Sustained Molecular Responses with Interferon α2a Maintenance Therapy after Imatinib Plus IFN Induction Treatment for Chronic Phase Chronic Myelogenous Leukemia.
Authors: Hochhaus Andreas , Neubauer Andreas , Mueller Martin C. , Napieralski Simone , Erben Philipp , Bostel Tilman , Hehlmann Ruediger , Burchert Andreas 
Published: October 2019

Abstract
Most patients with chronic myelogenous leukemia (CML) relapse after discontinuation of imatinib (IM, Glivec®/Gleevec™). Thus, current recommendations suggest a lifelong IM therapy even in complete molecular responders. However, in view of potential long term adverse effects there is a concern of tyrosine kinase inhibition. Hence, strategies to circumvent permanent kinase inhibitor therapy would be of substantial clinical value. Interferon α (IFN), in contrast to IM, elicits an autologous antileukemic immune response to control CML, and stopping IFN in complete cytogenetic responders is not associated with relapse in a significant proportion of patients. We therefore sought to determine efficacy and tolerability of an IFN maintenance immunotherapy after IM/IFN induction in newly diagnosed chronic phase CML patients. Twenty patients (14 m, 6 f; median age 44.6, range 23.5–74.1 years) have been investigated. Hasford score revealed low (n=13), intermediate (n=6), and high risk (n=1) diseases. IM therapy had been administered for 2.4 yrs (0.2–4.9), combined with PEG-IFNα2a (Pegasys®, n=17) or IFNα2a (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 three weeks to 180 μg PEG-IFN once weekly week, or alternatively between 2 to 5*3 Mill IU IFN/week. IM was stopped due to side effects (n=5) or after the patient’s individual request and informed consent (n=15). At the time of imatinib withdrawal, 19 patients were in complete cytogenetic remission and one patient did not show any cytogenetic response. Major molecular response was determined in peripheral blood leukocytes of 16 patients, including one patient with undetectable BCR-ABL transcripts. After a median observation time of 1.2 yrs (range 0.1–3.1), 15 patients showed major molecular response, seven of them were complete. Improvement of molecular response was observed in seven and a stable situation in ten patients. By 6 weekly assessments of BCR-ABL expression gradual molecular relapse was observed in three patients. All relapsing patients responded to readministration of IM. At the time of IM withdrawal and during IFN maintenance therapy myeloblastin (proteinase-3, PR3) mRNA expression was determined and compared to glucose-6-phosphate dehydrogenase transcripts as internal standard. During IFN monotherapy, median ratios PR3/G6PD increased from 0.06% (range, 0.02–3.5) to 0.14% (0.03–1.4; p=0.03). IFN response was associated with the detection of autoreactive PR3 specific T-lymphocytes during IFN maintenance therapy determined by a tetramer assay in 7/8 patients, suggesting that PR3-specific cytotoxic T lymphocytes contribute to the IFN-mediated antileukemic immunity. In conclusion, we report a high rate of improved or continuous molecular remissions in 17 of 20 patients (85%) on IFN monotherapy after prior induction with IM/IFN. This suggests a previously unrecognized beneficial role for IFN in the maintenance therapy after IM-mediated debulking and may impact future CML therapy.