Second-Line Therapies After Treatment with Fludarabine, Cyclophosphamide, and Rituximab (FCR) or Fludarabine and Cyclophosphamid Alone (FC) for Chronic Lymphocytic Leukemia (CLL) within the CLL8-Protocol of the German CLL Study Group (GCLLSG)
Authors: Cramer Paula , Fink Anna-Maria , Busch Raymonde , Eichhorst Barbara , Wendtner Clemens-Martin , Pflug Natali , Schubert Friederike , Döhner Hartmut , Rieger Michael , Kneba Michael , Mayer Jiri , Hallek Michael , Fischer Kirsten 
Published: October 2019

Abstract
Abstract 2863

Introduction:
The CLL8-trial is the first study that has shown not only an increase in complete remission rates and progression-free survival, but also an improved overall survival (OS) in physically fit, treatment-naúve CLL-patients (pts) with FCR-chemoimmunotherapy in comparison to FC alone [Hallek et al., Lancet 2010]. Despite this remarkable progress, CLL remains an incurable disease and virtually all pts will eventually relapse. So far, little is known about the efficacy of 2nd-line therapies of these pts.

Patients and Methods:
Between July 2003 and March 2006 817 pts in good physical fitness as defined by a cumulative illness rating scale (CIRS) score of ≤6 and creatinine clearance 70 ml/min were randomized within the trial and received 6 courses FC (n=409; F: 25mg/m2 i.v. d1–3 and C: 250 mg/m2 i.v. d1–3; q 28 days) without or with rituximab (n=408; 375 mg/m2 i.v. d0 cycle 1, 500 mg/m2 d1 of all subsequent cycles; q 28 days) for 1st-line treatment.

Results:
As of March 2009, 65% of the patients who had received FCR were free of progression compared to 45% of those who were treated with FC (p<0, 0001) [Hallek et al, Lancet, 2010]. Until July 2010, 232 pts were treated for relapsed CLL, among them 91 of 408 (22%) initially treated with FCR and 141 of 409 (35%) initially treated with FC. In 2nd-line treatment after FCR and FC, the drugs most frequently used either alone or in combination were rituximab (R, 52% of all 2nd-line therapies), fludarabine (F) and bendamustine (B) (21% each), as well as alemtuzumab (A, 12%). The combination of cyclophosphamide, doxorubicin, vincristine, prednisolone and rituximab (CHOP-R) was the most common treatment (35 pts, 15% of all 2nd-line therapies), applied mainly in cases with a relapse ≤24 months after FC/FCR, whereas FCR or BR were administered predominantly in case of relapse >24months (32 and 27 pts, 14% and 12%). Other prevalent 2nd-line therapies were single agent A (20 pts) or B (17 pts), CHOP and FC (11 pts respectively), chlorambucil (9 pts) as well as R monotherapy (7 pts). 9 pts underwent stem cell transplantations. Second-line therapies with FC+/−R and B+/−R were found to be more effective with regard to treatment-free survival (TFS, time to 2nd relapse) and OS when compared to A or CHOP-R and CHOP-like chemotherapies. However, the outcome of 2nd-line therapies seemed to be influenced by the 1st-line treatment. In pts initially treated with FC, FCR was found to be the most effective 2nd-line therapy (TFS: 23 months, OS: not reached), whereas in pts initially treated with FCR, a substitution of the chemotherapeutic agents FC by B seemed justified, as TFS was superior after 2nd-line treatment with B+/−R (16 and 18 months respectively) when compared to FC+/−R (11 and 8 months). Furthermore, in pts who had received FCR for 1st-line treatment, chemotherapy with FC or B was found to be at least equally or even more effective in prolonging OS than FCR or BR (OS calculated from beginning of 2nd-line therapy: FC: not reached, B: 45, FCR: 19, and BR 18 months).

Conclusion:
Second-line treatments of pts with a relapse after FC or FCR were found to be surprisingly heterogeneous even though the patient collective examined is comparatively homogenous due to the inclusion/exclusion criteria of a clinical trial. As the majority of CLL8-patients is still in remission and has not yet received a 2nd-line treatment, the therapies captured in this analysis are predominantly 2nd-line therapies for earlier relapses. Therefore and because of the short follow-up time, the results ought to be considered as preliminary and descriptive trends. The worse outcome of CHOP-like regimen and A-based therapies in comparison to more established CLL-therapies such as FC+/−R and B+/−R might be related to the fact, that these therapies were administered more often in case of an early relapse after FC/FCR, which is known to be related to other poor prognostic factors [Fink et al, ASH 2010]. Nevertheless, the observation of favorable TFS and OS times after 2nd-line treatment with FC+/−R and B+/−R supports the recommendation to repeat chemoimmunotherapy in case of a relapse >24 months after 1st-line treatment. Further analyses are needed to confirm the observation that chemotherapy (FC or B) without rituximab might be sufficient for for 2nd-line treatment after FCR.

Disclosures:
Cramer: Mundipharma: Travel Grants. Fink:F. Hoffmann La Roche:. Eichhorst:Hoffmann La Roche: Honoraria, Research Funding, Travel Grants; Mundipharma: Research Funding, Travel Grants; Gilead: Consultancy. Wendtner:Hoffmann La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Travel Grants. Pflug:Hoffmann La Roche:. Hallek:Roche: Consultancy, Honoraria, Research Funding; Mundipharma: Research Funding; Celgene: Honoraria. Fischer:Hoffmann La Roche:.