Alemtuzumab as a Single Agent or Combined with Methylprednisolone (MPD) or Fludarabine (FDR) for the Treatment of CLL Patients with p53 and ATM Deletions.

Genetic abnormalities are one of the most important prognostic factors in CLL. Indeed, p53 deletions/mutations are associated with progressive disease, refractoriness to alkylating or fludarabine (FDR) based regimes and short survival. Similarly, ATM deletion/mutations at chromosome band 11q22.3 are associated with shorter treatment free interval from diagnosis and decreased overall survival. Alemtuzumab (Alem) has shown to be effective in CLL patients (pts) with p53/ATM deletions, when used as a single agent especially in cases with p53 abnormalities. The aim of this study was to evaluate the efficacy of Alem alone or in combination with FDR or MPD in CLL pts with p53/ATM deletions.

Materials and Methods: Since Feb/02 to March/07 we have treated 21 pts (15M/6F, median age: 59 yrs, range:48–72) with p53 del (13/21) and ATM del (9/21). Two cases had both types of abnormality. Twenty cases had refractory disease to alkylating or FDR combinations, with a median number of 3 prior regimes. One pts was treated in first line with Alem+MPD. Seven cases had bulky lymphadenopathy (≥7cm). Fifteen pts had Rai stage II, 1 pts stage III and 5 stage IV disease. Eleven pts were treated with Alem 30mg thrice week up to 12 weeks (CAM30), 3 pts with FDR (20mg/m²iv ×3d) + cyclophosphamide (200mg/m²iv ×3d)+ Alem (20mg thrice week iv ×4weeks) every 28d ×2 cycles (FLUCYCAM) and 7 pts with concurrent Alem (30mg thrice week iv ×4weeks) and iv methylprednisolone 1g/m² days 1–5 every 28d up to 4 cycles (CAMPRED). Hematological responses were evaluated in PB and BM by four color flow cytometry. Genetic abnormalities were screened by G-banding and FISH. P53 mutations were analysed by direct sequencing.

Results: Overall, 18(85.7)/21 pts responded to Alem based therapy (6CR, 3nPR, 9PR, 3SD). P53 del was detected at diagnosis in 11/13 cases and ATM del in 6/9 pts. Out of 13 cases with p53del, 5 achieved CR, 1 nPR, 6PR and 1SD. 6 cases also showed associated mutations, but there were no differences in terms of response. Of 9 cases with ATM del, 1 reached CR, 1nPR, 5PR and 2SD. Clinical response according to treatment was as follow: CAM30 (2CR, 1nPR, 7PR, 1SD), FLUCYCAM (1PR, 2SD), CAMPRED (5CR, 3 of them MRD neg, and 2PR). Progression free survival (PFS) was 6 months, 3 months and not reached for CAM30, FLUCYCAM and CAMPRED regimes respectively. Infusional side effects were present in 80% of cases, myelotoxicity was more frequent with FLUCYCAM (100%) than CAM30 (30%) and CAMPRED (25%). Infections were seen in 42% of cases and CMV reactivation in 34%. 2 pts died of gram- sepsis. Richter transformation EBV+ was seen in 6(28%)21 pts and did not correlate with the number of prior treatments or with the type of genetic abnormality.

Conclusion: Alemtuzumab in monotherapy demonstrates clinical activity in CLL patients with p53 and ATM deletions, although this response is transient in most cases and less effective in patients with lymphadenopathy. The association with fludarabine shows similar effects but more toxicity. However, the combination with methilprednisolone is more effective in eradicating PB and BM lymphocytes and also on bulky lymphadenopathy in patients with p53 and ATM abnormalities.