LAUSR

The PCM1–JAK2 fusion gene resulting from a t(8;9)(p22; p24) translocation is a rare genomic abnormality reported in around 40 patients to date. This fusion gene is observed in both myeloid and lymphoid malignancies. The WHO classification of tumours of haematopoietic and lymphoid tissues classifies neoplasms with PCM1–JAK2 as a separate ‘provisional’ entity among the myeloid/lymphoid neoplasms with eosinophilia. Haematological features may be characteristic of myeloproliferative or myelodysplastic/myeloproliferative neoplasms, often with eosinophilia. Very rarely acute myeloid or lymphoblastic transformation can occur. Ruxolitinib, a JAK2 inhibitor, has been proven to be effective in some patients with myeloid neoplasms carrying the PCM1–JAK2 fusion gene. Here we describe the outcome of a patient who presented with a B-cell acute lymphoblastic leukaemia (B-ALL) and was treated with ruxolitinib after becoming refractory to firstand second-line therapy including blinatumomab. In September 2018, a 77-year-old woman was referred to the haematology department. She presented with a history of fatigue, night sweats and weight loss since several months. There was no adenopathy or hepato-splenomegaly. Diagnostic laboratory studies showed a white blood cell count of 32 6 9 10/l, no eosinophils and 58% blasts, mild anaemia (haemoglobin of 115 g/l) and low platelet count (28 9 10/ l). The bone marrow (BM) was hypercellular with 87% blasts and suppression of all three cell lineages (Fig 1A). Immunophenotyping of the malignant cells was diagnostic for pre-B-ALL according to European Group for the Immunological Characterization of Leukemias (EGIL) criteria. The B-lymphoblasts had the following phenotype: cyCD3 /CD3 /CD7 /CD10/CD13 /CD15 CD19/ CD20 /CD22/CD24/CD34/CD38 /CD45/CD58/ CD66c/cyCD79a/CD81/CD117 /CD123 /sIgM /cyIgM/ cyMPO /NG2 /TdT. BM trephine evaluation confirmed the findings in the BM aspirate. No fibrosis was present. Using HemaVision 28Q (DNA Diagnostic, Risskov, Denmark), the BCR–ABL1 fusion gene or other recurrent genetic abnormalities were not detected and a final diagnosis of B-lymphoblastic leukaemia/lymphoma, not otherwise specified, was made according to the 2016 WHO criteria. Cytogenetic analysis using R-banding demonstrated the following karyotype: 46,XX,t(8;9)(p22;p24)[1]/46,sl,der(8;9)(q10;q10),inc [5]/46,X,t(X;4)(p1?1;q13)[4]/46,XX[10] (Fig 1B). Fluorescence in situ hybridization study of the loci PCM1 (BAC RP11-383B10) and JAK2 (BACs RP11-140C18 and RP11635N21) showed the involvement of PCM1/8p22 and JAK2/ 9p24 in the translocation t(8;9) (Fig 1C). A nested polymerase chain reaction (PCR) identified the PCM1–JAK2 fusion transcript with a breakpoint located between PCM1 exon 36 and JAK2 exon 9. A quantitative reverse transcription (RT-)PCR was developed to quantify the PCM1–JAK2 fusion gene in future BM samples (Fig 2). A conventional ALL induction therapy was started and consisted of vincristine on days 1, 8, 15 and 22, daunorubicin on days 8 and 15, daily prednisone, and intrathecal methotrexate and dexamethasone on days 1 and 8. After induction therapy the BM aspirate showed only 0 21% residual malignant blasts by flow cytometry. The first consolidation was started with cytarabine, etoposide and 6thioguanine. The following second consolidation consisted of high-dose methotrexate, vincristine, 6-thioguanine and prednisone. Microscopic and flow cytometric evaluation of the BM after consolidation therapy demonstrated complete remission. However, a PCM1–JAK2/ABL1 ratio of 1 22%, and 20% aberrant metaphases with t(8;9)(p22;p24) were still found. Interphase therapy with vincristine, high-dose methotrexate, prednisone and thioguanine was started. A repeat BM aspirate 10 months from diagnosis confirmed morphological and immunophenotypic remission, although cytogenetic analysis and quantitative RT-PCR continued to show residual disease (Fig 2). Chemotherapy was replaced by immunotherapy with the anti-CD19 BiTE antibody blinatumomab (Fig 2). A followup BM after three months demonstrated complete morphological and immunophenotypic remission, but a further increase in fusion transcripts to a PCM1–JAK2/ABL1 ratio of 23 28%, and in aberrant metaphases harbouring the t(8;9) to 50% (Fig 2). In an attempt to eradicate residual disease, the patient was treated with ruxolitinib 10 mg bid after obtaining informed consent. This therapy was well tolerated and consecutive BM assessments were performed at 2, 4, 7, 9 and 12 months after initiation of ruxolitinib. All BM aspirates confirmed morphological and immunophenotypic remission. Over time fusion transcripts have slowly decreased to a PCM1–JAK2/ABL1 ratio of 3 22%, while cytogenetic analysis showed a decrease of aberrant metaphases with the t(8;9) from 50% to 5% (Fig 2). On the other hand ruxolitinib, or the underlying disorder, caused a persistent neutropenia (<0 7 9 10/l Correspondence