Dasatinib may overcome the negative prognostic impact of KIR2DS1 in newly diagnosed patients with chronic myeloid leukemia

To the editor:

Most chronic myeloid leukemia (CML) patients achieve complete cytogenetic response (CCyR) with tyrosine kinase inhibitors (TKI).¹  However, many relapse on therapy discontinuation.²  The curative effect of allogeneic stem cell transplantation (allo-SCT) in CML is believed to be mediated through the donor-derived graft-versus-leukemia effect. Natural killer (NK) cells are important components of this allo-immune effect³  and exert direct cytotoxicity against CD34⁺ Philadelphia-positive cells in vitro.⁴  The balance between signals from inhibitory and activating surface receptors determines NK-cell cytotoxicity.⁵  These receptors include killer immunoglobulin-like receptors (KIR), which are specific for allotypic determinants shared by HLA-class I (KIR ligands).

We recently reported that newly diagnosed CML–chronic phase (CP) patients carrying the activating KIR gene, KIR2DS1, have significantly lower probability of achieving CCyR on imatinib, and lower 2-year progression-free (PFS) and overall survival (OS).⁶  This effect was independent of Sokal and was validated in an independent cohort of 174 CML-CP patients treated with first-line imatinib in the multicenter United Kingdom SPIRIT-1 trial. The impact of KIR2DS1 on CCyR was even greater in the absence of the ligand for the corresponding inhibitory KIR (KIR2DL1), suggesting that in the presence of the ligand, KIR2DL1 may neutralize the effect of KIR2DS1. We concluded that KIR2DS1 may predict response to imatinib and identify patients at risk of treatment failure.

Here, we investigate whether KIR2DS1 could also predict response to dasatinib, a second-generation TKIs with more potent BCR-ABL inhibitor activity than imatinib. Dasatinib also inhibits other kinases such as SRC and TEC,⁷  key regulators of immune response, and may therefore exert an immunomodulatory effect.

We studied 130 CML-CP patients treated with first-line dasatinib on the United Kingdom multicenter SPIRIT-2 trial. All patients gave informed consent. Median follow-up was 18 months; 122 (93.8%) achieved CCyR and 94 (72.3%) achieved major molecular response (MMR).

KIR genotyping was performed as described previously.⁸  In dasatinib-treated patients, we found no significant impact of KIR genotype on outcome (Table 1). Specifically, KIR2DS1 was no longer a negative prognostic factor and the 2 year probabilities of CCyR and MMR for KIR2DS1-positive patients was not statistically different to KIR2DS1-negative patients, namely 100% versus 93.6% (P = .09) and 74.0% versus 74.9% (P = .77), respectively (Table 1). These data suggest that dasatinib may overcome the negative prognostic impact of KIR2DS1 on CCyR in newly diagnosed CML-CP patients treated with imatinib. Longer follow-up is needed to assess whether dasatinib also overcomes the negative impact of KIR2DS1 on PFS and OS.

Dasatinib suppresses NK-cell function in vitro,⁹  although recent studies report the expansion of BCR-ABL–negative NK cells in dasatinib-treated patients.¹⁰  The mechanism through which dasatinib may overcome the negative prognostic significance of KIR2DS1 in imatinib-treated patients could be related to its off-target kinase inhibition. These data provide a rationale for genotyping CML patients at diagnosis to identify KIR2DS1 positive patients at greater risk of treatment failure with imatinib. These patients who constitute nearly 30% of CML patients may benefit from upfront dasatinib treatment. Functional studies to determine the differential impact of imatinib and dasatinib on KIR2DS1-expressing NK-cell subsets are underway. A similar analysis in patients receiving upfront nilotinib, an analog of imatinib with minimal SRC kinase inhibition, would be of great interest.