German CLL Study Group Research Articles

Prognostic Impact of Immunohistochemistry and MRD Results in Bone Marrow after Frontline Chemoimmunotherapy of Chronic Lymphocytic Leukemia (CLL): Results of Central Laboratory Analyses of the CLL10 Trial of the German CLL Study Group (GCLLSG)

Prognostic Impact of Immunohistochemistry and MRD Results in Bone Marrow after Frontline Chemoimmunotherapy of Chronic Lymphocytic Leukemia (CLL): Results of Central Laboratory Analyses of the CLL10 Trial of the German CLL Study Group (GCLLSG)

High-Resolution SNP-Array Profiling of “Ultra-High Risk” CLL Cases Reveals New Recurrent Genomic Alterations

High-Resolution SNP-Array Profiling of “Ultra-High Risk” CLL Cases Reveals New Recurrent Genomic Alterations

RPS15 mutations and Treatment Outcome in Chronic Lymphocytic Leukemia - Results from the CLL11 Phase III Trial (Chlorambucil (Clb) with or without the Addition of Rituximab (R) or Obinutuzumab (GA101, G)) of the German CLL Study Group

RPS15 mutations and Treatment Outcome in Chronic Lymphocytic Leukemia - Results from the CLL11 Phase III Trial (Chlorambucil (Clb) with or without the Addition of Rituximab (R) or Obinutuzumab (GA101, G)) of the German CLL Study Group

Bendamustine Followed By Obinutuzumab and Idelalisib in Patients with Chronic Lymphocytic Leukemia (CLL): CLL2-BCG Trial of the German CLL Study Group (GCLLSG)

Bendamustine Followed By Obinutuzumab and Idelalisib in Patients with Chronic Lymphocytic Leukemia (CLL): CLL2-BCG Trial of the German CLL Study Group (GCLLSG)

Severe Infections in Patients with Chronic Lymphocytic Leukemia Treated with (Immuno-)Chemotherapy: A Pooled Analysis of Gcllsg Trials

Severe Infections in Patients with Chronic Lymphocytic Leukemia Treated with (Immuno-)Chemotherapy: A Pooled Analysis of Gcllsg Trials

Prognostic impact of prevalent chronic lymphocytic leukemia stereotyped subsets: analysis within prospective clinical trials of the German CLL Study Group (GCLLSG).

Almost one-third of all patients with chronic lymphocytic leukemia (CLL) express stereotyped B-cell receptor immunoglobulins (BcR IG) and can be assigned to distinct subsets, each with a particular BcR IG. The largest stereotyped subsets are #1, #2, #4 and #8, associated with specific clinico-biological characteristics and outcomes in retrospective studies. We assessed the associations and prognostic value of these BcR IG in prospective multicenter clinical trials reflective of two different clinical situations: (i) early-stage patients ('watch and wait' arm of the CLL1 trial) (n=592); (ii) patients in need of treatment, enrolled in three phase III trials (CLL8, CLL10, CLL11), treated with different chemo-immunotherapies (n=1,861). Subset #1 was associated with del(11q), higher CLL International Prognostic Index (CLL-IPI) scores and similar clinical course to CLL with unmutated immunoglobulin heavy variable (IGHV) genes (U-CLL) in both early and advanced stage groups. IGHV-mutated (M-CLL) subset #2 cases had shorter time-to-first-treatment (TTFT) versus other M-CLL cases in the early-stage cohort (hazard ratio [HR]: 4.2, confidence interval [CI]: 2-8.6, P<0.001), and shorter time-to-next-treatment (TTNT) in the advancedstage cohort (HR: 2, CI: 1.2-3.3, P=0.005). M-CLL subset #4 was associated with lower CLL-IPI scores and younger age at diagnosis; in both cohorts, these patients showed a trend towards better outcomes versus other MCLL. U-CLL subset #8 was associated with trisomy 12. Overall, this study shows that major stereotyped subsets have distinctive characteristics. For the first time in prospective multicenter clinical trials, subset #2 appeared as an independent prognostic factor for earlier TTFT and TTNT and should be proposed for risk stratification of patients. (Trials registered at clinical trials. gov identifiers: NCT00262782, NCT00281918, NCT2000769522, and NCT01010061).

Sequential Treatment with Bendamustine, Obinutuzumab (GA101) and Ibrutinib in Chronic Lymphocytic Leukemia (CLL): Final Results of the CLL2-BIG Trial of the German CLL Study Group (GCLLSG)

Sequential Treatment with Bendamustine, Obinutuzumab (GA101) and Ibrutinib in Chronic Lymphocytic Leukemia (CLL): Final Results of the CLL2-BIG Trial of the German CLL Study Group (GCLLSG)

Analysis of Outcomes of Younger (≤ 55 Years) Compared with Older (> 55 Years) Patients with Chronic Lymphocytic Leukaemia (CLL) in Seven Studies Conducted By the German CLL Study Group (GCLLSG)

Analysis of Outcomes of Younger (≤ 55 Years) Compared with Older (> 55 Years) Patients with Chronic Lymphocytic Leukaemia (CLL) in Seven Studies Conducted By the German CLL Study Group (GCLLSG)

Comparison of Overall Survival in High Risk Patients with Minimal Residual Disease after First-Line Treatment across Three Generations of Phase 3 Trials of the German CLL Study Group

Comparison of Overall Survival in High Risk Patients with Minimal Residual Disease after First-Line Treatment across Three Generations of Phase 3 Trials of the German CLL Study Group

A Randomized Phase 2 Study Comparing Acalabrutinib with or without Obinutuzumab in the Treatment of Early Stage High Risk Patients with Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)

A Randomized Phase 2 Study Comparing Acalabrutinib with or without Obinutuzumab in the Treatment of Early Stage High Risk Patients with Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)

PF390 FIRST-LINE TREATMENT WITH LENALIDOMIDE DOES IMPROVE OUTCOME IN ELDERLY/UNFIT PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA: RESULTS OF A SYSTEMATIC REVIEW AND META-ANALYSIS

Background: Chronic Lymphocytic Leukemia (CLL) treatment is evolving rapidly. But, except for a small subset of patients undergoing allogenic stem cell transplantation, CLL is still not curable. Therefore, new therapies are needed that improve survival outcomes without increasing toxicity. Lenalidomide (Len) is an oral immunomodulatory drug with multiple effects on the immune system. High response rates are observed in early trials, however, exact place and duration of len treatment is still not optimized. Aims: The aim of this systematic review and meta-analysis was to provide overview of efficacy and safety of len as induction and consolidation therapy compared to standard treatment in previously untreated CLL patients. Methods: A systematic review and meta-analysis on len induction and consolidation treatment in elderly/unfit and young/fit first-line patients was performed. PubMed, EMBASE, Clinicaltrials.gov and Cochrane were searched for relevant cohort studies. Both randomized and non-randomized studies were included. Overall response rates (ORR), progression free survival (PFS) and safety outcomes were compared to standard CLL treatment, i.e. FCR for young/fit and rituximab or obinutuzumab with chlorambucil (R-Clb, G-Clb) for elderly/unfit patients, of which results were used from the large CLL11 and CLL10 studies of the German CLL Study Group. A meta-analysis was performed on ORR for len induction treatment. For studies investigating consolidation treatment, results were compared descriptively. Results: Ten studies, of which 9 non-randomized studies and 1 randomized study, with a total of 571 patients that received len induction treatment were included in the meta-analysis. A subgroup analysis was performed for patients undergoing len monotherapy (Len-mono) and len combination therapy (Len-combo). The summarized ORR using the random effects model of the two Len-combo in elderly/unfit studies was higher compared to standard treatment with a pooled ORR of 82% [95% CI: 72 - 89%] compared to 65.7% for R-Clb and 77.3% for G-Clb (Fig1A). The summarized ORR of Len-combo in the 5 young/fit studies was 87% [95% CI: 70 – 95%] compared to 90.4% for FCR, however, the chemotherapy regimens differ between the studies (Fig1B). Treatment with Len-mono was not superior compared to standard treatment in both elderly/unfit and young/fit patients (Fig1A+B). Seven studies, including 2 randomized studies, with a total of 305 patients that received len consolidation treatment were compared descriptively. All studies showed an improvement in response or PFS during consolidation with len. Moreover, one placebo-controlled study showed a significant PFS advantage for patients treated with lenalidomide consolidation, although no difference in overall survival was found. Toxicity was slightly increased with len therapy. Neutropenia was the most common toxicity but was usually manageable. Tumor lysis syndrome and tumor flare response grade 3/4 occurred rarely when individualized dose escalation of len was performed and thrombo-embolic events occurred in less than 5% when aspirin prophylaxis was given.Summary/Conclusion: This meta-analysis demonstrates that elderly/unfit CLL patients benefit from treatment with len in combination with rituximab/chlorambucil compared to R-Clb and G-Clb. In young/fit patients, standard FCR treatment remains superior. When len was given as consolidation treatment after induction treatment, responses increased and PFS was prolonged. Toxicity was higher compared to standard treatment, but was manageable when adequate prophylaxis was used.

Small Lymphocytic Lymphoma: Analysis of Two Cohorts Including Patients in Clinical Trials of the German Chronic Lymphocytic Leukemia Study Group (GCLLSG) or in "Real-Life" Outside of Clinical Trials.

Only few studies have focused exclusively on patients with small lymphocytic lymphoma (SLL). In the present report, 103 SLL patients were analyzed from both, clinical trials of the German Chronic Lymphocytic Leukemia Study Group and Greek centers, and emphasis was placed on the therapeutic strategy. The impact of lymph node characteristics, such as the presence of proliferation centers (PCs) on response and survival was also assessed. SLL patients included in clinical trials were treated mostly with fludarabine-based regimens while those in "real-life" were staged and treated mostly as patients with low-grade lymphomas. Our analysis showed a trend for better survival for patients with SLL without detectable PCs. Patients with SLL outside of clinical trials are usually treated as cases of lymphoma. In addition, this analysis supports published data regarding the adverse prognostic value of the presence of PCs in lymphoid nodes in SLL.

Obesity Negatively Impacts Outcome in Female Patients with Chronic Lymphocytic Leukemia (CLL) Treated with Fludarabine, Cyclophosphamide and Rituximab (FCR): An Analysis of Three Phase III Studies of the German CLL Study Group (GCLLSG)

Obesity Negatively Impacts Outcome in Female Patients with Chronic Lymphocytic Leukemia (CLL) Treated with Fludarabine, Cyclophosphamide and Rituximab (FCR): An Analysis of Three Phase III Studies of the German CLL Study Group (GCLLSG)

Durable Remissions after Discontinuation of Combined Targeted Treatment in Patients with Chronic Lymphocytic Leukemia (CLL) Harbouring a High-Risk Genetic Lesion (del(17p)/TP53 Mutation)

Background:Based on the “sequential triple-T” concept of a tailored and targeted treatment aiming at total eradication of minimal residual disease (MRD) [Hallek M., ASH 2013], the German CLL study group (GCLLSG) performed three similar prospective, open-label, multicenter, phase-II-trials evaluating different combinations of targeted drugs in an all-comer population of treatment-naïve or relapsed/refractory CLL patients, irrespective of fitness and high-risk genetics [Cramer P., et al. Future Oncol 2018].Methods:A debulking with two cycles bendamustine was recommended for patients with relevant tumor burden (defined as absolute lymphocyte count > 25.000/µl and/or lymph nodes > 5cm). In the induction and maintenance phase, the CD20-antibodies obinutuzumab (G, for GA-101) or ofatumumab (O) were combined with the targeted agents ibrutinib (I) or venetoclax (A, for ABT-199) until achievement of a MRD negative complete remission or up to 24 months. I was combined with O in the CLL2-BIO trial and with G in CLL2-BIG, while A plus G was evaluated in CLL2-BAG. Central diagnostics included FISH cytogenetics/molecular genetics at baseline and MRD evaluations by 4-color flow cytometry.Results:Between 27th January 2015 and 4th October 2016 189 patients with CLL were enrolled in the 3 trials, among them 51 patients with a del(17p) or a TP53 mutation (Table 1). Median observation time of these 51 patients with high risk genetic features was 29 months (range 15-39 months). Twenty-one patients were treated with ibrutinib and ofatumumab (IO), 13 with ibrutinib and obinutuzumab (IG) and 17 with venetoclax and obinutuzumab (AG). Twenty-seven patients received a debulking with bendamustine prior to induction and maintenance treatment with the above mentioned combinations of targeted agents. After 8 months of induction treatment, the overall response rates were 81%, 100% and 94% with IO, IG and AG, respectively and the corresponding rates of MRD negativity (<10-4 by flow cytometry) in peripheral blood were 0%, 23% and 82%. Forty-eight patients continued treatment in a maintenance phase and until data-cutoff, 34 patients stopped all treatment. Reasons for discontinuation were completion of the full eight cycles (24 months) in 8 patients, progressive CLL in 7 patients, death and adverse events in 1 patient each. Seventeen patients discontinued treatment as per protocol due to MRD negativity (Figure 1); of these, 13 (77%) are still in remission after a median observation time of 16 (range 6-23) months after discontinuation.Conclusions:In patients with del(17p)/TP53 mutations, the rate of MRD negative remissions achieved with venetoclax and obinutuzumab is higher than with ibrutinib combined with either obinutuzumab or ofatumumab. Disease control seems durable in patients achieving a MRD negative remission by one of these combinations, as 13 of 17 patients show ongoing remissions after a median observation time of more than one year after termination of therapy. DisclosuresCramer:AstraZeneca: Consultancy; Acerta: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Abbvie: Consultancy, Honoraria, Other: Travel grants, Research Funding; GlaxoSmithKline: Research Funding; Roche: Honoraria, Other: Travel grants, Research Funding; Gilead: Other: Travel grants, Research Funding; Mundipharma: Other: Travel grants; Janssen: Consultancy, Honoraria, Other: Travel grants, Research Funding. von Tresckow:Janssen-Cliag: Consultancy, Honoraria, Other: Travel grants, Research Funding; Roche: Consultancy, Honoraria, Other: Travel grants, Research Funding; Celgene: Consultancy, Other: Travel grants; AbbVie: Consultancy, Honoraria. Bahlo:Roche: Honoraria, Other: Travel Grants. Tausch:AbbVie: Consultancy, Other: Travel grants; Celgene: Consultancy, Other: Travel grants; Gilead: Consultancy, Other: Travel grants. Langerbeins:Sunesis: Consultancy; AbbVie: Research Funding; Janssen: Consultancy, Honoraria, Other: Travel support, Research Funding; Mundipharma: Consultancy, Other: Travel grants; Roche: Consultancy, Other: Travel grants, Research Funding. Al-Sawaf:Abbvie: Honoraria; Gilead: Honoraria; Roche: Honoraria. Fink:Celgene: Consultancy, Research Funding; AbbVie: Consultancy, Other: travel geants; Roche: Other: travel grants; Mundipharma: Other: travel grants. Fischer:Roche: Other: Travel support. Wendtner:Roche: Consultancy, Honoraria, Other: travel support, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Other: travel support, Research Funding; Genetech: Consultancy, Honoraria, Other: travel support, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Other: travel support, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: travel support, Research Funding; MorphoSys: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding. Eichhorst:AbbVie, Celgene, Gilead, Janssen, Mundipharma, Novartis, Roche: Honoraria, Other: Travel support, Research Funding. Kneba:Roche: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Stilgenbauer:Roche: Consultancy, Honoraria, Other: travel support, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Other: travel support, Research Funding; Janssen: Consultancy, Honoraria, Other: travel support, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: travel support, Research Funding; Genetech: Consultancy, Honoraria, Other: travel support, Research Funding; Mundipharma: Consultancy, Honoraria, Other: travel support, Research Funding; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding; Amgen: Consultancy, Honoraria, Other: travel support, Research Funding; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding; Novartis: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding. Hallek:Celgene: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding.

Outcome of patients aged 80years or older treated for chronic lymphocytic leukaemia.

Clinical management of chronic lymphocytic leukaemia (CLL) in patients aged ≥80years is based on limited evidence due to the lack of published information. Therefore, we analysed CLL patients aged ≥80years using data from seven phase III clinical trials of the German CLL Study Group. Among 3552 participants, 152 were ≥80years old at initiation of first-line study treatment. Median age was 82years (range 80-90). Concomitant diseases were present in 99% of the patients, with a median cumulative illness rating scale score of 8 (0-18). Chemoimmunotherapy with chlorambucil-obinutuzumab (CLB-OB) or chlorambucil-rituximab (CLB-R) was administered to 61 (40%) and 56 (37%) patients. The remaining patients received CLB (n=19) or fludarabine (F, n=10), F/cyclophosphamide (FC, n=1), FC/rituximab (FCR, n=2) or bendamustine/rituximab (BR, n=3). Rates of grade 3 or 4 neutropenia and infections were 35% and 13%. Overall response rate was 77% with 13% complete remissions. Median progression-free survival and treatment-free survival were 17·2 and 32·3months, respectively. Median overall survival was 48·3months; adverse events (22%) and progressive CLL (16·4%) were the most frequent causes of death. These findings suggest that anti-leukaemic treatment including chemoimmunotherapy is feasible and efficacious in ≥80-year-old CLL patients. However, this group of patients lives for a shorter time than age-matched controls of the general population.

Comparison of different phase II studies using sequential combinations of targeted agents for treating chronic lymphocytic leukemia.

7513Background: The German CLL study group (GCLLSG) performed three similar phase-II-trials combining a CD20-antibody, ofatumumab (O) or obinutuzumab (G, for GA-101), with ibrutinib (I) or venetocl...

Lenalidomide maintenance after first-line therapy for high-risk chronic lymphocytic leukaemia (CLLM1): final results from a randomised, double-blind, phase 3 study

The combined use of genetic markers and detectable minimal residual disease identifies patients with chronic lymphocytic leukaemia with poor outcome after first-line chemoimmunotherapy. We aimed to assess lenalidomide maintenance therapy in these high-risk patients. In this randomised, double-blind, phase 3 study (CLLM1; CLL Maintenance 1 of the German CLL Study Group), patients older than 18 years and diagnosed with immunophenotypically confirmed chronic lymphocytic leukaemia with active disease, who responded to chemoimmunotherapy 2-5 months after completion of first-line therapy and who were assessed as having a high risk for an early progression with at least a partial response after four or more cycles of first-line chemoimmunotherapy, were eligible if they had high minimal residual disease levels or intermediate levels combined with an unmutated IGHV gene status or TP53 alterations. Patients were randomly assigned (2:1) to receive either lenalidomide (5 mg) or placebo. Randomisation was done with a fixed block size of three, and was stratified according to the minimal residual disease level achieved after first-line therapy. Maintenance was started with 5 mg daily, and was escalated to the target dose of 15 mg. If tolerated, medication was administered until disease progression. The primary endpoint was progression-free survival according to an independent review. The pre-planned interim analysis done by intention to treat was done after 20% of the calculated progression-free survival events. This study is registered with ClinicalTrials.gov, number NCT01556776; treatment in the lenalidomide group is still ongoing. Between July 5, 2012, and March 15, 2016, 468 previously untreated patients with chronic lymphocytic leukaemia were screened for the study; 379 (81%) were not eligible. Recruitment was closed prematurely due to poor accrual after 89 of 200 planned patients were randomly assigned: 60 (67%) enrolled patients were assigned to the lenalidomide group and 29 (33%) to the placebo group, of whom 56 (63%) received lenalidomide and 29 (33%) placebo, with a median of 11·0 (IQR 4·5-20·5) treatment cycles at data cutoff. After a median observation time of 17·9 months (IQR 9·1-28·1), the hazard ratio for progression-free survival assessed by an independent review was 0·168 (95% CI 0·074-0·379). Median progression-free survival was 13·3 months (95% CI 9·9-19·7) in the placebo group and not reached (95% CI 32·3-not evaluable) in the lenalidomide group. The most frequent adverse events were skin disorders (35 patients [63%] in the lenalidomide group vs eight patients [28%] in the placebo group), gastrointestinal disorders (34 [61%] vs eight [28%]), infections (30 [54%] vs 19 [66%]), haematological toxicity (28 [50%] vs five [17%]), and general disorders (28 [50%] vs nine [31%]). One fatal adverse event was reported in each of the treatment groups (one [2%] patient with fatal acute lymphocytic leukaemia in the lenalidomide group and one patient (3%) with fatal multifocal leukoencephalopathy in the placebo group). Lenalidomide is an efficacious maintenance therapy reducing the relative risk of progression in first-line patients with chronic lymphocytic leukaemia who do not achieve minimal residual disease negative disease state following chemoimmunotherapy approaches. The toxicity seems to be acceptable considering the poor prognosis of the eligible patients. The trial independently confirms the clinical significance of a novel, minimal residual disease-based algorithm to predict short progression-free survival, which might be incorporated in future clinical trials to identify candidates for additional maintenance treatment. Celgene Corporation.

Early, risk-adapted treatment with fludarabine in Binet stage A chronic lymphocytic leukemia patients: results of the CLL1 trial of the German CLL study group.

Early, risk-adapted treatment with fludarabine in Binet stage A chronic lymphocytic leukemia patients: results of the CLL1 trial of the German CLL study group

Impact of gender on outcome after chemoimmunotherapy in patients with chronic lymphocytic leukemia: a meta-analysis by the German CLL study group.

Impact of gender on outcome after chemoimmunotherapy in patients with chronic lymphocytic leukemia: a meta-analysis by the German CLL study group

Favorable Toxicity Profile and Long Term Outcome of Elderly, but Physically Fit CLL Patients (pts) Receiving First Line Bendamustine and Rituximab (BR) Frontline Chemoimmunotherapy in Comparison to Fludarabine, Cyclophosphamide, and Rituximab (FCR) in Advanced Chronic Lymphocytic Leukemia (CLL): Update Analysis of an International, Randomized Study of the German CLL Study Group (GCLLSG) (CLL10 Study)

Favorable Toxicity Profile and Long Term Outcome of Elderly, but Physically Fit CLL Patients (pts) Receiving First Line Bendamustine and Rituximab (BR) Frontline Chemoimmunotherapy in Comparison to Fludarabine, Cyclophosphamide, and Rituximab (FCR) in Advanced Chronic Lymphocytic Leukemia (CLL): Update Analysis of an International, Randomized Study of the German CLL Study Group (GCLLSG) (CLL10 Study)