Some recent papers have focused on the activity of imatinib-mesylate, a selective inhibitor of tyrosine kinase, in idiopathic hypereosinophilic syndrome (HES) [1], [2], [3] and [4]. In this setting, a possible therapeutic target was identified by Cools et al. [2], who described the fusion tyrosine-kinase gene FIP1L1/PDGFRA as the result of an interstitial deletion within chromosome 4 in nine out of sixteen (56%) patients affected by HES. Of interest, although in this study the response to imatinib was strictly correlated with the presence of FIP1L1/PDGFRA rearrangement (all patients with such a molecular lesion treated with imatinib responded), only five out of nine responding patients evidenced the abnormal transcript [2]. Among the possible alternative mechanisms for the activation of the PDGFRA tyrosine-kinase domain, these authors suggested there may be a different fusion gene

Carella, A

Catalano, G

Lo Coco, F

Minervini, M

Musto, P

Perla, G

Archivio della Ricerca - Università di Roma Tor vergata

Leukemia Research 28 (2004) 773–774
Letter to the Editor
Imatinib-mesylate for all patients with hypereosinophilic
syndrome?
Some recent papers have focused on the activity of
imatinib-mesylate, a selective inhibitor of tyrosine kinase,
in idiopathic hypereosinophilic syndrome (HES) [1–4]. In
this setting, a possible therapeutic target was identified by
Cools et al. [2], who described the fusion tyrosine-kinase
gene FIP1L1/PDGFRA as the result of an interstitial dele-
tion within chromosome 4 in nine out of sixteen (56%)
patients affected by HES. Of interest, although in this
Fig. 1. Panel (A) shows the results of fluorescence in situ hybridization (FISH) with Cy3-labelled (red) chromosome 2 and fluorescein-labelled (green)
chromosome 4 libraries (dual-color painting), confirming the cytogenetic evidence of t (2;4) (p24;q12). In panel (B), FISH analysis using a single locus
Spectrum-Orange-labelled (red) probe for N-myc shows the translocation of this oncogene from its normal site on chromosome 2 (p24), to the derivative
chromosome 4, in a region adjacent to where PDGFRA is located (q12). This strongly suggests the possibility of a N-myc-PDGFRA fusion gene.
study the response to imatinib was strictly correlated with
the presence of FIP1L1/PDGFRA rearrangement (all pa-
tients with such a molecular lesion treated with imatinib
responded), only five out of nine responding patients ev-
idenced the abnormal transcript [2]. Among the possible
alternative mechanisms for the activation of the PDGFRA
tyrosine-kinase domain, these authors suggested there may
be a different fusion gene.
We have recently observed a t (2;4) (p24;q12) recipro-
cal translocation in 64-year-old male affected by HES with
complete clinical, hematological and cytogenetic response
0145-2126/$ – see front matter © 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.leukres.2003.11.014
774 Letter to the Editor / Leukemia Research 28 (2004) 773–774
to imatinib (100 mg per day), currently maintained after ten
months of therapy with a dose of 100 mg given every other
day. A preliminary molecular screening performed accord-
ing to the previously described procedures [2] failed to de-
tect FIP1L1/PDGFRA in this patient. Cytogenetic and FISH
analyses (Fig. 1A) suggested the possibility of a molecu-
lar lesion different from FIP1L1/PDGFRA rearrangement.
Indeed, the fusion of PDGFRA with the oncogene N-myc
could be hypothesized (Fig. 1B).
A possible heterogeneity in the molecular pathogenetic
mechanisms inducing HES could justify the wide spectrum
of response observed in four consecutive patients we re-
cently treated with imatinib, which ranged from an impres-
sive and durable response to low doses in the patient with t
(2;4), to the need of administering higher doses of the drug
(400 mg per day) to achieve response, until to the evidence
of progressively acquired or primary resistance to doses up
to 800 mg per day [5].
Since not all HES patients respond to imatinib, a rele-
vant aspect to consider is the fact that clonal populations of
CD3−/CD4+ Th2 lymphocytes may secrete large amounts
of interleukin-5 (IL-5) and other cytokines, possibly in-
volved in the pathogenesis of at least some cases of HES
[6,7]. Although serum levels of IL-5 do not seem to represent
a surrogate marker of response to imatinib in this disease
[3], it is intriguing to note that all cases of HES responding
to imatinib so far reported did not evidence the presence of
T cell clones expansion, when tested [1,3]. By contrast, one
patient described by Pardanani et al. [3] and the only our
patient in whom an occult T cell clone could be detected,
did not respond to imatinib at all. It is conceviable that “T
cell-correlated” HES may have a different pathogenesis, not
including constitutive activation of tyrosine-kinases. There-
fore, it may be expected these forms are not responsive to
imatinib.
Imatinib-mesylate is certainly a promising treatment for
HES. However, the clinical and biological profile of patients
who are potential responders needs to be better defined.
References
[1] Gleich GJ, Leiferman KM, Pardanani P, Tefferi A, Butterfield JH.
Treatment of hypereosinophilic syndrome with imatinib mesylate.
Lancet 2002;359:1577–8.
[2] Cools J, De Angelo D, 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. New Engl J Med 2003;348:1201–14.
[3] Pardanani A, Reeder T, Porrata LF, Li CY, Tazelaar HD, Baxter
EJ, et al. Imatinib therapy for hypereosinophilic syndrome and other
eosinophilic disorders. Blood 2003;101:3391–7.
[4] Cortes JE, Ault P, Koller C, Thomas D, Ferrajoli A, Wierda W, et al.
Efficacy of imatinib mesylate in the treatment of hypereosinophilic
syndrome. Blood 2003;101:4714–6.
[5] Musto P, Falcone A, Sanpaolo G, Bodenizza C, Perla G, Minervini
MM. Heterogeneity of response to imatinib-mesylate (Glivec) in
hypereosinophilic syndrome: implications for dosing and pathogenesis.
Leuk Lymphoma 2004, in press.
[6] Roufosse F, Schandene L, Sibille C, Willard-Gallo K, Kennes
B, Efira A, et al. Clonal Th2 lymphocytes in patients with the
idiopathic hypereosinophilic syndrome. Br J Haematol 2000;109:
540–8.
[7] Bain BJ. Hypereosinophilia. Curr Opin Hematol 2002;7:21–5.
Pellegrino Musto ∗
Gianni Perla
Maria Marta Minervini
Angelo Michele Carella
Unit of Hematology and Stem Cell Transplantation
IRCCS “Casa Sollievo della Sofferenza”
71013 S. Giovanni Rotondo, Italy
∗Corresponding author. Tel.: +39-0882-411389;
fax: +39-0882-411389.
E-mail address: p.musto@tin.it (P. Musto).
Francesco Lo Coco
Gianfranco Catalano
Chair of Hematology, “Tor Vergata”
University, Rome, Italy
18 November 2003


Imatinib-mesylate for all patients with hypereosinophilic syndrome?

LO COCO, FRANCESCO

CATALANO, GIANFRANCO

Leukemia Research 28 (2004) 773–774Letter to the EditorImatinib-mesylate for all patients with hypereosinophilicsyndrome?Some recent papers have focused on the activity ofimatinib-mesylate, a selective inhibitor of tyrosine kinase,in idiopathic hypereosinophilic syndrome (HES)[1–4]. Inthis setting, a possible therapeutic target was identified byCools et al.[2], who described the fusion tyrosine-kinasegene FIP1L1/PDGFRA as the result of an interstitial dele-tion within chromosome 4 in nine out of sixteen (56%)patients affected by HES. Of interest, although in thisFig. 1. Panel (A) shows the results of fluorescence in situ hybridization (FISH) with Cy3-labelled (red) chromosome 2 and fluorescein-labelled (green)chromosome 4 libraries (dual-color painting), confirming the cytogenetic evidence of t (2;4) (p24;q12). In panel (B), FISH analysis using a single locusSpectrum-Orange-labelled (red) probe for N-myc shows the translocation of this oncogene from its normal site on chromosome 2 (p24), to the derivativechromosome 4, in a region adjacent to where PDGFRA is located (q12). This strongly suggests the possibility of a N-myc-PDGFRA fusion gene.study the response to imatinib was strictly correlated withthe presence of FIP1L1/PDGFRA rearrangement (all pa-tients with such a molecular lesion treated with imatinibresponded), only five out of nine responding patients ev-idenced the abnormal transcript[2]. Among the possiblealternative mechanisms for the activation of the PDGFRAtyrosine-kinase domain, these authors suggested there maybe a different fusion gene.We have recently observed a t (2;4) (p24;q12) recipro-cal translocation in 64-year-old male affected by HES withcomplete clinical, hematological and cytogenetic response0145-2126/$ – see front matter © 2004 Elsevier Ltd. All rights reserved.doi:10.1016/j.leukres.2003.11.014774 Letter to the Editor / Leukemia Research 28 (2004) 773–774to imatinib (100 mg per day), currently maintained after tenmonths of therapy with a dose of 100 mg given every otherday. A preliminary molecular screening performed accord-ing to the previously described procedures[2] failed to de-tect FIP1L1/PDGFRA in this patient. Cytogenetic and FISHanalyses (Fig. 1A) suggested the possibility of a molecu-lar lesion different from FIP1L1/PDGFRA rearrangement.Indeed, the fusion of PDGFRA with the oncogene N-myccould be hypothesized (Fig. 1B).A possible heterogeneity in the molecular pathogeneticmechanisms inducing HES could justify the wide spectrumof response observed in four consecutive patients we re-cently treated with imatinib, which ranged from an impres-sive and durable response to low doses in the patient with t(2;4), to the need of administering higher doses of the drug(400 mg per day) to achieve response, until to the evidenceof progressively acquired or primary resistance to doses upto 800 mg per day[5].Since not all HES patients respond to imatinib, a rele-vant aspect to consider is the fact that clonal populations ofCD3−/CD4+ Th2 lymphocytes may secrete large amountsof interleukin-5 (IL-5) and other cytokines, possibly in-volved in the pathogenesis of at least some cases of HES[6,7]. Although serum levels of IL-5 do not seem to representa surrogate marker of response to imatinib in this disease[3], it is intriguing to note that all cases of HES respondingto imatinib so far reported did not evidence the presence ofT cell clones expansion, when tested[1,3]. By contrast, onepatient described by Pardanani et al.[3] and the only ourpatient in whom an occult T cell clone could be detected,did not respond to imatinib at all. It is conceviable that “Tcell-correlated” HES may have a different pathogenesis, notincluding constitutive activation of tyrosine-kinases. There-fore, it may be expected these forms are not responsive toimatinib.Imatinib-mesylate is certainly a promising treatment forHES. However, the clinical and biological profile of patientswho are potential responders needs to be better defined.References[1] Gleich GJ, Leiferman KM, Pardanani P, Tefferi A, Butterfield JH.Treatment of hypereosinophilic syndrome with imatinib mesylate.Lancet 2002;359:1577–8.[2] Cools J, De Angelo D, Gotlib J, Stover EH, Legare RD, Cortes J, etal. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1genes as a therapeutic target of imatinib in idiopathic hypereosinophilicsyndrome. New Engl J Med 2003;348:1201–14.[3] Pardanani A, Reeder T, Porrata LF, Li CY, Tazelaar HD, BaxterEJ, et al. Imatinib therapy for hypereosinophilic syndrome and othereosinophilic disorders. Blood 2003;101:3391–7.[4] Cortes JE, Ault P, Koller C, Thomas D, Ferrajoli A, Wierda W, et al.Efficacy of imatinib mesylate in the treatment of hypereosinophilicsyndrome. Blood 2003;101:4714–6.[5] Musto P, Falcone A, Sanpaolo G, Bodenizza C, Perla G, MinerviniMM. Heterogeneity of response to imatinib-mesylate (Glivec) inhypereosinophilic syndrome: implications for dosing and pathogenesis.Leuk Lymphoma 2004, in press.[6] Roufosse F, Schandene L, Sibille C, Willard-Gallo K, KennesB, Efira A, et al. Clonal Th2 lymphocytes in patients with theidiopathic hypereosinophilic syndrome. Br J Haematol 2000;109:540–8.[7] Bain BJ. Hypereosinophilia. Curr Opin Hematol 2002;7:21–5.Pellegrino Musto∗Gianni PerlaMaria Marta MinerviniAngelo Michele CarellaUnit of Hematology and Stem Cell TransplantationIRCCS “Casa Sollievo della Sofferenza”71013 S. Giovanni Rotondo, Italy∗Corresponding author. Tel.:+39-0882-411389;fax: +39-0882-411389.E-mail address: p.musto@tin.it (P. Musto).Francesco Lo CocoGianfranco CatalanoChair of Hematology, “Tor Vergata”University, Rome, Italy18 November 2003

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LO COCO, F

CATALANO, G

Cineca Institutional Research Information System

https://art.torvergata.it/retrieve/handle/2108/49148/84963/imatinib-mesilate%20in%20all%20patients%20with%20HS.pdf

Imatinib-mesylate for all patients with hypereosinophilic syndrome?

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