Interferon Alpha 2a (IFN) Maintenance Therapy After Imatinib Plus IFN Induction Therapy in Chronic Myeloid Leukemia (CML) Induces Stable Long-Term Molecular Remissions and Is Associated with Increased Proteinase 3 (PR3) Expression and the Presence of PR1-Specific T-Cells.
Authors: Burchert Andreas , Müller Martin C , Kostrewa Philippe , Erben Philipp , Bostel Tilman , Liebler Simone , Hehlmann Rüdiger , Neubauer Andreas , Hochhaus Andreas 
Published: October 2019

Abstract
Abstract 647
Imatinib is a selective and very potent inhibitor of the BCR/ABL kinase. It induces ongoing complete cytogenetic remissions in the vast majority of chronic phase CML patients. However, BCR/ABL persistence is the rule despite ongoing imatinib therapy. This suggests that imatinib will not to cure CML and raises concerns about emerging imatinib resistance, long-term imatinib tolerability and compliance to therapy. We previously suggested that a combination of imatinib and immunotherapy by IFN may additionally control CML via induction of autologous cytotoxic T-cell (CTL) responses, such as those directed against the leukemia-associated antigen proteinase 3 (PR3). For example, induction of PR1-CTL which recognize PR3 on CML blasts was previously shown to be associated with IFN-, but not imatinib response. Indeed, we could recently demonstrate on a cohort of 20 newly diagnosed CML patients that low dose of IFN maintenance therapy alone was able to maintain or improve remissions obtained by a prior imatinib/IFN combination treatment (A. Hochhaus et al. , ASH 2007). After a median time of IFN maintenance therapy of 1.2 years 80% of the patients remained or improved molecular remission. Here we report a significantly longer follow up of these patients and translational studies to examine markers of IFN response. Twenty pts (14 m, 6 f; median age 45, range 23-74 yrs) with low (n=13), intermediate (n=6), and high risk (n=1) according to the Hasford score risk calculation have been investigated. Imatinib therapy had been administered for 2.4 yrs (0.2-4.9), combined with PEG-IFNa2a (Pegasys®, n=17) or IFN a2a (Roferon®, n=3). Maintenance therapy consisted of PEG-IFN (n=16) or IFN (n=4). Dose was adjusted according to response and tolerability and ranged between 135 μg PEG-IFN every 3 weeks to 180 μg PEG-IFN every week, or alternatively 2 to 5 * 3 Mill IU IFN/week. Imatinib was terminated due to side effects (n=5) or upon personal request of the patients after informed consent (n=15). At the time of imatinib withdrawal, two pts were in complete molecular remission (CMR) and 15 pts in major molecular remission (MMR). After a median observation time of 2.8 yrs (range 0.5-4.5), 15 pts were in MMR, 5 of them in CMR. Thus, the number of MMR patients increased from 2 at baseline to 5 after two years. Five patients relapsed within 0.4 years (range, 0.2-0.8) after imatinib discontinuation, but were rescued with imatinib, re-establishing molecular remission. Side effects to maintenance IFN were minor. We also studied putative markers of IFN response. IFN therapy was associated with an increase in the expression of PR3, and in the presence of auto-reactive PR1-CTL. PR1-CTL frequencies were prospectively assessed without prior in vitro amplification. In one of five assessable patients PR1-CTL were detected prior to imatinib withdrawal, but in four of seven assessable patients during IFN maintenance therapy. Longitudinal measurements of PR-1 CTL counts suggested an inhibition of the expansion of PR1-CTL by imatinib, implying that an optimal CTL expansion may occur preferentially in the absence of imatinib. This would explain the conversion to a CMR status in some patients only after imatinib withdrawal. Together, IFN maintenance after a prior imatinib/IFN induction therapy may be an effective alternative to permanent imatinib therapy, because it enables to safely discontinue imatinib even in those patients that have not achieved a CMR at the time of pausing imatinib. Induction of a PR1-specific CTL response by IFN may contribute to the particular efficacy of IFN after CML-debulking by imatinib.

Disclosures:
Burchert: Roche: Research Funding. Off Label Use: Pegasys(R) therapy in CML. Neubauer:Roche: Research Funding. Hochhaus:Roche, Novartis: Research Funding.