br Discussion There is an important need

Discussion There is an important need for new treatment options for AML in elderly patients. Their frailty imposes limitations upon the aggressiveness of the treatment which can be administered [6,24]. In addition, the poor prognostic disease features often seen in this GDC0068 cost mean that refractoriness and relapse are more frequent [10]. Treatments for this population require an optimal balance of tolerability and efficacy. The main aim in most cases is to prolong survival and reduce the impact of cytopenias without undue toxicity. AZA has demonstrated efficacy in high risk MDS, reducing transfusion requirements and prolonging survival. In this setting it had proven to be well tolerated including by those more elderly [25]. Based on this experience, several groups have tested the efficacy and safety of AZA in elderly patients with AML with promising results [16,17,19,26]. Our results are in line with previous reports that AZA is efficacious in the treatment of AML regardless of the blast count. The response rates and the overall survival observed in our study are in consonance to those reported by other groups [16,17,19,26]. It is noteworthy that the rates of CR obtained with AZA are equivalent to those obtained in some published series of elderly patients treated with IC [11]. The comparison of the cohort treated with AZA first line with the comparator group treated only with IC highlights the advantages brought by the former treatment modality. It is important to note that this finding has not been confirmed in a randomized trial [20]. However, 41% of the trial patients were treated with AZA following failure with ICT whereas our comparator group never received AZA. As AZA has demonstrated efficacy as second line therapy, this could explain the difference in our findings. The significantly lower survival of the IC cohort indicates that this population benefits from less intensive treatment options which target other pathophysiological processes.
Case report A 70 year old previously healthy man was diagnosed with Binet stage B Chronic Lymphocytic Leukemia (CLL) in 2008. The diagnostic work-up showed typical morphology and immunophenotyping with a 4/5 Matutes score [1], CD38+ and ZAP70+. Cyclin D1 was negative. The immunoglobulin heavy-chain variable (IGHV) gene was unmutated (UM), molecular cytogenetic analyses showed a chromosome 14q deletion. Serum β2-microglobulin and lactate dehydrogenase (LDH) levels were within the normal laboratory range. In 2010 he developed progressive lymphadenopathy and received 6 cycles of fludarabine, cyclophosphamide and rituximab without achieving a meaningful response. He was then treated by 6 cycles of bendamustine and rituximab (BR), attaining a <50% reduction of lymphadenopathy, i.e. stable disease according to NCI criteria. In the absence of disease-related symptoms no further treatment was given until 2013, when symptomatic disease progression occurred. Retreatment with BR was stopped after 1 course, due to grade 3 cutaneous toxicity and the patient received 10 cycles of cyclophosphamide and prednisone (CP) without attaining a significant response. In January 2015, after one month from the last CP course, the patient was enrolled on a named patient program (NPP) offering access to Ibrutinib treatment in refractory CLL in our country. The patients was in good general condition, with ECOG performance status 1. The lymphocyte count was 28×109/l with a normal neutrophil count, the hemoglobin level was 12gr/dL and the platelet count was 221×109 /l. Serum ferritin was normal and a moderate increase of LDH levels was noted. Molecular cytogenetic studies documented the absence of 17p-/TP53 mutations. A computed tomography (CT) scan revealed multiple adenopathies 3–5cm in size. Ibrutinib was prescribed at a daily dose of 420mg qd. After 7 days febrile neutropenia occurred. Due to persistent fever and fatigue Ibrutinib was hold on day 16, and four days later the patient was admitted to the hospital with fever (39,0°C), splenomegaly and upper airway infection, in the absence of pneumonia on a CT scan. Despite broad-spectrum antimicrobials the clinical condition rapidly worsened and, on day 24 he became critically ill with disseminated intravascular coagulation (DIC), associated with low fibrinogen level (77mg/dL), pancytopenia (neutrophils 500×109/l, hemoglobin 8.2gr/dL and platelets 23000×109/l), an impressive rise of serum ferritin up to >100,000ng/mL and an increase of LDH serum value (1193U/L) and an increase of serum triglycerides (385mg/dL). Given the presence of 5 out of 8 diagnostic criteria (fever >38.5°C, splenomegaly, cytopenias, raised ferritin and triglyceride levels) [2], a diagnosis of HLH syndrome was made. Due to high bleeding risk bone marrow and lymph-node biopsy were not performed. Epstein Barr Virus (EBV) reactivation was documented with a viral load of 7200 copies/mL. Cytomegalovirus (CMV) DNA was absent and herpes simplex viruses (HSV) serology was negative. Dexamethasone (16mg/bid) in combination with Cyclosporine A (100mg bid) and intravenous immunoglobulin (0.4g/kg/d day 1–3) were started, but no clinical improvement was observed. Because anticytokine treatment proved effective in the setting of HLH induced by Blinatumumab in ALL [3,4] or by chimeric antigen receptor-modified T cells (CART) [4], the patient was treated by the anti-interleukin(IL)−6 receptor Tocilizumab on day 30. However, irreversible multiorgan failure developed and the patient died on day 33 with fatal bleeding. The late availability of the EBV viral load result and the deteriorated clinical conditions did not allow us to administer rituximab.