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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.

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., (Copyright © 2016. Published by Elsevier Ireland Ltd.)

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-β-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., (Copyright © 2015. Published by Elsevier B.V.)

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.

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.

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., ((c) 2009 Wiley-Liss, Inc.)

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.

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.

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.

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., ((c) 2006 Wiley-Liss, Inc.)

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

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.

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.

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.

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.

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.

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.

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.

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.

Amsacrine (AMSA) was a high effective medicine of acute leukemia treatment. But it could lead to severe phlebitis with venous drip. 44 patients were treated 71 courses with AMSA. After we used fasting venous drip and diluting high concentration AMSA, occurrence of phlebitis remarkably decreased and patients of phlebitis could be cured with early comprehensive nursing.

The objective of this study was to compare allogeneic bone marrow transplantation (BMT) with high-dose cytarabine containing chemotherapy in children with acute myeloid leukemia (AML) in first complete remission (CR). One hundred and seventy-one children were enrolled on the LAME89/91 protocol. Induction chemotherapy was a combination of cytarabine and mitoxantrone. After achieving CR, patients who had an HLA-identical sibling donor underwent allogeneic BMT. Children not eligible for BMT received post remission chemotherapy which included two consolidation courses, the second consolidation consisting of high-dose cytarabine with amsacrine and asparaginase. CR was achieved in 149 children (87%). Thirty-two had an HLA-identical sibling donor and were eligible for BMT. These 32 patients, as well as an additional child who had a one antigen HLA-mismatched father, received BMT during first CR. Consequently, 33 patients were analyzed in the BMT group and 116 in the chemotherapy group. The 4-year probability of relapse was 26 +/- 15% in the BMT group and 47 +/- 10% in the chemotherapy group (P = 0.04). The risk of therapy-related death was 3% for BMT and 7.7% for chemotherapy. Disease-free survival (DFS) was 72 +/- 15% in the BMT group and 48 +/- 10% in the chemotherapy group (p = 0.02). We conclude that allogeneic BMT from a matched sibling donor is the treatment of choice for reducing the relapse risk and for increasing DFS in children with AML in first CR.

The efficacy and toxicity of a regimen consisting of amsacrine (m-AMSA), cytarabine, and thioguanine for remission-induction therapy in poor prognosis categories of acute myeloid leukaemia (AML) were determined in a single arm study of 46 patients. The study group consisted of 17 patients with disease refractory to daunorubicin plus cytarabine-based induction regimens, 22 patients with disease which had relapsed during daunorubicin plus cytarabine maintenance therapy, or following completion of this maintenance programme after receiving > or = 500 mg daunorubicin/m2, and 7 previously untreated patients where cardiac disease contraindicated anthracycline therapy. Complete remission (CR) was attained in 46%, and probability of survival was comparable to published results for first-line treatment with daunorubicin plus cytarabine regimens. There was no statistically significant difference in CR rate or probability of survival between these three categories of poor prognosis AML, and cardiotoxic complications were uncommon despite extensive anthracycline exposure in the majority. In the 43% of patients who were 60-76 years of age, there was no statistically significant difference in CR rate or probability of survival relative to patients < 60 years. This observation fails to support the view that less myelotoxic regimens with lesser efficacy should be the basic approach to treatment of AML in patients > or = 60 years of age.

Forty-eight patients with acute myelogenous leukemia (AML) not eligible for anthracycline or mitoxantrone treatment, mostly due to cardiac contraindications, were given aggressive therapy using m-amsacrine (AMSA) in combination with conventional or high-dose cytarabine for remission induction. Twenty-nine patients (60.4%) responded to treatment, and complete remission was attained in 19 (39.6%), partial remission in 4 (8.3%) and death in bone marrow aplasia without detectable blasts in 6 patients (12.5%). Median time to granulocyte recovery was 32 days, median duration of relapse-free survival 199 days. One patient experienced a serious cardiac adverse event; nausea and vomiting were observed in 73%, diarrhea in 44%, and hepatoxicity in 29% of patients. All potentially AMSA-related side effects were fully reversible, and a lethal complication did not occur. It is concluded that combination chemotherapy with AMSA and Ara-C is also effective and tolerable in leukemic patients in whom cardiotoxic drugs are contraindicated.

This clinical trial was designed to evaluate the role of high-dose cytarabine (ara-C) in the treatment of adults with acute myeloid leukaemia (AML) in first relapse. We also tested the hypothesis that the selective use of AMSA (100 mg/m2/d on days 7, 8 and 9) would increase the complete remission (CR) rate when leukaemia cells remained in the bone marrow immediately following 6 d of Ara-C (2-3 g/m2/12 h) alone. Of 155 patients evaluable for response, 115 (74%) experienced marked cytoreduction by day 6 and received no further induction chemotherapy; 53 (45%) of these patients achieved CR after one course and 45 (38%) had resistant disease. The 36 patients (23%) with inadequate cytoreduction after the 6 d of ara-C alone were randomly assigned either to no further chemotherapy (21 patients) or to 3 d of AMSA (15 patients). The CR rates after one course were 14% and 53%, respectively (P = 0.01), and the fractions with resistant disease were 76% and 40%, respectively. The fractional reduction of leukaemia cells in the day 6 bone marrow aspirate specimen (P < 0.0001) and the reduction in the leukaemia cell mass measured in the day 6 marrow biopsy (P = 0.001) were the strongest predictors for achieving CR versus having residual disease in univariate analyses. The median duration of remission was 5 months, but seven patients (10%) remain in CR after 30-92 + months. Among the 140 patients who received only the 6 d of ara-C, the pretreatment albumin (P = 0.002) and lactate dehydrogenase (P = 0.01) levels were the strongest predictors of response in univariate analyses, but only the albumin remained significant (P = 0.01) in a stepwise logistic regression analysis. Those patients with albumin > 4.0 mg/dl and LDH < 125% of normal had a 71% CR rate, and only 16% had resistant disease. Thus, pretreatment characteristics and rapid cytoreductin in the day 6 bone marrow sample identified a favourable subset of patients with AML in first relapse, some of whom responded quite well to 6 d of ara-C alone and have had long disease-free remissions.

Completely implantable ports have become increasingly popular for venous access in the treatment of cancer. An uncommon but very serious complication is reported here: extravasation of a cytostatic agent secondary to a damaged Port-a-Cath catheter. Guidelines to be observed in implantation are recommended.

The role of amsacrine in inducing remission in patients with cardiac disease and acute leukemia was evaluated. There were 17 patients with acute myelogenous leukemia (AML), six with acute lymphocytic leukemia (ALL), and one with biphenotypic leukemia. In this series of 24 patients whose disease had relapsed and who had reduced left ventricular ejection fraction, nine had a complete remission, seven with AML and two with ALL. In addition, four of six with newly diagnosed acute leukemia and reduced left ventricular ejection fraction also responded. Among nine patients who underwent endomyocardial biopsy, none had morphologic changes of sufficient degree to account for drug-induced heart failure. Patients with preexisting arrhythmias received amsacrine without incident if their serum potassium level was higher than 4.0 mEq/l at the time of drug administration. Amsacrine is safe and effective therapy for patients with acute leukemia and cardiac disease.

CI-921 (NSC 343499; 9-[[2-methoxy-4-[(methylsulphonyl)amino]phenyl]amino] -N,5-dimethyl- 4-acridinecarboxamide) is a topoisomerase II poison with high experimental antitumour activity. It was administered by 15 min infusion to 16 evaluable patients with non-small cell lung cancer (NSCLC) (7 with no prior treatment, 9 patients in relapse following surgery/radiotherapy) at a dose (648 mg/m2 divided over 3 days, repeated every 3 weeks) determined by phase I trial. Patients had a median performance status of 1 (WHO), and median age of 61 years. The histology comprised squamous carcinoma (11), adenocarcinoma (1), mixed histology (2), bronchio-alveolar carcinoma (1) and large cell undifferentiated carcinoma (1). Neutropenia grade greater than or equal to 3 was seen in 15 patients, infections with recovery in 3, and grand mal seizures in 1 patient. Grade less than or equal to 2 nausea and vomiting occurred in 66% courses and phlebitis in the infusion arm in 37%. 1 patient with squamous cell carcinoma achieved a partial response lasting 5 months. Further testing in this and other tumour types using multiple daily schedules is warranted.

52 patients with refractory or relapsed acute myeloid leukaemia (AML) were randomly assigned to receive a combination of high-dose cytosine arabinoside (HD Ara-C), 3 g/m2/d and either mitoxantrone (MTX), 7 mg/m2/d (5 mg if older than 60 yr) or m-amsacrine (AMSA), 120 mg/m2/d (90 mg if older than 60 yr) for 5 d. The overall response rate was 50% and did not differ significantly in the two groups (46% for AMSA and 56% for MTX, p = 0.415). The median survival was 11 months (8 months for AMSA and 12 months for MTX, p = 0.326) and the median duration of complete remission (CR) was 11 months for AMSA and 12 months for MTX (p = 0.643). In relapsed patients, the only significant predictive factor for obtaining a complete response was the length of first complete remission. Patients with a first CR shorter than 6 months had a CR rate of 36% while it was 65% if the first CR lasted more than 6 months (p = 0.03). Severe (WHO grade III-IV) gastro-intestinal toxicity was more frequent in the AMSA group (27% vs 4%, p = 0.021). Treatment-related death occurred in 4 patients in the AMSA group and in 2 patients in the MTX group (p = 0.097). We conclude that neither of these two treatment modalities was shown to be superior in terms of CR rate and survival, with a better tolerance for MTX.

Thirty adult patients with relapsed or refractory malignant lymphoma underwent a Phase I-II trial of salvage chemotherapy combining methyl-gag, high-dose Ara-C, M-Amsa, and ifosfamide (MAMI protocol). All patients had been extensively pretreated. At the time of salvage therapy, 21 patients had visceral involvement and 23 patients were refractory. The overall response rate was 50% (11 patients in complete remission and 3 patients in partial remission). The main toxicity was myelosuppression; 4 treatment-related deaths occurred and 17 patients died of tumor progression with a median of 5 months. The MAMI protocol showed similar antitumoral efficacy to that of other salvage chemotherapy regimens used for poor prognosis malignant lymphoma but was more toxic. However, a response rate of 45% in refractory patients should be taken into account and this drug association deserves further investigation with regard to the selection of patients for bone marrow transplants.

A series of 46 patients with acute leukaemia were treated with amsacrine (m-AMSA) and cytosine arabinoside (ara-C). Complete remission (CR) was achieved in 15 of 38 (40%) patients with acute myelogenous leukaemia (AML) and 4 of 8 (50%) patients with acute lymphoblastic leukaemia (ALL). The CR rate was significantly higher (P less than 0.05) for the younger, previously treated patients with AML (9/16) than for the older previously untreated ones (6/22), because of higher treatment mortality in the latter group. Myelosuppression was prolonged and profound. Major nonhaematological toxicity affected the gastrointestinal tract (nausea, vomiting, mucositis, bleeding and ileus associated with severe diarrhoea). Many patients also developed reversible hepatic dysfunction and two elderly patients died of cardiac arrhythmia. Further trials of this combination are justified in patients with relapsed or resistant leukaemia, but for older patients dose reduction is recommended.

Seventy-nine patients (aged 17-76 years) with acute myelogenous leukemia in first (56) or second (3) relapse, primary refractory leukemia (15) or leukemia occurring as secondary malignancy that developed after a preleukemic phase (3) or after another tumor (2) were given remission induction therapy consisting of cytosine arabinoside (Ara-C, 1 g/m2 as a 2-h infusion every 12 h for 6 days) and m-AMSA (120 mg/m2, i.v. on days 5, 6, 7). In total 45 patients (57%) achieved complete remission. Younger patients and those with a relatively low initial white blood cell count, a good performance status or in first relapse had a higher response rate. Thirty-five patients were given one or two courses of consolidation chemotherapy consisting of Ara-C (3 g/m2 as a 2-h infusion every 12 h for 4 days) and m-AMSA (120 mg/m2 i.v. on day 5). Three patients received an allogeneic bone marrow graft after the induction courses and four patients received an autologous bone marrow transplantation after consolidation therapy. The median of the disease-free survival curve was 21 weeks. The median duration of survival was 25 weeks. The response rate for this intermediate dose Ara-C regimen is satisfactory and does not differ from that reported for high dose Ara-C. The impact of consolidation chemotherapy in bad risk acute myelogenous leukemia is questionable.

AMSA was given to 22 evaluable patients with advanced head and neck cancer with measurable lesions. The starting dose was 90-120 mg/m2 by i.v. infusion over 45 min every 3 weeks. The dose of AMSA was escalated by 30 mg/m2 in absence of bone marrow toxicity. At least two cycles were given prior to the evaluation of response. Only one patient with oropharyngeal cancer achieved a partial response, lasting for 20 weeks. Toxicity was mild and mainly hematological. We conclude that AMSA given at this dose and schedule has little activity in head and neck cancer.

Twelve patients with recurrent and metastatic breast cancer were treated with a combination of adriamycin and amsacrine (m-AMSA) to evaluate its efficacy and toxicity. Adriamycin was given at 40 mg/m2 i.v. and m-AMSA at 50 mg/m2 i.v. every 3 weeks. No response was observed. One patient received an escalated m-AMSA dose at 70 mg/m2 and the same dose of adriamycin. She died of treatment-related leukopenia and infection. We conclude that the combination of adriamycin and amsacrine at the dose and schedule used in our trial has little antitumor effect in the treatment of advanced breast cancer.

Thirteen patients (7 male, 9 female) aged 22-71 years (means = 55 years) with acute non-lymphocytic leukemia and contraindications for anthracyclin therapy were treated with combined chemotherapy using m-amsacrine primarily or in relapse. The main reasons for avoiding cardiotoxic substances were overt cardiac insufficiency and former administration of daunorubicin with more than 540 mg/m2 body surface area. Amsacrine was combined with 6-thioguanine, VP 16-213 and cytosine arabinoside in conventional or high dosage. Eight out of 13 patients (62%) achieved complete remission after one or two courses of chemotherapy. One patient showed partial remission and could be brought into complete remission with another chemotherapy using high-dose ara-C and mitoxantrone. Three patients died in aplasia after chemotherapy and 1 other patient had to be regarded as a complete non-responder. Remission duration and survival time for the 8 successfully-treated patients so far is 1-12 months; however, medians have not yet been reached, since only one of the eight patients relapsed after 6 months of complete remission. These data indicate a high efficacy of m-amsacrine in combined chemotherapy for acute non-lymphocytic leukemia in high-risk patients with contraindications for anthracyclins.

A randomized phase II study of AMSA (amsacrine) alone and AMSA combined with DTIC (dacarbazine) was carried out in 31 and 39 patients with metastatic melanoma respectively. AMSA was used at a starting dose of 40 mg/m2/day X 3 days with escalation to 50-60 mg/m2/day X 3 days in 8 pts. For AMSA + DTIC the starting dose was: AMSA 30 mg/m2/day X 3 days; DTIC, 800 mg/m2 X 1 day. Additionally, seven pts received AMSA in a similar dose schedule but DTIC was used in a 5-day schedule of 250 mg/m2/day. Twenty-five patients were evaluable for response in the AMSA group and 36 in the AMSA + DTIC group. The objective response to AMSA included 1(4%) partial response compared with 11 complete or partial responses (30%) with AMSA + DTIC therapy. The median lowest absolute granulocyte count was 1100/microliters in AMSA group compared with 1000/microliters in the AMSA + DTIC group. Severe neutropenia of less than 500 granulocytes/microliter was observed in 5 pts in the AMSA group compared with 13 pts in the AMSA + DTIC group. We concluded that AMSA has no significant activity against melanoma, although the combination of AMSA + DTIC seemed to be more active than DTIC alone.

50 patients (aged 18-58 years) with acute myelogenous leukaemia after a preleukaemic phase (n = 14), acute myelogenous leukaemia that previously failed to respond to conventional chemotherapy (n = 9) or relapsed disease (n = 27) were given remission induction therapy consisting of cytosine arabinoside (1 g/m2 q 12 h x 12) and m-Amsa (115 mg/m2 for 1 or 3 days). Overall, 27 patients (54%) achieved complete remission. The complete remission rate for patients with acute myelogenous leukaemia after a preleukaemic phase (7/14) and those with primary refractory or relapsed leukaemia (20/36) seems superior to that obtained with conventional remission-induction therapy. 12 patients received 1-3 courses of consolidation chemotherapy with cytosine arabinoside (3 g/m2 q 12 h x 8) and m-Amsa (115 mg/m2 for 1 d). 3 of them subsequently underwent autologous bone marrow transplantation. The median duration of remission for the remaining 9 patients was 8 months. 11 patients did not receive consolidation therapy; their median duration of remission was 3 months. The difference between the two groups was not significant. 4 patients underwent allogeneic bone marrow transplantation after achievement of complete remission. The impact of high-dose cytosine arabinoside consolidation chemotherapy on poor-risk acute myelogenous leukaemia remains unclear.

Amsacrine, an antineoplastic agent currently undergoing clinical trials in the U.S., has been shown to be active against adult and pediatric leukemias, Hodgkin's disease, and non-Hodgkin's lymphomas. Amsacrine is highly bound to plasma proteins and is eliminated primarily via hepatic metabolism. Severe hepatic dysfunction will result in a decreased excretion rate of the drug. The primary side effect is a dose-related suppression of bone marrow function. Other reported toxic effects include mucositis, nausea, vomiting, cardiotoxicity, liver dysfunction, and alopecia. Despite these negative effects, amsacrine appears to have a role in the combination therapy of acute leukemias.

The combination of teniposide (VM-26) and amsacrine (AMSA) was evaluated in a dose-finding and efficacy study in 58 patients with relapsed or refractory acute leukemia. Both agents were given as simultaneous continuous infusions for 72 h through separate i.v. lines. All patients were evaluable for toxicity and 57 were evaluable for response; only 2 of 20 with acute lymphoblastic leukemia (ALL), acute mixed-lineage leukemia, or chronic myelogenous leukemia in blast crisis achieved a complete remission (CR). More encouraging was a second-remission rate of 43% (13 complete and 3 partial) in the 37 patients with acute nonlymphoid leukemia (ANLL). Responses occurred only in patients who received VM-26 doses of greater than or equal to 200 mg/m2 per day and AMSA doses of greater than or equal to 100 mg/m2 per day. Thus, the CR rate for relapsed ANLL patients who received the higher doses of both agents was 40% (13 of 33). All responders had previously received epipodophyllotoxin therapy and 40% had also received AMSA. All but one patient had severe leukopenia (less than 2.0 x 10(9) leukocytes/l) and thrombocytopenia (less than 50.0 x 10(9) platelets/l) as a results of therapy. Severe mucositis (grade 3 or 4) was the dose-limiting toxicity. Our results indicate that VM-26 plus AMSA, given by continuous infusion, is effective in the treatment of ANLL. Further phase II studies should consider using VM-26 at 200 mg/m2 per day and AMSA at 100 mg/m2 per day, but the best administration schedule remains unclear.

Twenty-nine evaluable patients with acute nonlymphoblastic leukemia (ANLL), either in relapse or resistant to initial induction therapy (ara C, daunorubicin + etoposide), received the ATA regime consisting of 100 mg/m2 per day Ara C by i.v. infusion for 4-5 days, 100 mg/m2 per day thioguanine orally for 4-5 days, and 100 mg/m2 per day amsacrine i.v. for 2-5 days. Each patient received 1-6 courses (median, 2) of the regime. There were 7 (24%) complete responders, and their duration of responses were 2, 2, 2, 5, 9+, 19, and 24+ months. The complete remission (CR) rate of patients who had a previous CR beyond 6 months (6/13, 46%) was significantly better (X2 = 4.25, p less than 0.05) than that of those who had previously relapsed within 6 months or were refractory to primary induction chemotherapy (1/16, 6%). The two groups of patients had similar patterns of treatment failure. Myelosuppression was the major toxic side effect, and nonhematological toxicities were mild and acceptable.

CI-921, an analogue of amsacrine with superior activity against in vivo and in vitro experimental tumor models, has been studied in 16 patients with solid tumors refractory to chemotherapy or for which conventional therapy does not exist. Thirty-nine cycles were given and doses escalated from 39 to 810 mg/m2. This total dose was divided over 3 consecutive days and administered by 15-min infusion each day, repeated three times weekly. Neutropenia (Eastern Cooperative Oncology Group) Grade greater than or equal to 3 occurred at Day 8 (range, 7-13) in 10/13 courses at 648 mg/m2 and in 2/2 courses at 810 mg/m2 with recovery in 10 (range, 4-20) days. At 810 mg/m2 Grade 2 mucositis and phlebitis were noted. Mild nausea and venous irritation occurred in some patients at doses greater than or equal to 288 mg/m2. No objective response was seen. Pharmacokinetics were evaluated following 65 infusions on Days 1 and 3 with plasma concentrations of CI-921 measured by high performance liquid chromatography. Peak plasma concentrations ranged from 3.36 to 85.6 mumol/liter and were significantly correlated with dose. Mean (range) model-independent pharmacokinetic parameters were: distribution half-life, 0.46 h (0.24-1.08); elimination half-life, 2.63 h (1.08-4.98); mean residence time, 2.0 h (1.05-3.35); plasma clearance, 158 ml/h/kg (95-290); and steady-state volume of distribution, 319 ml/kg (219-614) with no significant difference between Day 1 and 3. Toxicity as defined by absolute granulocyte count nadir was significantly correlated with dose, area under concentration-time curve, and peak plasma concentration. The recommended dose for Phase II studies in this schedule is 648 mg/m2 (216 mg/m2 daily for 3 days) repeated every three weeks.

Seventy-four previously treated patients with multiple myeloma were treated with Amsacrine (m-AMSA) 120 mg/m2 every 3 weeks. A good response was observed in two patients (3%), and improvement was seen in three patients (4%). Severe toxicity was observed in 33% of patients who received three or more courses of treatment. This dose and schedule of m-AMSA in multiple myeloma is usually ineffective.

Amsacrine is an acridine derivative that has been extensively evaluated for its antitumor activity in recent years. Amsacrine is active in the treatment of acute leukemias and lymphomas but largely ineffective in solid tumors. In acute myelogenous leukemia, amsacrine is as effective as the two most active drugs, cytarabine and daunorubicin and can produce complete remissions in patients refractory to these drugs. The addition of amsacrine to the limited therapeutic armamentarium for this disease offers the potential for improved remission rates and remission duration.