Targeted CD52 therapy in lymphoid malignancies : A clinical and immunological study

Abstract: There is a great need for developing new treatment alternatives in low grade non Hodgkin's lymphoma (NHL) including chronic lymphocytic leukemia (CLL). The CD52 antigen, which is expressed on almost all lymphoid malignancies, can be utilized as a target for CD52-directed monoclonal antibody therapy (alemtuzumab, Campath-1 H). The aim of this thesis is to evaluate the clinical, safety and immunological effects of alemtuzumab in low grade NHL or CLL. In the first trial, 50 patients with low grade NHL received alemtuzumab as i.v. infusions (30 mg tiw). The 0 R rate was 20%; marked anti-tumor effects were observed in blood (CR 94%) and bone marrow (CR 32% and PR 24%). At the time of initiating this study, antiviral and antibacterial prophylaxis was not routinely given and grade III-IV infections developed in one third of the patients. The trial served as the basis for alemtuzumab's subsequent development in lymphocytic leukemias and T-cell lymphomas. In the second study, 41 patients were received subcutaneous (s.c.) alemtuzumab therapy for up to 18 weeks. The OR rate was 8 1% (intention to treat). Median time to treatment failure was 18+ months. CR or nodular PR in bone marrow was achieved in 66%, which often required 18 weeks of therapy. Grade 1-2 local injection site reactions was observed in most patients, but disappeared within 2 weeks upon continued therapy. Four cases of CMV reactivation were observed (fever without pneumonitis, rapidly responding to ganciclovir). This trial shows a considerably higher response rate on alemtuzumab than in advanced B-CLL. A prolonged duration of therapy appears to be important for maximal efficacy. S.c. administration seemed to reduce the incidence and severity of general "first dose" side effects and may also reduce the costs of therapy. In the third study, B cells from healthy volunteers and patients with previously untreated B-CLL were analyzed by flow cytometry (MESF units) to quantify receptor intensity of CD20, CD22 and CD52 (which all are potential therapeutic target antigens). Receptor intensity analysis revealed that the expression of CD52 was >30 times greater than that of CD20 and CD22. A substantial variability over the time was seen and most pronounced for CD20. The effects of in vivo cytokine (interleukin-4) therapy on receptor density were also studied but a clear impact on receptor intensity expression could not be observed. Thus, effects described in vitro in other studies were not easily translated into the in vivo situation. In the fourth trial, 22 patients with advanced mycosis fungoides/Sezary's syndrome (MF/SS) were treated with alemtuzumab for 12 weeks. The OR rate was 55%, including 32% CRs. Less heavily pre-treated patients had an OR rate of 80% vs. 33% in refractory patients. Itching, self-assessed by VAS was reduced from a median of 8 before treatment to 2 at end of the therapy. CMV reactivation occurred in 4 patients (18%) and 3 patients had fever of unknown origin, which resolved following i.v. antibiotics. Except for CMV, all serious infectious adverse events occurred in the refractory patients. This study shows that alemtuzumab has a major activity in MF/SS patients. In a last study, immunological cell subpopulations were studied before and after therapy as well as during long-term unmaintained follow-up in CLL patients who had received alemtuzumab as first line therapy. CD4 and CD8 T cells were profoundly depleted from blood and remained at <25% of the baseline levels for >6 months in most patients. Also normal B cells, NK-, and NK-T cell populations were markedly suppressed. Monocytes and granulocytes were less affected by the therapy. The degree of suppression and time to recovery appeared not to be dose-dependent. No late occurring infections were observed. Antigen (CD52) negative T-cell populations were detected in blood and persisted for a prolonged period of time. Alemtuzumab is a new monoclonal antibody with significant effect in lymphoid malignancies, it induces long-lasting immune suppression and antibiotic prophylaxis is needed to prevent infectous complications.