Chronic myeloid leukemia (CML)-study IV was designed to explore whether treatment with imatinib (IM) at 400 mg/day (n=400) could be optimized by doubling the dose (n=420), adding interferon (IFN) (n=430) or cytarabine (n=158) or using IM after IFN-failure (n=128). From July 2002 to March 2012, 1551 newly diagnosed patients in chronic phase were randomized into a 5-arm study. The study was powered to detect a survival difference of 5% at 5 years. After a median observation time of 9.5 years, 10-year overall survival was 82%, 10-year progression-free survival was 80% and 10-year relative survival was 92%. Survival between IM400 mg and any experimental arm was not different. In a multivariate analysis, risk group, major-route chromosomal aberrations, comorbidities, smoking and treatment center (academic vs other) influenced survival significantly, but not any form of treatment optimization. Patients reaching the molecular response milestones at 3, 6 and 12 months had a significant survival advantage. For responders, monotherapy with IM400 mg provides a close to normal life expectancy independent of the time to response. Survival is more determined by patients' and disease factors than by initial treatment selection. Although improvements are also needed for refractory disease, more life-time can currently be gained by carefully addressing non-CML determinants of survival.
18105 Background: An emerging notion for the treatment of advanced solid malignancies in adults is to manage it as a chronic disease and aim to keep tumor burden and associated symptoms at the lowest possible level. One of the most promising strategies to achieve this is to target the tumor vasculature using modified, “metronomic”, dosing schedules. We conducted a pilot study of weekly docetaxel in combination with daily trofosfamide as a metronomic second-line regimen in patients (pts) with metastatic non-small cell lung cancer (NSCLC). Methods: From March 2003 to November 2005, 21 pts with stage IV disease who had one prior chemotherapy were enrolled. Pts received docetaxel 25 mg/m 2 on days 1, 8 and 15, every 4 weeks plus trofosfamide 50mg per day. Results: Median age: 60 years; gender: 18 male (85.7%), 3 female (14.3%); median Karnofsky PS: 80%; histologic subtypes: 8 squamous cell carcinomas (38.1%), 7 adenocarcinomas (33.3%), 6 large cell carcinomas (28.6%); previous chemotherapy: platinum-based in 15 pts (71.4%), platinum-free in 6 pts (28.6%). A total of 62 chemotherapy cycles were administered. The median number of cycles per pt was 3 (range 1 - 8). The intent-to-treat overall response rate was 19% (95% CI 5.5 - 41.9) 1 CR (4.8%), 2 PR (14.3%), 9 SD (42.9%), 8 PD (38.1%). The median overall survival from onset of second-line therapy was 6.9 months (95% CI 5.0 - 13.9 months), the median progression-free survival 2.9 months (95% CI 1.58 - 6.28 months), the 1-year survival rate 28.6% (95% CI 14.5 - 56.2%), and the 2-year survival rate 7.1% (95% CI 1.26 - 40.6%). Hematological and non-hematological toxicities were mild. No grade 4 toxicity was observed. Conclusions: To the best of our knowledge, this is the first trial that combines docetaxel and trofosfamide for the treatment of NSCLC. Our results suggest that the concept of metronomic chemotherapy is a valuable addition to the treatment of NSCLC. The combination of docetaxel and trofosfamide is active and well tolerated as second-line therapy in pts with metastatic NSCLC. No significant financial relationships to disclose.
Standard first-line therapy of chronic myeloid leukemia is treatment with imatinib. In the randomized German Chronic Myeloid Leukemia-Study IV, more potent BCR-ABL inhibition with 800 mg ('high-dose') imatinib accelerated achievement of a deep molecular remission. However, whether and when a de-escalation of the dose intensity under high-dose imatinib can be safely performed without increasing the risk of losing deep molecular response is unknown. To gain insights into this clinically relevant question, we analyzed the outcome of imatinib dose reductions from 800 mg to 400 mg daily in the Chronic Myeloid Leukemia-Study IV. Of the 422 patients that were randomized to the 800 mg arm, 68 reduced imatinib to 400 mg after they had achieved at least a stable major molecular response. Of these 68 patients, 61 (90%) maintained major molecular remission on imatinib at 400 mg. Five of the seven patients who lost major molecular remission on the imatinib standard dose regained major molecular remission while still on 400 mg imatinib. Only two of 68 patients had to switch to more potent kinase inhibition to regain major molecular remission. Importantly, the lengths of the intervals between imatinib high-dose treatment before and after achieving major molecular remission were associated with the probabilities of maintaining major molecular remission with the standard dose of imatinib. Taken together, the data support the view that a deep molecular remission achieved with high-dose imatinib can be safely maintained with standard dose in most patients. Study protocol registered at clinicaltrials.gov 00055874.
A 20‐yr‐old man with bulky mediastinal and retroperitoneal tumour masses identified as myeloblastoma is described. After a partial remission was induced by aggressive chemotherapy, mediastinal irradiation and retroperitoneal tumour resection, the patient received an allogeneic marrow graft from his HLA‐identical sister. The conditioning regimen consisted of high‐dose busulfan and cyclophosphamide. The patient has a well‐controlled secondary chronic graft‐versus‐host disease. He is in unmaintained complete remission and in good general condition at 20 months post‐transplantation.
Background: The aim of this pilot study was to evaluate the efficacy and safety of a chemotherapy containing docetaxel and oral trofosfamide as a 'metronomic' secondline treatment of patients with metastatic non-small cell lung cancer (NSCLC). Patients and Methods: 21 patients with stage IV disease NSCLC who had progressed under first-line chemotherapy were enrolled. Previous chemotherapy was platinum-based in 15 patients (71.4%), whereas 6 patients (28.6%) had received platinum-free combination chemotherapy. Patients received docetaxel 25 mg/m2 on days 1, 8, and 15 every 4 weeks plus trofosfamide 50 mg per day. Results: A total of 62 chemotherapy cycles were administered. The median number of cycles per patient was 3. The overall response rate to chemotherapy was 19%, median overall survival was 6.9 months, the median progression-free survival 2.9 months, the 1-year survival rate 28.6%, and the 2-year survival rate 7.1%. No grade IV toxicity was observed. Conclusions: Our results suggest that the combination of docetaxel and trofosfamide in a metronomic schedule is active and well tolerable as second-line therapy in patients with metastatic NSCLC. The concept of metronomic chemotherapy promises to be a valuable addition to the existing treatment options in NSCLC and warrants further investigation in phase III studies.
