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Cancer Chemotherapy and Pharmacology
Cancer Chemother Pharmacol. Apr 2011; 67(4): 967–969.
Published online Feb 17, 2011. doi:  10.1007/s00280-011-1582-3
PMCID: PMC3064899

Durable remission after treatment with very low doses of imatinib for FIP1L1-PDGFRα-positive chronic eosinophilic leukaemia

To the Editor,

The exquisite response to imatinib mesylate in patients with chronic eosinophilic leukaemia (CEL) harbouring the FIP1L1-PDGFRα (F/P) fusion transcript has been well documented [14]. In the up-to-date largest multicentre study, all 27 patients with detectable F/P mutation achieved complete haematological and molecular remission after imatinib therapy and have remained in continuous remission after median of 25 months [2].

The initial daily doses of imatinib ranged from 100 to 400 mg in a majority of published reports, but maintained imatinib doses were not fully established [2, 5]. It was also demonstrated that imatinib dose reduction or temporary discontinuation was associated with molecular and clinical relapse [6, 7]. Additionally, single cases of imatinib-resistant F/P-positive CEL have been reported [8].

As the response rate after imatinib is close to 100%, the current issue is (1) to establish a minimal effective imatinib dose needed to remission maintenance and (2) to evaluate the duration of imatinib response.

Recently, we reported on high efficacy of weekly imatinib schedule in 13 F/P-positive CEL patients. Imatinib at weekly dosage seemed to be sufficient to maintain haematological and molecular remission with a median of 21 months of follow-up in this studied subgroup [9].

Herein, we present long-term results of F/P-positive CEL after imatinib. The data were collected from ten centres in Poland. All patients gave written informed consent. Twenty male and two female patients at median age of 52 years (range 22–80 years) were included in this partially retrospective study. Organ involvement was demonstrated in 91% of patients, and splenomegaly was the most common clinical manifestation. At diagnosis, 23% of patients were asymptomatic. Median blood eosinophilia and median bone marrow eosinophil infiltration were 12 × 109/l (range 2.5–40) and 39.5% (range 7.0–80), respectively. The starting, de-escalated and maintained imatinib doses were left to the physician’s discretion. The initial imatinib doses were as follows: 100 mg/day (n = 18), 400 mg/day (n = 3) and 300 mg/day (n = 1). All treated patients achieved haematological remission after median of 13 days (range 3–90). Complete molecular remission by nested RT-PCR was confirmed after median of 10 months (range 3–24). They became free of symptoms. The maintained imatinib doses were following: 100 mg per week (n = 11), 200 mg per week (n = 2), 400 mg per week (n = 1), 100 mg twice a week (n = 2), 100 mg thrice a week (n = 2) and 100 mg a day (n = 4). Imatinib doses and duration of treatment were shown in Table 1. All studied patients remained in complete haematological and molecular remission after median follow-up of 41 months (range 11–71). Median time at maintained imatinib doses was 27 months (range 2–61). Imatinib plasma levels were measured using high-performance liquid chromatography-tandem mass spectrometry method [10]. Blood samples were taken 24 h after the last imatinib intake from eleven patients: from 9 patients on 100 mg weekly imatinib and from 2 on imatinib at 200 mg a week. Imatinib plasma levels appeared to be extremely low and ranged between 44 and 164 ng/ml and 103–203 ng/ml, respectively, for both analysed groups. Of note is that F/P negativity was confirmed at the same time points by nested RT-PCR.

Table 1
Imatinib doses and duration of therapy in F/P-positive CEL patients

With this large series of F/P-positive CEL patients, we can confirm that imatinib may induce durable remission with the maximum follow-up of 71 months until last contact. Most recently, Rondoni et al. [11] presented the follow-up results of 33 F/P-positive CEL patients on imatinib with a continuous remission after median of 51 months (range 30–92). In contrary to our report, the maintained imatinib doses were 100 mg a day. It is noteworthy that 18 patients from our study group received imatinib at total maintained doses of 400 mg a week or less. We have proved that treatment with such low imatinib doses may maintain molecular remission despite low imatinib plasma levels. Nevertheless, the longer follow-up is needed to confirm our encouraging results.

Open Access

This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.

References

1. Cools J, Angelo DJ, Gotlib J, Stover EH, Legare RD, Cortes J, et al. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med. 2003;348:1201–1214. doi: 10.1056/NEJMoa025217. [PubMed] [Cross Ref]
2. Baccarani M, Cilloni D, Rondoni M, Ottaviani E, Messa F, Merante S, et al. The efficacy of imatinib mesylate in patients with FIP1L1-PDGFRα positive hypereosinophilic syndrome. Results of a multicenter prospective study. Haematologica. 2007;92:1173–1179. doi: 10.3324/haematol.11420. [PubMed] [Cross Ref]
3. Helbig G, Stella-Holowiecka B, Grosicki S, Bober G, Krawczyk M, Wojnar J, et al. The results of imatinib therapy for patients with primary eosinophilic disorders. Eur J Haematol. 2006;76:535–536. doi: 10.1111/j.1600-0609.2006.00652.x. [PubMed] [Cross Ref]
4. Vandenberghe P, Wlodarska I, Michaux L, Zachee P, Boogaerts M, Vanstraelen D, et al. Clinical and molecular features of FIP1L1-PDGFRA (+) chronic eosinophilic leukemia. Leukemia. 2004;18:734–742. doi: 10.1038/sj.leu.2403313. [PubMed] [Cross Ref]
5. Metzgeroth G, Walz C, Erben P, Popp H, Schmitt-Graeff A, Haferlach C, et al. Safety and efficacy of imatinib in chronic eosinophilic leukaemia and hypereosinophilic syndrome-a phase-II study. Brit J Haematol. 2008;143:707–715. doi: 10.1111/j.1365-2141.2008.07294.x. [PubMed] [Cross Ref]
6. Klion AD, Robyn J, Maric I, Fu W, Schmid L, Lemery S, et al. Relapse following discontinuation of imatinib mesylate therapy for FIP1L1/PDGFRA-positive chronic eosinophilic leukemia: implications for optimal dosing. Blood. 2007;110:3552–3556. doi: 10.1182/blood-2007-07-100164. [PMC free article] [PubMed] [Cross Ref]
7. Jovanovic J, Score J, Waghorn K, Cilloni D, Gottardi E, Metzgeroth G, et al. Low-dose imatinib mesylate leads to rapid induction of major molecular response and achievement of complete molecular remission in FIP1L1-PDGFRA positive chronic eosinophilic leukemia. Blood. 2007;109:4635–4641. doi: 10.1182/blood-2006-10-050054. [PubMed] [Cross Ref]
8. Lierman E, Michaux L, Beullens E, Pierre P, Marynen P, Cools J, et al. FIP1L1-PDGFRα D842 V, a novel panresistant mutant, emerging after treatment of FIP1L1-PDGF T674I eosinophilic leukaemia with single agent sorafenib. Leukemia. 2009;23:845–851. doi: 10.1038/leu.2009.2. [PubMed] [Cross Ref]
9. Helbig G, Moskwa A, Świderska A, Urbanowicz A, Całbecka M, Gajkowska J, et al. Weekly imatinib dosage for chronic eosinophilic leukaemia expressing FIP1L1-PDGFRA fusion transcript: ectended follow-up. Brit J Haematol. 2009;145:132–134. doi: 10.1111/j.1365-2141.2008.07546.x. [PubMed] [Cross Ref]
10. Titier K, Picard S, Ducint D, Teilhet E, Moore N, Berthaud P, et al. Quantification of imatinib in human plasma by high-performance liquid chromatography-tandem mass spectrometry. Ther Drug Monit. 2005;27:634–640. doi: 10.1097/01.ftd.0000175973.71140.91. [PubMed] [Cross Ref]
11. Rondoni M, Ottaviani E, Cilloni D, Piccaluga P, Paolini S, Iacobucci I, et al. Chronic eosinophilic leukemia with FIP1L1-PDGFRA rearrangement: the response to imatinib is durable. A report of 33 patients with a follow-up of 30 to 92 months. Blood. 2009;114:22.
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