German CLL Study Group Research Articles

Bendamustine Combined with Rituximab (BR) in First-Line Therapy of Advanced CLL: A Multicenter Phase II Trial of the German CLL Study Group (GCLLSG).

Abstract 205 Introduction:Bendamustine has shown considerable activity in monotherapy for lymphoid malignancies including chronic lymphocytic leukemia (CLL). In vitro studies have demonstrated synergistic pro-apoptotic effects of bendamustine and the CD20 antibody rituximab (BR) in primary CLL cells. Encouraging results have also been obtained using the BR combination treatment in previously treated CLL. This multicenter phase II trial (CLL2M) is the first study assessing the efficacy and toxicity of bendamustine in combination with rituximab in previously untreated CLL patients (pts). Patients and Methods:Between March 2007 and September 2008 117 pts with untreated CLL requiring therapy were enrolled into the protocol. Bendamustine was given at a dose of 90 mg/m2 on day 1 and 2, combined with 375 mg/m2 rituximab for the first cycle and 500 mg/m2 for subsequent cycles. BR treatment was administered every 28 days for up to 6 courses. Blood samples were taken for analysis by fluorescence in situ hybridization (FISH), the IgVH mutational status and expression of ZAP70/CD38. Minimal residual disease (MRD) was evaluated in peripheral blood and bone marrow by 4-color flow cytometry. Results:Data on the entire study population of 117 pts (median age 64 years) with a total of 583 treatment cycles are available. As of June 2009 the median observation time was 15.4 months (mo). 11.1% of the pts presented with stage Binet A, 41.0% with Binet B and 47.9% with Binet C disease. A mean number of 5.0 courses were delivered. 114 pts were evaluable for toxicity, 110 for response and 113 for progression free survival (PFS). The most frequent adverse events based on 583 treatment cycles were myelosuppression and infections: grade 3/4 anemia occurred in 4.9%, grade 3/4 leukopenia in 14.6%, grade 3/4 neutropenia and thrombocytopenia in 6.5% and 6.1% of all given courses, respectively. 29 episodes of CTC grade >3 infections were documented (5.1% of all courses). Treatment related mortality occurred in 2.6% of the pts: one liver failure after attempt of suicide with antihistamines, one fatal pneumonia and one sepsis in neutropenia. The overall response rate was 90.9% with 32.7% (36 pts) clinical complete remissions (CR). A nodular partial remission (nPR) was achieved in 2.7% (3 pts) and a partial response (PR) in 55.5% of the pts (61 pts), respectively. 9.1% of the pts (10 pts) had stable disease (SD) whereas none of the pts was progressive (PD). After 18 mo 75.8% of the pts were still in remission, median PFS has not been reached. An MRD level below 10E-4 was observed after completion of therapy in 29 of 50 evaluable pts in peripheral blood, while 7 of 25 pts achieved MRD negativity in bone marrow. Differences in response were observed among the genetic subgroups: 19 of 21 pts with 11q- achieved a remission with 10 PR and 9 CR (ORR: 90.5%). Accordingly, 17 of 19 patients with +12 responded (14 PR, 3 CR, ORR: 89.5%). In the high-risk group with 17p-, 3 of 7 pts showed a partial response (ORR: 42.9%). 56 of 63 pts (ORR: 88.9%) with unmutated IgVH status responded to BR. Conclusion:Bendamustine plus rituximab (BR) is effective and safe in the first-line treatment of CLL. Major side effects (myelosuppression and infections) were infrequent. Based on these encouraging phase II data the German CLL Study group is presently investigating the efficacy of BR in comparison to fludarabine-based immunochemotherapy (FCR) in the first-line treatment of CLL within a randomized phase III trial (CLL10 protocol). Disclosures:Fischer:Roche: travel expenses. Cramer:Roche: travel grants. Stilgenbauer:Bayer: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding. Fink:Roche: . Boettcher:Roche: Research Funding. Ritgen:Roche: Research Funding. Kneba:Roche: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Döhner:Roche: Research Funding. Eichhorst:Roche: Honoraria, Research Funding; Mundipharma: Research Funding; Hospira: Honoraria. Hallek:Roche: Consultancy, Honoraria, Research Funding. Wendtner:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer Schering: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

First-Line Treatment with Fludarabine (F), Cyclophosphamide (C), and Rituximab (R) (FCR) Improves Overall Survival (OS) in Previously Untreated Patients (pts) with Advanced Chronic Lymphocytic Leukemia (CLL): Results of a Randomized Phase III Trial On Behalf of An International Group of Investigators and the German CLL Study Group.

Abstract 535 Introduction: In 2008, first results of a multicenter, international randomized phase III trial (CLL8) were presented, showing superiority of FCR chemoimmunotherapy for response rates and progression-free survival (PFS) when compared to FC chemotherapy. We now report updated results with a longer median observation time of 37.7 months (mo). Methods and Patients: 817 treatment-naive patients (pts) with good physical fitness and CD20-positive CLL randomly (1:1) received treatment with 6 courses of either FCR or FC therapy. Both treatment arms were well balanced with regard to sex, age, stage, genomic aberrations and IGVH gene status. The median age was 61 years (range 30 to 81), 25.7% pts were female in both arms, 64.1% were Binet B, 31% Binet C and 4.9% Binet A. The median cumulative illness rating scale (CIRS) score was 1 (range 0-8). The overall incidences of trisomy 12 and abnormalities of 13q, 11q23, and 17p13 detected by FISH were 12%, 57%, 25%, and 8%, respectively. A mean number of 5.2 treatment courses were delivered in the FCR arm vs 4.8 courses in the FC arm (p=0.006). Dose reductions by more than 10% in at least one treatment course were performed in 47% (FCR) and 27% (FC) of pts (p Results: As of June 2009, the median observation time was 37.7 (mo). 761 pts (FCR 388; FC 371) were evaluable for response, 790 pts (FCR 401; FC 389) for PFS and all for OS. FCR induced a higher overall response rate than FC (95.1 vs 88.4%) and more complete remissions (44.1 vs 21.8%; p As previously reported more hematologic adverse events, particularly neutropenia, were observed with FCR treatment, but this did not result in an increased infection rate. More deaths have occurred in the FC arm (86/396, 21.7%) than in the FCR arm (65/404, 16.1%). In the majority of cases, the underlying cause of death was progressive disease (FC 48/86, FCR 33/65), secondary malignancies (FC 13/86, FCR 5/65) or unrelated causes of death such as myocardial infarction (FC 15/86, FCR 17/65). Treatment related mortality occurred in 8 (2.0%) of pts in each arm. Of these, 7 FC-treated pts and 5 FCR-treated pts died from infections related to treatment. In 7 pts (3 FC vs. 4 FCR), treatment was discontinued before the third treatment course due to fatal toxicity. Multivariate analysis was performed to evaluate factors predicting outcome. Age, sex, FCR-treatment, response, number of cycles (0-3), 17p-deletion, increased serum levels of thymidine kinase and β2-microglobulin and unmutated IGVH genes were independent prognostic factors predicting OS or PFS. Conclusion: Treatment with FCR chemoimmunotherapy is more effective than FC chemotherapy. The partial failure to demonstrate a benefit for FCR in Binet stage C patients may be related to an insufficient treatment intensity in these patients with higher tumor load. To our knowledge, this is the first time that a randomized trial is able to demonstrate that a specific first-line treatment for CLL results in an improved overall survival. The results corroborate the recommendation to use FCR as standard therapy in physically fit pts with CLL requiring therapy. Disclosures: Hallek: Roche: Consultancy, Honoraria, Research Funding. Fingerle-Rowson: Roche: Honoraria, travel grants. Fink: Roche: Travel grants. Mayer: BMS: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Research Funding; GSK: Consultancy; Fresenius: Consultancy; Roche: Research Funding; Pfizer: Research Funding. Hensel: Roche: Honoraria, Travel Grants; Bayer: Honoraria. Hopfinger: Roche: Membership on an entity9s Board of Directors or advisory committees. Hess: Roche: Honoraria. Bergmann: Roche: Honoraria for monitoring and CRFs. Catalano: Roche: Honoraria, Research Funding, Travel grants. Seymour: Bayer Schering: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Travel grants; Roche: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Travel Grants. Berrebi: Roche: travel grants. Jaeger: Roche: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Travel grants. Trneny: Roche: Honoraria, Research Funding. Westermann: Roche: Travel Grants. Wendtner: Mundipharma: Honoraria, Research Funding; Roche: Honoraria, Research Funding. Eichhorst: Roche: Honoraria, Research Funding; Mundipharma: Research Funding; Hospira: Honoraria. Staib: Roche: Research Funding. Boettcher: Roche: Honoraria, Research Funding, Travel grants. Ritgen: Roche: Research Funding. Mendila: Roche: Employment. Kneba: Roche: Honoraria, Research Funding. Doehner: Roche: Research Funding. Stilgenbauer: Roche: Consultancy, Honoraria, Research Funding, travel grants. Fischer: Mundipharma: Research Funding; Roche: travel grants.

Health Related Quality of Life (HRQOL) in Patients Receiving Chemoimmunotherapy with Fludarabine (F), Cyclophosphamide (C), and Rituximab (R) (FCR) or Fludarabine and Cyclophosphamide (FC) for First Line Therapy with Advanced Chronic Lymphocytic Leukemia (CLL).

Abstract 3438Poster Board III-326 INTRODUCTIONChemoimmunotherapies like the FCR combination have been shown to increase complete remission rates and progression-free survival in patients with CLL in comparison to chemotherapies without biologicals (Hallek et al., ASH 2008). Until now little is known on HRQOL outcome of CLL patients receiving chemoimmunotherapy. Therefore we assessed the HRQOL in patients with advanced CLL, who were randomized between FC and FCR treatment within an international randomized trial of the German CLL Study Group (GCLLSG). METHODS817 pts with good physical fitness as defined by a cumulative illness rating scale (CIRS) score of up to 6 and a creatinine clearance (cr cl) ≥ 70 ml/min were enrolled between July 2003 and March 2006. Pts were randomly assigned to receive 6 courses of either FC (N=409; F 25mg/m2 i.v. d1–3 and C 250 mg/m2 i.v. d1–3; q 28 days) or FC plus R (N=408; 375 mg/m2 i.v. d 0 at first cycle and 500 mg/m2 d1 all subsequent cycles; q 28 days). The EORTC C30 questionnaires were sent to all patients included in Germany or Austria at baseline, after 3, 6, 12 months (mo) and then in yearly follow-up (FU). In all other countries questionnaires were handed out to the patients personally on the same time points during their visits in the study center. The analysis of the questionnaires was performed according to the EORTC recommendations (Aaronson et al., 1993). The questionnaire contained a global health scale, five functional scales (physical, role, cognitive, emotional and social), three symptom scales (fatigue, pain, nausea and vomiting) as well as six single items (dyspnea, appetite loss, sleep disturbances, financial impact, constipation and diarrhea). Mean score values of the EORTC scales ranged between 0 and 100. High scores in the functional scales represent good HRQOL, low scores in the symptom scales a low symptom burden. RESULTSHRQOL was evaluated in 763 (93%) of the included patients who completed at least one questionnaire (376 (49%) FC and 387 (51%) FCR treated patients). The compliance rate was significantly higher in those countries, where the questionnaire was handed out personally (96% in other countries versus 92% in Germany and Austria; P=0.013). Pts answering the baseline questionnaire and at least one further questionnaire (444; 58%) were compared to those how did not (319, 42%): pts with only one or a missing baseline questionnaire had a significantly higher CIRS score (1,7 vs 1,4; P=0.007) and more frequently leukocytopenias (24% CTC grade 3 and 4 leukocytopenias vs 13%; P< 0.001). Age, distribution of Binet stages, gender, poor prognostic factors (del(11q) or del(17p), unmutated IgVH) and treatment arms were similar distributed between both groups. There were also no differences in the rate of other toxicities or response rates. A total of 482 questionnaires were available initially, 406 at interim staging, 454 at final staging, 496 after 12 mo FU, 414 after 24 mo FU and 198 after 36 mo FU.A comparison of the two treatment arms at interim or final staging after 3 and 6 months respectively showed no significant difference between both arms with regards to the global health status, functional scales and symptom scales. Dyspnoe was scored significantly higher during FC treatment in comparison to FCR (23 versus 18; P = 0.023). At 12, 24 and 36 months of FU no significant difference between FC and FCR in all functional scales, symptom scales, single item and global health status was found. Both treatment arms showed slight improvement (defined as difference of 5-10 points) of global health status at 12 months FU in comparison to baseline (FC: 62 at baseline vs 68 at FU 12; FCR: 62 vs 70). CONCLUSIONSAlthough the FCR regimen is associated with a higher rate of cytopenias in patients' perception this increased hematological toxicity does not result in a difference in HRQOL between both treatment arms. After a median observation time of 38 mo the better efficacy of the FCR regimen with regards on response rates and progression-free survival does not yet result in an improved HRQOL. For the final evaluation of HRQOL outcome after chemoimmunotherapy a longer is FU is needed. DisclosuresEichhorst:Roche: Honoraria, Research Funding; Mundipharma: Research Funding; Hospira: Honoraria. Fischer:Roche: Travel Grand; Munipharma: Travel Grand. Fink:Roche: Travel Grand. Fingerle-Rowson:OrthoBiotech: Employment; Roche: Honoraria. Westermann:Roche: Travel Grand. Wendtner:Roche: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; BayerSchering: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Hallek:Roche: Research Funding, Speakers Bureau; Mundipharma: Research Funding, Speakers Bureau.

Chemoimmuno-Therapy with Fludarabine, Cyclophosphamide and Alemtuzumab (FC-Cam) in Patients with Relapsed or Genetic High-Risk CLL: Final Analysis of the CLL2L Trial of the German CLL Study Group.

Abstract 209 Introduction:Purine nucleoside combination therapy has become the standard treatment approach in B-CLL. In order to enhance efficacy, various combinations with monoclonal antibodies are under investigation. Alemtuzumab has been proven to be the most effective antibody in CLL treatment. Since the combination of Fludarabin and Campath (FluCam) resulted in impressive responses, we developed a multicenter phase II trial combining fludarabine, cyclophosphamide and alemtuzumab in a 4-weekly schedule Methods:Fludarabine 25mg/m2 iv, cyclophosphamide 200mg/m2 iv and alemtuzumab 30 mg sc were given on days 1 – 3 and repeated on day 29 for up to six cycles. A 2-day escalation of alemtuzumab was administered prior to the first cycle. Minimal residual disease (MRD) was measured by 4-color flow cytometry. Antiinfective prophylaxis consisted of TMP-SMZ DS twice daily 3d/wk and valacyclovir during and at least two months after completion of treatment. CMV antigen in blood was tested in 14-days intervals. Results:Target recruitment of 61 patients has been reached, 5 patients were excluded due to protocol violation (withdrawn consent, secondary malignancies, death prior to therapy). Data for all 56 patients are available for response and adverse event analysis. Median age is 63 years (range 36–78) with a medium number of 1 prior regimen (range 0–4); 38/56 patients completed at least four cycles with a median number of 5 given cycles. Pretreatment included fludarabine (15/56), fludarabine and cyclophosphamide (24/56) or rituximab combinations (16/56). CTC grade III/IV thrombocytopenia and neutropenia were the most common serious side effects. 12/56 patients died during or within 6 months after last chemoimmunotherapy, of which 5 were related to therapy, 3 were related to concomitant disease and 4 patients died due to progressive disease. Serious adverse events (SAE) included CMV-reactivation (5 patients), herpes-zoster-reactivation (1 patient), pneumonia (5 patients, 2 of which had Aspergillosis-pneumonias), AIHA (1 patient) and fever of unknown origin (12 patients). Four of 56 treated patients were excluded from response analysis: 1 patient stopped therapy because of secondary malignancy, 3 patients died within therapy. The overall response rate for the remaining 52 patients was 68% with 11 CR (22%), 6 CRu (11%), 18 PR (35%), 8 SD (15%) and 9 PD (17%), response was independent of FISH status. A correlation of response with prior treatment was observed, with 81% ORR for fludarabine pre-treatment versus only 63% for those patients pretreated with fludarabine and cyclophosphamide. Finalized data of all patients will be presented. Conclusions:The concomitant application of fludarabine, cyclophosphamide and alemtuzumab is as an effective approach for patients with relapsed CLL. There is some increased toxicity due to the addition of cyclophosphamide compared to the original FluCam regimen. Disclosures:Elter:BayerSchering AG: Honoraria, Research Funding. Off Label Use: The anti-CD52 antibody Alemtuzumab (Campath, MabCampath) is normally administered three-weekly as monotherapy. We are using a four-weekly schedule in combination with fludarabin for the same indication.. Stilgenbauer:BayerScheringAG: Honoraria, Research Funding. Hallek:BayerScheringAG: Honoraria, Research Funding. Engert:BayerScheringAG: Honoraria, Research Funding.

First-line therapy with fludarabine compared with chlorambucil does not result in a major benefit for elderly patients with advanced chronic lymphocytic leukemia

AbstractAlthough chronic lymphocytic leukemia (CLL) is a disease of elderly patients, subjects older than 65 years are heavily underrepresented in clinical trials. The German CLL study group (GCLLSG) initiated a multicenter phase III trial for CLL patients older than 65 years comparing first-line therapy with fludarabine with chlorambucil. A total of 193 patients with a median age of 70 years were randomized to receive fludarabine (25 mg/m2 for 5 days intravenously, every 28 days, for 6 courses) or chlorambucil (0.4 mg/kg body weight [BW] with an increase to 0.8 mg/kg, every 15 days, for 12 months). Fludarabine resulted in a significantly higher overall and complete remission rate (72% vs 51%, P = .003; 7% vs 0%, P = .011). Time to treatment failure was significantly shorter in the chlorambucil arm (11 vs 18 months; P = .004), but no difference in progression-free survival time was observed (19 months with fludarabine, 18 months with chlorambucil; P = .7). Moreover, fludarabine did not increase the overall survival time (46 months in the fludarabine vs 64 months in the chlorambucil arm; P = .15). Taken together, the results suggest that in elderly CLL patients the first-line therapy with fludarabine alone does not result in a major clinical benefit compared with chlorambucil. This trial is registered with www.isrctn.org under identifier ISRCTN 36294212.

What's new in the management of chronic lymphocytic leukemia? 2008 ASH Review (New York Medical College, January 31, 2009)

What's new in the management of chronic lymphocytic leukemia? 2008 ASH Review (New York Medical College, January 31, 2009)

Treatment of elderly patients with chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is dramatically increased in patients above the age of 65 years up to an incidence rate of 22–30/100 000. Although elderly patients represent the largest group of CLL patients they are clearly underrepresented in clinical trials. One important prognostic factor in the elderly is the burden of comorbidity. Survival is significantly impaired in CLL patients with multiple comorbidities (≥2) or with severe comorbidity (Charlson score ≥2). Therefore, not only age but also the incidence and burden of comorbidity should influence the choice of treatment strategy for every patient individually. A reliable tool for measuring comorbidity is the Cumulative Illness Rating Scale. The German CLL Study Group (GCLLSG) has used this tool within their clinical trials to distinguish between physically fit and non-fit patients. Although chlorambucil is still the standard treatment of choice in non-fit patients, dose-reduced purine analogue-based combination therapies with or without immunotherapy are currently investigated within clinical trials. Because full-dosed combination treatment might cause increased toxicity rates in relapse situation, dose-reduced combination therapies should be considered in this situation. An adequate supportive treatment is necessary for the prevention of toxicities as well as for the improvement of health-related quality of life. In summary, the treatment decision in elderly CLL patients is carefully to be made in each patient individually considering not only the stage and risk factors of the disease but also the patients' physical condition and social environment.

Consolidation with alemtuzumab improves progression‐free survival in patients with chronic lymphocytic leukaemia (CLL) in first remission – long‐term follow‐up of a randomized phase III trial of the German CLL Study Group (GCLLSG)

Alemtuzumab has shown considerable activity in untreated and relapsed chronic lymphocytic leukaemia. We report our long-term experience in 21 patients within a randomized phase III trial investigating the role of alemtuzumab for consolidation therapy after first-line fludarabine +/- cyclophosphamide, which was stopped prematurely due to severe infections. However, after a median follow-up of 48 months, progression-free survival was significantly prolonged for patients receiving alemtuzumab consolidation compared to those with no further treatment (P = 0.004). Minimal residual disease (MRD) levels were persistently reduced after consolidation. Therefore, despite toxicity, MRD reduction by alemtuzumab consolidation translates into a significantly improved long-term clinical outcome.

The Performance of Computed Tomography (CT) Scans or Ultrasound Has No Clinical Relevance in Treatment of Patients with Chronic Lymphocytic Leukemia (CLL): Results of a Metaanalysis from Three Phase III Studies of the German CLL Study Group (GCLLSG).

Introduction: Staging of CLL is based on simple methods to estimate the prognosis of CLL at the time point of diagnosis. Both, the Rai and Binet staging systems, are based on physical examination and peripheral blood count. According to the recently updated IWCLL guidelines for CLL (Hallek et al., Blood, 2008) no radiological examinations are needed for staging and response evaluation outside clinical trials. Previously, it was shown that CT scans add no benefit to the response criteria defined by the National Cancer Institute (NCI) (Byrd et al., 2007). However, it is still unclear, how much additional information can be gained by using CT scans by routine at pretherapeutic evaluation and during follow-up phase. Therefore the GCLLSG initiated a metaphase analysis based on the results of three phase III studies (CLL4, CLL5 and CLL8 protocol of the GCLLSG), in order to evaluate the clinical relevance of CT scans on disease outcome.Patients: A total of 1372 patients (pts) receiving first line therapy for CLL within a phase III trial of GCLLSG were included in this analysis. 362 pts younger than 65 years were included in the CLL4 trial, 193 pts older than 64 years in the CLL5 trial and 817 pts with normal renal function and a comorbidity score ≤ 6 were included in the CLL8 trial. 100 pts received chlorambucil, 257 fludarabine (F), 590 F plus cyclophosphamide (FC) and 408 FC plus rituximab. Response as well as progression during later follow-up was assessed according to the NCI-WG criteria (Cheson et al., Blood 1996). CT scan or other radiological examinations were not performed by routine, but were recommended at pretherapeutic staging, interim and final staging and during the follow-up phase, if clinically indicated.Results: The median follow up time for pts alive in the CLL4 trial was 54 months (mo), 40 mo in CLL5 and 27 mo in CLL8 (overall 31 mo). During follow-up a total of 11.103 CT scans, 22.728 ultrasounds as well as 2.350 chest x-rays were performed in 1372 pts. In contrast, 59.742 physical examinations were performed either additionally to radiological examination or alone. In a first step we evaluated the number of pts for whom the radiological examination was crucial in order to reconcile progressive disease (PD) according to the NCI criteria. A total 491 pts were considered as progressive during treatment or follow-up. In 100 pts the definition of PD by the treating physician could not be confirmed by a strict, independent application of the NCI-WG criteria and were therefore excluded from the analysis. In the remaining 391 pts PD was clinical apparent in 326 (83%), while CT scans were relevant for the decision of PD in 39 pts (10%) only and ultrasound in 26 pts (7%). In a next step we assessed the number of pts for whom CT scan or ultrasound had a clinical consequence by initiating relapse treatment because of bulky disease (defined as a lymph node of > 5 cm) in the thorax or abdomen. Out of 176 pts receiving relapse treatment due to PD, in only 2 pts (1%) the retreatment decision was based on the result of the CT scan or ultrasound: in these pts a new bulk was detected by radiological examination, while physical examination and blood count were normal. Moreover, an initially detected bulky disease by radiological examination had no prognostic value as well. Pts with initially detected bulky disease showed a higher rate of complete remissions in comparison to pts without bulky disease (29% versus 22%, p = 0.02). Interestingly, no difference in overall response rates (86% versus 89%, p = 0.2), as well as progression free survival (36 versus 39 months, p = 0.2) and overall survival (OS) (median OS not reached vs. 85 months, p = 0.08) was assessed.Conclusion: These data from 1372 patients included in three prospective phase III trials show that the use of CT scans has no apparent clinical benefit for the evaluation of PD or the decision to initiate relapse treatment in the follow-up phase of CLL. In 1% of the relapse treatment receiving pts only the result of the CT scan was crucial for retreatment decision. Moreover, the initial detection of bulky disease by CT scan or ultrasound had no prognostic impact. Our data suggest that physical examination and blood count remain the methods of choice for clinical follow-up of patients with CLL.

Bendamustine in Combination with Rituximab (BR) for Patients with Relapsed Chronic Lymphocytic Leukemia (CLL): A Multicentre Phase II Trial of the German CLL Study Group (GCLLSG)

Introduction: Bendamustine, an alkylating agent with additional properties of a purine analogue, has shown considerable activity in monotherapy for solid and lymphoid malignancies including chronic lymphocytic leukemia (CLL). In vitro studies have demonstrated synergistic pro-apoptotic effects of bendamustine and the CD20 antibody rituximab (BR) in primary CLL cells. Encouraging clinical results have been obtained using BR combination treatment in relapsed/refractory and previously untreated Non-Hodgkin's lymphoma. This phase II trial represents the first study evaluating the efficacy and toxicity of bendamustine in combination with rituximab in patients (pts) with relapsed or refractory CLL.Patients and Methods: 81 pts with a median number of 2 (1–3) pretreatments were enrolled between March 2006 and June 2007. Patients received 70 mg/m² bendamustine on day 1 and 2 combined with 375mg/m² rituximab for the first cycle and 500 mg/m² for the second and subsequent cycles. BR treatment was administered every 28 days for up to 6 courses. Blood samples were taken for molecular cytogenetics by fluorescence in situ hybridization (FISH) and analysis of the immunoglobulin heavy chain (IgVH) mutational status prior to the first treatment course. Assessment for minimal residual disease (MRD) was performed by four-colour flow cytometry of peripheral blood and bone marrow. Primary endpoint of the trial was the overall response rate (ORR). Secondary endpoints included toxicity, duration of response, event-free survival, MRD response rate and overall response rate in biological defined risk groups.Results: 81 pts (mean age 66.7 years) received a total of 328 treatment cycles. A mean number of 4.5 courses was administered. In total 123 CTC grade 3/4/5 adverse events were reported, most frequently on myelosuppression and infections: grade 3/4 anemia occurred in 6.1%, grade 3/4 leukopenia/neutropenia and thrombocytopenia in 11.9% and 9.1% of all given courses, respectively. 16 episodes (4.9%) of CTC grade ≥3 infections were documented, most of them could be successfully managed. However, treatment related mortality occurred in 3.7% of pts: three pts died due to severe infections associated with treatment related neutropenia including 1 fatal pneumonia, one sepsis after diagnosis of Richter's syndrome and 1 urosepsis. In 62 pts data for response assessment were available: 19 pts were not evaluable for response due to withdrawal or missing of consent, violation of enrolment criteria or early discontinuation of therapy. The overall response was 77.4% with complete remissions (CR) in 14.5% (9 pts) and a partial response (PR) in 62.9% of pts (39 pts). An MRD level below 10E-4 was measured after completion of therapy in 2 of 30 evaluable pts in peripheral blood, while none of the pts achieved MRD negativity in bone marrow. Stable disease (SD) was achieved in 17.7% (11 pts) whereas 3 pts (4.8%) had progressive CLL (PD). Differences in response were observed among genetic subgroups: 12 of 13 pts with 11q- achieved a remission with 11 PR and 1 CR (ORR: 92.3%). Accordingly, 8 of 8 patients with +12 responded (7 PR, 1 CR). In the high-risk group with 17p-, four of nine pts showed a partial remission (ORR: 44,4%). 29 of 39 pts (ORR: 74.4%) with unmutated IgVH status were responsive to BR.Conclusion: Bendamustine plus rituximab is an effective treatment regimen for pts with relapsed and/or refractory CLL and has notable activity in high-risk CLL disease. Major but tolerable treatment toxicities were myelosuppression and infections. Ongoing trial follow-up analysis will define response duration and long-term safety. In a forthcoming trial the German CLL Study group will investigate the efficacy of BR in comparison to fludarabine-based immunochemotherapy (FCR) for first-line treatment of CLL.

Immunochemotherapy with Fludarabine (F), Cyclophosphamide (C), and Rituximab (R) (FCR) Versus Fludarabine and Cyclophosphamide (FC) Improves Response Rates and Progression-Free Survival (PFS) of Previously Untreated Patients (pts) with Advanced Chronic Lymphocytic Leukemia (CLL)

Introduction: Previous phase II studies have suggested that a combination of FCR may increase the outcome of both untreated and relapsed CLL pts. In order to validate this concept the German CLL study group (GCLLSG) initiated a multicentre, multinational phase III trial, CLL8, to evaluate the efficacy and tolerability of FCR versus FC for the first-line treatment of pts with advanced CLL.Methods and Patients: 817 pts with good physical fitness as defined by a cumulative illness rating scale (CIRS) score (Extermann et al., JCO 1998) of up to 6 and a creatinine clearance (cr cl) □d 70 ml/min were enrolled between July 2003 and March 2006. Pts were randomly assigned to receive 6 courses of either FC (N=409; F 25mg/m2 i.v. d1–3 and C 250 mg/m2 i.v. d1–3; q 28 days) or FC plus R (N=408; 375 mg/m2 i.v. d 0 at first cycle and 500 mg/m2 d1 all subsequent cycles; q 28 days). Both treatment arms were well balanced with regard to age, stage, genomic aberrations and VH status. 64% were Binet B, 32% Binet C and 5% Binet A. The median age was 61 years (range 30 to 81), the median CIRS score was 1 (range 0–8). The overall incidences of trisomy 12 and abnormalities of 13q, 11q23, and 17p13 detected by FISH were 12%, 57%, 25%, and 8%, respectively, with no statistically significant differences between treatment arms. A mean number of 5.2 courses was given in the FCR arm versus 4.8 courses in the FC arm (p=0.006). 74% (FCR) and 67% (FC) of pts received 6 cycles. Dose was reduced by more than 10% in at least one treatment course in 43% (FCR) and 30% (FC) of pts, and in 21% (FCR) and 17% (FC) of all treatment courses given. 17 pts did not receive any study medication, 10 due to violation of enrolment criteria (4 decreased renal function, 2 active secondary malignancies, 2 active infections, 1 autoimmune thrombocytopenia, 1 pt not requiring treatment), 3 due to withdrawal of consent, 2 due to worsened concomitant diseases. 2 pts were lost before start of treatment. 56 pts were not evaluable for response: 17 did not receive any study medication, 16 withdrew consent before interim staging, 7 due to violation of enrolment criteria, 4 discontinued treatment due to toxicity and 12 due to early death (caused by toxicity, progression or secondary malignancy). Prophylactic use of antibiotics or growth factors was not generally recommended in the protocol.Results: At the time of analysis, June 2008, the median observation time was 25.5 months (mo). 761 pts (FCR 390; FC 371) were evaluable for response, 787 pts (FCR 400; FC 387) for PFS and all for OS. The overall response rate (ORR) was significantly higher in the FCR arm (95%; 370/390) compared to FC (88%; 328/371 (p=0.001). The complete response rate of the FCR arm was 52% as compared to 27.0% in the FC arm (p<0.0001). PFS was 76.6% at 2 years in the FCR arm and 62.3% in the FC arm (p<0.0001). There was a trend for an increased OS rate in the FCR arm (91% vs 88% at 2 years p=0.18). Hazard Ratio for PFS was 0.59, for OS 0.76. The largest benefit for FCR was observed in Binet stage A and B with regard to CR, ORR and PFS (A: p=0.01, B: p<0.0001). FCR treatment was more frequently associated with CTC grade 3 and 4 adverse events (47% of FC vs 62% of FCR treated pts). Severe hematologic toxicity occurred in 55% (FCR) versus 39% (FC) of all patients. Significant differences were observed for neutropenia (FCR 33,6%; FC 20,9% p=0.0001) and leukocytopenia (FCR 24%; FC 12,1% p<0.0001) but not for thrombocytopenia (FCR 7,4%; FC 10,8% p=0.09) and anemia (FCR: 5,4% FC 6,8% p=0.42). The incidence of CTC grade 3 or 4 infections was not significantly increased in the FCR arm (18,8% versus 14,8% in the FC arm, p=0.68). Tumor lysis syndrome (FCR 0,2% FC 0,5%) and cytokine release syndrome (FCR 0,2% FC 0,0%) were rarely observed in both arms. Treatment related mortality occurred in 2.0% in the FCR and 1.5% in the FC arm. Multivariate analyses were performed to evaluate factors predicting outcome. Amongst these variables age, sex, Binet stage, CIRS score, renal function (cr cl < 70 ml/min) were independent prognostic factors predicting OS or PFS.Conclusion: Treatment with FCR chemoimmunotherapy improves response rates and PFS when compared to the FC chemotherapy. FCR caused more neutropenia/leukopenia without increasing the incidence of severe infections. These results suggest that FCR chemoimmunotherapy might become the new standard first-line treatment for physically fit CLL patients.

Chemoimmuno-Therapy with Fludarabine, Cyclophosphamide and Alemtuzumab in Patients with Relapsed/Refractory CLL: Interim Analysis of the CLL2L Trial of the German CLL Study Group

Introduction: Purine nucleoside combination therapy has become the standard treatment approach in B-CLL. In order to enhance efficacy, various combinations with monoclonal antibodies are under investigation. As alemtuzumab has proven to be the most effective antibody in CLL treatment, we developed a multicenter phase II trial combining fludarabine, cyclophosphamide and alemtuzumab in a 4-weekly scheduleMethods: Fludarabine 25mg/m2 iv, cyclophosphamide 200mg/m2 iv and alemtuzumab 30 mg sc were given on days 1 – 3 and repeated on day 29 for up to six cycles. A 2-day escalation of alemtuzumab was administered prior to the first cycle. Minimal residual disease (MRD) was measured by 4-color flow cytometry. Antiinfective prophylaxis consisted of TMP-SMZ DS twice daily 3d/wk and valacyclovir during and at least two months after completion of treatment. CMV antigen in blood was tested in 14-days intervals.Results: A total of 55 patients of a planned sample size of 61 patients were included in this phase-II study so far, of which 24 patients are evaluable for response and safety analysis. Median age is 63 (range 47–78) years with a medium number of 1 prior regimen; 19/24 patients completed at least four cycles with a median number of 5 cycles. Pretreatment consisted of fludarabine (8/24), fludarabine and cyclophosphamide (13/24) or rituximab combinations (3/24). Thrombocytopenia and neutropenia were the most serious side effects and detailed data will be presented. 3 CMV-reactivations, 1 Herpes-zoster-reactivation and 12 fever of unknown origin have been reported. The overall response rate was 83% with 9 CR(6 CRu) (38%), 9 PR (46%), 3 SD and 1 PD, response was independent of FISH status. A correlation of response with prior treatment was observed, with 100% ORR for fludarabine pre-treatment versus only 77% for those patients pretreated with fludarabine and cyclophosphamide. Updated data of 30 patients and MRD data will be presented.Conclusions: The concomitant application of fludarabine, cyclophosphamide and alemtuzumab appears as a safe and effective approach for patients with relapsed CLL.

Treatment of patients with relapsed/refractory CLL using a combination of fludarabine, cyclophosphamide and alemtuzumab: First safety analysis of the CLL2L trial of the German CLL Study Group

7053 Background: Purine nucleoside combination therapy has become the standard treatment approach in B-CLL. In order to enhance efficacy, various combinations with monoclonal antibodies are under investigation. As alemtuzumab has proven to be the most effective antibody in CLL treatment, we developed a multicenter phase II trial combining fludarabine, cyclophosphamide and alemtuzumab in a 4-weekly schedule. Methods: Fludarabine 25mg/m2 iv, cyclophosphamide 200mg/m2 iv and alemtuzumab 30 mg sc were given on days 1 - 3 and repeated on day 29 for up to six cycles. A 2-day escalation of alemtuzumab was administered prior to the first cycle. Minimal residual disease (MRD) was measured by 4-color flow cytometry. Antiinfective prophylaxis consisted of TMP-SMZ DS twice daily 3d/wk and valacyclovir during and at least two months after completion of treatment. CMV antigen in blood was tested in 14-days intervals. Results: A total of 39 patients of a planned sample size of 61 patients were included in this phase-II study so far, of which 20 patients are evaluable for response and safety analysis. Median age is 64 (range 48–78) years with a medium number of 1 prior regimen; 14/20 patients completed at least four cycles with a median number of 4.5cycles. Pretreatment consisted of fludarabine (8/20), fludarabine and cyclophosphamide (12/20) or rituximab combination (1/20). Thrombocytopenia and neutropenia were the most serious side effects and detailed data will be presented. 2 CMV-reactivations, 1 Herpes-zoster-reactivation and 12 fever of unknown origin have been reported. The overall response rate was 70% with 5 CR (25%), 9 PR (45%), 2 SD and 2 PD. All complete responders became MRD negative in peripheral blood or bone marrow; response was independent of FISH status. A correlation of response with prior treatment was observed, with 88% ORR for fludarabine pre-treatment versus only 65% for those patients pretreated with fludarabine and cyclophosphamide. Conclusions: The concomitant application of fludarabine, cyclophosphamide and alemtuzumab appears as a safe and effective approach for patients with relapsed CLL. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bayer Schering AG, Schering AG Schering AG

Bendamustine in Combination with Rituximab (BR) for Patients with Relapsed Chronic Lymphocytic Leukemia (CLL): A Multicentre Phase II Trial of the German CLL Study Group (GCLLSG).

Introduction: Bendamustine has shown considerable activity in monotherapy for solid and lymphoid malignancies including CLL and has been used for more than 30 years in anti-cancer treatment. In vitro and ex vivo studies have demonstrated synergistic pro-apoptotic effects of bendamustine and the CD20 antibody rituximab (BR) in primary B-CLL cells. Encouraging clinical results have been obtained using BR combination treatment in relapsed/refractory NHL or mantle cell lymphoma. The present phase II trial represents the first study assessing efficacy and toxicity of bendamustine in combination with rituximab in pts with relapsed/refractory B-CLL.Patients and Methods: Between March 2006 and June 2007 81 pts with relapsed/refractory B-CLL and a median number of 2 pretreatments were enrolled into this trial. Bendamustine was given at a dose of 70 mg/m2 on day 1 and 2, combined with 375mg/m2 rituximab for the first cycle and 500 mg/m2 for the second and subsequent cycles. BR treatment was administered every 28 days up to 6 courses. Blood samples were taken for molecular cytogenetics by fluorescence in situ hybridization (FISH), analysis of the IgVH mutational status and expression of ZAP70/CD38. Assessment of minimal residual disease (MRD) was evaluated in peripheral blood and bone marrow by 4-colour flow cytometry.Results: So far data of 31 pts (median age 66 years) with a total of 126 treatment cycles are available for analysis. There was notable toxicity with 48 reported CTC grade 3/4 adverse events, particularly myelosuppression and infections: grade 3/4 anemia occurred in 6.3.%, leukopenia/neutropenia in 10.8% and thrombocytopenia in 11.9% of all courses. 6 episodes of CTC grade 3/4 infections were documented: 1 sinusitis maxillaris, 1 FUO and 1 abscess, all of them being reversible after antibiotics. However, 3 pts died due to severe infections including 2 fatal pneumonias and 1 urosepsis. One pt died due to myocardial infarction. Regarding efficacy, 23 pts were evaluable for response: The overall response rate (ORR) was 65.2% with a CR rate of 13.0% (3 pts) and a PR rate of 52.2% (12 pts). No molecular remission was observed by 4-colour cytometry. Stable disease (SD) was achieved in 26.1% (6 pts) whereas 2 pts had progressive CLL (PD, 8.7%). Responses were observed in the majority of pts with genomic aberrations 11q deletion (ORR: 4/5) and trisomy 12 (ORR: 2/3), while none of the pts with 17p deletion (ORR: 0/4) was responsive (P=0.006).Conclusion: Bendamustine plus rituximab is an effective regimen in refractory/relapsed B-CLL. Major treatment toxicities were myelosuppression and infections. Updated data with respect to toxicity and efficacy based on the entire study population will be available for the Meeting.

Prospective Evaluation of Prognostic Parameters in Early Stage Chronic Lymphocytic Leukemia (CLL): Results of the CLL1-Protocol of the German CLL Study Group (GCLLSG).

Background: Early stage CLL is a heterogeneous disease with a prognosis ranging from an overall survival of a few months to two decades. Prognostic markers helping to predict the individual course of CLL are highly warranted. The CLL1 trial was initiated to investigate all major prognostic parameters used at the time of its initiation for prediction of the course of CLL.Patients: From 1997 to 2004 877 Binet A pts (median age 60 yrs) were enrolled. The median follow up was 45 months (mo). Risk stratification was possible for 788 pts. Pts with high risk (HR) were defined by elevated thymidine kinase (TK) or beta-2-microglobulin (beta-2-MG)) and either short lymphocyte doubling time (LDT, <12 months)) or diffuse bone marrow infiltration (BMI). 99 pts were not eligible due to trial violation. HR pts were randomized to W&W vs. immediate therapy with fludarabine. Treated pts (n=104) were excluded from this analysis. Analyses on PFS and OS on 585 pts are presented. Progression was defined by slightly modified NCI-WG criteria.Results: 114 pts (19.5%) were stratified to HR, 471 pts (80.5%) to low risk (LR). At enrolment there was no significant difference with regard to age, performance state, comorbidity. Significantly more male pts were assigned to HR (p=0.03). Beside parameters for stratification the cohorts differed in leukocyte/lymphocyte count (p<0.001), cervical and inguinal lymphadenopathy (LN) (p=0.001 resp. 0.005) and splenomegaly (p=0.02). B symptoms, hemoglobin, platelets, hepatomegaly and axillary LN were similar distributed in both groups. The median PFS for all was 57.3 mo. The median PFS for HR was significantly shorter than for LR (88 vs.18 mo; p<0,001). Although the median OS was not reached for both, HR had significantly shorter OS time (p<0,001). Pts had a significantly shorter PFS (25 vs. 88 mo; p<0.001) if they had TK>7 U/L, beta-2-MG>3.5 mg/L (13 vs. 75 mo; p<0.001) or LDT <12 mo (20 vs. 75 mo; p<0.001). For these parameters OS was also significantly shorter for HR, although the median OS was not reached. Pts with diffuse BMI had shorter PFS (49 vs. 75 mo; p=0.003), but OS was not different (p=0.2). Furthermore lymphocyte counts >30 G/L (PFS 17 vs. 88 mo; p<0.001) or non-smouldering CLL (PFS 46 mo vs. n.r.; p<0.001) predicted shorter PFS/OS. Male pts had shorter PFS (49 mo vs. n.r.; p=0.001), but not OS (p=0.08). OS was significantly shorter for older pts than 55 (p=0.014) or 65 yrs (p<0.001), while PFS was not different. A multivariate Cox analysis revealed that TK, LDT, beta-2-MG, absolute lymphocyte count, sex and age were independent variables for PFS, while LDT, beta-2-MG, lymphocytes and age were also independent for OS.Conclusion: This prospective trial defined clinical and biological factors (TK, LDT, beta-2-MG, absolute lymphocyte count, age, sex) which help to predict progression in early CLL. Our model for risk stratification reliably separated between HR and LR. Due to the weak impact of BMI we do not further recommend the use of BM biopsy for assessment of prognosis in CLL.

No Significant Clinical Benefit of First Line Therapy with Fludarabine (F) in Comparison to Chlorambucil (Clb) in Elderly Patients (pts) with Advanced Chronic Lymphocytic Leukemia (CLL): Results of a Phase III Study of the German CLL Study Group (GCLLSG).

Introduction: Treatment regimens based on purine analogues as F have become standard in first line therapy of younger or physically fit CLL pts. In these pts purine analogue-based regimens resulted in higher response rates and prolongation of progression free survival (PFS). Because it is not clear if elderly or physically non-fit pts benefit from more intense first line strategies as well, Clb is still widely used in first line therapy of elderly CLL pts. The GCLLSG initiated a phase III study (CLL5 protocol) to evaluate the effect of F versus (vs.) Clb in first line therapy of elderly patients with advanced CLL.Patients: 206 pts (F 101; Clb 105), older than 64 years, were enrolled between July 1999 and September 2004. 13 pts had to be excluded due to violation of exclusion/inclusion criteria. 15% of the pts were in Binet stage A, 47% in stage B, and 38% in stage C. The median pt age was 70 years (range 64 to 80). Pts were randomized to receive either F 25mg/mi.v. d1–5 q 28 days for 6 courses or Clb 0,4mg/kg ideal bodyweight (BW) (dose escalation up to 0.8mg/kg) q15d for up to 12 months. The mean number of administered courses was 4.9 in the F arm, the median duration of Clb treatment was 6.5 months (median dose 0.5 mg/kg).Results: After a median observation time of 41,5 months (mo) (range 1–89 mo) 165 pts (F 78; Clb 87) were evaluable for response and 184 (F 88; Clb 96) for progression free survival (PFS). In spite of a significantly higher complete remission rate (CRR) and overall response rate (ORR) in the F arm (CRR8% vs. 0%; p=0.008; ORR86% vs. 59%; p<0.001) no difference in the PFS was assessed (median PFS time 18.7 mo for F vs. 17.8 mo for Clb; p=0.72). Moreover, 46% of F treated pts in comparison to 34% Clb treated pts died so far, but overall survival (OS) curves showed no significant difference (median OS 45.9 mo vs. 63.6 mo, p=0.21). Analyzing PFS and OS separately for pts <70 years and ≥70 years no difference between both arms was assessed as well. Impaired creatinine clearance did not have any effect on PFS and OS as well as gender. Pts in the Clb arm received rescue treatment more frequently than F recipients (62% vs. 39%). Pts initially treated with Clb received for first relapse treatment Clb in 20%, F in 43%, F-based combinations in 17% and in 20% others. ORR to 2nd line F was 53% (10 of 19). Pts initially treated with F received in 26% each F-based combinations and CHOP regimen. Retreatment with F was administered in 12%, while 2 pts only received Clb.Conclusion: This long-term follow-up analysis shows that elderly pts have no significant clinical benefit from first line therapy with F in comparison to Clb. Though higher CRR and ORR F failed to show any benefit in terms of PFS and OS. A possible explanation for this phenomenon is the longer treatment period with Clb, that might prevent earlier relapses. Moreover, in case of relapse F treated pts received either no treatment at all or more intense regimen in comparison to Clb. In conclusion, Clb and F are similar potent first-line treatment options for elderly CLL pts.

Dose Escalation Study To Evaluate Dose Limiting Toxicity (DLT), Maximum Tolerated Dose (MTD) and Safety of Alemtuzumab for Consolidation Therapy in Patients with Chronic Lymphoycytic Leukemia: Phase I/II Trial of the German CLL Study Group (GCLLSG).

Introduction: Alemtuzumab has shown considerable activity in both relapsed/refractory chronic lymphocytic leukemia (CLL) and frontline treatment setting. In a prior randomised phase III trial we have demonstrated that consolidation with alemtuzumab significantly improves progression-free survival and the rate of molecular remissions in CLL patients after fludarabine based chemotherapy. However, significant toxicity including severe infections were observed. This ongoing phase I/II trial investigates the maximum tolerated dose (MTD) of alemtuzumab consolidation in patients with CLL after 2nd line chemotherapy.Methods: 12 patients (pts) in complete or partial remission after induction chemotherapy with either fludarabine plus cyclophosphamide (FC) or fludarabine plus cyclphosphamide plus rituximab (FCR) were eligible to receive alemtuzumab consolidation 90 to 150 days after last chemo infusion. Alemtuzumab was administered in 2 different cohorts either intravenously (iv, cohort A) or subcutaneously (sc, cohort B), once weekly for 8 weeks. Dose escalation was started with 10 mg iv/sc and increased in 10 mg intervals per dose level, each dose level including a minimum of 3 pts. All pts received standard premedication and infection prophylaxis. Blood samples were taken to determine pharmacokinetics in week 4 and 8. MRD was evaluated in peripheral blood and bone marrow by 4-colour flow cytometry at week 8 and 3-monthly thereafter.Results: 10 pts (median age 68 years) in complete or partial remission (1 CR, 1 nPR, 8 PR) after FC/FCR were treated with alemtuzumab in cohort A. Due to 2 dose limiting toxicities (DLT) at dose level 2 (20 mg iv, 1 FUO requiring iv antibiotics, 1 exacerbated erythema exsudativum multiforme) the MTD of alemtuzumab was determined at 10 mg iv. In cohort B, so far 2 patients (1 CR, 1 PR) have been treated with 10 mg alemtuzumab sc and no DLT has been observed. Besides the 2 DLT overall toxicity was tolerable in both cohorts with 8 CTC grade III cytopenias reversible in less then 2 weeks, 1 FUO and 2 subclinical CMV reactivations. All infections were successfully treated. After the last dose of alemtuzumab (week 8) the clinical response status of 4 pts converted from PR to CR. Up to a median follow up of 22 months 3 pts presented with PD, 2 of them died due to disease progression. MRD negativity (< 1 × 10E-4) was achieved in 3/10 pts in cohort A and 1/2 pts in cohort B. The median PFS of all pts was 19.9 months. For the majority of patients examined alemtuzumab plasma concentrations in week 4 and 8 showed rapid accumulation with stable levels after administration in the range of 100 to 300 ng/ml.Conclusion: Consolidation with alemtuzumab in CLL pts after 2nd line therapy is safe and able to achieve response improvement including MRD negativity. Dose escalation of alemtuzumab has determined a MTD of 10 mg, if administered intravenously. Ongoing trial activity is attempting to determine the MTD, pharmacokinetic and clinical efficacy of subcutaneous alemtuzumab consolidation.

TPLL-1 Protocol of the German CLL Study Group (GCLLSG) - A Prospective Phase II Trial of Fludarabine Phosphate, Mitoxantrone and Cyclophosphamide (FMC) Followed by Alemtuzumab Consolidation in T-PLL.

Introduction: T-cell prolymphocytic leukemia (T-PLL) is an aggressive disease with a poor median overall survival of <12 months. To improve results in T-PLL, the GCLLSG initiated the T-PLL-1 protocol evaluating the efficacy of induction therapy with fludarabine, mitoxantrone and cyclophosphamide (FCM) followed by antibody therapy with alemtuzumab. Patients (pts) andMethods: Between November 2001 and December 2006 a total of 26 pts were entered in this trial. At the time of analysis eighteen pts. are available with confirmed diagnosis of T-PLL. Twelve patients were untreated and six pretreated. All patients were planned to receive 4 cycles of fludarabine phosphate 25 mg/m2 on Days 1–3, mitoxantrone 8 mg/m2 on Day 1, and cyclophosphamide 200 mg/m2 (FMC) on Days 1–3, which was repeated on Day 29. After 4 courses of chemotherapy, all responding patients were scheduled to receive alemtuzumab 30 mg IV 3 times per week as consolidation therapy for up to 12 weeks. Patients with stable or progressive disease at interim staging, after second cycle of FMC, were treated immediately with alemtuzumab. The median age was 71 years (range 46–75yrs). Median time from diagnosis to study entry was 2 months (range 0.2–6 months). All patients showed a typical marked hyperleukocytosis with a median of 141.600/μl (range 19.9–436.700/μl).Results: A total of 63 cycles of FMC therapy were documented and a total of 129 weeks of Alemtuzumab at 30 mg with a median of duration of 8 weeks therapy per pt (range 2–12 weeks) were administered, which corresponds to a medium Alemtuzumab dose of 720 mg (range 6 mg -1.033 mg). The overall response (OR= complete response (CR) + partial response (PR)) rates following FMC and alemtuzumab therapies were 66% and 86%, respectively. The best response to FMC therapy included 4 pts who achieved a CR, while 8 pts achieved a PR, 5 pts had SD, and 1pt had PD. Alemtuzumab was subsequently administered as consolidation therapy to 15 pts. Of responding pts. with CR 3 of 4 and with PR 7 of 8 received alemtuzumab as consolidation therapy. The pt with PD received alemtuzumab therapy as well, but the disease continued to progress. In addition, 2 pts with SD after FMC subsequently achieved a CR following alemtuzumab therapy and three pts with SD after FMC achieved a PR. One pt with PR after FMC had a progressive disease during Alemtuzumab therapy. The median overall survival (OS) of patients with T-PLL after FMC and alemtuzumab therapy was 19.2 months and progression free survival (PFS) was 10.6 months. Only one fatal adverse event presenting as myocardial infarction during alemtuzumab run-in phase was observed. FISH analysis was performed in 12 of 20 pts showing typical involvement of the chromosome 14 (t (14; 14), t (14q11)). Furthermore, in 12 pts expression of TCL-1 was tested by PCR. However, no correlation to OS or PFS was detected according to the level of expression.Conclusion: The combination of a fludarabine phosphate-containing regimen with subsequent alemtuzumab therapy shows clinical benefit in pts with T-PLL. To increase outcome study evaluating FMC combined with alemtuzumab followed by an alemtuzumab maintenance therapy is currently under investigation.

Early and Risk-Adapted Therapy with Fludarabine in High-Risk Binet Stage A CLL Patients Prolongs Progression Free Survival but Not Overall Survival: Results of the CLL1 Protocol of the German CLL Study Group (GCLLSG).

Background: Most patients (pts) with CLL present at early stages of their disease. This group is not homogenous with regard to its prognosis, and some pts show progression within 12 months after diagnosis. So far it is not clear if these pts benefit from early risk-adapted therapy. The CLL1 protocol, a randomized phase III trial of the GCLLSG, was conducted to assess if the early use of fludarabine prolongs progression free survival (PFS) in high risk (HR) CLL pts. High risk was defined by an elevated thymidine kinase (>7 U/L) or beta-2-microglobulin (>3,5 mg/L) and short lymphocyte doubling time (<12 months) or diffuse bone marrow infiltration. Combining the biological and clinical factors, at least one parameter of each group needed to be positive to qualify for the high risk cohort.Patients: From 09/1997 to 12/2004 877 previously untreated Binet A pts were enrolled. 788 pts could be stratified, 471 pts (68,3%) to the low risk (LR), 218 pts (31,6%) to the HR cohort for disease progression. 99 pts were not eligible due to violation of inclusion/exclusion criteria. 104 pts (HRF) were randomized to treatment with fludarabine (fludarabine IV 25 mg/m2/d, day 1–5, every 28 days), 114 pts (HRWW) to “watch and wait”. 30 pts were not eligible for PFS and OS. Analyses on PFS and OS on 188 pts are presented here. Response was defined by NCI-WG criteria (Cheson et al., 1996), progression was defined by slightly modified NCI-WG criteria with regard to the early stage.Results: The median observation time was 45.3 months (95% CI, 3.2–96 mo) for HRF and 40.4 months (95% CI, 6.9–92 mo) for HRWW. The median age in the HRF arm was 61 vs. 62 yrs in the HRWW arm. The HRWW arm contained significantly more male pts (p=0.03). All other parameters used for risk stratification and other characteristics like age, performance state, comorbidity, B symptoms, absolute lymphocyte count, hemoglobine, platelets, lymphadenopathy, splenomegaly or hepatomegaly were not significantly different at time of randomization. Response to fludarabine could be evaluated in 70 pts. The overall response rate was 91%, 11 pts had complete remission (16%), 5 pts had nodular partial remission (PR) (7%), 48 pts (69%) had PR, 3 pts (4%) had stable disease and 3 pts (4%) had progressive disease. Main toxicities (grade 3 or grade 4 CTC) were leukocytopenia and infections. Infections were not significantly higher in the treatment arm (p=0.12). Dose reduction was necessary in 20% of pts due to toxicity. 20 deaths were reported in the HRF arm, 12 deaths were reported in the HRWW arm (p=0.47).Discussion: On an intent-to-treat analysis PFS was significantly longer in the HRF arm in comparison to the HRWW arm (24.2 vs. 15.9 mo, p=0.03). Though the median OS was not yet reached, no significant difference between both groups in OS was assessed (p= 0.47).Conclusion: CLL pts of Binet stage A but with risk features have a median time to progression of 15.9 months. Fludarabine prolongs the PFS, but not the OS in this group of patients.

Health-Related Quality of Life in Younger Patients With Chronic Lymphocytic Leukemia Treated With Fludarabine Plus Cyclophosphamide or Fludarabine Alone for First-Line Therapy: A Study by the German CLL Study Group

To date, only a few studies have evaluated the health-related quality of life (HRQOL) of patients with chronic lymphocytic leukemia (CLL) receiving chemotherapy. Therefore, the German CLL Study Group assessed HRQOL in younger patients with advanced CLL receiving first-line chemotherapy with fludarabine or fludarabine plus cyclophosphamide (FC). Three hundred seventy-five patients younger than 66 years with advanced CLL were randomly assigned to receive either fludarabine alone (fludarabine 25 mg/m2/d for 5 days intravenously [IV], repeated every 28 days) or FC (fludarabine 30 mg/m2/d for 3 days IV plus cyclophosphamide 250 mg/m2/d for 3 days, repeated every 28 days). Six courses of treatment were planned to be administered. The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 was sent to all patients at baseline and after 6, 12, and 24 months. Eighty-nine percent of 362 included patients completed at least one questionnaire (163 fludarabine- and 158 FC-treated patients). Comparing the baseline levels of 249 CLL patients with the general German population, significant differences in nearly all HRQOL scales were assessed between the two groups. A multivariate analysis showed no significant differences in all HRQOL scales between both arms. In both treatment arms, symptoms such as fatigue, insomnia, and appetite loss improved to lower levels after the end chemotherapy. Except for lower physical status, no significant difference in HRQOL between male and female patients was evaluated. Fludarabine-based treatment seems to improve HRQOL little to moderately in younger patients with advanced CLL. No significant difference between fludarabine- and FC-treated patients was observed.