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[valiantchong]

http://jco.ascopubs..../28/8/1429.full

DISCUSSION

Indefinite imatinib therapy is currently the recommended standard therapy in CML. However, permanent TKI intake raises concerns regarding the evolution of drug resistance,¹⁰ long-term safety and tolerability,¹¹ compliance issues,¹² and costs.¹³ The results presented here challenge the current view of permanent imatinib treatment as the unequivocal standard of care in CML. The conviction that ongoing ABL-TKI therapy is necessary to control CML is based primarily on in vivo evidence showing detectable BCR-ABL even after years of imatinib therapy^3,7,27 and furthermore by in vitro data demonstrating that CML precursors and stem cells may be inherently resistant to any form of ABL-TKI therapy.^4-6 Therefore, considerable efforts are being undertaken to identify means to target residual CML, with the ultimate goal to cure the disease and to discontinue imatinib.

So far, there is little evidence that imatinib can be successfully discontinued in patients who have achieved a CMR.^28-30 However, CMR is infrequent using sensitive RT-PCR methods, and the majority of patients may still experience relapse after CMR without imatinib.^8,28,29 Recent data from the French "Stop Imatinib" trial suggested that approximately 41% of the CMR cohort may eventually remain progression free after imatinib discontinuation, but follow-up is still short (21 months).³¹

With a median follow-up of 2.4 years in a small cohort of patients, we here provide evidence that the sequence of an imatinib/IFN-based first-line therapy followed by IFN maintenance results in sustained remissions in the majority of patients, irrespective of the prior achievement of CMR. This may have two major implications. By enabling discontinuation of imatinib, IFN maintenance addresses two major concerns of permanent ABL-TKI therapy: First, the evolution of drug resistance from a still-ambiguous reservoir of TKI-refractory, persisting CML stem cells and the issue of unknown long-term side effects. Second, IFN apparently targets residual BCR-ABL-positive cells, which may be insensitive to TKI therapy. This notion is at least supported by the fact that IFN alone increased the depth of a molecular remission after imatinib was stopped.

Several reasons may account for this unprecedented treatment efficacy of IFN in the context of a sequential imatinib/IFN induction and IFN maintenance concept. On the one hand, the TKI-based vigorous CML debulking upfront may be an important cornerstone of subsequent IFN responsiveness, because it has been shown that high tumor burden induces T-cell senescence and apoptosis, thereby depleting antileukemic T-cell clones with the highest antileukemic potential.³² On the other hand, imatinib was shown to inhibit T-cell activation^33-36 and the immunogenicity of CML cells via downregulating expression of BCR-ABL-associated self-antigens such as proteinase-3.^37,38 Thus only discontinuation of imatinib after debulking may hypothetically release the full immune-stimulatory potential of IFN.¹⁸ Indeed, proteinase-3 mRNA levels and the frequencies of PR1-CTL further increased after patients had stopped imatinib (Figs 3 and 5). Circumstantial evidence for a direct inhibition of the expansion of PR1-CTL by imatinib was also prospectively documented in patient 3 and one patients with CML (patient 21) who was not part of the clinical study (Appendix Fig A1, online only). Recent observations also seem to imply that IFN may sensitize dormant stem cells to imatinib-induced apoptosis by inducing their cell cycle entry.³⁹ Altogether these data support the conclusion that a combined imatinib/IFN induction therapy could be of advantage compared with imatinib monotherapy and that IFN may overcome inhibitory effects of imatinib on the elicitation of antileukemic T-cell responses. However, the results presented here are only applicable to IFN maintenance treatment that follows an imatinib/IFN combination therapy. Whether IFN maintenance is as effective after imatinib monotherapy for induction cannot be inferred from this study. Of the five patients who lost remission during the IFN maintenance phase, all five experienced relapse within the first 9 months after discontinuation of imatinib, but regained their prior depth of molecular remission with resumption of imatinib. Of the three patients who had not obtained an MMR, two patients experienced relapse under IFN monotherapy, as opposed to only three IFN failures among the 17 patients who were in MMR at baseline. This suggests that lack of MMR increases the likelihood of IFN maintenance failure.

The toxicity profile of IFN during maintenance therapy was low, with no grade 3 or 4 adverse events (Table 1). This supposedly owes to the relatively low doses of IFN that were injected and the fact that 16 (80%) of 20 patients received pegylated IFN, with improved tolerability compared with standard IFN.

In summary, the concept of an upfront imatinib/IFN combination therapy aiming to obtain an MMR followed by IFN monotherapy to maintain this remission may become an attractive alternative to lifelong TKI therapy. Given the excellent long-term outcome of complete cytogenetic responders pausing IFN,^17,23 the induction/maintenance concept may even hold the promise to achieve durable disease control without any further therapy.