Safety and efficacy of the combination of pegylated interferon-α2b and dasatinib in newly diagnosed chronic-phase chronic myeloid leukemia patients

Abstract

Dasatinib (DAS) and interferon-α have antileukemic and immunostimulatory effects and induce deep responses in chronic myeloid leukemia (CML). We assigned 40 newly diagnosed chronic-phase CML patients to receive DAS 100 mg o.d. followed by addition of pegylated interferon-α2b (PegIFN) after 3 months (M3). The starting dose of PegIFN was 15 μg/week and it increased to 25 μg/week at M6 until M15. The combination was well tolerated with manageable toxicity. Of the patients, 84% remained on PegIFN at M12 and 91% (DAS) and 73% (PegIFN) of assigned dose was given. Only one patient had a pleural effusion during first year, and three more during the second year. After introduction of PegIFN we observed a steep increase in response rates. Major molecular response was achieved in 10%, 57%, 84% and 89% of patients at M3, M6, M12 and M18, respectively. At M12, MR(4) was achieved by 46% and MR(4.5) by 27% of patients. No patients progressed to advanced phase. In conclusion, the combination treatment appeared safe with very promising efficacy. A randomized comparison of DAS±PegIFN is warranted.

Dasatinib Changes Immune Cell Profiles Concomitant with Reduced Tumor Growth in Several Murine Solid Tumor Models

“…In first-line treated CML patients, dasatinib has already been combined with another immunomodulatory drug (interferon-a; ref. 48), and no additional toxicities-including pleural effusions, which are typical dasatinib-related side effects (49, 50)-were observed. Similarly, in a published prostate cancer study, dasatinib was safely combined with chemotherapy agent docetaxel, and no major additional toxicities occurred (51).…”

CML patients with deep molecular responses to TKI have restored immune effectors and decreased PD-1 and immune suppressors

“…19 Several studies of combination TKI therapy and IFN-a have been completed recently, with several reporting increased rates of DMR. [20][21][22] A phase 1 trial (NCT02011945) of dasatinib and nivolumab, a PD-1 inhibitor, is recruiting, with MMR and DMR incidence as planned outcome measures. LAAs such as WT1, PRAME, PR3, and BMI-1 in CML patients represent attractive targets for immunotherapy, [23][24][25][26][27][28][29] with efficacy demonstrated in vaccination, including dendritic cell vaccination, [30][31][32][33] and, more recently, T-cell receptor-mimic antibodies.…”

Tyrosine kinase inhibitors and interferon‐α increase tunneling nanotube (TNT) formation and cell adhesion in chronic myeloid leukemia (CML) cell lines

“…Interestingly, we find both increased adhesion and a change in morphology in the CML cell line Kcl‐22 following treatment with imatinib, nilotinib, or IFNα accompanied by a significant increase in TNT formation (Figures A, A,B, and A). IFNα was the first effective CML therapy and is now re‐evaluated in combination with TKIs for more rapid disease control and possibly cure . One of the proposed mechanisms for the efficacy of IFNα in treatment of CML patients is indeed through restored adhesion of CML cells to the bone marrow stroma .…”

“…IFNα was the first effective CML therapy and is now re-evaluated in combination with TKIs for more rapid disease control and possibly cure. 49,73 One of the proposed mechanisms for the efficacy of IFNα in treatment of CML patients is indeed through restored adhesion of CML cells to the bone marrow stroma. 74 Similarly, TKI treatment has been reported to increase CML cell adherence to fibronectin.…”

“…[46][47][48] Restoration of the adhesion defect in CML cells seems therefore to be a significant feature of the effective CML therapy, recently revisited in the therapeutic combination of TKIs and IFNα eradicating CML progenitor cells resulting in non-detectable disease. 5,49 Here, we investigate the role of TKIs and IFNα treatment on TNT formation in CML cell models connecting TNT formation to increased cell attachment to fibronectin coated surfaces.…”