of >2 favorable variables (32 % of patients), median EFS/OS durations of 18/48 months were observed which progressively declined with 2 and <2 favorable parameters to 6/11 months (28% of patients) to 3/5 months (40% of patients) (P = 0.0001/0.0001). At 10 years, 10 and 20% of patients with >2 favorable variables were event-free and alive, which was also true for the 37 patients receiving MEL 140 plus TBI. To appreciate possible long-term contributions of supportive care or treatment intensity, landmark analyses performed at 1, 2, 4 and 6 months revealed virtually identical ranking orders of prognostically favorable variables to those seen pre-HDT; once supportive care was accounted for, regimen intensity with added TBI did not emerge as an independent favorable feature.     

Autologous stem-cell transplantation for non-Hodgkin's lymphomas: the role of graft purging and radiotherapy posttransplantation--results of a retrospective analysis on 120 patients autografted in a single institution

PURPOSE: To analyze retrospectively survival and prognostic factors of patients with non-Hodgkin's lymphoma (NHL) autografted from 1979 to 1995 in a single institution. PATIENTS AND METHODS: A total of 120 patients, 64 with aggressive and 56 with low-grade NHL, were autografted. The carmustine (BCNU), etoposide, cytarabine, and melphalan (BEAM) regimen was used in 104. The autograft was marrow in 101 patients. Marrow was purged in vitro by mafosfamide for 63 patients (adjusted dose [AD] in 32; unique dose [UD] in 31); 27 patients received a CD34+-selected graft. Following intensification, 45 patients received additional radiotherapy on previous sites of involvement. RESULTS: Outcome at 5 years for patients transplanted with low-grade NHL in first complete remission (CR1), in first partial remission (PR1), and in second complete remission (CR2) or beyond showed an event-free survival (EFS) of 75% +/- 12%, 46% +/- 18%, and 57% +/- 24%, a relapse incidence (RI) of 21% +/- 12%, 49% +/- 19%, and 43% +/- 25%, and a transplant-related mortality (TRM) of 5% +/- 5%, 10% +/- 7%, and 0%, respectively. For patients with aggressive NHL transplanted in CR1, in PR1, in CR2 or beyond, and in resistant relapse or in primary refractory disease, the EFS was of 73% +/- 9%, 58% +/- 19%, 29% +/- 16%, and 10% +/- 9%, the RI 22% +/- 9%, 14% +/- 9%, 77% +/- 18%, and 66% +/- 20%, and the TRM 6% +/- 6%, 32% +/- 21%, 11% +/- 10%, and 71% +/- 22%, respectively. In patients autografted upfront in first remission, additional radiotherapy was associated with a higher EFS, in univariate (P = .03) and multivariate analysis (P = .02, relative risk [RR] = .021). The role of graft purging with mafosfamide on the outcome reflected by the dose of colony-forming unit-granulocyte-macrophage (CFU-GM) per kilogram infused postpurging was assessed by univariate analysis: patients in first remission who received lower doses of CFU-GM had a lower RI and a higher EFS. CONCLUSION: This retrospective analysis suggests that marrow purging and posttransplant radiotherapy improve the outcome of patients with NHL autografted in first remission.     

Demonstration of dermatophyte dissemination from the infected soles using the foot-press method

The toxicity and outcome after high-dose ara-C/daunorubicin (HDara-C/DNR) consolidation therapy in de novo AML was compared in 11 patients who received an idarubicin-containing induction therapy (IDA; from June 1995 to March 1997) and 16 patients pretreated with daunorubicin (DNR; from July 1990 to May 1995) for induction. The DNR group consisted of two cohorts, one (n = 6) of patients who had received, as had the IDA group, two induction and one intermediate-dose ara-C consolidation courses, and another (n = 10) of patients who had been pretreated with one induction and one consolidation course prior to HDara-C/DNR. There was no difference in the relative dose between the three cohorts. Following HDara-C/DNR, the IDA-pretreated patients experienced a more prolonged myelosuppression during consolidation therapy compared with the DNR group. Duration of neutropenia (< 500 neutrophils/microl) following HDara-C/DNR was 31.2 +/- 16 days (mean +/- SEM) in the IDA group compared with 18.7 +/- 5 days in the DNR group (p < .001 Mann-Whitney U-test). The duration 'of thrombocytopenia (platelets < 25000/microl) was 34.8 +/- 20 days in the IDA group vs. 18.5 +/- 6 days in the DNR group (p < .005). The more prolonged myelosupression was associated with a longer duration of fever (18.9 +/- 24 vs. 6.9 +/- 5.2 days). A greater incidence, length (11 +/- 8 vs. 1.2 +/- 2 days), and severity of diarrhea were observed in the IDA-pretreated group. Three of 11 IDA patients experienced WHO grade III-IV diarrhea. In the IDA group two patients developed severe enterocolitis with Candida septicemia, and one of these patients died. One patient in the IDA group died during prolonged aplasia. In the DNR group 6/16 patients experienced grade I-II diarrhea. Two patients in each group died during consolidation therapy. The CR rate was 87% in the IDA group and 79% in the DNR group. Relapse-free survival after HDara-C is 50% at a median follow-up of 60 months in the DNR group and 45% after a median follow-up of 17 months in the IDA group. Whether the advantage of the superior response rate in the IDA-treated patients may be lost during HDara-C consolidation treatment due to increased toxicity remains to be proven in larger trials.     

Experimental hepatitis E: pathogenesis in cynomolgus macaques (Macaca fascicularis)

Children with acute lymphoblastic leukemia (ALL) who have completed 2.5 to 3 years of initial chemotherapy have an off-therapy relapse rate of approximately 20%. In an attempt to improve the survival of children with a late bone marrow (BM) relapse (ie, occurring greater than 6 months after cessation of primary therapy), the Pediatric Oncology Group designed a randomized study to compare the efficacy of doxorubicin/prednisone and cytarabine/teniposide in a multidrug retreatment chemotherapy program. Treatment consisted of remission reinduction with vincristine, prednisone, and doxorubicin, central nervous system prophylaxis with triple intrathecal chemotherapy, and continuation therapy (for 132 weeks) with alternating cycles of oral 6-mercaptopurine/methotrexate and intravenous vincristine/cyclophosphamide. Patients received intermittent courses of either prednisone/doxorubicin (regimen 1) or teniposide/cytarabine (regimen 2) during continuation therapy and a late intensification phase with either vincristine, prednisone, and doxorubicin (regimen 1) or teniposide and cytarabine (regimen 2). One hundred two of 105 evaluable patients (97%) achieved a second complete remission. Twenty-eight of 50 patients on regimen 1 have failed compared with 28 or 52 patients on regimen 2 (log-rank analysis, P = .68), indicating that this trial was inconclusive as to which treatment regimen was superior. The overall 4-year event-free survival for children with a late BM relapse was 37% +/- 6%. Age less than 10 years at initial diagnosis (P < or = .001), white blood cell count less than 5,000/microL at relapse (P = .036) and duration of first remission greater than 54 months (P = .039) were independently associated with a more favorable outcome. While the randomized trial was inconclusive, prolonged second complete remissions were secured in more than one-third of children with a late BM relapse of ALL. The prognostic factors identified may help select children with a late BM relapse who can be successfully retreated with chemotherapy alone.     

Treatment of patients with acute lymphoblastic leukemia with bulky extramedullary disease and T-cell phenotype or other poor prognostic features: randomized controlled trial from the Children's Cancer Group

BACKGROUND: Children with acute lymphoblastic leukemia with multiple poor prognostic factors and who have a lymphomatous mass at diagnosis, whether of T- or non-T-immunophenotype, are at increased risk of short term remission and extramedullary recurrence, and are in need of better therapies. METHODS: Six hundred and ninety-four eligible patients ranging in age from 1-20 years were entered on the study. Sixty-five percent of the patients had T-cell immunophenotype. Of these, 678 were randomized to one of four regimens: Regimen A: Berlin-Frankfurt-Munster (BFM) 76/79; Regimen B: LSA2-L2 with cranial irradiation; Regimen C: LSA2-L2 without cranial irradiation; and Regimen D: the New York (NY) regimen. RESULTS: Complete remission was induced in 97% of patients. The overall event free survival (EFS) +/- the standard deviation was 60 +/- 4% 6 years after diagnosis, in contrast to 36 +/- 6% in a comparable historic group. The EFS of the 371 T-cell patients was 62 +/- 7%. EFS was best on the NY (67 +/- 7%) and the BFM (67 +/- 6%) arms. These were significantly better than the EFS on the 2 LSA-L2 regimens, with an EFS of 53 +/- 8% (Regimen B) and 42 +/- 11% (Regimen C) (P = 0.03 and 0.0003 for NY vs. Regimen B and NY vs. Regimen C; P = 0.01 and 0.0001 for BFM vs. Regimen B and BFM vs. Regimen C). Regimen C had a 3-fold greater central nervous system (CNS) recurrence rate than the identical chemotherapy Regimen B (16 +/- 5% vs. 6 +/- 4%; P = 0.02), although the difference in overall EFS did not reach the required level for significance. Testicular recurrence varied from 2-8% in comparison with 20% in the historic group. EFS was not influenced by age, gender, CNS disease at diagnosis, morphology, or immunophenotype. In addition to treatment regimen and early response rate, initial leukocyte count, hemoglobin level, liver, spleen, and lymph node enlargement, and the presence of a mediastinal mass had univariate prognostic influence on EFS. In multivariate analysis, only the kinetics of response, leukocyte count (unfavorably, P < 0.0001), and mediastinal mass status (favorably, P = 0.01) were prognostic. CONCLUSIONS: The adverse prognostic implications of lymphomatous ALL can be minimized by the NY and BFM regimens. Cranial irradiation resulted in better CNS disease control when added to the LSA2-L2 regimen, but did not improve the overall disease free survival. With improved systemic chemotherapy, there was no excess of lymph node, testicular, or other local recurrence without prophylactic irradiation to sites of initial bulk disease or to the testes.     

Treatment of multiple myeloma with high-dose chemotherapy and transplantation of autologous hematopoietic stem cells and subsequent maintenance therapy with interferon alfa-2b or interferon alfa 2b and dexamethasone. Report of the ongoing study of the "4W" Czech Myeloma Group

We report our results with high-dose chemotherapy in previously untreated multiple myeloma patients (4 courses of VAD chemotherapy, collection of PBSC after priming with cyclophosphamide, 5 g/m2, high-dose chemotherapy with melphalan, 200 mg/m2). Second transplantation was indicated only for patients who did not achieve remission after the first high-dose therapy (paraprotein lower than 25% of the pretreatment value). For the second transplantation melphalan (200 mg/m2) with methylprednisolone (1.5 g for 5 days) were used as conditioning regimen. After high-dose therapy all patients were randomized into two arms of maintenance therapy: interferon alpha-2b or sequential maintenance therapy (interferon alpha-2b for 3 months followed after 4 week pause by 40 mg of dexamethasone days 1-4, 10-13 and 20-23. The administration of interferon alpha was resumed four weeks after the last dexamethasone for next three months. The maintenance therapy continued for 48 months or until the progression. Fifty-five patients were enrolled in the study from January 1996 to August 1997. Thirty-five patients have undergone the first transplantation and 57% of them reached complete remission. There were 10% of non-responders after the first high-dose regimen. The mean time to reach white blood cell count above 1 x 10(9)/L after the application of high dose melphalan and platelets more than 50 x 10(9)/L were 12.2 (range 6-16 days) and 12.4 (range 0-25 days), respectively. Grade 4 mucositis according to SWOG classification requiring total parenteral nutrition was presented in 40% of the patients. The mean number of 1 unit of platelets and 2 units of packed red blood cells transfusions were given within the posttransplant period. Early transplant related mortality was 3%. This paper describes the response and tolerance of each particular step of therapy. The follow-up has been too short to evaluate event-free and overall survivals.     

Busulfan and melphalan as conditioning regimen for autologous peripheral blood stem cell transplantation in multiple myeloma

Twenty-four patients with multiple myeloma (MM), three (12.5%) in complete remission (CR) and 21 (87.5%) in partial remission (PR) were treated with high-dose chemotherapy (HDCT) (busulfan 12 mg/kg+melphalan 140 mg/m2) as preparative regimen for autologous peripheral blood stem cell (PBSC) transplantation. These cells were previously collected by leukapheresis after mobilization by high-dose cyclophosphamide (HD Cy)+rhGM-CSF (18 patients) or rhG-CSF alone (six patients). Considering 23 evaluable patients following HDCT, the CR rate was 58% (14 patients) and the PR rate was 38% (nine patients). One transplant-related death occurred following this regimen (4%). With a median follow-up of 20 months (range 4-34) after transplantation, 21 patients are alive (87%). Disease progression after transplantation was observed in four patients. Overall and relapse-free actuarial survival at 24 months was 91% and 74%, respectively. 12 patients (50%) remain in CR 15 months (4-34) post transplant. The major toxicity was mucositis. Busulfan+melphalan is a safe and feasible conditioning regimen for APBSCT in MM with acceptable toxicity and a high objective response rate, which may result in prolonged survival.     

Treatment of neuroblastoma stage 4 with 131I-meta-iodo-benzylguanidine, high-dose chemotherapy and immunotherapy. A pilot study

Disseminated neuroblastoma after infancy has a prognosis of approximately 10-20% with conventional therapy. We investigated the role of high-dose chemotherapy (HDCT) with peripheral blood stem cell (PBSC) rescue in combination with 131I-metaiodobenzylguanidine ([131I-m]IBG). 11 children with neuroblastoma stage 4 were pretreated within the German Neuroblastoma Trial NB90 and included in a high-dose concept for consolidation. Remission was documented by ultrasound, CT, NMR, or [123I-m]IBG scanning. HDCT was a combination of melphalan (180 mg/m2), carboplatin (1,500 mg/m2) and etoposide (40 mg/kg). All children were treated by [131I-m]IBG (0.58 GBq/kg) prior to high-dose treatment. All 11 children were additionally treated with antiGD2 murine- or chimeric-antibody (ch14.18). 4 children had no change to their remission status but three achieved a complete response (from a partial response to first line) and one a partial response (from no response to first line). The other 3 children progressed, 2 dying of their disease. Using Kaplan-Meier analysis, the probability of progression-free survival was 0.70 +/- 0.15 with a median observation time of 19 months. 9/11 children are alive, 8 without progression or relapse, whilst 2 have died of their disease. The combination of mIBG plus high-dose chemotherapy with PBSC support supplemented by immunotherapy with antiGD2 antibody appears to be a feasible and effective treatment regimen for disseminated neuroblastoma in this limited series. Larger numbers of patients should be treated to confirm these results.     

Compomers and glass ionomers: bond strength to dentin and mechanical properties

Twenty-six patients with newly diagnosed ALL (age range 15-49 years, median 32 years) received treatment comprising: cycles 1 and 2: adriamycin 30 mg/m2 days 1-3, vincristine: 2 mg days 1, 8, and 15, with prednisolone 40 mg daily, given until complete remission (CR). L-asparaginase 10000 units/m2, days 1-14, was given only with the first cycle. Cycle 3 consisted of 100 mg/m2 etoposide orally, days 1-5, and 1 gm/m2 bd cytosine arabinoside (ara-C) days 1-5. Cycles 1-3 were then repeated. Intrathecal methotrexate (MTX) 12.5 mg was given on day 1 of each treatment cycle. The first 12 consecutive patients received this chemotherapy alone, the subsequent 14 received, in addition, 3 micrograms/kg GM-CSF subcutaneously, from day 4 of cycles 1,2,4 and 5 (and from day 6 of cycles 3 and 6) until the absolute neutrophil count had reached 0.5 x 10(9)/1. All patients in whom CR was achieved then received prophylactic cranial irradiation. With the exception of those with T-ALL, this was followed by oral maintenance therapy consisting of 6-mercaptopurine, MTX, and cyclophosphamide for 3 years. Patients receiving GM-CSF did not have shorter intercycle times or a lower incidence of documented infections than those who did not receive it. The CR rate was 89% overall-uninfluenced by GM-CSF, but higher than that achieved previously at St Bartholomew's Hospital in an equivalent age-group.