Long‐term therapy‐free remission in a patient with platelet‐derived growth factor receptor beta‐rearranged myeloproliferative neoplasm
Authors: marco cerrano, elena crisà, enrico gottardi, chiara aguzzi, mario boccadoro, dario ferrero
Journal: American Journal of Hematology (2016)

To the Editor: Myeloid neoplasms harboring a translocation involving platelet-derived growth factor receptor beta (PDGFRB) are rare hematologic malignancies which present with leukocytosis, often with monocytosis and eosinophilia, usually accompanied by anemia and thrombocytopenia. More than 20 PDGFRB fusion partners have been identified, the most frequent being ETV6, and the natural history of this neoplasm has been radically changed by the introduction of imatinib, which can lead to complete remission in the vast majority of patients 1. Here we present the case of a 59-year-old man diagnosed with PDGFRB-ETV6 myeloproliferative neoplasm who achieved a long-term therapy-free remission after obtaining complete response with imatinib. In June 2002 he was referred to our clinic because of an incidental finding of neutrophilic leukocytosis (leukocytes 29,900/µL, neutrophils 54%) and mild thrombocytopenia (platelets 106,000/µL). Peripheral blood smear showed the presence of immature precursors (mielocytes 1.6% and metamyelocytes 14.5%), with a 3.3% of eosinophils and a 1.4% of monocytes. Physical examination revealed mild splenomegaly. Morphological examination demonstrated a hypercellular bone marrow with mild myeloid hyperplasia, mild megacaryocyte dysplasia, and no excess of blasts. BCR-ABL1 transcript was absent. Cytogenetic evaluation showed a t(5;12)(q33;p13) and the Real Time-Polymerase Chain Reaction (RT-PCR) confirmed the presence of PDGFRB-ETV6 fusion transcript. The patient was started on imatinib 400 mg/die in December 2002 and achieved hematologic remission in one month. Complete cytogenetic response was obtained in July 2003 and molecular remission was demonstrated by both RT- and nested-PCR in October 2004. In January 2011, in consideration of the confirmed long lasting cytogenetic and molecular remission, imatinib dosage was reduced to 100 mg/die and in April 2012 it was definitely stopped due to strong patient's desire. After discontinuing imatinib, the patient was closely monitored and the PDGFRB-ETV6 fusion transcript remained negative. In April 2016, 4 years after stopping his treatment, our patient is doing well, in complete hematologic, cytogenetic, and molecular remission. Recently, two studies tried to identify genetic variants that might contribute to disease pathogenesis, phenotype, and clinical outcome in PDGFR-rearranged neoplasms, using next generation sequencing. Genetic variants in myeloid disease-relevant genes could be found only in 2 out of 10 patients with FIP1L1-PDGFRA and in none of the 3 ones with PDGFRB translocations 2, 3, confirming that PDGFR translocations are the driver mutations in these neoplasms. This finding could explain the excellent therapeutic results with imatinib and supports the feasibility of treatment discontinuation for patients in persistent molecular remission. Nowadays therapy discontinuation has become a topic of increasing interest in chronic hematologic malignancies, since very effective treatments are available and the goal of cure might be achievable in some patients. In chronic myeloid leukemia, imatinib discontinuation for patients in persistent molecular remission has been proven to be safe and it is entering in routine clinical practice 4. In PDGFRA-rearranged neoplasms, a few studies regarding imatinib cessation are available. While in a first report by Klion et al. all the 4 patients who stopped imatinib relapsed 5, another experience demonstrated that some patients can remain off therapy without losing their response 6. Indeed, two recent studies reported that around 50% of the patients with PDGFRA translocation who achieved complete molecular remission with imatinib maintained it after stopping treatment 7, 8. Importantly, all the patients who relapsed regained a complete response after restarting imatinib 5, 7, 8. For PDGFRB-related diseases data are lacking. In a recent report by Cheah et al. 9, 3 among 26 patients with PDGFRB-rearranged neoplasms discontinued imatinib: two of them were non-responders or intolerant and the other one received allogeneic stem cell transplantation. Excluding the aforementioned post-transplant case, to our knowledge this is the first report describing a patient with PDGFRB-rearranged neoplasm experiencing a long-term remission after imatinib discontinuation. Therefore, our experience suggests that imatinib cessation is feasible also in PDGFRB-rearranged neoplasms, even though more data are necessary in order to advise it in routine clinical practice. DF, MC, CA and EC treated the patient. MC collected data. MC, DF and EC wrote the paper. EG performed molecular analysis. MB supervised the research. All the authors reviewed the manuscript and approved it. Marco Cerrano,1 Elena Crisà,1 Enrico Gottardi,2 Chiara Aguzzi,1 Mario Boccadoro,1 and Dario Ferrero1* 1Hematology Division, Università Degli Studi Di Torino, Turin, Italy; 2AOU San Luigi Gonzaga, SCDU Internal Medicine II, Orbassano, Italy