G. Solbu

Mitoxantrone versus daunorubicin in induction-consolidation chemotherapy--the value of low-dose cytarabine for maintenance of remission, and an assessment of prognostic factors in acute myeloid leukemia in the elderly: final report. European Organization for the Research and Treatment of Cancer and the Dutch-Belgian Hemato-Oncology Cooperative Hovon Group.

PURPOSE AND METHODSnOptimization of remission-induction and postremission therapy in elderly individuals with acute myeloid leukemia (AML) was the subject of a randomized study in patients older than 60 years. Remission-induction chemotherapy was compared between daunomycin (DNR) 30 mg/m2 on days 1, 2, and 3 versus mitoxantrone (MTZ) 8 mg/m2 on days 1, 2, and 3, both plus cytarabine (Ara-C) 100 mg/m2 on days 1 to 7. Following complete remission (CR), patients received one additional cycle of DNR or MTZ chemotherapy and were then eligible for a second randomization between eight cycles of low-dose (LD)-Ara-C 10 mg/m2 subcutaneously every 12 hours for 1 2 days every 6 weeks or no further treatment.nnnRESULTSnA total of 242 patients was randomized to DNR and 247 to MTZ. Median age of both study groups was 68 years. Secondary AML was documented in 26% and 25% of patients in either arm. The probability of attaining CR was greater (P = .069) with MTZ (47%) than with DNR (38%). Median duration of neutropenia was 19 (DNR) and 22 days (MTZ). The greater response rate to MTZ therapy correlated with reduced occurrence of chemotherapy resistance (32% v 47%, P = .001). With a median follow-up of 6 years, 5-year disease-free survival (DFS) is 8% in each arm. Overall survival estimates are not different between the groups (6% v 9% at 5 yrs). Poor performance status at diagnosis, high WBC count, older age, secondary AML, and presence of cytogenetic abnormalities all had an adverse impact on survival. Secondary AML and abnormal cytogenetics predicted for shorter duration of CR. Among complete responders, 74 assessable patients were assigned to Ara-C and 73 to no further therapy. Actuarial DFS was significantly longer (P = .006) for Ara-C-treated (13% [SE = 4.0%] at 5 years) versus nontreated patients (7% [SE = 3%]), but overall survival was similar (P = .29): 18% (SE = 4.6%) versus 15% (SE = 4.3%). Meta-analysis on the value of Ara-C postremission therapy confirms these results.nnnCONCLUSIONnIn previously untreated elderly patients with AML, MTZ induction therapy produces a slightly better CR rate than does a DNR-containing regimen, but it has no significant effect on remission duration and survival. Ara-C in maintenance may prolong DFS, but it did not improve survival.

Quality of life in patients with acute myelogenous leukemia in prolonged first complete remission after bone marrow transplantation (allogeneic or autologous) or chemotherapy: a cross-sectional study of the EORTC-GIMEMA AML 8A trial

A cross-sectional study of quality of life (QOL) was performed in 98 patients in continued first complete remission (CR) for 1–7.4 years, after inclusion in the AML 8A trial which prospectively compared allogeneic bone marrow transplantation (AlloBMT), autologous BMT (ABMT) and intensive consolidation chemotherapy. Several significant differences between the three treatment groups were observed, on the basis of patient self-reports, with regard to somatic symptoms (mouth sores, cough, hair loss, headache), repeated acute medical problems, physical functioning, role functioning, leisure activities and, above all, sexual functioning. There were also significant differences for overall physical condition, and overall quality of life. For all these parameters, the ranking was uniformly AlloBMT lower than ABMT lower than chemotherapy. These differences remain significant after adjustment for time interval between CR and QOL evaluation, sex or age. These results, confirming a higher risk of permanent impairment of QOL after BMT, may have an impact on medical decisions and warrant further studies.

The influence of HLA-matched sibling donor availability on treatment outcome for patients with AML: an analysis of the AML 8A study of the EORTC Leukaemia Cooperative Group and GIMEMA

To determine whether patients with a HLA‐identical sibling donor have a better outcome than patients without a donor, an analysis on the basis of intention‐to‐treat principles was performed within the framework of the EORTC‐GIMEMA randomized phase III AML 8A trial. Patients in complete remission (CR) received one intensive consolidation course. Patients with a histocompatible sibling donor were then allocated allogeneic bone marrow transplantation (alloBMT), the patients without a donor were randomized between autologous BMT (ABMT) and a second intensive consolidation (IC2). 831 patients <46 years old and alive >8 weeks from diagnosis were included. HLA typing was performed in 672 patients. AlloBMT was performed during CR1 in 180 (61%) out of 295 patients with a donor. Another 38 patients were allografted: five in resistant disease, 14 during relapse and 19 in CR2. ABMT was performed in 130 (34%) out of 377 patients without a donor in CR1, in six (2%) patients during relapse and in 38 (10%) patients during CR2. The disease‐free survival (DFS) from CR for patients with a donor was significantly longer than for patients without a donor (46% v 33% at 6 years; Pu2003=u20030.01, RR 0.78, 95% confidence interval 0.63–0.96). The overall survival from diagnosis for patients with a donor was longer, but not statistically significant, than for patients without a donor (48% v 40% at 6 years; logrank Pu2003=u20030.24). When patients were stratified according to prognostic risk groups, the same trend in favour of patients with a donor was seen for survival duration and the DFS remained significantly longer for this group of patients.

Cyclosporin A combined with vincristine, doxorubicin and dexamethasone (VAD) compared with VAD alone in patients with advanced refractory multiple myeloma: an EORTC–HOVON randomized phase III study (06914)

Patients with multiple myeloma (MM) refractory to alkylating agents frequently express P‐glycoprotein (Pgp), which is associated with the multidrug resistance (MDR) phenotype. We have conducted a randomized phase II/III study of the MDR reversal agent cyclosporin A combined with VAD (vincristine, doxorubicin, dexamethasone) compared with standard VAD in patients with MM stage IIA/IIIA who were refractory to or progressive after treatment with alkylating agents. Out of 81 patients who were randomized, 75 were eligible and evaluable: 34 in the VADu2003+u2003cyclosporin A arm versus 41 in the VAD arm. Toxicities of grade 2–3 were observed more often with VADu2003+u2003cyclosporin A than with VAD only: nausea (30% versus 8%, Pu2003=u20030·015), mucositis (18% versus 5%, Pu2003=u20030·13), infection (45% versus 35%, Pu2003=u20030·50). The treatment results were similar in the two arms: 53% versus 49% responded [95% CI (−18·5%, 26·9%)]. The median progression‐free survival (PFS) was 8·6u2003months (VADu2003+u2003cyclosporin A) versus 5·8u2003months (VAD): [log rank Pu2003=u20030·16, hazard ratiou2003=u20030·71, 95% CI (0·44, 1·15)], and median overall survival was 13u2003months versus 14·6u2003months [log rank Pu2003=u20030·89, hazard ratiou2003=u20030·96, 95% CI (0·62, 1·72)]. The cause of death was progressive disease (85%), toxicity (10%) or other (5%). Bone marrow analysis performed in 23 patients showed that the response rate was 67% in Pgp‐positive versus 55% in Pgp‐negative patients. Cyclosporin A combined with VAD is relatively well tolerated. There is no effect of cyclosporin A on the overall response rate, PFS and overall survival with VAD.

A modular questionnaire for the assessment of longterm quality of life in leukaemia patients: The MRC/EORTC QLQ-LEU

We describe the psychometric analysis of a supplementary quality of life measure (MRC/EORTC QLQ-LEU) for evaluating long term sequelae of leukaemia treatments. The questionnaire under development was administered to 388 patients entered into the EORTC-GIMEMA AML 8A and the MRC AML10 clinical trials who were in complete remission for at least one year after completion of treatment on these trials. Results indicated a measure which is useful in evaluating the long-term effects of treatment in relation to chronic graft-vs-host disease and infection susceptibility. The performance of this measure in terms of its sensitivity and specificity between treatment arms was established by comparisons between the three treatment modalities in the above-mentioned trials and is the subject of further investigation. The new Leukaemia Module can be recommended for use alongside generic QOL instruments as a measure of long-term quality of life in leukaemia trials.

Salvage treatment for primary resistant acute myelogenous leukemia consisting of intermediate-dose cytosine arabinoside and interspaced continuous infusions of idarubicin: A phase-II study (no. 06901) of the EORTC Leukemia Cooperative Group

Abstractu2002Twenty-one patients with acute myeloid leukemia (AML) who failed to enter complete remission (CR) after first-line standard-dose remission-induction therapy with 7 days of cytarabine and 3 days of daunorubicin were treated with a salvage regimen containing intermediate-dose cytosine arabinoside (Ara-C) 2×500 mg/m2/day during 7 days in combination with continuous infusions of idarubicin 12 mg/m2/day on days 1, 3, and 5. Twenty patients were considered primary resistant, and one patient had a partial remission after two remission-induction courses. Overall, 11 patients (52%, 95% confidence interval: 30–74%) entered CR. Three patients died during hypoplasia and seven patients had resistant disease or a partial remission. The remission rate in this study compares favorably with the results obtained in similar patient categories. The toxicity of this salvage regimen was remarkably mild. No extramedullary toxicity was observed except for hepatic dysfunction in seven patients. The median duration of remission was 8.5 months, and ultimately, all complete remitters have relapsed except the patient who died from infectious complications after allogeneic bone marrow transplantation (BMT). This study shows that new intensive chemotherapy regimens may be effective after failure of primary treatment. Salvage regimens containing intermediate/high-dose Ara-C and/or alternative anthracyclines or anthracenes should be induced in the treatment of young patients with de novo AML.

Interleukin-3 plus Low-Dose Cytosine Arabinoside for Advanced Myelodysplasia: A Pilot Study

In an attempt to reestablish normal hematopoiesis in symptomatic myelodysplasia (MDS) and to show the tolerability of a combination treatment of low-dose cytosine arabinoside (LD AraC) and interleukin-3 (IL-3), we treated 31 patients (pts., median age 65 years) who had more than 10% blasts in the bone marrow (BM) and hematopoietic failure with LD AraC (2 x 10 mg/m2 sc, day 1-14) plus IL-3 (once daily sc, day 8-21) at different dose steps (1.0, 2.5, 5.0, and 10.0 micrograms/kilogram body weight). The numbers of each 21-day cycle varied between 1 (3 pts.), 2 (6 pts.), 3 (8 pts.), 4 (1 pt.), 5 (5 pts.), and 6 (8 pts.), in total 116 cycles on an outpatient basis. Subjective tolerability was good in 20 cases (65%). Toxicities were fever (29 pts.), flu-like symptoms (17 pts.), infections (15 pts.), hepatic toxicity (10 pts.), and skin reactions (8 pts.). Overall response was seen in 13 cases (42%) and 5 complete responses (CR), while 10 pts. had stable disease (SD), 5 progressed (2 to acute leukemia), 2 were considered toxic deaths, and 1 died due to the disease. Median survival is 18 months, progression-free survival is 12.5 months (18.0 months in responding pts.), with an actuarial follow-up of 31 months. The data from this phase I/II study show that a combination of LD-AraC and IL-3 is well tolerated and that stable responses can be achieved in MDS by means of an easy outpatient therapy.

Professor Maurice Staquet, MD, MS (1930 - 2013).

Maurice Staquet, the founding father of the International Society for Clinical Biostatistics, passed away on 13 May 2013. He laid the groundwork for the founding of the Society in 1978 and defined the Society’s goal ‘to stimulate research into the principles and methodology used in the design and analysis of clinical research’. He hosted the first meeting of the Society in Brussels, in May 1979. Maurice Staquet was the first director of the Data Center of the European Organization for Research and Treatment of Cancer (EORTC). Under his leadership, the EORTC Data Center (now the EORTC Headquarters), the first of its kind in Europe, developed into a world class scientific research unit, providing support for the design, conduct, and analysis of EORTC clinical trials. He had obtained his MD from the Université Libre de Bruxelles. From 1958 to 1960, he participated as medical doctor in the Belgian Expedition to the Antarctic and later obtained a Master’s Degree in Biostatistics from Columbia University in New York. He was professor at the Université Libre de Bruxelles and Honorary Associate Professor at Stanford University in Palo Alto, California, where he continued his research during several sabbatical leaves. He was awarded the medal of Chevalier de l’Ordre de Léopold II by the King of Belgium. We all had the privilege of working for Dr. Staquet at the EORTC Data Center. It was a time when funding was scarce, depending mostly on a grant from the US National Cancer Institute. Nevertheless, the Data Center prospered and its personnel were able to carry out their work with enthusiasm and considerable scientific freedom. Maurice Staquet was an inspiring leader, who helped shape the career of many individuals who admired his solid leadership and treasured his unconditional support. He had the long-term vision that helped build the EORTC into the internationally recognized research organization that it is today. He also was instrumental in launching the International Society for Clinical Biostatistics, which has become a vibrant forum for clinical biostatisticians and epidemiologists to meet, in keeping with the goal that he had set for the Society 35 years ago.

Postremission Therapy: The Role of Allogeneic Bone Marrow Transplantation in Acute Myelogenous Leukemia: An Analysis of the AML8A EORTC-GIMEMA Protocol

The AML8A protocol of the European Organization for Research on Treatment of Cancer (EORTC) and GIMEMA Cooperative Groups studied the value of allogeneic (allo-BMT) and autologous bone marrow transplantation (autoBMT) in adult acute myelogenous leukemia (AML) when performed during first complete remission (CR). Following one or two courses of remission induction treatment, 66% of patients achieved a CR. Then 168 patients who had an HLA-identical sibling were assigned to alloBMT, while 254 were randomized for an autoBMT or for a second intensive consolidation course. Disease-free survival (DFS) of the intensive chemotherapy arm was 30% at 4 years, the DFS in the alloBMT and autoBMT arms were 55% and 48%, respectively. The two BMT arms gave significantly better results than the intensive chemotherapy arm (p = 0.03). The main reason for failure is relapse in both the autoBMT and the chemotherapy arms, while treatmentrelated mortality is higher in the alloBMT arm.