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  • Evidence of a variant induction of apoptosis

    2019-05-15

    Evidence of a variant induction of apoptosis to vorinostat in different DLBCL cell lines according to HAT mutational status implies that defects in CREBBP/EP300 could potentially explain the heterogeneous observations in clinical trials of vorinostat in NHL. These findings, however, need to be confirmed in future clinical studies. The efficacy of HDACi in HAT-mutation stratified DLBCL may be further optimized by testing the numerous different HDACi considering their different target specificities.
    Acknowledgments
    Case report During a routine clinical evaluation he reported fevers and was subsequently admitted with neutropenic fever and hypoxia presumed to be secondary to Pneumocystis carinii pneumonia. His blood work on admission was significant for a white blood cell count of 1.2×109/L, absolute neutrophil count of 0.6×109/L, leukotriene receptor antagonist of 8.2g/dL, and a platelet count of 37×1012/L. He was empirically treated with broad-spectrum antibiotic, antiviral and antifungal therapy. Extensive workup for an infectious cause of fevers which included adenovirus, parvovirus B19, human herpes virus -6, HIV, histoplasma, Cryptococci, aspergillus, respiratory syncytial virus, influenza and legionella was all non-revealing. His hypoxia improved after several days; however he continued to remain febrile and pancytopenic despite multiple transfusions. Given his unexplained cytopenias 30 days after completion of chemotherapy even with subcutaneous granulocyte colony stimulating factor and worsening clinical picture, a bone marrow biopsy was performed suspecting progressive marrow involvement with CLL versus transformation versus delayed recovery from chemotherapy. The biopsy however, did not show changes compared to previous biopsy in terms of percent CLL involvement (Fig. 1). Additional studies on the marrow noted a prominent population of CD68+ macrophages (Fig. 2) with active hemophagocytosis (Fig. 3). This finding, in combination with cytopenias led to further studies which included elevated serum ferritin (13,000ng/ml), triglycerides (319mg/dl), and hypofibrinogenemia (145mg/dl) all pointing to the diagnosis of HLH. As per the HLH-2004 guidelines (which reports the use of dexamethasone, etoposide and cyclosporine for 8 weeks, with subsequent intrathecal methotrexate and stem cell transplant), patient was initially treated with cyclosporine and dexamethasone for several days with poor clinical and hematologic response.[1] The literature was reviewed again and it was felt that the patient\'s HLH could be a secondary phenomenon related to his underlying CLL and the decision was made to pursue aggressive treatment of CLL. He received one cycle of R- CHOP with continued deterioration of his clinical status over the next 3 weeks leading to acute renal failure and respiratory failure, requiring intubation. Given his poor prognosis he was transitioned to comfort care and passed away shortly thereafter.
    Discussion HLH generally affects children; however cases of older adults with this disease have also been reported. Infectious agents typically involved include Epstein Barr Virus (EBV), cytomegalovirus, parvovirus B19 and HIV. Bacteria, parasitic, and fungal pathogens have also been implicated.[2] Extensive evaluation for underlying infection was unrevealing in our patient. In previous reports lack of infection was linked to adverse outcomes. Malignancy associated HLH represents a heterogeneous group of mostly hematologic malignancies with the hemophagocytic syndrome appearing either before or during treatment. The clinical course in most of these patients is complicated by infections which can shadow the diagnosis of HLH. T-cell lymphoma associated HLH both with and without EBV positivity has been well documented.[3,4] In comparison, only a few cases of B-cell lymphoma associated HLH have been reported and are predominantly of the large B cell histologic subtype.[5] HLH in association with acute myeloid leukemia is rare and little is known of outcomes.[6]