Systematic use of fluorescence in-situ hybridisation and clinicopathological features in the screening of PDGFRB rearrangements of patients with myeloid/lymphoid neoplasms.

AIMS: Rearrangement of the platelet-derived growth factor receptor B (PDGFRB) gene defines a unique group of myeloid/lymphoid neoplasms with frequent eosinophilia and high sensitivity to tyrosine kinase inhibitors. This genetic abnormality is also rarely reported in Philadelphia-like B-cell acute lymphoblastic leukaemia/lymphoma (B-ALL). PDGFRB rearrangement was initially thought to only occur in cases with 5q31-33 rearrangement as determined with conventional cytogenetics; however, there are reported cases with cryptic rearrangements. We aim to develop a broader strategy for screening of PDGFRB rearrangements of patients with myeloid/lymphoid neoplasms. METHODS AND RESULTS: We performed fluorescence in-situ hybridisation (FISH) for PDGFRB rearrangement in 197 patients, including 70 with B-ALL, 10 with myeloid neoplasms with 5q31-33 rearrangements, and 117 with eosinophilia (≥0.5 × 109 /l in peripheral blood or ≥5% in bone marrow), and identified PDGFRB rearrangement in four of 197 (2.0%) cases. In an attempt to identify clinicopathological and genetic features that may have a stronger association with PDGFRB rearrangement, we analysed 13 patients with confirmed PDGFRB rearrangements, including 10 with myeloid neoplasms and three with B-ALL. Among the 10 patients with myeloid neoplasms, eosinophilia was present in eight, monocytosis in two, 5q31-33 rearrangement in seven, and abnormal bone marrow morphology in all. All patients with myeloid neoplasms showed an excellent response to imatinib, including a patient in blast crisis. The three B-ALL patients presented de novo, showed no eosinophilia, had a complex karyotype including 5q31-33 rearrangement, and had clinically aggressive courses with ultimate patient demise. CONCLUSIONS: These findings suggest that a higher yield for the identification of PDGFRB rearrangement may result from an index of suspicion in patients with eosinophilia, monocytosis, bone marrow features of a myeloid neoplasm, and 5q31-33 rearrangement, and patients with Philadelphia-like B-ALL.

Imatinib in myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRB in chronic or blast phase.

We evaluated clinical characteristics and outcome on imatinib of 22 patients with myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRB. Median age was 49 years (range 20-80), 91% were male. Fifteen different PDGFRB fusion genes were identified. Eosinophilia was absent in 4/19 (21%) cases and only 11/19 (58%) cases had eosinophils ≥1.5×109/L. On imatinib, 17/17 (100%) patients in chronic phase achieved complete hematologic remission after median 2 months (range 0-13)​. Complete cytogenetic remission and/or complete molecular remission by RT-PCR were achieved in 12/13 (92%) and 12/14 patients (86%) after median 10 (range 3-34) and 19 months (range 7-110), respectively. In patients with blast phase (myeloid, n = 2; lymphoid, n = 3), treatment included combinations of imatinib (n = 5), intensive chemotherapy (n = 3), and/or allogeneic stem cell transplantation (n = 3). All 3 transplanted patients (complex karyotype, n = 2) experienced early relapse. Initially, patients were treated with imatinib 400 mg/day (n = 15) or 100 mg/day (n = 7), the dose was reduced from 400 mg/day to 100 mg/day during follow-up in 9 patients. After a median treatment of 71 months (range 1-135), the 5-year survival rate was 83%; 4/22 (18%) patients died (chronic phase; n = 2; blast phase, n = 2) due to progression (n = 3) or comorbidity while in remission (n = 1). Of note, 3/4 patients had a complex karyotype. In summary, the most important characteristics of myeloid/lymphoid neoplasms with rearrangement of PDGFRB include (a) male predominance, (b) frequent lack of hypereosinophilia,

Myeloid neoplasm with a novel cryptic PDGFRB rearrangement detected by next-generation sequencing.

Rearrangements of PDGFRB are defining cytogenetic abnormalities seen in "Myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRB" and are generally evident by common cytogenetic methods. Here we present an unique case in which karyotyping and fluorescence in situ hybridization (FISH) analysis were negative, and the PDGFRB rearrangement was detected by next-generation sequencing (NGS) analysis. The patient presented with approximately one-year history of leukocytosis including neutrophilia, eosinophilia, basophilia and granulocytic left shift. Bone marrow biopsy revealed a hypercellular marrow with panmyelosis, eosinophilia and mast cell hyperplasia. Blasts were not increased. Ancillary studies revealed a normal karyotype and absence of BCR-ABL1 fusion gene. NGS identified AFAP1L1-PDGFRB fusion, which was confirmed by polymerase chain reaction amplification followed by direct Sanger sequencing. The patient was treated with imatinib and showed normalization of peripheral blood leukocytosis, which lasted for at least six months. This case highlights that cytogenetics/FISH study alone may be insufficient to detect all PDGFRB rearrangement, which is critical for the patient's management. We suggest that molecular analysis capable of detecting fusion genes should be performed in all similar cases.

Myeloid/Lymphoid Neoplasm with PDGFRB Rearrangement with t (5;10) (q33;q22) Harboring a Novel Breakpoint of the CCDC6-PDGFRB Fusion Gene.

Myeloid/lymphoid neoplasms with PDGFRB rearrangement are a distinct type of myeloid neoplasms that occur in association with rearrangement of PDGFRB at 5q32. The hematological features most often show prominent eosinophilia. We herein report a patient with myeloid/lymphoid neoplasms with PDGFRB rearrangement with t (5;10) (q33;q22) who showed atypical chronic myeloid leukemia-like clinical features without eosinophilia and achieved an optimal response to imatinib. A sequence analysis showed a CCDC6-PDGFRB fusion gene with a new break point in the PDGFRB gene. This is the sixth case of myeloid/lymphoid neoplasm with PDGFRB rearrangement harboring a CCDC6-PDGFRB fusion gene, and it has a new breakpoint in the PDGFRB fusion gene.

[Pediatric myeloid neoplasms associated with eosinophilia and platelet-derived growth factor receptor beta gene rearrangement: a case report and literature review].

Objective: To investigate the clinical features and therapeutic strategies of childhood myeloid neoplasms associated with eosinophilia and platelet-derived growth factor receptor beta (PDGFRB) gene rearrangement. Methods: Clinical data of myeloid neoplasms associated with eosinophilia and t (1;5) (q21;q33) chromosomal translocation of PDGFRB gene rearrangement in a child hospitalized in Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences on May 2015 was collected and analyzed. Using'eosinophilia child'and'PDGFRB'as keywords, the relevant reports in literature were searched from China National Knowledge Infrastructure (CNKI), Wanfang Data Knowledge Service Platform, and Biomedical Literature Database (PubMed) until April 2017. Results: The patient was a boy, 19 months old, who began to get sick at six months after birth, with the main clinical manifestations of high fever, diarrhea, epistaxis and hepatosplenomegaly. Peripheral blood smear showed a significant elevation in white blood cells (127×10(9)/L) and eosinophils(20.32×10(9)/L). Bone marrow examination showed hyperplastic marrow, increased proportion of granulocytes, apparent visible eosinophils and decreased megakaryocytes. Chromosome karyotype detection revealed t (1; 5) (q21; q33) translocation. Fluorescence in situ hybridization (FISH) examination uncovered that PDGFRB gene rearrangement was positive. The final diagnosis was myeloid neoplasms with eosinophilia and PDGFRB gene rearrangement. After treatment with oral imatinib 100 mg, once a day for 2 months, complete hematologic remission, complete cytogenetic and molecular remission were all achieved. The relevant literature was reviewed, no Chinese cases had been reported, 6 reports in English literature have complete clinical data. Four cases had t (1; 5) translocation. Four pediatric patients treated with imatinib achieved complete remission. Conclusion: Myeloid neoplasms associated with eosinophilia and PDGFRB gene rearrangement is extremely rare in children. Imatinib treatment can make these patients quickly achieve complete hematologic remission, complete cytogenetic and molecular remission. Imatinib should be recommended as the first line treatment of these patients.

Multiple MYO18A-PDGFRB fusion transcripts in a myeloproliferative neoplasm patient with t(5;17)(q32;q11).

BACKGROUND: Myeloproliferative neoplasms (MPNs), typically defined by myeloid proliferation and eosinophilia, and are only rarely caused by platelet-derived growth factor receptor beta (PDGFRB) gene rearrangements. CASE PRESENTATION: Here, we report a unique case of MPN that is negative for eosinophilia and characterized by a novel PDGFRB rearrangement. After cytogenetic analysis revealed a karyotype of t(5;17) (q32;q11), we used fluorescence in situ hybridization to specifically identify the PDGFRB gene at 5q31-q33 as the gene that had been translocated. Subsequently, RNA sequencing identified a new MYO18A-PDGFRB gene fusion. This fusion presented a previously undescribed breakpoint composed of exon 37 of MYO18A and exon 13 of PDGFRB. Furthermore, both RT-PCR and Bi-directional Sanger sequencing confirmed this out-of-frame fusion. Interestingly, we simultaneously identified the presence of another three PDGFRB transcripts, all of which were in-frame fusions. After treating the patient with imatinib, the t(5;17) translocation was no longer detected by conventional cytogenetics or by FISH, and at the time of the last follow-up, the patient had been in complete remission for 26 months. CONCLUSION: We prove that MYO18A-PDGFRB fusions are recurrent genetic aberrations involved in MPNs, and identify multiple fusion transcripts with novel breakpoints.