Imatinib mesylate

The pathologic features of some cases of HES are reminiscent of those of other MPD, such as BCR/ABL-positive CML. The groundbreaking success of targeted treatment of CML with imatinib mesylate28 prompted its empirical use in patients with HES who failed other therapies. The first reported patient treated with imatinib mesylate achieved a complete response after only 2 weeks of treatment at 100 mg a day,66 a fraction of the standard dose used for treatment of CML.28 This observation, followed by reports of similar responses in additional patients with HES,67-72 ushered in what appears to be a new era of HES management and reclassification.

This clinical success prompted a search for an ima-tinib mesylate target in patients with HES, leading to the seminal discovery of a new fusion gene, the product of which is the molecular basis of HES in some patients. Deletion of an 800-kilobase part of the PDGFRa gene leads to fusion of its 5' end to the 3' end of a new gene FIP1L1 on chromosome 4.69-73,77,79,86,108 The FIP1L1/PDGFRa gene product, an intracellular protein with TK function, is unique because it is autophosphorylated due to deletion of the portion of PDGFRa gene coding for the juxtamembrane portion of the PDGFRa receptor known to inhibit phosphoryla-tion of the ATP-binding site, and thus promotes uncontrolled growth. The most convincing documentation that the FIP1L1-PDGFR« TK is a target of imatinib was imatinib's loss of inhibitory action in cells with acquired mutation (T671I) in the TK domain of the FIP1L1/PDGFRa fusion gene, which implies that the mutation confers resistance to imatinib mesylate.6974

The clinical experience with imatinib mesylate in managing HES and CEL can be summarized as follows: In most responding patients, daily oral doses of 100 mg effectively induced complete responses. The median time to response was 4 weeks, but responses were seen within the first 2 weeks of treatment. In only a few cases, increasing the imatinib dose to 400 mg was required for response.71 The adverse effects were minimal and similar to those experienced by patients with Ph-positive CML.28 33 The exceptions were two cases of congestive heart failure, both in responding patients, ensuing shortly after initiation of imatinib treatment.72 108 Administration of steroids resulted in the resolution of symptoms in both cases, raising the question of whether steroids should be used during initial therapy with imatinib (with or without monitoring of troponin levels), particularly in patients with existing cardiac involvement. All HES and CEL patients with the FLIP1L1/PDGFRa abnormality responded regardless of the disease stage, and no cases of primary resistance have been reported.69 109 In one study, however, four of nine patients who achieved a complete response with imatinib had no detectable FIP1L1-PDGFR«.69 This observation not only indicated the presence of other imatinib targets but also argued in favor of an empirical trial of imatinib in patients with HES or CEL. Such a trial would ensure that no patient missed a potential therapeutic benefit, contribute further to a therapeutically meaningful classification of HES and CEL, and provide clinical feedback and guidance for ongoing translational research.

The complete responses were associated with normalization of eosinophil counts and normalization of hematologic parameters with resolution of clinical symptoms.69,109 Among 41 patients with HES or CEL included in seven reports, 29 (71%) achieved CRs and one achieved a PR.109 Of six patients monitored for FLIP1L1-PDGFRa transcripts, molecular remissions were documented in five after 1-12 months of treatment with 400 mg imatinib daily.71 The treatment effect on end-organ damage is unknown because the experience is limited. No amelioration of cardiac disease was noted in three patients at the time they achieved CR,71 but the clearing of interstitial pulmonary infiltrates,71,110 normalization of pulmonary function tests,71 and a major improvement in the bone marrow fibrosis of responding HES patients was encouraging.71,109

What is the optimal treatment strategy for patients with HES and CEL and FIP1L1/PDGFR«? Although the clinical experience with imatinib mesylate is limited, these disease categories are clearly highly sensitive to the agent. Thus, the starting daily dose of 100 mg is recommended after the expression level of the fusion transcripts has been determined, if possible with PCR. In HES patients with cardiac disease, use of prophylactic oral steroids during the first week of treatment should be considered. Because the median time to optimal response was 4 weeks, failure to respond should prompt consideration of dose escalation. The benefit of dose escalation is supported by experience in a limited number of HES cases and is corroborated by extensive experience on dose response to imatinib in patients with Ph-positive CML.111112 For patients who achieve CRs, the treatment strategy developed for CML should be adapted; they could continue on the same daily dose and be monitored for minimal residual disease by PCR every 3-6 months and for degree of end-organ damage (e.g., heart damage every 6 months with cardiac sonography). In patients with CRs but positive for minimal residual disease, after 6-12 months, dose escalation according to clinical tolerance is an option worth to investigate.

A similar treatment approach should be used for imatinib-mesylate-responsive patients lacking FIP1L1/ PDGFRa. Hematologic status, and end-organ damage and function must be monitored.

Recently, a lemtuzumab (Campath-1HTM) has shown remarkable activity in patients with FIP1LI/ PDGFRa-negative HES. Normalization of absolute eosinophil counts was observed in 8 of 9 patients within 4 weeks of treatment with weekly cycles of alemtuzumab.113 The mechanism of action is likely by direct interaction with CD52 target antigen on eosinophils. Although dosing and maintenance must be optimized and safety of the treatment documented, the preliminary results justify further clinical investigation.

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