Nefeli Giannakopoulou

An Adult Patient with Systemic Mastocytosis and B-Acute Lymphoblastic Leukemia

Mastocytosis is a myeloproliferative neoplasm characterized by clonal expansion of abnormal mast cells, ranging from the cutaneous forms of the disease to mast cell leukemia. In a significant proportion of patients, systemic mastocytosis (SM) coexists with another hematologic malignancy, termed systemic mastocytosis with an associated hematologic nonmast cell lineage disorder (SM-AHNMD). Despite the pronounced predominance of concomitant myeloid neoplasms, the much more unusual coexistence of lymphoproliferative diseases has also been reported. Imatinib mesylate (IM) has a role in the treatment of SM in the absence of the KITD816V mutation. In the setting of SM-AHNMD, eradicating the nonmast cell malignant clone greatly affects prognosis. We report a case of an adult patient with SM associated with B-lineage acute lymphoblastic leukemia (B-ALL). Three cases of concurrent adult ALL and mastocytosis have been reported in the literature, one concerning SM and two concerning cutaneous mastocytosis (CM), as well as six cases of concomitant CM and ALL in children.

Prognostic significance of signal transducer and activator of transcription 5 and 5b expression in Epstein–Barr virus-positive patients with chronic lymphocytic leukemia

Signal transducer and activator of transcription (STAT) proteins have been intensively studied in hematologic malignancies, and the efficacy of agents against STATs in lymphomas is already under research. We investigated the expression of total STAT5 and STAT5b in peripheral blood samples of patients with chronic lymphocytic leukemia (CLL) in correlation with the presence of Epstein–Barr Virus (EBV) and its major oncoprotein (latent membrane protein 1, LMP1). The EBV load was measured in the peripheral blood by real‐time PCR for the BXLF1 gene and the levels of LMP1 by PCR and ELISA. Western blotting was performed for total STAT5 and STAT5b in protein extracts. STAT5b was only expressed in patients (not in healthy subjects) and STAT5 but particularly STAT5b expression was correlated with the presence of the virus (77.3% vs. 51.2%, P = 0.006 for STAT5b) and to the expression of LMP1 (58.3% vs. 21.6%, P = 0.011 for STAT5b). Moreover, the expression of STAT5b and the presence of EBV and LMP1 were strongly negatively correlated with the overall survival of the patients (log‐rank test P = 0.011, 0.015, 0.006, respectively). Double positive (for EBV and STAT5b) patients had the lowest overall survival (log‐rank test P = 0.013). This is the first report of a survival disadvantage of EBV+ patients with CLL, and the first time that STAT5b expression is correlated with survival. The correlation of STAT5 expression with the presence of the virus, along with our survival correlations defines a subgroup of patients with CLL that may benefit from anti‐STAT agents.

An Adult Patient with Early Pre-B Acute Lymphoblastic Leukemia with t(12;17)(p13;q21)/ZNF384-TAF15

This is a case report of a 46-year-old man diagnosed with early pre-B acute lymphoblastic leukemia (ALL), bearing the translocation t(12;17)(p13;q21) as the sole chromosomal abnormality. This is a rare chromosomal abnormality that has been reported in approximately 25 cases worldwide. FISH analysis revealed a rearrangement of ZNF384 (12p13) and TAF15 (17q12) genes, which is usually associated with a pre-B ALL phenotype with co-expression of the myeloid markers CD13 and/or CD33. ZNF384 encodes a zinc finger protein, which acts as a transcription factor, regulating the expression of several matrix metalloproteinases and TAF15 belongs to the FET (FUS, EWS, and TAF15) family, consisting of RNA and DNA-binding proteins. Unlike most of the cases where CD10 expression was absent or weak, in our case CD10 was highly expressed. The prognostic significance of ZNF384/TAF15 fusion is not very clear since several reports support a generally good prognosis, while others support a poor clinical outcome. Our patient was treated with the German multicenter ALL (GMALL) protocol for B-ALL, but experienced a fulminant gram-negative sepsis and eventually died during induction therapy.

Hypereosinophilic Syndrome as a Rare Cause of Reversible Biventricular Heart Failure

Hypereosinophilic syndrome is a rare entity that can develop secondary to overproduction of eosinophilopoietic cytokines or as idiopathic disease. Cardiac involvement, which occurs often, is divided into 3 stages, the latter of which is nonreversible and leads to severe heart failure. Early detection and treatment of the syndrome is essential. For this reason, genetic testing for the FIP1L1-PDGFRA fusion gene has recently been added to the diagnostic algorithm. Patients with this mutation are at increased risk for the development of cardiac involvement and typically respond to treatment with the tyrosine kinase inhibitor imatinib mesylate.

Staphylococcus aureus meningitis in a patient with mantle cell lymphoma under treatment with ibrutinib

Dear Editor, Spontaneous hematogenous non-surgical staphylococcal meningitis is a rare entity with high mortality. Risk factors for Staphylococcus aureus bacteremia (SAB) include age, HIV infection, hemodialysis, and intravenous drug use (IDU) [1], but the risk of meningitis among patients with SAB is <1% [2], and the only identifiable risk factor for meningitis is IDU. We present a patient with mantle cell lymphoma (MCL) under treatment with ibrutinib that developed meningitis from S. aureus. A 72-year-old man was admitted to the hospital due to confusion, headache, and low-grade fever. The patient had been diagnosed with stage IV MCL 23 months earlier. His medical history was unremarkable except for a chronic mechanical low back pain. After three lines of immunochemotherapy, he had a recurrence and was started on ibrutinib that he had been taking for 5 months till the day of admission. Fifteen days earlier, he had a low back pain exacerbation and was treated with a series of non-steroidal anti-inflammatory drug intramuscular injections. Upon admission, nuchal rigidity was detected. The lumbar puncture and cerebrospinal fluid (CSF) analysis revealed pleocytosis (360/ mm; 50% neutrophils), low glucose, and high total protein levels. Immunophenotypic analysis detected no lymphoma cells in the CSF. The patient had grade 3 neutropenia and thrombocytopenia and grade 4 acute kidney injury. The serum C-reactive protein levels were markedly high. He tested negative for HIV. He was started on vancomycin, ceftriaxone, and ampicillin, but he soon developed septic shock and disseminated intravascular coagulation. Both blood and CSF cultures were positive for a methicillin-susceptible S. aureus (MSSA). Evaluation with the CT scans and a heart ultrasound did not reveal any other loci of infection. The patient was intubated and transferred to the intensive care unit where he died 2 days later. In large series, S. aureus has been identified as the cause of community-acquired meningitis in 1–6% of the cases [3–5]. In a series of 12,480 SAB cases, 81 cases (0.6%) of nonsurgical, community-acquired, bacteremic S. aureusmeningitis were identified; 61% of them had an unknown primary focus. Patients with neutropenia were excluded from the study [2]. Several molecular mediators for the pathogenesis of MCL have been identified. Bruton’s tyrosine kinase (BTK) is essential for B cell receptor (BCR) signaling. Aberrant BCR signaling is involved in the pathogenesis of MCL, while loss-offunction mutations of BTK result in X-linked agammaglobulinemia (XLA) [6], a non-lethal inherited immune deficiency, characterized by recurrent viral and bacterial infections from encapsulated bacteria and S. aureus [7]. Pyogenic central nervous system infections have also been reported [8]. The BTK inhibitor ibrutinib blocks BCR signaling and has been approved for the treatment of MCL. About one fourth of the patients treated with ibrutinib experience a serious infection and one case of non-fatal SAB was reported at the approval study [9], but no cases of meningitis have been reported. Ibrutinib use may mimic XLA, potentially placing patients in danger of severe bacterial infections. This case underscores the need for close monitoring of patients treated with BTK * Panagiotis T. Diamantopoulos pandiamantopoulos@gmail.com