Randomized clinical study comparing aggressive chemotherapy with or without G-CSF support for high-risk myelodysplastic syndromes or secondary acute myeloid leukaemia evolving from MDS

One hundred and five consecutive primary high-risk myelodysplastic syndromes (MDS) or secondary acute myeloid leukaemia (sAML) evolving from MDS (performance status 0–3, ECOG) entered this study. Induction chemotherapy (CT) consisted of idarubicine 12 mg/m² i.v. on days 1 and 2, etoposide 60 mg/m²/12 h i.v. for 5 d, Ara-C 120 mg/m²/12 h i.v. for 5 d (one or two courses). Patients were randomized to receive or not G-CSF (5 μg/kg/d subcutaneously 48 h after the end of CT). 52 cases underwent CT alone and 53 CT+G-CSF. The CT + G-CSF patients had a significantly shorter duration of neutropenia (8 v 16 d) with a lower incidence of infections and significantly better responses (CR+PR: 74% v 52%, P  < 0.05). 40 patients entered CR: 17 with CT and 23 with CT+G-CSF. Responders underwent two consolidation courses with the same CT, followed by high-dose Ara-C (2 g/m² every 12 h for 3 d). Most CRs were clonal. At present 21 responders have relapsed (median relapse-free survival 4.5 months). Eight responders received an allo-BMT, six are alive in CR 7–57 months post-transplant. Therefore allo-BMT only increases the chance of a long survival and possible cure. In conclusion, CT+G-CSF did not prolong either CR duration or survival; the growth factor support, however, increased the number of allo-transplantable cases by inducing higher remission rates and improving clinical conditions.     

Treatment of acute myelogenous leukaemia in patients aged 50–65: idarubicin is more effective than zorubicin for remission induction and prolonged disease-free survival can be obtained using a unique consolidation course

From December 1987 to June 1992, 251 patients aged 50–65 with de novo acute myelogenous leukaemia (AML) were recruited to a multi-institutional randomized clinical trial. Induction therapy consisted of Ara-C (200 mg/m², continuous infusion, days 1–7) with either zorubicin (ZRB) (200 mg/m², i.v., days 1–4) or idarubicin (IDR) (8 mg/m², i.v., days 1–5). Consolidation therapy consisted of a single course of intensive chemotherapy with high-dose Ara-C (3 g/m², 3 h infusion, q 12 h, days 1–4) and m-Amsa (100 mg/m²/d, i.v., days 5–7).
The complete remission (CR) rate was (73%) with Ara-C/IDR versus (60%) with Ara-C/ZRB ( P  = 0.033). In multivariate analysis, factors found to be significant in predicting CR were normal karyotype and treatment with IDR. With a median follow-up of 73 months, the median disease-free survival (DFS) duration of all CR patients and the probability of CR at 6 years were 17 months and 29%. In multivariate analysis the only factor associated with an increased DFS duration was a normal karyotype. The median event-free survival (EFS) duration for all evaluable patients and the median overall survival duration for all eligible patients were respectively 7 and 12 months without any difference between induction arms.
The study shows that in patients aged 50–65 idarabicin is more effective than zorubicin for remission induction. However, the type of anthracycline did not influence overall survival duration. Using a unique consolidation course, we observed a prolonged DFS which compares favourably with results obtained with more prolonged consolidation therapy or maintenance treatment.     

Quinine improves the results of intensive chemotherapy in myelodysplastic syndromes expressing P glycoprotein: results of a randomized study

Intensive chemotherapy produces a lower complete remission (CR) rate in the myelodysplastic syndromes (MDS) than in de novo acute myeloid leukaemia (AML), possibly due in part to a higher incidence of P glycoprotein (PGP) expression in MDS blast cells. We designed a randomized trial of intensive chemotherapy with or without quinine, an agent capable of reverting the multidrug resistance (mdr) phenotype, in patients aged  65 years with high-risk MDS. Patients were randomized to receive mitoxantrone 12 mg/m²/d days 2–5 + AraC 1 g/m²/12 h days 1–5, with (Q⁺) or without (Q⁻) quinine (30 mg/kg/d). 131 patients were included. PGP expression analysis was successful in 91 patients. In the 42 PGP-positive cases, 13/25 (52%) patients in the Q⁺ group achieved CR, compared to 3/17 (18%) patients in the Q⁻ group ( P  = 0.02) and median Kaplan-Meier survival was 13 months in the Q⁺ group, and 8 months in the Q⁻ group ( P  = 0.01). No life-threatening toxicity was observed with quinine. In conclusion, the results of this randomized study show that quinine increases the CR rate and survival in PGP-positive MDS cases treated with intensive chemotherapy.     

Attenuated-dose idarubicin in acute myeloid leukaemia of the elderly: pharmacokinetic study and clinical results

AML in the elderly is characterized by intrinsic biological features implying an enhanced chemoresistance. Intensive chemotherapy should be the treatment of choice, but the standard doses could induce unacceptable rates of aplastic deaths. We evaluated the efficacy of an induction protocol with attenuated-dose idarubicin (IDA) 8 mg/m² for 3 d plus cytarabine and etoposide in 26 AML patients aged >60. 18 patients (69%) achieved CR, five (19%) were non-responders and three (12%) died during induction. To compare the pharmacokinetics of IDA between elderly and young patients, we assayed daily the serum level of the drug and of its metabolite (idarubicinol, IDAol) in a group of eight elderly patients who received a dose of 8 mg/m² (group A) and in a group of nine younger AML patients treated with 12 mg/m² (group B). The apparent terminal half-life of IDAol was significantly longer in the elderly than in the younger patients (mean half-life 59–7h versus 41–4h, P< 0–05). The values of the area under the serum concentration curve of IDAol indicated that the two patient groups received a very similar exposure to the drug despite the different doses.
In conclusion, this protocol, based on attenuated doses of IDA, compares well with the results obtained previously in similar age-matched patient series.     

Phase I trial of fludarabine, bortezomib and rituximab for relapsed and refractory indolent and mantle cell non-Hodgkin lymphoma

Based on the hypothesis that bortezomib may potentiate fludarabine activity by inhibiting DNA repair, we designed a phase I trial using this combination with rituximab in patients with relapsed and refractory indolent and mantle cell non-Hodgkin lymphoma. Twenty-four patients were enrolled. Non-Hodgkin lymphoma subtypes included 12 patients with follicular lymphoma, four with marginal zone lymphoma, three with lymphoplasmacytic lymphoma, three with mantle cell lymphoma and two with small lymphocytic/chronic lymphocytic leukaemia. Fludarabine and bortezomib were escalated in cohorts of three patients. Rituximab was added to the maximum tolerated dose of fludarabine and bortezomib and added significant dose-limiting myelosuppression. The maximum tolerated dose was fludarabine 25 mg/m² on days 1–3, bortezomib 1·3 mg/m² on days 1, 4, 8, 11, with rituximab 375 mg/m² on day 1 administered every 21 d. Clinical responses were observed in 11 patients, five of whom were refractory to their most recent treatment regimen. Six additional patients had stable disease for a median of 10 months (range 4–30+). Cumulative myelosuppression and neuropathy was observed. The combination of fludarabine, bortezomib, and rituximab appears to be an active regimen with manageable toxicity for relapsed NHL.     

Granulocyte colony-stimulating factor given in addition to interferon-α to mobilize peripheral blood stem cells for autologous transplantation in chronic myeloid leukaemia

In order to potentially mobilize and harvest the Ph⁻ cells observed in most patients with chronic myeloid leukaemia (CML) during interferon-α (IF-α) therapy, G-CSF (filgrastim), 5 μg/kg/d, was administered subcutaneously together with IF-α to 30 CML patients in haematological remission but with various degrees of cytogenetic remission, after IF-α therapy. Peripheral blood stem cells (PBSC ) were harvested using standard aphereses from day 5 of G-CSF. Patients underwent one to four (median three) aphereses. Median total yields/kg were 7.6 (range 3.8–25) × 10⁸ MNC, 3.4 (0–140) × 10⁶ CD34⁺ cells, and 17 (1.1–107) × 10⁴ CFU-GM. No patient had a significant increase in the percentage of Ph⁺ cells in the bone marrow under G-CSF therapy. The percentage of Ph⁺ cells in apheresis products tended to decrease between the first and the last apheresis ( P  = 0.05). 14 patients who were not responsive to IF-α were transplanted after conditioning with busulphan 16 mg/kg and melphalan 140 mg/m². Median time to neutrophils > 0.5 × 10⁹/l was 20 d (16–114 d) and to platelets > 50 × 10⁹/l 18 d (12–149 d). Nine patients had a major cytogenetic response post graft, which correlated with the amount of Ph⁺ cells reinfused with the graft ( P  = 0.02). We conclude that this procedure is feasible, allowing the harvest of enough PBSC, some of them Ph⁻ in patients who responded to IF-α, to allow autologous transplantation.     

Allogeneic blood or marrow transplantation for chronic lymphocytic leukaemia: timing of transplantation and potential effect of fludarabine on acute graft-versus-host disease

The outcome of allogeneic haemopoietic transplants including the rate of immune complications for patients with chronic lymphocytic leukaemia (CLL) refractory to or relapsing after chemotherapy with fludarabine was analysed.
Fifteen patients with advanced CLL who received allogeneic transplantation were prospectively analysed. All patients had previously received chemotherapy with fludarabine for 3–15 courses; 12 were refractory. The median number of circulating CD4^{^plus;} and CD8^{^plus;} lymphocytes at the time of transplant was 0.49 ×10⁹ l and 0.23 ×10⁹ l, respectively. One patient was transplanted from a one HLA-antigen mismatched unrelated donor. Three others received a one or two antigen mismatched graft and 11 had HLA-identical sibling donors. Patients received cyclosporine or tacrolimus in addition to methotrexate or methylprednisolone for prophylaxis of acute graft-versus-host disease (aGVHD).
Fourteen patients engrafted; one patient had graft failure, but recovered after therapy with intravenous immunoglobulin. 13 (87%) achieved complete remission (CR). Nine (53%) remain alive and in CR with a median follow-up of 36 (range 3–60) months. None developed visceral graft-versus-host disease. These data compared favourably to published reports in other leukaemia patients and for patients with CLL who received a comparable immunosuppressive therapy but without prior fludarabine exposure.
This data indicates that allogeneic haemopoietic transplantation can induce durable remission in patients with CLL refractory to fludarabine and that it is reasonable to delay transplantation until failure of fludarabine therapy. It also suggests that prior exposure to fludarabine may decrease the incidence of severe aGVHD, possibly through its immunosuppressive effects. Further studies are warranted to evaluate this observation.     

Use of fludarabine in the treatment of acute myeloid leukemia

Acute myeloid leukemia (AML) is a disease, which when left untreated, is invariably fatal. The disease is more common in elderly people, who also fare worse than younger patients with AML due to a higher rate of unfavorable prognostic factors, such as poor performance status, multiple comorbidities, reduced tolerance to treatment, 'unfavorable' chromosomal abnormalities and multidrug resistant protein-1 expression. While many patients achieve a complete remission, the rate of relapse is high and prognosis after relapse very poor. Promising results have been published in recent years using fludarabine-containing combination therapy for AML, most commonly fludarabine +cytarabine + granulocyte colony-stimulating factor (G-CSF) [FLAG], FLAG + mitoxantrone (FLANG), or FLAG + idarubicin (FLAG-Ida). Such combinations maximize favorable cytotoxic interactions between cytarabine and G-CSF, and between cytarabine and fludarabine. In small studies, such combinations used as second-line therapy have resulted in complete response (CR) rates of 36-59%. Early retrospective analyses suggested higher CR rates in patients with refractory AML than in those with relapsed AML, but this observation has not been confirmed in recent prospective trials. Fludarabine-containing combinations have also been evaluated as first-line therapy in high-risk patients and resulted in CR rates of 34-70%, with median survival from 7 to 16 months. The current large MRC randomized high-risk study will provide further data on the use of fludarabine-containing regimens in patients with poor prognosis AML. Further studies are investigating the use of fludarabine in combination with other agents, such as gemtuzumab ozogamicin and gemcitabine, in patients with AML.     

Treatment of newly-diagnosed acute myelogenous leukaemia in patients aged 80 years and above

In order to assess outcome following treatment of acute myeloid leukaemia (AML) in patients aged 80 years and above, we have studied 33 patients aged ≥80 years treated between 1980 and 1994; 29 of these received treatment. The median age was 82 years (range 80–89). Three patients received daunorubicin (≥60mg/m² daily × 3) alone or with low-dose ara-C, two patients received '3+7' with post-treatment GM-CSF; 24 patients had higher doses of ara-C, generally with anthracyclines or fludarabine, and in nine cases with G or GM-CSF.
The median survival of the treated patients was 3–4 weeks and only two were alive after 1 year (at 66 and 79 weeks). Complete remission (CR) occurred in 9/29 (31%). Only one of the nine remains alive in remission, at 76 weeks after the date of CR, whereas the other eight died in remission or had disease recurrence at a median of 11 weeks (range 5–37 weeks) after CR. The median survival of the four untreated patients was 10 weeks (range 3–38). Patients aged ≥80 had, on average, worse outcomes than those observed in patients aged 70–79.
Our results confirm that currently available chemotherapy is generally not indicated in patients aged 80 or over with AML.     

Cytidine deaminase genotype and toxicity of cytosine arabinoside therapy in children with acute myeloid leukemia

Cytosine arabinoside (ara-C) is irreversibly deaminated to a non-toxic metabolite by cytidine deaminase (CDA). A common polymorphism, A79C, in the gene encoding cytidine deaminase ( CDA ) changes a lysine residue to glutamine resulting in decreased enzyme activity. CDA A79C genotypes were determined in 457 children with acute myeloid leukaemia (AML) treated on the Children's Cancer Group (CCG) 2941 and 2961 protocols and analyzed the impact of CDA genotype on therapy outcomes. Postinduction treatment-related mortality (TRM) was significantly elevated in children with the CC genotype (5-year TRM 17 ± 13% CC vs. 7 ± 4% AA, 5 ± 4% AC, P  = 0·05). This was more notable in children who received idarubicin, fludarabine, ara-C, and granulocyte colony-stimulating factor (IDA-FLAG; ara-C = 7590 mg/m²) (5-year TRM 24 ± 21% CC vs. 6 ± 6% AA, 6 ± 7% AC, P  = 0·07) as consolidation therapy compared to idarubicin, dexamethasone, cytarabine, thioguanine, etoposide and daunomycin (IDA-DCTER; ara-C = 800 mg/m²) (5-year TRM 15 ± 20% CC vs. 8 ± 6% AA, 4 ± 6% AC; P  = 0·29). Relapse-free survival was non-significantly increased in children with the CC genotype treated with IDA-FLAG (76 ± 20% CC vs. 59 ± 12% AA and 55 ± 14% AC; P  = 0·40). These data indicate that children with a low activity CDA genotype are at increased risk of TRM with ara-C based therapy for AML.     

Bortezomib, low-dose intravenous melphalan, and dexamethasone for patients with relapsed multiple myeloma

This multicenter phase I/II study investigated the maximum tolerated dose (MTD), safety, and efficacy of low dose intravenous (IV) melphalan in combination with bortezomib for patients with relapsed multiple myeloma (MM). Patients received bortezomib 1·3 mg/m² on days 1, 4, 8, and 11 and escalating doses of IV melphalan (2·5–10·0 mg/m²) on day 2 of a 28-day cycle for a maximum of eight cycles. Dexamethasone 20 mg was added for progressive or stable disease. Fifty-three patients were enrolled. The MTD was defined at melphalan 7·5 mg/m² and bortezomib 1·3 mg/m². The overall response rate (ORR) was 68% (23% complete or near-complete responses [CR/nCR]) whilst at the MTD ( n  = 33) the ORR was 76% (34% CR/nCR). After median follow-up of 17 months, the median progression free survival was 10 months, rising to 12 months at the MTD ( P  < 0·05 vs. non-MTD regimens). The median overall survival was 28 months, but was not yet reached at the MTD. Grade 3/4 adverse events included thrombocytopenia (62%), neutropenia (57%), infection (21%), and neuropathy (15%). Bortezomib and low-dose IV melphalan combination therapy is a safe and highly effective regimen for patients with relapsed MM. These data suggest further investigation of this combination is warranted.     

Improved outcome of adult acute lymphoblastic leukaemia by moderately intensified chemotherapy which includes a 'pre-induction' course for rapid tumour reduction: preliminary results on 66 patients

Sixty-six consecutive adult patients with acute lymphoblastic leukaemia (ALL) were treated with intensified chemotherapy which included a 'pre-induction' course of cytarabine (AraC) and etoposide (VP16) when the white blood cell count (WBC) was ≥30 × 10⁹/l (18 patients), and maintenance chemotherapy with regular intensifications for a total treatment duration of 3 years. Patients with a mediastinal mass (17) received consolidation courses with intermediate-dose AraC and VP16 followed by mediastinal irradiation. 11 patients underwent allogeneic bone marrow transplantation in first complete remission (CR). 58 patients (87.9%, CI 77.5–94.6) attained CR; with a median follow-up of 7 years, 35 of them (60.3%, CI 46.6–73.0) remain in CR. Toxicity was mild, although three patients died during remission induction, including two who were over 70 years of age. 23 patients (39.7%, CI 27.1–53.4) relapsed, seven of them primarily in the central nervous system (CNS), necessitating intensification of CNS-directed therapy. Only one of 13 patients with WBC 30–100 × 10⁹/l, but eight of nine with WBC >100 × 10⁹/l, relapsed. The survival of older patients in CR did not differ from younger patients. The outcome of ALL in adult patients could thus be improved by slight intensification of treatment whilst keeping the toxicity within acceptable limits. 'Pre-induction' with AraC and VP16 might improve the prognosis, especially in patients with WBC <100 × 10⁹/l. Patients with WBC >100 × 10⁹/l, however, almost always relapse, and the intensified chemotherapy might not be tolerated well by patients over 70 years of age.     

Cladribine combined with high doses of arabinoside cytosine, mitoxantrone, and G-CSF (CLAG-M) is a highly effective salvage regimen in patients with refractory and relapsed acute myeloid leukemia of the poor risk: a final report of the Polish Adult Leukemia Group

Objectives:  Patients with primary refractory AML and with early relapses have unfavorable prognoses and require innovative therapeutic approaches. Purine analogs fludarabine (FA) and cladribine (2-CdA) increase cytotoxic effect of Ara-C in leukemic blasts and inhibit DNA repair mechanisms; therefore its association with Ara-C and mitoxantrone (MIT) results in a synergistic effect. In the current report, we present the final results of multi-center phase II study evaluating the efficacy and toxicity of CLAG-M salvage regimen in poor risk refractory/relapsed AML patients.
Methods:  The induction chemotherapy consisted of 2-CdA 5 mg/m², Ara-C 2 g/m², MIT 10 mg/m², and granulocyte-colony stimulating factor. In the case of PR, a second CLAG-M was administered. Patients in CR received consolidation courses based on high doses of Ara-C and MIT with or without 2-CdA.
Results:  One hundred and eighteen patients from 11 centers were registered; 78 primary resistant and 40 relapsed. Sixty-six patients (58%) achieved CR after one or two courses of CLAG-M, 49 (35%) were refractory, and 8 (7%) died early. WBC >10 g/L and age >34 yr were factors associated with increased risk of treatment failure. Hematological toxicity was the most prominent toxicity of this regimen. The probability of OS at 4 yr was 14% (95% CI 4–23%). OS was influenced by age, WBC >10 g/L and poor karyotype in both univariate and multivariate analyses. The probability of 4 yr DFS was 30% for all 66 patients in CR (95% CI 11–49%). Poor karyotype was the only factor associated with decreased probability of DFS.
Conclusions:  We conclude that CLAG-M is a well-tolerated and highly effective salvage regimen in poor risk refractory/relapsed AML.     

De novo acute myeloid leukemia with multilineage dysplasia: treatment results and prognostic evaluation from a series of 44 patients treated with fludarabine,cytarabine and G-CSF (FLAG)

OBJECTIVES: To evaluate therapeutic results and prognostic factors from a series of 44 patients affected by de novo acute myeloid leukemia with multilineage dysplasia (MD-AML), treated with the combination of fludarabine, cytarabine and G-CSF (FLAG). METHODS: Forty-four patients with de novo MD-AML were treated with the FLAG regimen. The median age was 61 yr (range 31-75 yr). Induction therapy consisted of the FLAG regimen; consolidation included idarubicin plus cytarabine. Patients with a compatible donor and aged less than 55 yr were programmed to receive allogeneic bone marrow transplantation (BMT), while in those without a donor and aged less than 65 yr autologous transplantation with peripheral blood stem cells mobilized by a consolidation regimen plus G-CSF was planned. Bone marrow harvest was performed in poor mobilizers. RESULTS: Complete remission (CR) was achieved in 28 out of 44 patients (64%). Death in induction occurred in four patients (9%), while 12 patients (27%) were resistant to FLAG. Toxicity of consolidation was negligible. Most patients aged less than 60 yr and achieving CR were eligible for transplantation procedures, the main reason of exclusion being early relapse. Median overall survival and disease free survival were 16 and 22 months, respectively. Unfavorable cytogenetics was the only parameter significantly related to inferior clinical outcome following multivariate analysis. CONCLUSION: Multilineage dysplasia per se is not an adverse prognostic factor in AML patients treated with the FLAG regimen. Favorable results are obtained in patients with intermediate karyotype, while in those with adverse cytogenetics new approaches are clearly needed. The toxicity of the regimen is also acceptable in the elderly, and following induction/consolidation, most patients may be submitted to transplantation procedures.     

Sequential phase II Southwest Oncology Group studies (S0112 and S0301) of daunorubicin and cytarabine by continuous infusion, without and with ciclosporin, in older patients with previously untreated acute myeloid leukaemia

Attempts to overcome multi-drug resistance in acute myeloid leukaemia (AML) have been limited by toxicities. To investigate the effect of reducing peak drug levels, we performed sequential phase II studies using continuous infusion daunorubicin and cytarabine without (AD) and then with ciclosporin (ADC) in older patients with AML. Untreated patients (age 56+ years) received daunorubicin (45 mg/m² per day for 3 d) and cytarabine (200 mg/m² per day for 7 d), both by continuous infusion, without (S0112, 60 patients) and then with (S0301, 50 patients) the addition of ciclosporin. Complete response (CR) rates were 38% on S0112 and 44% on S0301. Fatal induction toxicities occurred in 17% and 12% respectively, arising primarily from infection and haemorrhage. Median overall and relapse-free survival was 7 and 8 months for AD respectively, and 6 and 14 months for ADC. Patients with phenotypic or functional P-glycoprotein had somewhat higher CR rates with ADC than AD, although confidence intervals overlapped. In these sequential trials, continuous infusion AD produced CR rates comparable to those with bolus daunorubicin. The addition of ciclosporin did not cause undue toxicities, produced a similar CR rate, and possibly improved relapse-free survival. Further correlate analyses did not identify a subpopulation specifically benefitting from the addition of ciclosporin.     

Fludarabine, cytosine arabinoside, granulocyte-colony stimulating factor with or without idarubicin in the treatment of high risk acute leukaemia or myelodysplastic syndromes

The combination of fludarabine (FDR), high dose cytarabine and granulocyte colony stimulating factor (FLAG) with or without idarubicin (Ida) was used in the treatment of poor risk acute leukaemia or myelodysplastic syndrome (MDS) in a single centre experience. A total of 105 patients were treated over a 4-year period with 59% achieving a complete remission (CR); no statistical difference observed between FLAG and FLAG-Ida. For patients responding to FLAG +/- Ida, the median event-free survival (EFS) was 11 months and 23% at 5 years. Such patients proceeded either to further chemotherapy or a haematopoietic stem cell transplant (HSCT). The median EFS (13 months vs. 8 months) and projected 5-year survival (37% vs. 13%) of patients undergoing HSCT was significantly better than those who did not (P = 0.021). In all, 14 of 72 patients remain alive in continuing CR (median duration 43 months) with 10 of 31 having had a HSCT vs. four of 41 that did not (P = 0.033). Both regimens were well tolerated, with the majority of patients experiencing grade 1 or less non-haematological toxicity (mainly nausea and vomiting). The median time to neutrophil and platelet recovery was 28 and 31 d, respectively. No significant differences were seen with the addition of ida. There was a 17% incidence of treatment-related deaths, of which 39% was caused by invasive aspergillus infection. The results show that FLAG +/- Ida is an effective and well-tolerated remission induction regimen for poor risk leukaemia and MDS.     

Fludarabine, cytarabine, G-CSF and idarubicin (FLAG-IDA) for the treatment of poor-risk myelodysplastic syndromes and acute myeloid leukaemia

Nineteen patients with high-risk myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) received fludarabine, cytarabine, granulocyte-colony stimulating factor (G-CSF), and idarubicin chemotherapy ( de novo MDS/MDS-AML, nine; relapsed/refractory MDS/AML, seven; therapy-related MDS, three). Median age was 44 years and median disease duration 10 months. 16/19 (84%) patients had abnormal cytogenetics with seven (37%) harbouring abnormalities of chromosome 7. 18/19 (94.7%) patients responded to FLAG-idarubicin with 12 (63%) achieving complete remission (CR) (<5% blasts and normal cytogenetics). 7/9 (78%) patients with de novo MDS/MDS-AML achieved CR compared to 5/10 (50%) with alternative diagnoses. Response was associated with age < 50 years, disease duration < 3 months, and cytogenetics other than abnormalities of chromosome 7. Haemopoietic regeneration was rapid in most patients and there were no toxic deaths. Nine patients received a second course of chemotherapy, three have proceeded to allogeneic bone marrow transplant and three to autologous blood stem cell/bone marrow transplantation. Follow-up is short (median 10 months). 12/19 (63%) patients remain alive and 5/12 (42%) have relapsed at a median 5 months following CR achievement. FLAG-idarubicin was well tolerated. High rates of morphological and cytogenetic remission, especially in de novo MDS, offer a window of opportunity for assessment of autologous BMT in this group of diseases where no treatment except alloBMT has led to prolongation of survival.     

Ifosfamide and vinorelbine: an active regimen for patients with relapsed or refractory Hodgkin's disease

Twenty-six patients with relapsed or refractory Hodgkin's disease (HD) were treated with an intensive salvage regimen combining ifosfamide (3000 mg/m²/d, days 1–4 through continuous intravenous infusion) and vinorelbine (25 mg/m², i.v. days 1 and 5) with mesna uroprotection and G-CSF support. Courses were given at 3-week intervals.
Ten patients achieved a complete and 10 patients a partial response, yielding an overall response rate of 77%. The main toxic effect was neutropenia and the combination was well tolerated.     

The impact of dose escalation and resistance modulation in older patients with acute myeloid leukaemia and high risk myelodysplastic syndrome: the results of the LRF AML14 trial

The acute myeloid leukaemia (AML)14 trial addressed four therapeutic questions in patients predominantly aged over 60 years with AML and High Risk Myelodysplastic Syndrome: (i) Daunorubicin 50 mg/m² vs. 35 mg/m²; (ii) Cytarabine 200 mg/m² vs. 400 mg/m² in two courses of DA induction; (iii) for part of the trial, patients allocated Daunorubicin 35 mg/m² were also randomized to receive, or not, the multidrug resistance modulator PSC-833 in a 1:1:1 randomization; and (iv) a total of three versus four courses of treatment. A total of 1273 patients were recruited. The response rate was 62% (complete remission 54%, complete remission without platelet/neutrophil recovery 8%); 5-year survival was 12%. No benefits were observed in either dose escalation randomization, or from a fourth course of treatment. There was a trend for inferior response in the PSC-833 arm due to deaths in induction. Multivariable analysis identified cytogenetics, presenting white blood count, age and secondary disease as the main predictors of outcome. Although patients with high Pgp expression and function had worse response and survival, this was not an independent prognostic factor, and was not modified by PSC-833. In conclusion, these four interventions have not improved outcomes in older patients. New agents need to be explored and novel trial designs are required to maximise prospects of achieving timely progress.