Imatinib mesylate elicits positive clinical response in atypical chronic myeloid leukemia involving the platelet-derived growth factor receptor beta

Atypical chronic myeloid leukemia (aCML) is a chronic myeloproliferative disorder with a clinical and hematologic picture similar to chronic myelocytic leukemia (CML) but lacking Philadelphia chromosome and BCR-ABL rearrangement. Cytogenetic studies have shown either a normal karyotype or numeric chromosomal changes.¹  Recently the molecular cloning of t(5;10)(q33;q22) has been reported in 2 patients with aCML.^2,3  This translocation creates a H4(D10S170)/platelet-derived growth factor receptor beta (PDGFβR) fusion transcript and suggests an association between deregulated tyrosine kinases and aCML. We report on a patient with an aCML and a t(5;10) who achieved a clinical and cytogenetic response after imatinib mesylate therapy.

The patient, a 44-year-old man, presented with leukocytosis and splenomegaly. The white blood cell count was 158 × 10⁹/L (3% myelocytes; 6% metamyelocytes; 4% bands; 68% neutrophils; 8% eosinophils; 10% lymphocytes; 1% monocytes), hemoglobin level was 91 g/L, and platelet count was 352 × 10⁹/L. Analysis of peripheral blood smear revealed a remarkable dysplasia in myeloid cells. Cytogenetic analysis showed the following: 46,XY,t(5;10)(q33;q22)[24]/46,XY[1] after G-banding and fluorescence in situ hybridization (FISH) studies (Figure 1A). Both FISH and polymerase chain reaction (PCR) studies failed to demonstrate the presence of BCR-ABL fusion. Therefore, nested reverse transcriptase (RT)-PCR analysis using specific primers flanking the predicted breakpoints was performed. Using 2 different sets of primers the region implicated in the translocation was amplified (Figure 1B). These results demonstrated that t(5;10)(q33;q22) involved the genes H4 and PDGFβR. Sequencing of the amplified bands confirmed that there was a fusion H4-PDGFβR occurring at exactly the same breakpoint as found in the previous t(5;10) reports.^2-4  Based on the presence of PDGFβR rearrangement, the patient began treatment with imatinib, at a daily dose of 400 mg. The therapy was well tolerated, without obvious side effects. Clinical and cytogenetic complete response to imatinib was achieved after 3 weeks of therapy. At 8 weeks after initiation of imatinib therapy, semiquantitative RT-PCR analysis showed a 99% reduction in H4/PDGFβR expression in peripheral blood compared with blood samples taken prior to treatment (Figure 1D). The patient remains in complete response after one year of therapy.

Imatinib mesylate has been shown to efficiently inhibit the activity of certain tyrosine kinases, including BCR-ABL, c-Kit, PDGFβR, PDGFαR, and ARG kinase.^5,6  Thus to further investigate the role of chimeric protein H4/PDGFβR, imatinib mesylate was tested in bone marrow primary cultures. Interestingly, bone marrow primary cultures from the t(5;10) patient displayed marked apoptosis when treated with imatinib (Figure 1C).

Our results demonstrate the efficiency of imatinib in the treatment of patients displaying the translocation involving H4 and PDGFβR genes. Imatinib binds tightly into the adenosine triphosphate (ATP)-binding pocket within the tyrosine kinase domain of BCR-ABL,⁷  and we predict a similar mode of action with PDGFβR. Hence, the observed positive response strongly suggests that inhibition of PDGFβR activity may also be effective in other myeloproliferative diseases involving this tyrosine kinase receptor.

We are thankful to Witte-Maria Weber and Novartis for providing imatinib (CGP 57148B) used for the in vitro culture studies.