Interferon-alpha (IFN-a) Given Alone to CML Patients with Undetectable Disease after Imatinib (IM) Is Able To Maintain Their Complete Molecular Remission after IM Discontinuation.

Cytotoxic lymphocytes (CTLs) which recognize distinct antigenic peptides on CML cells, contributed greatly to the cure after allografting. Previously, BCR-ABL specific peptides and the PR1 non-apeptide, were found to elicit a CML-specific CTL response (Molldrem, 1996/1997; Bocchia 1996, Clark 2001). PR1 is a peptide derived from myeloblastin (MBN), also known as proteinase 3. MBN is abundantly expressed in azurophil granules of normal myeloid cells and is substantially overexpressed in certain immature myeloid leukemia cells where it may be important for the maintenance of a leukemic phenotype. PR1-specific CTLs (PR1-CTLs) lyses and inhibits the proliferation of CML cells but not of normal myeloid precursors. The association between the emergence of PR1-CTLs and the response to IFN-a in vivo strongly implied that IFN-a can induce remissions via induction of a CML-specific PR1-CTLs response (Molldrem et al, 2000). Recent data demonstrating a failure of IM to kill cell cycle-arrested CML precursors advice us to be attentive to arising escape mechanisms of even chronic phase CML; therefore the sequential combination therapy of IFN-a given alone to CML patient with undetectable disease achieved with IM, might be more effective than any current monotherapy. We have treated until now 4 CML patients who had undetectable residual disease for at least one year after IM therapy. The patients discontinued IM and started IFN-a at the dose of 3 M/U/m² weekly. The median duration of IM therapy was 58 (range, 31–68) months before IM interruption. At a median follow-up of 5 months (range, 3–12 months) after IFN-a, all patients still have an undetectable level of BCR-ABL transcript. The details of patients characteristics will be discussed during the presentation. These preliminary results demonstrate that treatment with low dose IFN-a in CML patients with undetectable disease is feasible and did not lead to a molecular relapse. We are starting a large prospective randomized study to evaluate the role of IFN-a employed alone after 1 year of complete molecular remission achieved with IM (Arm A) vs contination of IM alone (Arm B). The main objective of this study is to verify the real effect of the immune modulation following IFN-a in CML patients with undetectable disease.