Refractory chronic lymphocytic leukemia--new therapeutic strategies

Abstract

Treatment outcome of chronic lymphocytic leukemia (CLL) has considerably improved since the introduction of fludarabine (F) as part of the standard therapy. Nevertheless, refractoriness to fludarabine occurs in a significant number of patients and is associated with an unfavorable prognosis. Important risk factors are 17p deletion and/or mutation of TP53. For this subgroup the CD52 antibody alemtuzumab (A) presents a new treatment approach and has already been approved. Meanwhile we have to face also refractoriness to alemtuzumab. Importantly, the monoclonal CD20 antibody ofatumumab has now shown efficacy in F and A double-refractory CLL. The next generation CD20 antibody GA-101 is currently compared to rituximab (R) and will possibly be its more potent successor. Further B-cell antigens are targeted by lumiliximab (CD23), TRU-016 (CD37) and blinatumomab (CD19). Apart from monoclonal antibody therapies, a great number of small molecules are examined for the treatment of refractory and relapsed CLL. Most of these agents aim to overcome apoptosis resistance in CLL cells or influence the microenvironment. Typical targets are regulators of the cell cycle and antiapoptotic molecules like the members of the Bcl-2 family. Up to now the most promising agents appear to be flavopiridol and lenalidomide among others.

Figure 1. FCR as first-line treatment in CLL at M. D. Anderson Cancer Center.[1,45]

A) Overall survival after response. B) Time to progression after response

Figure 2. OS in different first line treatment strategies

[1] Historical comparison of overall survival for fludarabine (F), fludarabine and cyclophosphamid or mitoxantrone (FC/M) and FCR as CLL first line treatment at M. D. Anderson Cancer Center.

Figure 3. Overall survival (OS) of genetic subgroups in the CLL4 trial (F vs. FC) of the German CLLSG (both treatment arms combined). [7]

OS of the group with 17p13 deletion (n=16; grey), sole TP53 mutation (without 17p13 deletion) (n=14; yellow) and the remaining patients (n=277; blue). Median OS was significantly shorter for patients with 17p13 deletion (19.2 months) and sole TP53 mutation (30.2 months) than for patients without either abnormality (not reached; P < 0.001).

Figure 4. Lack of prognostic impact of genomic aberrations in chemotherapy-refractory chronic lymphocytic leukemia after therapy with alemtuzumab.[14]

Genomic subgroups compared were 17p13 deletion (n=31; black graphs), 11q22-q23 deletion (n=20; red graphs) and all other subgroups (n=49; green graphs). A) Median values for overall survival were 18.3, 22.7 and 18.6 months, respectively (log-rank P = 0.661). B) Median values for time to treatment failure were 5.8, 6.8 (95% CI, 3.5 to 10.9) and 5.4 months, respectively (log-rank P = 0.842).

Figure 5. Overall survival in a phase II trial of ofatumumab as single-agent [19]

A) Overall survival in fludarabine- and alemtuzumab refractory patients (FA-ref). B) Overall survival in fludarabine-refractory patients with bulky disease (BF-ref)