Imatinib discontinuation for hypereosinophilic syndrome harboring the FIP1L1-PDGFRA transcript

A subset of patients with hypereosinophilic syndrome (HES) may harbor an interstitial deletion in chromosome 4, leading to the creation of the FIP1L1-PDGFRA (F/P) fusion gene which has been found to be highly imatinibsensitive [1]. Although imatinib mesylate (IM) is a treatment of choice for F/P HES, data on the possibility of disease eradication after IM discontinuation remain scarce. Safety and efficacy of IM cessation have originally been demonstrated for patients with chronic-phase chronic myeloid leukemia (CML). There have been several controlled attempts in patients who had sustained undetectable BCR-ABL by polymerase chain reaction (PCR) on IM for at least 2 years [2–4]. At 2 years, treatment-free remission was found to be 47% and most relapses occurred within the first 4 months after IM stopping. It is noteworthy that all patients who had relapsed remained sensitive to IM re-initiation. These results have shown that IM can be discontinued safely in at least some CML patients [4]. However, according to the current European LeukemiaNet (ELN) recommendations, IM should be continued indefinitely in responding patients, even if BCR-ABL remains undetectable using strict sensitivity criteria [5]. The constitutive kinase activity of F/P was found to be 100-fold more sensitive to IM than BCR-ABL [1] and patients with this mutation respond dramatically to IM achieving an excellent response rate ( 100%) [1,6,7]. Nevertheless, both the initial and maintenance IM dose are still a matter of debate. Our previous study has demonstrated that a 100 mg weekly maintenance dose of IM can be successful for obtaining long-term hematologic and molecular responses in F/P HES [6]. To date, only one prospective study reported on the results of IM discontinuation for F/P HES. Unfortunately, all five patients who stopped the treatment relapsed [8]. In contrary, our group has demonstrated the fresh data of 2 F/P HES patients who remained free of disease 2 years off therapy [9]. A trial of IM cessation in HES harboring F/P transcript has been attempted in seven patients treated in three Polish centers. The updated results of two previously reported patients have been included in the current analysis. Briefly, there were seven males at a median age at diagnosis of 57 years (28–71 years). Median leukocyte count was 18.9 10/l (range1⁄4 13.4–34.8) with a median absolute eosinophil count of 10.9 10/l (range 1⁄4 5.6–19.4). Median eosinophilic infiltration of bone marrow was 47% (range1⁄4 30–88). Median serum IgE, tryptase and vitamin B12 levels were within normal ranges. Organ involvements were present in six studied patients at disease onset. Details on patients characteristics are presented in Table I. The FIP1L1-PDGFRA fusion transcript was screened by nested RT-PCR using the previously reported primers [1] and monitored every 3–6 months while the patient was on IM and every 3 months after IM discontinuation. The Mann-Whitney test was used to compare variables between relapsed and non-relapsed sub-groups. Relapse-free survival (RFS) was estimated using the Kaplan-Meier method; p 5 0.05 was considered significant. All computations were performed with StatSoft Poland analysis software (version 10.0). The initial IM dose was 100 mg daily in six patients, whereas 400 mg daily was administered for one. Median time from diagnosis to IM introduction was 5 months (range1⁄4 0.2–50). All patients achieved complete hematologic (CHR) and molecular remission (CMR) after a median of 14 days (range1⁄4 4–67) and 6 months (range1⁄4 1–24 months), respectively. Then, IM dose was decreased to 100 mg weekly as a maintenance in all patients. Median time from IM initiation and CMR