In addition, patients treated with G-CLB had significantly longer overall survival in comparison to CLB alone (median OS not reached in either group, death rate 9% vs. a significant increase in severe (grade III/IV) neutropenia (34% vs. 21%, 0.0001) but without significantly elevated occurrence of infections. Patients with del 17p and/or p53 mutation have typically lower response rates to FCR, but this regimen can still be used for first-line treatment outside clinical trials, as monotherapy with alemtuzumab in the same setting did not yield better efficacy  and the combination of alemtuzumab and high-dose corticosteroids, the most effective approach for patients with defective p53 so far, has been reported only in a small number of untreated patients (= 17) . Elderly/comorbid patients require a different approach, as the number and severity of comorbid conditions contribute to inferior tolerance of chemotherapy . In particular, full-dose fludarabine regimens in elderly patients may result in unacceptable toxicity [37, 38]. Chlorambucil (CLB) was introduced into CLL therapy in the 1950s  but could be considered the backbone of treatment in frail patients until recently as no other regimens proved to be superior. Several dosing schedules of chlorambucil are possible, e.g.: 1) 0.4C0.8 mg/kg administered every 2 weeks (used by the German CLL Study Group, GCLLSG) , 2) 10 mg/m2 days 1C7 Lofexidine repeated every 28 days . Overall response rate (ORR) and progression-free survival (PFS) ranged from 37% to 72% and 9 to 20 months, depending on the patient population. Complete responses are infrequent with CLB monotherapy. The German CLL5 study showed that although fludarabine Rabbit Polyclonal to STEA2 induced significantly more overall responses (ORR) and complete remissions (CR) than CLB in untreated patients 65 years in (ORR: 72% vs. 51%, = 0.003; CR: 7% vs. 0%, = 0.011), it did not translate into longer progression-free (median: 19 vs. 18 months, = 0.7) or overall survival (median: 46 vs. 64 months, = 0.15) . Recently, two randomized studies published in abstract form showed for the first time significant improvement over CLB monotherapy. The German CLL11 study randomized 589 untreated patients with significant comorbidities (cumulative CIRS score 7 and/or creatinine clearance 70 ml/min) in 1 : 2 : 2 fashion between CLB monotherapy (0.5 mg/kg days 1 and 15, for a maximum of 6 cycles), CLB + rituximab (R-CLB, 375 mg/m2 0.0001). In addition, patients treated with G-CLB had significantly longer overall survival in comparison to CLB alone (median OS not reached in either group, death rate 9% vs. 20%, = 0.002). Differences in CR rate and PFS were also significantly better with G-CLB vs. R-CLB. Obinutuzumab caused more severe infusion-related toxicity than rituximab (21% vs. 4%) and more frequent severe neutropenia than rituximab or CLB (34% vs. 25% vs. 15%), but this did not translate into an increased rate of severe infections (6% vs. 8% vs. 11%) . Based on these results, obinutuzumab was approved for first-line treatment of CLL in comorbid patients. Combination of CLB and ofatumumab, a fully human anti-CD20 antibody with enhanced complement-dependent cytotoxicity, was compared against CLB monotherapy in another large phase III randomized study. A total of 447 untreated CLL patients older than 65 years were randomized between CLB (10 mg/m2 days 1C7 repeated every 28 days for a maximum of 12 cycles) and CLB Lofexidine + ofatumumab (O-CLB, 300 mg 0.001) as well as longer PFS (22.4 months vs. 13.1 months, 0.001) with no unexpected toxicity. Serious infusion-related reactions occurred in 10% . Taken together, these two studies indicate that combination of CLB and anti-CD20 monoclonal antibody is becoming a new standard of care in untreated comorbid CLL patients. Bendamustine is a unique cytostatic agent with combined properties of Lofexidine an alkylating agent and purine analog, originally developed in the 1960s in the former East Germany. An international phase III study randomized 305 untreated CLL patients between bendamustine (100 mg/m2 = 102; ORR: 79%; median PFS: 20 months) as well as relapsed/refractory disease (= 97;.
- T-cell epitopes are peptides derived from antigens and identified by the T-cell receptor (TCR) when bound to MHC molecules displayed within the cell surface of APCs
- Cloning of gene fragments encoding diagnostic antigens
- Epitopes are present on a single HLA (private epitope) or shared by multiple antigens (public epitope)
- Spleens were harvested in 1 (C) or 2 wpi (B, C) and cells were analyzed by movement cytometry in comparison to na?ve mice
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