Augmented Reduced-Intensity Regimen Does Not Improve Postallogeneic Transplant Outcomes in Acute Myeloid Leukemia.

PURPOSE: Reduced-intensity conditioning (RIC) regimens have extended the curative potential of allogeneic stem-cell transplantation to older adults with high-risk acute myeloid leukemia (AML) and myelodysplasia (MDS) but are associated with a high risk of disease relapse. Strategies to reduce recurrence are urgently required. Registry data have demonstrated improved outcomes using a sequential transplant regimen, fludarabine/amsacrine/cytarabine-busulphan (FLAMSA-Bu), but the impact of this intensified conditioning regimen has not been studied in randomized trials. PATIENTS AND METHODS: Two hundred forty-four patients (median age, 59 years) with high-risk AML (n = 164) or MDS (n = 80) were randomly assigned 1:1 to a fludarabine-based RIC regimen or FLAMSA-Bu. Pretransplant measurable residual disease (MRD) was monitored by flow cytometry (MFC-MRD) and correlated with outcome. RESULTS: There was no difference in 2-year overall survival (hazard ratio 1.05 [85% CI, 0.80 to 1.38] P = .81) or cumulative incidence of relapse (CIR) (hazard ratio 0.94 [95%CI, 0.60 to 1.46] P = .81) between the control and FLAMSA-Bu arms. Detectable pretransplant MFC-MRD was associated with an increased CIR (2-year CIR 41.0% v 20.0%, P = .01) in the overall trial cohort with a comparable prognostic impact when measured by an unsupervised analysis approach. There was no evidence of interaction between MRD status and conditioning regimen intensity for relapse or survival. Acquisition of full donor T-cell chimerism at 3 months abrogated the adverse impact of pretransplant MRD on CIR and overall survival. CONCLUSION: The intensified RIC conditioning regimen, FLAMSA-Bu, did not improve outcomes in adults transplanted for high-risk AML or MDS regardless of pretransplant MRD status. Our data instead support the exploration of interventions with the ability to accelerate acquisition of full donor T-cell chimerism as a tractable strategy to improve outcomes in patients allografted for AML.

Integrated scientific data bases review on asulacrine and associated toxicity.

Asulacrine (ASL), a weakly basic and highly lipophilic drug was synthesized in 1980's in cancer research laboratory of Auckland by modifications to the acridine portion of amsacrine on 3-, 4- and 5-substitution patterns. In contrast to its precursor amsacrine (m-AMSA), ASL was effective not only against leukemia and Lewis lung tumor system but also a wide variety of solid tumor. Its metabolic pathway is not same to amsacrine hence different side effects, hepatotoxicity and excretion was observed. Asulacrine is under phase II clinical trials and has showed promising results but its toxicity especially phlebitis is stumbling block in its clinical implementation. This review is an effort to give a possible clue, based on scientifically proven results, to the researchers to solve the mystery of associated toxicity, phlebitis. Review covers the available literature on asulacrine and other acridine derivatives regarding pharmacology, pharmacokinetics, quantitative structure activity relationship and toxicology via electronic search using scientific databases like PubMed and others. To date, all abstracts and full-text articles were discussed and analyzed. The tabulated comparisons and circuitry mechanism of ASL are the added features of the review which give a complete understanding of hidden aspects of possible route cause of associated toxicity, the phlebitis.

Post-insertion of poloxamer 188 strengthened liposomal membrane and reduced drug irritancy and in vivo precipitation, superior to PEGylation.

The ultimate aim of this study was to develop asulacrine (ASL)-loaded long-circulating liposomes to prevent phlebitis during intravenous (i.v.) infusion for chemotherapy. Poly(ethylene)glycol (PEG) and poloxamer 188-modified liposomes (ASL-PEGL and ASL-P188L) were developed, and ASL was loaded using a remote loading method facilitated with a low concentration of sulfobutyl ether-ß-cyclodextrin as a drug solubilizer. The liposomes were characterized in terms of morphology, size, release properties and stability. Pharmacokinetics and venous tissue tolerance of the formulations were simultaneously studied in rabbits following one-hour i.v. infusion via the ear vein. The irritancy was assessed using a rat paw-lift/lick model after subplantar injections. High drug loading 9.0% w/w was achieved with no drug leakage found from ASL-PEGL or ASL-P188L suspended in a 5% glucose solution at 30days. However, a rapid release (leakage) from ASL-PEGL was observed when PBS was used as release medium, partially related to the use of cyclodextrin in drug loading. Post-insertion of poloxamer 188 to the liposomes appeared to be able to restore the drug retention possibly by increasing the packing density of phospholipids in the membrane. In rabbits (n=5), ASL-P188L had a prolonged half-life with no drug precipitation or inflammation in the rabbit ear vein in contrast to ASL solution. Following subplantar (footpad) injections in rats ASL solution induced paw-lick/lift responses in all rats whereas ASL-P188L caused no response (n=8). PEGylation showed less benefit possibly due to the drug 'leakage'. In conclusion, drug precipitation in the vein and the drug mild irritancy may both contribute to the occurrence of phlebitis caused by the ASL solution, and could both be prevented by encapsulation of the drug in liposomes. Poloxamer 188 appeared to be able to 'seal' the liposomal membrane and enhance drug retention. The study also highlighted the importance of bio-relevant in vitro release study in formulation screening.

High-dose cytarabine consolidation with or without additional amsacrine and mitoxantrone in acute myeloid leukemia: results of the prospective randomized AML2003 trial.

PURPOSE: To assess the treatment outcome benefit of multiagent consolidation in young adults with acute myeloid leukemia (AML) in a prospective, randomized, multicenter trial. PATIENTS AND METHODS: Between December 2003 and November 2009, 1,179 patients (median age, 48 years; range, 16 to 60 years) with untreated AML were randomly assigned at diagnosis to receive either standard high-dose cytarabine consolidation with three cycles of 18 g/m(2) (3× HD-AraC) or multiagent consolidation with two cycles of mitoxantrone (30 mg/m(2)) plus cytarabine (12 g/m(2)) and one cycle of amsacrine (500 mg/m(2)) plus cytarabine (10 g/m(2); MAC/MAMAC/MAC). Allogeneic and autologous hematopoietic stem-cell transplantations were performed in a risk-adapted and priority-based manner. RESULTS: After double induction therapy using a 3 + 7 regimen including standard-dose cytarabine and daunorubicin, complete remission was achieved in 65% of patients. In the primary efficacy population of patients evaluable for consolidation outcomes, consolidation with either 3× HD-AraC or MAC/MAMC/MAC did not result in any significant difference in 3-year overall (69% v 64%; P = .18) or disease-free survival (46% v 48%; P = .99) according to the intention-to-treat analysis. Furthermore, MAC/MAMAC/MAC led to additional GI and hepatic toxicity and a higher rate of infection and bleeding, resulting in significantly shorter 3-year overall survival in the per-protocol analysis compared with 3× HD-AraC (63% v 72%; P = .04). CONCLUSION: In younger adults with AML, multiagent consolidation using mitoxantrone and amsacrine in combination with high-dose cytarabine does not improve treatment outcome and confers additional toxicity.

Early allo-SCT for AML with a complex aberrant karyotype--results from a prospective pilot study.

In AML, a complex aberrant karyotype is associated with poor response to chemotherapy and dismal prognosis. We prospectively studied the concept of allogeneic haematopoietic SCT (HSCT), performed early and regardless of response to induction treatment in patients with complex karyotype AML (CK-AML). The preparative regimen consisted of fludarabine, Ara-C and amsacrine (FLAMSA) chemotherapy, followed by reduced intensity conditioning (RIC) 3 days later. In vivo T-cell depletion by anti-thymocyte globulin was used to protect from early GvHD, and prophylactic donor lymphocyte transfusion was given from day+120 to augment the GvL effect, once tolerance was established. Eighteen consecutive patients with CK-AML (median age: 53 years) received HSCT from related (n=7) or unrelated (n=11) donors. Before FLAMSA-RIC, nine patients each had received one and two induction courses. Stage at start of FLAMSA-RIC was CR/CRi (n=8) or persistent disease (n=10). Following HSCT, 16 patients achieved CR. After a follow-up of 51 months, 11 patients are alive in CR, whereas seven have died in remission (n=3), or from leukaemia (n=4). Cumulative incidence of relapse, non-relapse mortality, acute GvHD≥II and chronic GvHD were 0.222±0.098, 0.235±0.104, 0.367±0.120 and 0.481±0.123, respectively. Four-year survival from HSCT is 61%. Early HSCT following FLAMSA-RIC may improve the outcome of this unfavourable AML subgroup.

Citrulline as a marker for chemotherapy induced mucosal barrier injury in pediatric patients.

BACKGROUND: The currently used National Cancer Institute (NCI) adverse events criteria for mucosal barrier injury (MBI) are insufficient for use in children. We searched for objective, easily measurable indicators for MBI in children with cancer. PURPOSE: In children with acute myeloid leukemia, various MBI-related clinical and laboratory tests were investigated, reflecting clinical severity (NCI symptomatic adverse events criteria (gold standard), daily gut score (DGS)), inflammation (plasma and fecal interleukin-8 (IL-8), fecal calprotectin), enterocytic loss (plasma citrulline, ratio fecal human DNA/total DNA) and intestinal permeability (sugar absorption tests). RESULTS: Intestinal MBI as detected by the NCI adverse events criteria was found in 55% of chemotherapy cycles, correlating well with the continuous DGS (n = 55, rho = 0.581; P < 0.001). Intestinal cell loss as measured by the ratio fecal human DNA/total DNA and plasma citrulline correlated well with both NCI criteria (n = 61, rho = 0.357, P = 0.005 resp. n = 58, rho = -0.482; P < 0.001) and DGS (n = 54, rho = 0.352, P = 0.009 resp. n = 55, rho = -0.625; P < 0.001). Plasma IL-8 correlated strongly to plasma citrulline (n = 46, rho = -0.627; P < 0.001). CONCLUSIONS: MBI was reflected by parameters indicating inflammation (IL-8) and cell loss (plasma citrulline, ratio fecal human DNA/total DNA). We conclude that plasma citrulline might be a good parameter for MBI. Further studies are needed to show whether plasma citrulline can be used as a marker for MBI in future research.

The chemotherapeutic agents nocodazole and amsacrine cause meiotic delay and non-disjunction in spermatocytes of mice.

Aneuploidy of germ cells contributes to reduced fertility, foetal wastage and genetic defects. The possible risk of aneuploidy induction by the cancer chemotherapeutic drugs amsacrine (AMSA) and nocodazole (NOC) was investigated in male mice. Two molecular cytogenetic approaches were used: (1) the BrdU-incorporation assay to test the altered duration of meiotic divisions and (2) the sperm-FISH assay to determine aneuploidy induction during meiosis by observing hyperhaploid and diploid sperm. Sperm were sampled from the Caudae epididymes of treated and solvent control males. Single intraperitoneal injections with NOC (35 mg/kg) and AMSA (15 mg/kg) caused a meiotic delay of 24h. The timing of sperm sampling for the sperm-FISH assay was adjusted accordingly, i.e. 23 days after treatment. Mice were treated with 18, 35 and 50 mg/kg of NOC, or 5, 10, 15 and 20 mg/kg of AMSA. Significant dose-dependent increases above the concurrent controls in the frequencies of hyperhaploid sperm were found with both agents. Significant increases in the frequencies of diploid sperm were found only with AMSA. These results provide a basis for genetic counselling of patients under AMSA or NOC chemotherapy. During a period of 3-4 months after the end of chemotherapy, they may stand a higher risk of siring chromosomally abnormal offspring.

Autologous stem cell transplantation after complete remission and first consolidation in acute myeloid leukemia patients aged 61-70 years: results of the prospective EORTC-GIMEMA AML-13 study.

BACKGROUND AND OBJECTIVES: The optimal post-remission treatment for elderly patients with acute myeloid leukemia (AML) is presently unknown. Recent studies have reported the feasibility of autologous peripheral blood stem cell transplantation (PBSCT) in this population. We evaluate the outcome of this post-remission approach after complete remission (CR) and consolidation in elderly patients included in the EORTC-GIMEMA AML-13 trial. DESIGN AND METHODS: PBSCT after induction and consolidation chemotherapy was evaluated in patients aged 61 to 70 years with a WHO performance status 0-1. The induction therapy was mitoxantrone, etoposide and cytarabine (MICE) with or without granulocyte colony-stimulating factor (G-CSF) during and/or after chemotherapy. The consolidation therapy consisted of non-infusion or infusional idarubicin, etposide and cytarabine (mini-ICE). RESULTS: Sixty-one patients were scheduled for stem cell harvest by leukapheresis after s.c. recombinant human G-CSF administration initiated after hematopoietic recovery from consolidation. Stem cells were effectively harvested from 54 patients. A median of two aphereses (range, 1-5) were performed, resulting in a median collection of 11.7 x 10(8) nucleated cells/kg (range, 2.4-99.8) containing 40.2 x 10(4) CFU-GM/kg (range, 0-786.8), and 5 x 10(6) CD34+ cells/kg (range, 0.1-99.8). For the whole group of 61 patients, the median disease-free survival (DFS) was 1.0 years and the 3-year DFS rate was 21%, while the median overall survival (OS) was 1.4 years and the 3-year OS rate was 32%. A total of 26 patients could not be autografed due to inadequate/no harvest (21 patients), early relapse (3 patients), or treatment refusal (2 patients). Autologous transplantation was performed in 35 patients following conditioning with the BAVC regimen. The median time for granulocyte recovery >0.5 109 yen/L was 24 days and for platelets >20 x10(9)/L was 23 days following transplantation. After a median follow-up of 5.0 years from transplantation, the median DFS and OS were 1.1 and 1.6 years respectively, and the 3-year rates were 28% and 39% respectively. Eight autografted patients were still in continuous complete remission, 22 patients had relapsed and five had died in CR. INTERPRETATION AND CONCLUSIONS: Intensification of remission including autologous PBSCT is feasible in about half of harvested patients aged 61 to 70 years old, and did not improve the general outcome. This shows the limitations of autologous PBSCT and other intensive treatment modalities in elderly AML patients. Key words: acute myeloid leukemia, elderly, autologous stem cell transplantation.

Effect of priming with granulocyte-macrophage colony-stimulating factor in younger adults with newly diagnosed acute myeloid leukemia: a trial by the Acute Leukemia French Association (ALFA) Group.

In a multicenter trial, 259 young adults (15-49 years) with newly diagnosed acute myeloid leukemia (AML) were first randomized to receive a timed-sequential induction regimen given either alone (135 patients) or concomitantly with granulocyte-macrophage colony-stimulating factor (GM-CSF) (124 patients). Patients reaching complete remission (CR) were then randomized to compare a timed-sequential consolidation to a postremission chemotherapy including four cycles of high-dose cytarabine followed by maintenance courses. In the appropriate arm, GM-CSF was given concurrently with chemotherapy during all cycles of consolidation. CR rates were significantly better in the GM-CSF arm (88 vs 78%, P<0.04), but did not differ after salvage. Patients receiving GM-CSF had a higher 3-year event-free survival (EFS) estimate (42 vs 34%), but GM-CSF did not impact on overall survival. Patients with intermediate-risk cytogenetics benefited more from GM-CSF therapy (P=0.05) in terms of EFS than patients with other cytogenetics. This was also confirmed when considering only patients following the second randomization, or subgroups defined by a prognostic index based on cytogenetics and the number of courses required for achieving CR. Priming of leukemic cells with hematopoietic growth factors is a means of enhancing the efficacy of chemotherapy in younger adults with AML.

Improved outcome in childhood acute myeloid leukemia in Singapore with the MRC AML 10 protocol.

BACKGROUND: The introduction of the United Kingdom Medical Research Council's 10th AML trial (MRC AML 10) protocol incorporating high-dose anthracycline therapy has improved outcome of children with acute myeloid leukemia (AML). In this study, we review the results of childhood AML therapy in a Singapore university hospital over the last 17 years emphasizing toxicity and outcome. PROCEDURE: Retrospective analysis revealed 34 children with AML between 1988 and 2003. Prior to September 1996, therapy consisted of: POG-8498 (n = 10), others (n = 9). From September 1996, all but one of 15 children received MRC AML 10 treatment. RESULTS: At the time of analysis, 17 had died from disease, and 17 patients were alive among whom 2 had relapsed. MRC AML 10-treated patients (n = 14) had significantly better 3-year overall, event-free, and disease-free survival (74% vs. 35%, 77% vs. 20%, 83% vs. 31%; P = 0.019, P = 0.002, and P = 0.010, respectively) and were likelier to achieve complete remission (CR) than non-MRC AML 10 patients (P = 0.102). Among patients who achieved CR, MRC AML 10-treated patients were significantly more likely to achieve CR after only one cycle of chemotherapy (P = 0.016). Hematologic toxicity was similar among the different regimens (P = 0.9). CONCLUSIONS: These findings suggest that MRC AML 10 treatment results in significantly superior survival, without excess toxicity. Future studies should attempt to elucidate the relative importance of individual MRC AML 10 components and reduce the high cumulative anthracycline dose without compromising outcome.

Risk-adapted induction and consolidation therapy in adults with de novo AML aged

We treated 305 de novo acute myeloid leukemia (AML) patients aged

A study of amsalog (CI-921) administered orally on a 5-day schedule, with bioavailability and pharmacokinetically guided dose escalation.

PURPOSE: Amsalog is a derivative of 9-aminoacridine. Phase I studies using intravenous (i.v.) amsalog have shown the dose-limiting toxicity (DLT) to be phlebitis and myelosuppression. Phase II studies using a variety of schedules have shown evidence of activity in patients with large-cell lung, breast, and head and neck cancers. Preclinical studies demonstrated that amsalog is active orally: a clinical study of the oral bioavailability of amsalog was therefore performed. METHODS: A group of 20 patients with refractory malignancies were treated. There were two phases of the study: a pharmacokinetic comparison of i.v. against oral amsalog, followed by a pharmacokinetically guided oral dose escalation study. In the first phase of the study, 11 patients were treated. Amsalog 50 mg/m2 was administered i.v., and 50 mg/m2 and 200 mg/m2 orally. In the second phase of the study, 9 patients were treated in three cohorts of three. On day 1 of a 5-day schedule, amsalog was administered i.v. at the maximum tolerated dose (MTD) of 200 mg/m2. Subsequent doses were given orally, starting at a dose of 200 mg/m2 per day, with intrapatient dose escalation of up to 100% for the second cycle. Doses were escalated further in subsequent cohorts, based on oral bioavailability and toxicity. RESULTS: Oral bioavailability of 50 mg/m2 amsalog was 34%. In the dose escalation phase, DLT was neutropenia; other toxicities included malaise and nausea. The MTD was 1600 mg/m2 per day for 5 days. The plasma AUC using 1600 mg/m2 by the oral route was higher than that achieved using 200 mg/m2 by the i.v. route. CONCLUSION: Amsalog can be tolerated orally on a 5-day schedule at doses up to 1600 mg/m2. The recommended dose for further evaluation is 800 mg/m2 daily for 5 days, repeated three weekly.

A phase I trial of amsalog (CI-921) administered by intravenous infusion using a 5-day schedule.

PURPOSE: Amsalog, a derivative of 9-aminoacridine, is an inhibitor of topoisomerase II. Early studies of intravenous amsalog administered either once weekly, or daily for 3 days repeated every 3 weeks, showed that myelosuppression is the dose-limiting toxicity (DLT). Phase II studies showed only limited activity in breast, head and neck, and non-small-cell lung cancer. The activity of other topoisomerase inhibitors is schedule-dependent. We therefore performed a phase I study to evaluate the use of amsalog on a more prolonged schedule. METHODS: A group of 19 patients with refractory malignancies were treated in six cohorts using 2-h infusions of amsalog daily for 5 days, repeated every 3 weeks. RESULTS: Myelosuppression was seen as DLT at 200 mg/m2 per day. Other toxicities included nausea and vomiting, fatigue, and, when administered via a peripheral venous line, severe phlebitis necessitating administration via an indwelling central venous catheter for doses greater than 100 mg/m2. Pharmacokinetic studies showed a linear relationship between Cmax and AUC, and dose. The terminal half-life was 2 h, consistent with previous studies. CONCLUSION: We conclude that amsalog can be safely given on a 5-day schedule every 3 weeks at doses up to 200 mg/m2. The dose recommended for further studies is 180 mg/m2 per day for 5 days repeated every 3 weeks. However, in view of the phlebitis, which necessitated the use of central venous catheters for administration, other routes of administration, for example oral formulations, should be explored.

Analysis of messy longitudinal data from a randomized clinical trial. MRC Lung Cancer Working Party.

The randomized clinical trial, LU19, conducted by the Medical Research Council Lung Cancer Working Party, was designed to compare ACE (doxorubicin, cyclophosphamide and etoposide) chemotherapy plus G-CSF (granulocyte colony-stimulating factor) at 2-week intervals versus ACE chemotherapy alone at standard 3-week intervals in patients with small-cell lung cancer. This trial investigated whether more intensive administration of ACE would improve overall survival and affect the quality of life of patients. The report on overall survival and other outcome measures will be published in the Journal of Clinical Oncology. In this paper we focus on methods of analysing aspects of data reflecting quality of life. Twelve symptoms of lung cancer and its treatment - cough, haemoptysis, pain, nausea, vomiting, hoarse voice, sore mouth, rash, lethargy, lack of appetite, alopecia, and dysphagia - were scheduled to be assessed on seven occasions for the ACE arm and on eight occasions for the ACE+G-CSF arm by clinicians during the first 18 weeks of the treatment period. However, in practice the number of assessment forms completed per patient ranged from 1 to 9, and assessment time-points were very different from those planned. These 'messy' longitudinal data are explored by both a summary measure approach, in which experience of a symptom is summarized by a single value, and an extensive model-based statistical approach, which explicitly takes into account correlation within repeated measures. These analyses provide a clear picture of symptom comparisons between the two treatments. The application of various methods offers not only an approach to assessing the robustness of the results but also a basis for investigating reasons for inconsistency of results across methods. We conclude that except lethargy, which is worse in the ACE+G-CSF arm, all symptoms are similar across the two arms during the treatment period.

Prophylactic platelet transfusion threshold during therapy for adult acute myeloid leukemia: 10,000/microL versus 20,000/microL.

BACKGROUND AND OBJECTIVE: The threshold for prophylactic platelet transfusions has been classically established at 20,000/microL. In 48 patients with de novo acute myeloblastic leukemia (AML) we analyzed the effect of reducing the threshold for prophylactic platelet transfusion from 20,000/microL (group A) to 10,000/microL (group B) after induction and consolidation chemotherapy. DESIGN AND METHODS: Forty-eight adult patients with de novo AML diagnosed in a single institution in a nine year period were enrolled in the study. Between January 1989 and December 1993 the patients received prophylactic platelet transfusions when their platelet count was below 20,000/microL (group A), and from January 1994 to March 1998 prophylactic platelet transfusions were indicated below 10,000/microL or between 10,000/microL and 20,000/microL if there was any consumption factor. RESULTS: The mean number (SD) of platelet transfusions during induction was 8.4 (5.3) in group A and 8.5 (5.5) in group B; and during consolidation 4.7 (3.4) in group A and 4.6 (3.8) in group B (p = n.s.). Excluding the cases with consumption factors from the analysis, group B patients required 34% fewer transfusions during induction and 15.5% fewer during consolidation (p = 0.04). There were no differences between groups regarding major bleeding episodes. INTERPRETATION AND CONCLUSIONS: Our data show that the threshold for prophylactic platelet transfusion can be safely set at 10,000 microL during induction and consolidation chemotherapy for adult patients with de novo AML.

Toxicity of cytostatic drugs to normal bone marrow cells in vitro.

In this study we compared how different concentrations and periods of incubation of anthracyclines, amsacrine, and cytosine arabinoside would affect normal hematopoietic bone marrow cells in terms of interindividual differences in toxicity, the age of the donor, and the proliferative capacity of the bone marrow. Bone marrow was obtained from 36 donors in connection with bone marrow transplantation. After separation the mononuclear cell fraction was incubated with doxorubicin, 4-epidoxorubicin, daunorubicin, idarubicin, aclarubicin, mitroxantrone, amsacrine, and cytosine arabinoside for 1 h, for 3 h, or continuously. The cells were thereafter cultured in soft agar and CFU-GM were counted after 10-12 days. The results showed a large interindividual variation in toxicity for all drugs tested. Daunorubicin, idarubicin, aclarubicin, and mitoxantrone had a pronounced cytotoxic effect after 1 h of incubation. Doxorubicin and 4-epi-doxorubicin showed the greatest cytotoxic effect after 3 h and were also more toxic to normal bone marrow cells from donors over 40 years of age. Ara-C had a low cytotoxic effect after 1 and 3 h of incubation, even at high concentrations, but exerted a pronounced degree of toxicity during continuous incubation. Daunorubicin, idarubicin, and ara-C also showed increased toxicity to cell samples with a low proliferating capacity in the control. The conclusions drawn from these results are that interindividual variation, proliferation capacity, incubation conditions, and the age of the donors are factors of importance in the toxicity of drugs to normal hematopoietic bone marrow cells.

Marked improvements in outcome with chemotherapy alone in paediatric acute myeloid leukemia: results of the United Kingdom Medical Research Council's 10th AML trial. MRC Childhood Leukaemia Working Party.

359 eligible children with acute myeloid leukaemia (AML) entered the MRC AML 10 trial between May 1988 and March 1995. Patients received four courses of intensive induction and consolidation chemotherapy, with or without subsequent autologous (A-BMT) or allogeneic (allo-BMT) bone marrow transplant. There were randomized comparisons of thioguanine versus etoposide in induction and of A-BMT versus not. Allo-BMT was recommended for patients with a HLA-matched sibling and was evaluated by donor versus no donor comparison. The complete remission rate was 92%. In first remission there were 20 deaths during consolidation chemotherapy and 11 after BMT (8/61 allo-BMTs. 1/60 A-BMTs and 2/4 matched unrelated donor transplants). The relapse rate was low, decreasing from 26% in the first year to 2% in the fourth. Long-term outcome was excellent with survival at 7 years from entry of 56% and event-free survival of 48%. There were no significant differences between thioguanine and etoposide, whereas both A-BMT and allo-BMT reduced relapse risk but did not produce a significant survival benefit. It appears that over half the children entered into AML 10 are cured, a result which compares favourably with other reported series. We conclude that four courses of intensive chemotherapy are an effective approach to the treatment of paediatric AML, which avoids the acute toxicity and long-term side-effects of BMT and also avoids the need for prolonged maintenance therapy or cranial irradiation.

[Phase III clinical trial on domestic amsacrine in patients with acute leukemias].

OBJECTIVE: To further evaluate the efficacy and side-effects of domastic amsacrine. METHODS: Two handred and ninty-one patients with acute leukemias, including initial, relapsed and refractory cases, were treated with regimens combining the amsacrine with other antileukemic drugs. RESULTS AND CONCLUSION: The total CR rate was 43.3% in ALL and 49.0% in ANLL. The CR rates of relapsed/refractory ALL and ANLL was 28.9% and 34.4%, respectively. The side effects and toxicity of the amsacrine-based regimen were similar to that of other antileukemia regimens. The pharmacokinetic parameters of the domastic amsacrine, C12h/C6h, K21 were correlated with therapeutic effectiveness.

BAVC regimen and autograft for acute myelogenous leukemia in second complete remission.

Since 1984 we have autografted a total of 60 patients with AML in second complete remission (CR) utilizing the BAVC (BCNU, amsacrine, vepesid, cytosine-arabinoside) conditioning regimen and unpurged marrow. Projected disease-free survival (DFS) probability in 42% at 10 years. Autografting was performed at a median interval of 2 months (range 1-13) from second CR. The median duration of first CR was 14 months (range 1-43) and lasted < or = 12 months in 27/60 patients. Three early deaths (5%) occurred, 30 patients relapsed after a median of 6 months from transplant (range 2-28) and, of the remaining 27 patients, 26 are in continuous CR (CCR) after a median follow up of 60 months (range 6-122), while the last patient committed suicide 7 years after ABMT when she was still in CCR. A first CR duration > 12 months is correlated with a significantly better overall survival probability (61 vs 25%, P = 0.02), while no factors influence DFS. Outcome of patients who relapsed after autografting has been analyzed separately; a longer overall survival after relapse is correlated with a longer duration of the second CR (62% at 34 months for patients who relapsed after > 12 months from the autograft vs 5% for the others, P = 0.001). These results confirm that AML patients autografted in second CR with BAVC regimen and unpurged marrow have the possibility of becoming long-term DFS and can therefore be cured.