Flow cytometry analyses reveal association between Lu/BCAM adhesion molecule and osteonecrosis in sickle cell disease

To the Editor The identification of the FIP1L1-PDGFRA (F/P) fusion gene provided the molecular basis for the use of imatinib mesylate (IM) in a small proportion of patients with hypereosinophilic syndrome (HES). In vitro studies have demonstrated that the tyrosine kinase activity of the F/P fusion is 100 times more sensitive to inhibition by IM than BCR-ABL1 transcript detected in chronic myeloid leukemia (CML) [1]. This finding may explain the exquisite hematologic and clinical response to treatment with low doses of IM in F/Pmutated HES. The initial dose of IM is found to be 100 mg daily in a majority of studies [2,3], but the most appropriate maintained dose has not been determined yet. A total of 100 mg weekly maintenance dose of IM has been successfully used in our institution [4]. The attempt of IM discontinuation despite F/P eradication led to the fusion gene reappearance and eosinophilia recurrence. Nevertheless, some patients may remain in remission for several months. It is noteworthy that re-initiation of IM treatment resulted in a new molecular remission; however it may require higher IM dose. These findings show that F/P-positive clone was suppressed rather than eliminated [5]. In contrary, the cessation of IM was demonstrated to be safe and effective in 40–50% of patients with CML while in complete molecular remission and on prior IM for at least 2 years. These results may suggest that some patients may eventually be cured [6,7]. To date, there have been no reports of an unmaintained remission in F/P-mutated HES. Herein, we report on two F/P-mutated HES patients in whom IM cessation led to durable response. Some data of these two patients have been presented in our previous article [4]. Shortly, there were male with multi-organ involvements at diagnosis and prior ineffective treatment with steroids, hydroxyurea, and interferon. On admission, their blood eosinophilia was greater than 5.0 3 10/L and bone marrow was occupied by eosinophils in about 50%. Karyotyping was diploid. The starting IM dose was 100 mg daily and this treatment resulted in hematologic and molecular remission (13 days vs. 67 days and 6 months vs. 24 months, respectively). IM dose was decreased to 200 mg weekly while in hematologic remission and then to 100 mg weekly as a maintenance. They remained on maintained IM dose for 6.5 and 5.5 years, respectively. The total duration of IM treatment exceeded 6.5 years for both cases. Prior IM discontinuation, the F/P transcript was undetectable by PCR for more than 4 years. Patients gave an informed consent for IM cessation and the study was approved by Local Ethics Committee. Throughout the treatment period, patients were monitored for the presence of the FIP1L1-PDGFRA fusion gene every 3–6 months and every 3 months after IM cessation. Currently, both patients remain free of disease 26 and 24 months off-therapy, respectively. To date, there was only one study that reported the details on slow tapering and subsequent interruption of IM in F/P-mutated HES [5]. In this study, five patients discontinued IM while in molecular remission for a minimum of 1 year and all relapsed within the next few months. It is noteworthy that the depth of molecular response remains a predictor of relapse in CML [6,7] and it is likely to be the case in F/P-mutated HES. However, one patient relapsed within 6 months after cessation of IM despite 5 log reduction of F/P transcript [8]. It seems that the utility of quantitative PCR in this cohort needed to be validated in further studies. Our small case series has shown that IM may result in a unmaintained remission in a proportion of patients with F/P-mutated HES; however a longer follow-up involving more patients is needed to confirm this observation.