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Blood, 15 January 2005, Vol. 105, No. 2, pp. 904-905.
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CORRESPONDENCE
To the editor:
Imatinib mesylate in the treatment of c-kit–positive acute myeloid leukemia: is this the real target?
Kindler et al1 reported that 5 of 21 acute myeloid leukemia (AML) patients responded to treatment with imatinib mesylate, which is a c-kit inhibitor. From February 2003 to November 2003, we treated with imatinib 36 c-kit–positive AML patients who were not amenable to conventional chemotherapy. Of the patients, 51% were refractory/relapsed and 49% were previously untreated. The median age was 66 years (range, 26-79 years). The median white blood cell count was 4.8 x 109/L (range, 0.7-88 x 109/L). In addition to a diagnostic panel of monoclonal antibodies, the leukemic blast cells of all the patients were assessed by flow cytometry for c-kit and platelet-derived growth factor receptor  (PDGF-R; phycoerythrin-conjugated anti-CD117 and anti-CD140 monoclonal antibodies; Becton Dickinson, Mountain View, CA) and by reverse-transcription–polymerase chain reaction (RT-PCR) for bcr/abl rearrangement. All of the patients had c-kit–positive blasts (median, 55%; range, 16%-96%), with a high mean fluorescence index (median, 30; range, 17-100; evaluated on 17 cases). Only one patient overexpressed PDGF-R on blast cells (46%). No patient was positive for bcr/abl rearrangements. The median administered dose was 600 mg/d (range, 200-700 mg/d), for a median of 31 days (range, 2-311+ days). Nonhematologic toxicity was mild and not different from the one found in chronic myeloid leukemia imatinib trials. While on therapy with imatinib, 6 patients died (2 with multiorgan failure, 2 of disease progression, and 2 of cerebral stroke). During the follow-up, 15 patients died mainly due to disease progression. No patient achieved a complete or a partial remission. In 2 patients, the disease remained stable as defined by no peripheral blood or bone marrow modification. They are now continuing imatinib after 270 and 311 days. The patient with PDGF-R overexpression had a platelet increase that lasted for one year with transfusion independence. In the meanwhile, blast cells became PDGF-R negative.
Our purpose was to evaluate the in vivo effect of imatinib on c-kit–positive leukemic blasts. In accordance with the findings of Cortes et al2 and Heinrich et al,3 we did not find a significant in vivo activity of imatinib, even though the drug is a proven c-kit in vitro inhibitor. On the other hand, Kindler et al1 obtained 5 hematologic responses, complete and partial. We agree with the hypothesis that multiple gene aberrations sustain leukemic proliferation and that c-kit itself may be useful but not necessary for leukemic cell survival and proliferation. One positive effect was observed in the PDGF-R–positive patient. In vivo PDGF-R–positive blast cells may be more sensitive to the drug, as previously reported.4 This is in line with the reports on the efficacy of imatinib in the hypereosinophilic syndrome, where PDGF-R expression is secondary to the rearrangement of the PDGF-R gene with the FIP1L1 gene.5,6 Since the percentage of AML patients with PDGF-R rearrangement or overexpression is unknown, it could be interesting to screen all patients at diagnosis, for a prospective and proper use of imatinib in the patients who are positive or rearranged.
Michele Malagola,
Giovanni Martinelli,
Michela Rondoni,
Stefania Paolini,
Stavrula Gaitani,
Mario Arpinati,
Pier Paolo Piccaluga,
Marilina Amabile,
Constanza Basi,
Emanuela Ottaviani,
Anna Candoni,
Enrico Gottardi,
Daniela Cilloni,
Monica Bocchia,
Giuseppe Saglio,
Francesco Lauria,
Renato Fanin,
Giuseppe Visani,
Maria Carla Marrè,
Michela Maderna,
Francesca Rancati,
Vincenza Vinaccia,
Domenico Russo, and
Michele Baccarani
Correspondence: Michele Malagola, Institute of Hematology and Medical Oncology "L and A Seràgnoli," Policlinico S Orsola-Malpighi, Via Massarenti 9, 40138, Bologna, Italy; e-mail: acute{at}med.unibo.it; mmalagola{at}hotmail.com.
Footnotes
Supported in part by COFIN 2002-2003 (M.B.), by AIRC, Ateneo 60% (M.B.), and by fondazione del monte di Bologna e Ravenna (M.B.).
References
- Kindler T, Breitenbuecher F, Marx A, et al. Efficacy and safety of imatinib in adult patients with c-kit-positive acute myeloid leukemia. Blood. 2004;103: 3644-3654.[Abstract/Free Full Text]
- Cortes J, Giles F, O'Brien S, et al. Results of imatinib mesylate therapy in patients with refractory or recurrent acute myeloid leukemia, high-risk myelodisplastic syndrome, and myeloproliferative disorders. Cancer. 2003;97: 2760-2766.[CrossRef][Medline]
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- Heinrich MC, Griffith DJ, Druker BJ, et al. Inhibition of c-kit receptor tyrosine kinase activity by STI-571, a selective tyrosine kinase inhibitor. Blood. 2000;96: 925-932.[Abstract/Free Full Text]
- Apperley JF, Gardembas M, Melo IV, et al. Response to imatinib mesylate in patients with chronic myeloproliferative diseases with rearrangements of the platelet-derived growth factor receptor beta. N Engl J Med. 2002;347: 481-487.[Abstract/Free Full Text]
- Martinelli G, Malagola M, Ottaviani E, Rosti G, Trabacchi E, Baccarani M. Imatinib mesylate can induce complete molecular remission in FIP1L1-PDGFR
 positive idiopathic ipereosinofilic syndrome. Haematologica. 2004;89: 236-237.[Free Full Text]
- Cortes J, Ault P, Koller C, et al. Efficacy of imatinib mesylate in the treatment of idiopathic hypereosinophilic syndrome. Blood. 2003;101: 4714-4716.[Abstract/Free Full Text]
Response:
Imatinib in patients with c-kit–positive acute myeloid leukemia
We agree with the notion raised by Malagola and colleagues that in acute myeloid leukemia (AML), platelet-derived growth factor receptor (PDGF-R) rearrangement or overexpression is an interesting target for imatinib treatment. However, apparent differences in response rates observed between the study of Malagola and colleagues and our trial may not solely be due to differences in c-kit and/or PDGF-R expression, but may be brought on by patient selection: in our trial, clinically significant responses were observed in patients with low bone marrow blast infiltration and relatively low absolute blast counts in peripheral blood.1 In addition, complete hematologic remissions were achieved only in patients starting imatinib during hematopoietic reconstitution in a refractory situation after chemotherapy.
While analysis of PDGF-R expression using immunohistochemistry of bone marrow biopsies indicated moderate expression of PDGF-R and in patients responding to imatinib, high PDGF-R expression, per se, was not indicative of response to imatinib in our trial.
Potential mechanisms for biologic activity of imatinib in AML may include (1) constitutive activation of c-Kit and/or PDGF-Rs in leukemic blasts due to autocrine/paracrine signaling or inactivation of inhibitory phosphatases, and (2) c-KIT and/or PDGF-R mutations or aberrations. In this context, it is interesting to note that 2 recent papers reported coexpression of Fms-like tyrosine kinase 3 (Flt3) receptor and Flt3 ligand (FL) and of c-Kit receptor and stem cell factor (SCF) in the majority of primary AML samples investigated.2,3 This suggests that in some patients, these receptors may contribute to leukemic proliferation through autocrine and/or paracrine stimulation. Thus, inhibition of wild-type c-Kit and/or Flt3 may be useful in some AML patients, and a therapeutic benefit may be achieved in combining this approach with chemotherapy. We are currently testing this hypothesis in a phase 2 clinical trial.
Thomas Kindler,
Florian Heidel, and
Thomas Fischer
Correspondence: Thomas Kindler III, Medical Department, Johannes Gutenberg-University of Mainz, Langenbeckstrasse 1, 55130 Mainz, Germany; e-mail: thomas.fischer{at}3-med.klinik.uni-mainz.de.
References
- Kindler T, Breitenbuecher F, Marx A, et al. Efficacy and safety of imatinib in adult patients with c-kit-positive acute myeloid leukemia. Blood. 2004;103: 3644-3654.[Abstract/Free Full Text]
- Zheng R, Klang K, Corin NC, Small D. Lack of KIT or FMS internal tandem duplications but co-expression with ligands in AML. Leuk Res. 2004;28: 217-218.[CrossRef][Medline]
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- Zheng R, Levis M, Piloto O, et al. FLT3 ligand causes autocrine signalling in acute myeloid leukemia cells. Blood. 2004;103: 267-274.[Abstract/Free Full Text]
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Related Article in Blood Online:
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Efficacy and safety of imatinib in adult patients with c-kit–positive acute myeloid leukemia
- Thomas Kindler, Frank Breitenbuecher, Andreas Marx, Joachim Beck, Georg Hess, Birgit Weinkauf, Justus Duyster, Christian Peschel, Charles J. Kirkpatrick, Matthias Theobald, Harald Gschaidmeier, Christoph Huber, and Thomas Fischer
Blood 2004 103: 3644-3654.
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