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The combination of Imatinib (IM) and hydroxyurea (HU) was explored for the treatment of chronic myelogenous leukemia (CML).AfterAdditive specific inhibition of CML cells by IM/HU was detectedIM/HU combination was more potent in selectively inhibiting CML cells

The randomised, controlled OSHO#39 study showed promising results using first-line mitoxantrone, chlorambucil and prednisolone (MCP) chemotherapy plus rituximab in patients with advanced symptomatic follicular lymphoma (FL) in need of therapy. The aim of this long-term follow-up was to investigate whether clinical benefits are maintained after up to 9 years of observation.Following the 4-year follow-up of OSHO#39, 77 FL patients who received rituximab plus MCP (R-MCP) and 52 patients who received MCP (129 patients alive and not previously censored in total) were followed for 5 additional years in this prospective, non-interventional, observational study. For the efficacy analysis, data were jointly analysed with OSHO#39 data (FL intention-to-treat population: 105 patients R-MCP, 96 MCP). Patients not included in the 5-year follow-up were censored.For surviving patients, median follow-up was 102 months (R-MCP) and 87 months (MCP). Although median overall survival (OS) was not yet reached, OS was longer for patients with R-MCP compared with MCP (p = 0.0057), with 8-year-survival rates of 76.1 versus 55.9%. Further time-to-event data were substantially longer for the R-MCP group than for MCP alone: median progression-free survival (PFS) was 93.4 versus 34.9 months, and median event-free survival (EFS) 89.6 versus 26.5 months. Unplanned subanalyses of patients with and without interferon maintenance showed improved PFS and EFS without an impact on OS.The addition of rituximab to first-line MCP chemotherapy improves clinical outcomes in advanced FL patients and translates into long-term OS benefits. R-MCP remains a promising standard option for this patient group.

The therapy of patients with relapsed or refractory indolent lymphoma relies on the development of new drug combinations. The drugs bendamustine and fludarabine have cytotoxic activity as monotherapy in indolent lymphoma and show synergism in vitro. In this study, we combined both drugs in a multicenter clinical phase I/II trial to evaluate their toxicity and efficacy. Bendamustine was given at 30 or 40 mg/m 2 /d (dose levels 1 and 2), fludarabine at 30 mg/m 2 /d, each drug on days 1 to 3. Six cycles were to be given every 4 weeks. A total of 29 patients with relapsed or refractory indolent lymphoma were included in the study. During phase I, 9 patients were treated at dose level 1 and 7 patients at dose level 2. Thirteen patients were added to the study during phase II. Fourteen patients had follicular lymphoma, 11 patients mantle cell lymphoma, 2 patients lymphoplasmocytic and 2 patients nodal marginal zone lymphoma. Median age was 62 years (range 39 – 74). All patients were in stages III or IV of their disease and had received prior chemotherapy with or without additional radioor immunotherapy. The dose limiting toxicity was hematotoxicity in all cases and occurred in 3 of 7 evaluable patients at dose level I and in 3 of 7 patients at dose level 2. One patient at dose level 2 died of sepsis in neutropenia with persistent thrombocytopenia. The study was continued at dose level 1 (phase II). Analysis of 19 evaluable patients treated at dose level 1 reveiled hematotoxicity CTC grade III in 47% and grade IV in 26%. Neutropenic fever occurred in 4 patients (21%). On an intent-to-treat basis, 45% or 32% of all patients at dose level 1 reached CR or PR, respectively. Nine of 9 patients with mantle cell lymphoma responded to therapy. The overall response rate was 77%. Eight of 15 responders relapsed after a median follow-up time of 14 months (range 2 – 43). The major complication of fludarabine in combination with bendamustine is hematotoxicity. Dose level 1 with 30 mg/m 2 /d of both drugs on days 1 to 3 was defined as the recommended dose. Despite unfavorable prognostic features (histologic subtype, stage of disease, pretreatment) response rates were good with this regimen.

Purpose To assess the efficacy of a second-line regimen of oxaliplatin and folinic acid–modulated fluorouracil in patients with advanced pancreatic cancer who have experienced progression while receiving gemcitabine monotherapy. Patients and Methods A randomized, open-label, phase III study was conducted in 16 institutions throughout Germany. Recruitment ran from January 2004 until May 2007, and the last follow-up concluded in December 2012. Overall, 168 patients age 18 years or older who experienced disease progression during first-line gemcitabine therapy were randomly assigned to folinic acid and fluorouracil (FF) or oxaliplatin and FF (OFF). Patients were stratified according to the presence of metastases, duration of first-line therapy, and Karnofsky performance status. Results Median follow-up was 54.1 months, and 160 patients were eligible for the primary analysis. The median overall survival in the OFF group (5.9 months; 95% CI, 4.1 to 7.4) versus the FF group (3.3 months; 95% CI, 2.7 to 4.0) was significantly improved (hazard ratio [HR], 0.66; 95% CI, 0.48 to 0.91; log-rank P = .010). Time to progression with OFF (2.9 months; 95% CI, 2.4 to 3.2) versus FF (2.0 months; 95% CI, 1.6 to 2.3) was significantly extended also (HR, 0.68; 95% CI, 0.50 to 0.94; log-rank P = .019). Rates of adverse events were similar between treatment arms, with the exception of grades 1 to 2 neurotoxicity, which were reported in 29 patients (38.2%) and six patients (7.1%) in the OFF and FF groups, respectively (P < .001). Conclusion Second-line OFF significantly extended the duration of overall survival when compared with FF alone in patients with advanced gemcitabine-refractory pancreatic cancer.

Purpose The oral fluoropyrimidine carbamate, capecitabine, is a highly active and well-tolerated treatment for metastatic breast cancer. In patients treated previously with anthracyclines and taxanes, capecitabine is an approved single-agent therapy. Trastuzumab, a monoclonal antibody targeting the human epidermal growth factor receptor 2 (HER-2), is also highly active in HER-2–overexpressing breast cancer. We have conducted a phase II study to confirm activity and feasibility of capecitabine and trastuzumab in combination in HER-2–overexpressing advanced/metastatic breast cancer. Patients and Methods Twenty-seven patients with HER-2–overexpressing metastatic breast cancer previously treated with anthracyclines and/or taxanes received oral capecitabine 1,250 mg/m2 bid for 14 days followed by a 7-day rest period combined with intravenous trastuzumab 4 mg/kg body weight on day 1 (loading dose) followed by 2 mg/kg weekly. Results Capecitabine/trastuzumab treatment achieved objective responses in 12 patients (45%), including complete response in four patients (15%) and partial response in eight patients (30%). Disease was stabilized in an additional nine patients (33%). The median overall survival time was 28 months, and the median progression-free survival time was 6.7 months. The safety profile of the combination was favorable and predictable, with a low incidence of grade 3/4 adverse events. The most common adverse events were pain, hand-foot syndrome, and GI toxicities. Severe myelosuppression was rare and severe alopecia did not occur. Conclusion These data confirm that the combination of capecitabine and trastuzumab is highly active in patients with HER-2–overexpressing anthracycline- and/or taxane-pretreated breast cancer, with only slight restrictions regarding quality of life.

Background: Clinical superiority of R-MCP (rituximab, mitoxantrone, chlorambucil, prednisolone) vs. MCP alone in patients with advanced stage indolent Non-Hodgkin’s-Lymphoma was demonstrated in a prospective, randomized, controlled, multicenter clinical trial (n=358). Data on resource utilization were collected alongside this clinical trial. Objective: To evaluate the health economic consequences, i.e. total cost and cost-consequences, of R-MCP vs. MCP from the perspective of a German payer (statutory sickness fund). Methods: Resource utilization data on 329 patients were collected and analyzed for the treatment phase (8 month). In addition, an interim analysis of the first 3 years of the subsequent observation period (planned: 7 years) was conducted. Data on resource utilization for initial chemotherapy, chemotherapy administration, treatment of adverse events, treatment of complications/progressive disease, subsequent chemotherapies and treatment for other reasons were collected. Several sensitivity analyses were performed to address different cost environments (e.g. treatment at university hospital vs. municipal hospital vs. private practice) and discounting scenarios. Results: Mean cost of the treatment phase in the base case analysis was EUR 35,890 for R-MCP (95%CI: EUR 33,178 – 38,602 and EUR 21,508 MCP per patient (95%CI: EUR 17,703 – 25,314). More treatment cycles were administered in the R-MCP arm (1,026 MCP, 1,237 R-MCP). Mean cost per active treatment cycle was EUR 4,932 for R-MCP (95%CI: EUR 4,512 – 5,353) and EUR 3,270 for MCP (95%CI: EUR 2,619 – 3,922). Mean (undiscounted) cost per patient in the observation period amounted to EUR 9,973 for R-MCP (95%CI: EUR 6,015 – 13,931) and EUR 15,896 for MCP (95%CI: 13,407 – 18,385). Mean observation time, after end of active treatment, was similar in both arms, 28.5 months for R-MCP, 27.5 months for MCP. Costs for treatment of adverse events, new chemotherapies and other reasons were reduced by 23%–39%, cost for treatment of progressive disease by 76% in the R-MCP arm compared to MCP alone. Extrapolating data to a full 3-year observation period results in savings of EUR 8,214 per patient with R-MCP compared to MCP alone. This compensates approx. 60% of the higher costs from the treatment phase. Clinically, R-MCP resulted in an objective response rate of 85.6% vs. 65.5% with MCP. After two years, based on Kaplan Maier estimate, event free survival for R-MCP was 69% vs. 44% for MCP alone (p< 0.001) (For more detailed clinical results see abstract by Herold et al.) Conclusion: Initial treatment costs with R-MCP were EUR 14,382 higher compared to MCP alone. However, approx. 60% of additional costs are regained during the first three years after therapy due to savings for subsequent treatments, particularly for progressive disease. Combined with the clinical superiority of R-MCP, a favorable cost-effectiveness ratio may be expected when more mature data are available.

Rituximab proved to be effective in relapsed and refractory indolent NHL as a single agent and generated impressive results in phase II studies in combination with chemotherapy. In a prospective randomized trial we compared the efficacy and toxicity of rituximab (375 mg/m² d 1) plus MCP-chemotherapy ( mitoxantrone 8 mg/m² d 3 + 4, chlorambucile 3 x 3 mg/m² d 3 – 7, prednisolone 25 mg/m² d 3 – 7 ) given every 28 days for a total of 8 cycles versus MCP (d 1 – 5) x 8 cycles alone in advanced indolent NHL and MCL. Efficacy endpoints included overall and complete response rates, event free survival, progression free survival, overall survival and toxicity. For response assessment classical definitions have been used. Between 10/98 and 09/03 we randomized 358 patients (pts) with advanced stage follicular lymphoma (FL) (grade 1 + 2), lymphoplasmacytic lymphoma and MCL to either R-MCP or MCP. The study arms are well balanced for all demographic factors. 201/358 pts (56%) had FL. Both regimens were well tolerated with a low incidence of serious adverse events. The overall response rate (RR) and the complete response rate (CR) for all pts was 85,5% and 42% in the R-MCP arm versus 65,5% and 20% in the MCP arm (p