Imatinib induces rapid and durable complete hematologic and molecular remissions in FIP1L1-PDGFRA-positive chronic eosinophilic leukemia. Primary resistance has not yet been reported and secondary resistance seems to be rather rare. In a German-wide registry, we currently oversee the clinical course of 57 patients who have been treated with imatinib for a median of 36 months (range 1–82) at doses ranging between 100 mg every other day and 400 mg/day. Recently, we identified the first case of secondary resistance in a 50-year-old male patient, 7 months after imatinib 400 mg/day was started. The patient presented in hematologic relapse with leukocytosis (37 × 109/l, 71% eosinophils), anemia (Hb 9.8 g/dl), thrombocytopenia (37 × 109/l) and splenomegaly. The karyotype was normal, but reverse transcription-PCR with primers covering the juxtamembrane and tyrosine kinase domains of platelet-derived growth factor receptor A (PDGFRA) (exons 11–18) and subsequent sequence analysis identified a C>T change that predicts a T674I mutation in the ATP-binding region of PDGFRA (PDGFRAT674I).
Including the case presented here, seven cases of secondary resistance to imatinib have now been reported in FIP1L1-PDGFRA-positive chronic eosinophilic leukemia.1, 2, 3, 4, 5, 6, 7 We analyzed the clinical and molecular characteristics from four patients with a T674I mutation,1, 3, 5, 7 one patient with a D842V mutation6 and one patient with a T674I mutation, followed by a D842V mutation (Table 1).4 All patients were male, the median age at diagnosis was 39 years (range 25–67). Imatinib had been administered at doses of 100 mg every other day (1/5), 100 mg/day (2/5) or 400 mg/day (2/5); in two cases, the dose of imatinib had been not reported. The median time to imatinib resistance was 5 months (range 2–9). Marrow blasts were increased in five of seven patients, suggesting accelerated/blast phase. Four patients died, three of them within 5 months after diagnosis of secondary resistance to imatinib (time interval was not reported in the fourth patient).3, 4, 6, 7
The cases above indicate that secondary resistance is rare, but it is also notable that only two different mutations (T674I, D842V) have yet been identified. A possible explanation was recently reported by von Bubnoff et al.,8 who demonstrated that the PDGFR kinase domain only contains a limited number of residues, where exchanges critically interfere with binding of and inhibition by available PDGFR kinase inhibitors at achievable concentrations. Although the PDGFRAT674I mutation corresponds to the ABLT315I mutation in BCR-ABL-positive CML, in vitro studies suggested different sensitivity to second-generation tyrosine kinase inhibitors. Although ABLT315I is resistant to nilotinib and dasatinib, but sensitive to ponatinib, PDGFRAT674I is sensitive to nilotinib, midostaurin (PKC412), sunitinib and also sorafenib, at nanomolecular concentrations. The PDGFRAD842V mutation corresponds to the KITD816V mutation, frequently identified in systemic mastocytosis and rarely in gastrointestinal stroma tumors, which confers full resistance to nilotinib and dasatinib.
On the basis of favourable in vitro sensitivity of PDGFRAT674I towards second-generation tyrosine kinase inhibitors, we treated our patient with nilotinib 400 mg twice a day. However, no response was observed within 4 weeks of treatment and in fact, eosinophil numbers increased. We therefore switched to sorafenib 400 mg twice a day. Similar to nilotinib, there were no signs of response within 2 months of treatment (stable disease). Of interest, a second patient treated with sorafenib only showed a short-lived clinical response (3 months) due to the rapid emergence of a D842V mutant.4 Meanwhile, a brother of our patient was identified as a fully HLA-identical sibling stem cell donor. Allogeneic stem cell transplantation was performed 5 months after first detection of imatinib-resistance. The conditioning regimen was a modified FLAMSA-RIC protocol, consisting of fludarabine 30 mg/m2, high-dose cytarabine 2 g/m2, and amsacrine 100 mg/m2 from days −14 to −11, busulvex 3.2 mg from days −7 to −5, and anti-thymocyte globin (ATG) total 30 mg/kg fractionated from day −4 to −1. Posttransplant, he developed steroid-responsive grade II graft-versus-host-disease of the skin and subsequently limited chronic graft-versus-host-disease. Complete hematopoietic chimerism was achieved 4 months after transplant. At the time of reporting (+392 days), the patient is well and in complete hematologic and molecular remission.
Nilotinib, sorafenib and midostaurin demonstrated excellent activity at nanomolar concentrations towards PDGFRAT674I in cell lines, transfected cells and in mouse models. The lack of clinical activity of two of these drugs in a patient with PDGFRAT674I raises concerns regarding (i) additional molecular abnormalities conferring resistance independent of the underlying point mutation or (ii) other unknown factors that are contributing to potentially misleading results from in vitro studies. In this respect, it should be noted that the situation is similar to the KITD816V mutation in patients with systemic mastocytosis. Nilotinib, dasatinib and midostaurin have been shown to suppress the malignant clone in cells and mice at therapeutic concentrations. However, only midostaurin, but not nilotinib or dasatinib, have yet shown adequate clinical activity. The activity regarding hematological and molecular remissions of Janus kinase inhibitors in JAK2V617F positive myeloproliferative neoplasms is also clearly inferior to what we would have expected from in vitro experiments.
Treatment with imatinib is associated with an excellent prognosis in FIP1L1-PDGFRA-positive chronic eosinophilic leukemia in first chronic phase. Secondary resistance is rather rare, but occurs predominantly within the first year of diagnosis. Resistance is associated with PDGFRA kinase domain mutations that are sensitive in vitro to second-generation tyrosine kinase inhibitors, but these compounds seem to have limited activity in clinical practice. Because of an aggressive clinical course and lack of alternative conventional treatment options, allogeneic stem cell transplantation should be performed in eligible patients, as it might be the only effective and curative treatment option.
This work was supported by the ‘Deutsche José Carreras Leukämie-Stiftung e.V.’ (AR R09/29f), Germany.