Acute leukemia with cytogenetically cryptic FGFR1 rearrangement and lineage switch during therapy: A case report and literature review.

OBJECTIVES: Myeloid/lymphoid neoplasms with FGFR1 rearrangement are a rare group of neoplasms that share features of eosinophilia and lineage promiscuity. First, we described a challenging case of acute leukemia with lineage switch and cytogenetically cryptic FGFR1. Second, we aimed to systemically review this phenomenon in published literature. METHODS: A 68-year-old man with a history of chemotherapy exposure presented with acute leukemia of myeloid lineage without eosinophilia or 8p11 abnormalities on karyotyping. Over a refractory and relapsing course, the blast phenotype shifted to B lymphoid. RESULTS: Fluorescence in situ hybridization identified a cytogenetically cryptic FGFR1 rearrangement, likely a paracentric inversion. We identified 26 published cases of FGFR1-rearranged acute leukemia with ambiguous, mixed, or switching lineage. Although there was variability in the partner gene, anatomical location of different phenotypes, and timing of lineage switch, the prognosis was consistently poor in the absence of novel therapy. CONCLUSIONS: Ours is the only reported case of FGFR1-rearranged neoplasms with a disease sequence of acute myeloid leukemia transforming to B-cell acute lymphoblastic leukemia and 1 of only 3 reported cases with cytogenetically cryptic FGFR1 rearrangement. Fluorescence in situ hybridization testing for FGFR1 rearrangement should be a standard investigation in leukemia of mixed or switching lineage.

Successful treatment of Epstein-Barr virus-associated primary central nervous system lymphoma due to post-transplantation lymphoproliferative disorder, with ibrutinib and third-party Epstein-Barr virus-specific T cells.

Primary central nervous system lymphoma (PCNSL) occurring following organ transplantation (post-transplantation lymphoproliferative disorder [PTLD]) is a highly aggressive non-Hodgkin lymphoma. It is typically treated with high-dose methotrexate-based regimens. Outcomes are dismal and clinical trials are lacking. It is almost always Epstein-Barr virus (EBV) associated. Two patients (CA1-2) presented with EBV-associated PCNSL after renal transplant. CA1 was on hemodialysis and had prior disseminated cryptococcus and pseudomonas bronchiectasis, precluding treatment with methotrexate. CA2 was refractory to methotrexate. Both were treated off-label with the first-generation Bruton's tyrosine kinase inhibitor ibrutinib for 12 months. Cerebrospinal fluid penetration at therapeutic levels was confirmed in CA1 despite hemodialysis. Both patients entered remission by 2 months. Sequencing confirmed absence of genetic aberrations in human leukocyte antigen (HLA) class I/II and antigen-presentation/processing genes, indicating retention of the ability to present EBV-antigens. Between Weeks 10 and 13, they received third-party EBV-specific T cells for consolidation with no adverse effects. They remain in remission ≥34 months since therapy began. The strength of these findings led to an ongoing phase I study (ACTRN12618001541291).

Point-of-care derived INR does not reliably detect significant coagulopathy following Australian snakebite.

INTRODUCTION: Point-of-care international normalised ratio (INR) has been suggested as a way to screen for venom-induced consumption coagulopathy following snakebite, but has not been validated for this. This study aimed to assess the diagnostic reliability of point-of-care INR for venom-induced consumption coagulopathy. METHODS: This was a prospective study of snakebite patients recruited between January 2011 and May 2012 where a point-of-care INR was done and compared to an INR done on a laboratory coagulation analyser, as part of a quality assurance exercise. Data was obtained for each patient, including demographics, information on the snake bite, the point-of-care INR results and any laboratory derived coagulation studies. Snake identification was confirmed by expert identification or venom specific enzyme immunoassay. RESULTS: There were 15 patients with a median age of 29 years (2 to 68 y) and 13 were male. Four of the 7 patients with venom-induced consumption coagulopathy had an abnormal point-of-care INR (3 false negatives) and 1 of the 7 non-envenomed patients had an abnormal point-of-care INR (1 false positive). The patient with a falsely elevated point-of-care INR was given antivenom prior to formal coagulation studies. The point-of-care INR was also negative in the patient with an anticoagulant coagulopathy. CONCLUSIONS: The study shows that point-of-care INR testing devices should not be used in suspected snakebite cases in Australia to diagnose venom-induced consumption coagulopathy.

A novel mutation of the erythropoietin receptor gene associated with primary familial and congenital polycythaemia.

Primary familial and congenital polycythaemia (PFCP) is a rare form of inherited erythrocytosis caused by heterozygous mutations in the erythropoietin receptor gene (EPOR). We present a novel mutation in the EPOR in a 15-year-old male who was referred to our clinic for investigation of a persistently elevated haemoglobin level. A significant family history of unexplained erythrocytosis spanning four generations of the patient's family was established. The family history was also significant for an apparent increased rate of cerebrovascular disease in individuals with erythrocytosis. The mutation detected in our patient resides in exon 8 of EPOR, similar to all other EPOR mutations responsible for PFCP. These mutations result in truncation of the cytoplasmic domain of the receptor and impair down-regulation of signalling via the erythropoietin receptor (EPOR). Clinical manifestations in published cases have varied widely and there is a paucity of firm recommendations regarding the management of affected patients. Given the strong family history of complications attributable to erythrocytosis we have recommended venesection with a haematocrit target of ≤0.45 for our patient.