Advances in clinical management of chronic lymphatic leukemia CLL

1. Advances in clinical management of chronic lymphatic leukemia (CLL) Maria Cristina Pasquini UO-Ematologia CTMO Fondazione Policlinico, Mangiagalli Regina Elena, Università degli Studi Milano

3. The present the incidence is increasing one-third of B-CLL patients are younger than 55 years old. the majority CLL-patients dies for CLL-related complications. considerable progress has been made in defining the molecular basis for the pathogenesis of CLL finding new therapeutic options

4. Advances in molecular basis of CLL Two types of CLL: pregerminal and post germinal origin with unmutated or mutated status of variable heavy chain genes(IgVH) This differential mutational status of IgVH genes has a significant impact on patients survival ( MUTATED good prognosis, UNMUTATED poor prognosis) FISH have been demonstrated several typical abnormalities with clinical impact : 13q- low risk +12 intermediate risk 11q- , 17p- high risk

5. Specific genetic features such as del(17), del(11), p53 mutation, and unmutated Ig VH can now identify patients with clinically aggressive disease and suboptimal responses to current treatments.

6. Advances in therapy Historically, chlorambucil has been the most frequently used chemotherapeutic agent in the treatment of CLL. Chlorambucil remains an aviable treatment choice for elderly patients and whenever pallation is needed. The introduction of purine analogs in 1980s invigored clinical research in CLL and dramatically changed the treatment disease.

7. The introduction of purine analogs has increased CR, OR, PFS compared to single-agent alkylator Fludabine in frontline setting*: higher remission rate longer remission duration 80% OR rate but low CR (20-30%) * Randomized trials Rai NEJM 2000, Johnson Lancet 1996, Leporrier Blood 2001

9. Monoclonal antibodies

10. Rituximab Rituximab is a chimeric anti-CD20 monoclonal antibody. Response rates in relapsed CLL to standard-dose (375 mg/m2) were disappointingly low Improved efficacy was demonstrated using higher dose(500 to 2250 mg/m2 x dose) or more intensive schedule. Higher responses has also been achieved in previously untreated patients. In addition, in vitro studies demonstrated sensitization of CLL cells by rituximab to the cytotoxic effects of a number of chemotherapy drugs ( including fludarabine and CTX) and vice versa.

13. Alemtuzumab Alemtuzumab (Campath 1H) binds specifically to the CD52 antigen. CD52 is highly expressed on the surface of : normal and abonrmal B and T lymphocytes monocytes, macrofages small percentage of granulocyte, CD52 is not expressed on the surface of erithrocytes, platelets or bone marrow stem cells. Data on the activity of alemtuzumab in patients with CLL is rapidly accumulating. better efficacy in CLL as single therapy instead of Rituximab

15. Alemtuzumab therapy: First line therapy: CAM 307( open label, international phase III study) 297 patients were enrolled and randomized to received Alemtuzumab 30 mgX3/w iv x 12weeks Chlorambucil 40 mg/m2 orally once every 28 days X 12 cycles. Alemtuzumab is clearly superior to CHL as front line therapy OR 83% compared to 56%, and CR 24% vs 2% Subcutaneous administration 41 previously untreated patients with CLL (Lundin, Blood 2002) Alemtuzumab 30 mg subcutaneously x3/w x18 weeks ORR 87% ( CR 19%, PR 68%) The subcutaneous route reduces the number and the severity of first-dose site effects ( such as rigor) with a preserved clinical efficacy

16. Alemtuzumab therapy Consolidation treatment of CLL (Montillo Haematologica 2002 , O’Brien Cancer 2003, Moreton JCO 2006) Patients who achieved an MRD-negative complete response have a significantly longer treatment-free survival and overall survival compaired with MRD-positive responders. Combination therapy ( FLUCAM, FR) Several studies are ongoing. The most successful strategy has not been defined yet, but will likely involve a combination of cytotoxic chemotherapy and immunotherapy Alemtuzumb activity is largely p-53 indipendent enabling this MoAb to be effective also in very poor-risk 17p-patients

17. SCT approach Autologous transplants may prolong survival in selected patients The experience by Montillo successully demonstrated that low doses of alemtuzumab can safely applied as consolidation to CLL patients candidates to HSC autograft, with the aim of improving quality of response and realizing an in vivo purging with this MoAb.

18. SCT approach Allogeneic stem-cell transplant rapresents the only curative therapy for CLL GvL High morbidity and TRM GVHD Age <55 y (just 10% of patients diagnosed with this disease) Examination of outcome with this approach in several series demonstrates similar PFS and plateau is reached at 3-5 years f.u. RIC ( non myeloablative transplant) Lower toxic deaths GvL GVHD Age <70 y To test the efficacy of non-myeloablative stem cell transplant in CLL, it will be necessary to apply this therapy earlier in the course of the disease.

30. Gene therapy in CLL CD40 is expressed on normal B cells CD40 Ligand (CD40 or CD154) is expressed on activated CD4+T cells. The CD40/40L interaction stimulates the B cell. The first clinical trial was conducted by Kibbs with CLL transfected cells with an adenovirus vector wich expresses CD40L as transgene. Clinically reduction in leukemia cells count and lymph-node sizes was demonstred. The activation of CLL cells makes them sensitive to agents that activate the extrinsic pathway of apoptosis Ongoing work aims to optimize this strategy to identify the appropiate and optimal patient subset in wich apply vaccine therapy.

31. Conclusions The last two decades have seen a major paradigm shift in the therapy of CLL The treatment goal moves from symptom palliation to the attainment of maximal disease control using the most effective frontline regimens avaible, thus prolonging survival and possibly leading to cure