In 2002, a t(4;22)(q12;q11) translocation fusing BCR to platelet-derived growth factor receptor-alpha (PDGFRA) was first reported in two patients with Philadelphia chromosome-negative (Ph-neg) chronic myelogenous leukemia (CML).1 Owing to the lack of imatinib, these patients underwent allogeneic stem cell transplantation. More recently, the same translocation was observed in two other patients with Ph-neg CML. Besides the inhibition of the aberrant BCR/ABL tyrosine kinase imatinib also affects other tyrosine kinases such as c-kit and the PDGFRs. Therefore, these patients received imatinib and achieved a hematologic and cytogenetic remission.2, 3 and 4
Here, we report on a third patient with a t(4;22)(q12;q11) who is in hematological, cytogenetic and molecular long-term remission following treatment with imatinib at a dose of 100 mg/day.
In 2004, a 35-year-old male with an unremarkable medical report presented at our outpatient unit complaining about night sweat, loss of appetite and loss of weight of 6 kg. He had developed these symptoms during the last 2 months. He also suffered from nose, gum and petechial skin bleeding. He was a worker in a leather tannery having been exposed to varnish, colors and aromatic acids. For the last 2 years, before the onset of the symptoms, he worked as a truck driver.
He received ceterizin, magnesium and zinc tablets as well as xylometazolin nose spray for several years because of allergic symptoms related to the respiratory system without any side effects. His father died of cancer of the bladder and prostate, and his mother has meningeoma. He has six healthy siblings (three sisters and three brothers) of whom one sister is HLA identical. Physical examination showed splenomegaly without peripheral lymphadenopathy. This finding was confirmed by sonographical examination. The white blood cell count was elevated with a concentration of 58 000/μl, whereas a left shift in the differential blood count was noted. The hemoglobin level was 12.8 g/dl and the platelet count was 140 × 103/μl. An increase in LDH level (570 IU/l) was the only remarkable finding with regard to the serum biochemistry. The coagulation parameters were normal. The findings of the histological and cytomorphological bone marrow examination were compatible with a CML in chronic phase. Still, the results of a nested and multiplex RT-PCR performed were negative for BCR/ABL. Cytogenetic analyses were performed on the patient's bone marrow and peripheral blood and 22 metaphases were examined according to the ISCN 1995 guidelines. The analysis showed no Philadelphia chromosome but a translocation t(4;22)(q12;q11) in 18–22 metaphases. The translocation was further investigated by fluorescence in situ hybridization (FISH) using a probe mix consisting of a BAC probe (RP11-545H22, distal of PDGFRA) with the BCR-ABL Vysis probe. Nearly fused signals on the derivative chromosome 22 indicated a fusion between the genes PDGFRA and BCR. With interphase analysis we could show that 70–80% of the cells in the bone marrow harbor this translocation. To confirm the formation of a BCR/PDGFRA fusion gene, FISH analyses with probes around the PDGFRA gene region were performed. A mixture of the probes RP11-571I18 (red, proximal of PDGFRA) and RP11-58C6 (green, covers the PDGFRA gene) was used to demonstrate the direct participation of PDGFRA. The BAC probe (green, RP11-58C6) containing the PDGFRA gene hybridizes to the derivative chromosomes 4 and 22 demonstrating a disruption of the gene (Figure 1).
After identification of the involvement of PDGFRA, the patient received imatinib from October 2004 until the time of writing this report. Fortunately, having started the therapy, a rapid hematological response was noted. With 2 months of therapy with imatinib, the white blood count and lactate dehydrogenase (LDH) level became normal (Figure 2). At the time of diagnosis, there were 80% FISH-positive cells in bone marrow and 70% positive cells in peripheral blood. Following 1 month of treatment, there were 6% FISH-positive cells and after 6 months of therapy, the translocation was no longer detectable until today. As a result of the hematological remission, there were no more bleeding episodes. It is worth mentioning that after 10 days of treatment, the dose of imatinib had to be reduced gradually from 400 to 200 mg and after 10 more days to 100 mg due to severe bone and ankle pain. From December 2004 until the time of writing this report, the patient tolerated this dose of 100 mg of imatinib daily without any side effects.
Other rearrangements involving the PDGFRA gene have been described. Constitutive activation of PDGFRA resulting from the fusion of the Fip1-like 1 gene named FIP1L1 to the PDGFRA gene was identified to be one reason for idiopathic hypereosinophilic syndrome and was shown to be sensitive to imatinib treatment.5 Most recently, a novel fusion between KIF5B at 10p11 and PDGFRA at 4q12 has been described and also responded to imatinib.6 Only two patients have been reported so far with the t(4;22)(q12;q11) translocation fusing BCR to PDGFRA who were treated with imatinib and subsequently achieved a rapid clinical and molecular response, demonstrating in vivo activity of this agent against PDGFRA.3, 4 We describe a third patient's long-term remission with only 100 mg of imatinib. The low dosage needed might be not surprising as also the protein product of the fusion gene FIP1L1/PDGFRA is inhibited by low concentrations of imatinib representing a 2-log higher sensitivity to inhibition compared to BCR/ABL. Therefore, it can be speculated that PDGFRA is susceptible to lower amounts of the drug.5 It is also worth noting that the patient presented with a 4-week history of severe bleeding although the thrombocytes tended to be nearly normal and he had no irregularities in the coagulation system. Selheim et al.7 described that human platelets have functionally active PDGFRA and that the PDGFR inhibits thrombin–, thrombin receptor agonist peptide SFLLRN- and collagen-induced platelet aggregation. Therefore, the overactivation of PDGFRA by translocation to BCR might explain the bleeding problems of the patient and their disappearance during imatinib-induced PDGFRA blocking. We conclude that these rare forms of diseases have an obvious clinical and biological implication for the long-term treatment with imatinib.
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Neumann, F., Poelitz, A., Hildebrandt, B. et al. The tyrosine-kinase inhibitor imatinib induces long-term remission in a patient with chronic myelogenous leukemia with translocation t(4;22). Leukemia 21, 836–837 (2007) doi:10.1038/sj.leu.2404557
Cancer Genetics (2015)