The Use of Chemoimmunotherapy Improves the Outcome of Patients with Chronic Lymphocytic Leukaemia (CLL) – a Metaanalysis of Five Trials of the German CLL Study Group (GCLLSG)
Authors: Cramer Paula , Isfort Susanne , Bahlo Jasmin , Busch Raymonde , Langerbeins Petra , Fink Anna-Maria , Goede Valentin , Elter Thomas , Bergmann Manuela A. , Stauch Martina Beate , Stilgenbauer Stephan , Wendtner Clemens-Martin , Fischer Kirsten , Hallek Michael , Eichhorst Barbara F. 
Published: October 2019

Abstract
Abstract 3936

Introduction:
A substantial improvement of treatment outcomes in patients with CLL was achieved during the last decades, but almost all patients (pts) eventually relapse. According to ESMO-guidelines, a repetition of 1st-line therapy is a reasonable approach in case of a relapse >24 months after initial treatment [Eichhorst et al., Ann Oncol., 2011]. This recommendation has not yet been confirmed by clinical trials and little is known which therapy should be chosen in case of an earlier relapse.

Methods:
1558 pts treated in five prospective trials of the GCLLSG were included in the analysis. Three randomised phase-III-trials for 1st-line treatment evaluated fludarabine (F) vs. F + cyclophosphamide (FC) [CLL4], chlorambucile (Clb) vs. F [CLL5] and FC without or with rituximab (FCR) [CLL8]. Two trials were designed for both 1st-line and relapse treatment and tested FC + alemtuzumab (FCC) [CLL2L] as well as bendamustine + rituximab (BR) [CLL2M]. For statistical analyses Kaplan-Meier estimators and curves, as well as log-rank tests were used.

Results:
Most common 1st-line therapies were those tested in the above mentioned five GCLLSG-trials: 588 pts received FC (38%), 402 pts FCR (26%), 299 pts F (19%), 134 pts Clb with/without steroids (9%) and 116 pts BR (7%). Treatment-free (TFS) and overall survival (OS) were shorter in pts treated with Clb, F or FC in comparison to patients treated with FCR or BR chemoimmunotherapy (see figure 1).
So far, 704 of 1558 pts received 2nd-line treatment for progressive CLL. These 2nd-line therapies were quite heterogeneous, most common regimen were: FC (79 pts, 11%), BR (75 pts, 11%), F (65 pts, 9%), B with/without steroids (63 pts, 9%), CHOP-R (56 pts, 8%), Clb with/without steroids (55pts, 8%), FCR (54 pts, 8%), as well as alemtuzumab with/without steroids (43 pts, 6%) and FCC (32 pts, 5%).
Patients treated with antibody-based regimen had a significantly longer OS than patients never treated with antibodies (OS after 60 months: 76% vs 64%, p<0,001). However, the timepoint of administration of the antibody (1st-line vs. ≥2nd-line treatment) appeared to be less important.
315 pts requiring a 2nd-line therapy within 24 months after initial treatment were identified. Treatment regimen were heterogeneous, most common therapies were the combination of cyclophosphamide, doxorubicine, vincristine, and prednisolone either with rituximab (R-CHOP, n=32) or without (CHOP, n=24) and alemtuzumab (n=27). Treatment regimens were summarized to 3 different groups: therapies containing an antibody with/without <3 cytotoxic agents, single-agent chemotherapies, and therapies containing anthracyclines and/or ≥3 cytotoxic agents. TFS for all three groups was 24.5, 18.7 and 16.4 months (p=0.009) and OS was 78.3, 58.2, and 42.0 months (p=0.012). Aside from a higher median age in the single-agent chemotherapy group no differences in other baseline-characteristics were found.

Conclusion:
This metaanalysis confirms that the use of monoclonal antibodies in 1st-line and relapse therapy leads to a prolongation of TFS and OS. In patients with a relapse ≤24 months, the use of standard-chemoimmunotherapies or single-agent alemtuzumab seems to be more efficient compared to therapies that contain ≥3 cytotoxic agents and/or anthracyclines (e.g. R-CHOP, CHOP or FCM). In addition, the poor outcome of early relapsing patients underscores the need for alternative treatment approaches with either allogeneic stem cell transplantation or use of novel drugs in order to further improve the survival of these pts.

Disclosures:
Cramer: Roche: Travel grant Other; Mundipharma: Travel grant, Travel grant Other. Bahlo:Roche: Honoraria. Fink:Roche: Travel grant Other. Goede:Roche: Honoraria, Travel grant Other. Elter:Roche: Honoraria, Travel grant Other. Stilgenbauer:Roche: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau. Wendtner:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Fischer:Roche: Honoraria, travel grants Other; Mundipharma: Honoraria. Hallek:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Eichhorst:Roche: Honoraria, Research Funding; Mundipharma: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees.