Second-line treatment after CLL8

What do the early relapsers from CLL8 actually get as second line treatment and does it work? The information in this German ASH abstract tells us and the results are rather surprising.

2863 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)

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. 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.

The combination 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 less than 24months (32 and 27 pts, 14% and 12%). Other prevalent 2nd-line therapies were single agent Alemtuzumab(A) (20 pts) or Bendamustine (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).

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. 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.