Treatment of patients with chronic lymphocytic leukemia (CLL) who show p53 mutations or deletions remains problematic. Conventional agents such as chlorambucil, fludarabine and rituximab are ineffective in this sub-group. Possible therapeutic options for such patients include alemtuzumab and/or high dose methlylprednisolone. The literature provides 2 pieces of evidence; an initial case report (

Stilgenbauer et al, New England Journal of Medicine. 2002; 347:452–3
), and more recently a case series of 36 patients (
Lozanski et al, Blood 2004.103: 3278–81
), describing the response of patients with p53 deletions to alemtuzumab. We review the treatment of 26 patients using alemtuzumab, and focus on responses in relation to the presence or absence of p53(17p) deletions as detected by fluorescence in situ hybridization (FISH). The patients were treated with alemtuzumab (CAMPATH-1H) between 1994 and 2004. This included 25 men and 1 woman with median age at diagnosis of 50 years (range 27–74). 8 patients had p53 deletion (31%). The group was heavily pre-treated with a median of 4 previous agents (range 1–11) which included fludarabine in 92% and autologous stem cell transplantation in 8%. Alemtuzumab was used 61 months from diagnosis (range 2.4–329.9) for Binet stage B or C disease (22 patients) with 3 patients receiving alemtuzumab during the terminal phase of their CLL. Duration of treatment ranged from 1 to 12 weeks with a median dose of 695mg. Three patients are still on treatment. Responses are currently evaluable in 23 patients. Good clinical responses (CR/PR) as assessed by revised NCI criteria, were documented in 12 patients (52%) and included 5 CRs, and 7 PRs. All CRs were observed in the p53 negative group although 1 patient with p53 deletion achieved CR in every respect except for mild anemia (Hb 10.2g/dl). Overall responses were seen in 3 of 7 (43%) patients with p53 deletions, and 9/16 (56%) of those without (NS) and lasted 4.1 months (range 2.8–22.2). Compared with prior agents, alemtuzumab was able to induce equivalent best responses in 7 patients or superior responses in 7 patients. In 8 of 9 cases where responses were inferior, alemtuzumab was able to transiently control the disease. Notably six patients were safely retreated with alemtuzumab with one patient receiving up to 4 courses. Toxicity was observed in 10 patients with asymptomatic CMV reactivation in 4, cytopenias with infection in 4 and anorexia in 1. One patient had evidence of pulmonary CMV, which contributed to his death. There were two other deaths due to progressive disease while on treatment. Alemtuzumab was able to induce responses in patients with progressive, refractory CLL, regardless of p53 status. Catovsky et al (ASH abstract submitted) observed few responses to conventional chemotherapy in CLL patients with >20% cells possessing 17p deletion. In the majority of our patients (6/7 cases), p53 was deleted in >20% of lymphocytes (range 36% – 91% of cells). All three PR’s in our series were seen in the patients in whom >20% of lymphocytes had p53 deletion. Responses to alemtuzumab even in these patients, provides a rationale for pre-emptive identification of this sub-group to prevent unnecessary exposure to toxicity from less effective agents and/or delayed use of alemtuzumab following multiple previous lines of therapy.

Topics:
alemtuzumab, chronic b-cell leukemias, chronic lymphocytic leukemia, craniosynostosis, cytokine release syndrome, fludarabine, lung compliance, toxic effect, anemia, autologous stem cell transplant

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2005, The American Society of Hematology
2004
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