Abstract 1248

Poster Board I-270

Background

There has recently been substantial work to identify factors that correlate with clinical outcome for patients with CLL. Identifying and validating factors may give understanding and insight into the biology of the disease and may help guide management of patients. TP53 is a gene located on the short arm of chromosome 17 (17p). The protein product of TP53, p53, is a transcription factor that regulates cell cycle and functions as a tumor suppressor. Therefore, p53 is critically important for the survival of CLL cells. In addition, p53 is critical for the therapeutic response to chemotherapy, particularly for alkylating agents and purine analogues. Thus patients with loss (17p del) or mutation of TP53 have inferior response to standard treatments, shorter remission duration, and shorter overall survival. We previously reported outcomes for untreated patients with de novo loss of 17p identified by FISH (Tam et al. Blood 114:957, 2009). In that analysis, there were patients with 17p del who did not require treatment and were observed for a prolonged period, however, it was clear that once treatment was required, outcomes markedly deteriorated. The current analysis summarizes outcomes for previously treated patients with 17p del who went on salvage therapy at MD Anderson Cancer Center.

Methods and Results

We identified 95 previously treated patients who were evaluated at MDACC, had 17p del by FISH, and went on a salvage therapy from March 2004 to May 2009 (Table). There were 10 patients known to have de novo 17p del prior to frontline therapy and 9 patients with acquired mutations (76 unknown). In addition to 17p del, 18 also had 11q del, 17 had +12, 53 had 13q del; 26 had no additional, 53 had 1 additional, 13 had 2 additional, and 3 had 3 additional chromosome abnormalities by FISH analysis. The median number of prior treatments was 3 (range 1-10); prior treatment regimens in hierarchical order consisted of multi-agent-based chemotherapy (N=18); fludarabine combination-based (N=59); single purine analogue or alkylating agent-based (N=13); and monoclonal antibody- (mAb) or steroid-based (N=4). For this analysis follow-up began from the first salvage therapy after discovery of 17p del by FISH. Salvage therapies included alemtuzumab or alemtuzumab with rituximab (N=15); other mAb-based (N=12); lenalidomide-based (N=8); fludarabine-based combinations (N=24); combined oxaliplatine, fludarabine, cytarabine, rituximab (OFAR) (N=28), and others not fitting any of these categories (N=8). The outcomes for these patients were very poor (Table). The complete remission (CR) rate with salvage therapy was 6% and the overall response rate (ORR) was 36%. The median follow-up was 10 months, time to treatment failure was 4.1 months, and overall survival was 14 months. Sixteen patients proceeded on to allogeneic stem cell transplant with a median OS of 27 months.

Table.

17p del patient characteristics and outcome

CharacteristicN% CR% ORTTF (mos)OS (mos)
All Patients 95 36 4.1 13.7 
Sex      
    Female 26 12 42 15 
    Male 67 33 14 
Age (yrs)      
    < 60 35 14* 40 16 
    60 – 70 27 22 14 
    > 70 33 42 5.5 11 
Rai Stage      
    0 - II 37 14 46 21 
    III – IV 58 2* 29 3* 9* 
b2M (mg/L)      
    < 4 34 15 53 22 
    361 2* 26* 3* 10** 
# Prior Treatments      
    1 - 3 60 10 43 16 
    335 23 3* 7.5* 
% cells with 17p del by FISH      
    < 25% 26 12 54* 7* 28* 
    25-75% 34 35 14 
    > 75% 35 23* 
IgVH Status      
    Mutated 10 20 30 17 NR 
    Unmutated 68 41 14 
ZAP-70      
    < 20% positive 13 23 3.5 11 
    3 20% positive 54 41* 14 
Salvage Treatment      
    OFAR 28 39 16 
    F-based combo 24 13 42 
    Alemtuzumab-based 15 13 53 16 
    Lenalidomide-based 13 38 4.5 11 
    mAb 12 17 23 
    Other 
CharacteristicN% CR% ORTTF (mos)OS (mos)
All Patients 95 36 4.1 13.7 
Sex      
    Female 26 12 42 15 
    Male 67 33 14 
Age (yrs)      
    < 60 35 14* 40 16 
    60 – 70 27 22 14 
    > 70 33 42 5.5 11 
Rai Stage      
    0 - II 37 14 46 21 
    III – IV 58 2* 29 3* 9* 
b2M (mg/L)      
    < 4 34 15 53 22 
    361 2* 26* 3* 10** 
# Prior Treatments      
    1 - 3 60 10 43 16 
    335 23 3* 7.5* 
% cells with 17p del by FISH      
    < 25% 26 12 54* 7* 28* 
    25-75% 34 35 14 
    > 75% 35 23* 
IgVH Status      
    Mutated 10 20 30 17 NR 
    Unmutated 68 41 14 
ZAP-70      
    < 20% positive 13 23 3.5 11 
    3 20% positive 54 41* 14 
Salvage Treatment      
    OFAR 28 39 16 
    F-based combo 24 13 42 
    Alemtuzumab-based 15 13 53 16 
    Lenalidomide-based 13 38 4.5 11 
    mAb 12 17 23 
    Other 
*

p<0.05,

**

p<0.001

Conclusion

Previously treated patients with 17p del have extremely poor prognosis and outcomes based on low response rate to salvage treatment, short time to treatment failure and overall survival, including with alemtuzumab-containing treatment. This is a population who clearly needs new and active treatment regimens that have a p53-independent mechanism of action. Experience with allogeneic stem cell transplant in this population is limited and requires further investigation.

Disclosures

No relevant conflicts of interest to declare.

Author notes

*

Asterisk with author names denotes non-ASH members.

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