for the EBMT Working Party on Aplastic AnemiaOptimal management of aplastic anemia (AA) is not confined to immediate diagnosis, early decision making and timely initiation of major treatment strategies (immunosuppression or SCT) but also involves supportive treatment as a crucial part of patient care. Patients are threatened by complications of cytopenia. Here, we summarize current recommendations for prevention and early treatment of fungal, bacterial and viral infections, transfusion strategy and iron chelation and assess the evidence basis. In fact, many recommendations for patients with AA are not based on randomized studies in AA itself, but they are deduced from other conditions with similar severity of cytopenia. Prevention and treatment of complications like hemorrhage, bacterial and fungal infections and of secondary events like alloimmunization to blood products and iron overload have a significant impact on the prognosis of AA patients and need to be carefully observed in daily practice. More controlled studies on supportive care should be performed in this rare disease.Bone Marrow Transplantation (2013) 48, 168-173; doi:10.1038/bmt.2012.220; published online 3 December 2012Keywords: aplastic anemia; supportive treatment; infection; transfusion; hematopoietic growth factors INTRODUCTION Survival of patients with aplastic anemia (AA) after both immunosuppression and allogeneic BMT improved substantially over the past 30 years. 1 For patients who received immunosuppression, this improvement was not restricted to patients who responded to the specific treatment. 2 Remarkably, the prognosis of non-responders to initial immunosuppression also improved substantially over time. 2 This is most likely due to the impact of supportive treatment on the overall survival of patients. The individual risk of a patient is mainly determined by the neutrophil, and monocyte counts. 2-8 During the past two decades, infection-related mortality and invasive fungal infections decreased. 2 However, infections are still the major threat for patients with severe or very severe AA. In the most recently published large clinical trials in AA, the most prevalent complications and the major causes of death still were bacterial and fungal infections. [3][4][5] In the following sections, we will summarize recommendations on the major aspects of supportive treatment in AA, that is, prophylaxis and early treatment of infections, transfusion strategy and treatment of iron overload.

Objectives As new, effective therapies emerge for acute lymphoblastic leukaemia (ALL), the results of clinical trials need to relate to standard of care. Methods We used the population‐based Swedish ALL Registry to evaluate characteristics, treatment and long‐term outcome in 933 patients with diagnosis between 1997 and 2015. Results The median age was 53 years. The frequency of Philadelphia (Ph)‐positive leukaemia was 34% of examined B‐ALL with a peak incidence at 50‐59 years. Five‐year overall survival (OS) improved between 1997‐2006 and 2007‐2015; in patients 18‐45 years from 50% (95% CI 43‐57) to 65% (95% CI 58‐72), 46‐65 years from 25% (95% CI 18‐32) to 46% (95% CI 37‐55) and >65 years from 7% (95% CI 2.6‐11) to 11% (95% CI 5.9‐16) (P < 0.05). Men with Ph‐neg B‐ALL 46‐65 years had inferior OS compared with women (P < 0.01). Standardised mortality ratio was 5.7 (95% CI 5.0‐6.3) for patients who survived 5 years from diagnosis. In multivariable analysis, Ph‐positive disease was not associated with impaired prognosis but with lower risk of death in 2007‐2015. Conclusions In a population‐based cohort, OS has improved in adult ALL, especially for Ph‐positive disease but for middle‐aged men with Ph‐negative B‐ALL outcome was poor. Cure without late toxicity or relapse is still desired.

2675 Background: Resminostat is an oral pan-histone deacetylase (HDAC) inhibitor that has shown anti-tumor activity in a broad panel of preclinical models and revealed a favorable safety and efficacy profile in a first-in-man phase I study in patients (pts) with various solid tumor types. Resminostat is currently in phase II clinical development in pts with hepatocellular carcinoma (HCC), colorectal carcinoma (CRC) and Hodgkin Lymphoma (HL). Methods: The SAPHIRE trial involved HL pts who relapsed or progressed after prior therapy including high-dose chemotherapy and autologous stem cell transplantation (ASCT) or were refractory to treatment. The study was designed as an open-label, single-arm, international trial consisting of two recruitment stages according to the Simon Minimax design. Resminostat was administered orally at a once daily dose of 600 mg during the 1st recruitment stage and at a higher daily dose of 800 mg in the 2nd stage. Patients were treated in cycles of five consecutive days followed by a nine-day treatment-free period (5+9 schedule), constituting one 14 day cycle. Patients underwent assessment of their disease status by computed tomography in combination with positron emission tomography (PET/CT) after Cycle 3 and Cycle 6 and thereafter every fourth cycle during an optional extension phase of the study in which pts continued on treatment until disease progression. The primary endpoint of the study was defined as the overall objective response rate (ORR) based on the best response during treatment. Response was defined as complete response (CR) or partial response (PR) according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007) or as partial metabolic response (PMR) according to EORTC criteria (Young 1999). Secondary endpoints include time to response (TTR), duration of response (DOR), progression free survival (PFS), overall survival (OS), safety and tolerability and the evaluation of drug regulated biomarkers including the CC thymus and activation related chemokine TARC. Results: The enrolment was complete in June 2011 with 37 pts at 5 study sites available for safety evaluation. Median age of the safety population was 34 years (range 19–64 years). 21 pts (57%) had ASCT and 14 pts (67% of all ASCT pts) relapsed within one year after ASCT. 26 patients (70%) had ≥ 5 prior lines of therapy; median number of prior regimens was 6 (range 1–12). Stage of disease according to Ann Arbor classification at baseline was: 6 pts with stage 2, 4 pts with stage 3 and 27 pts with stage 4. 17 pts had B-symptoms at baseline (46%). Dosing with 600 mg or 800 mg resminostat was well tolerated with common treatment-related grade 2–3 AEs being anemia and thrombocytopenia that were well manageable by dose modification. Assessment of PK parameters confirmed the favorable profile of the oral administration route and dose dependent resminostat plasma concentrations. As of August 2011 out of 37 pts 35 pts had ≥ 1 post-baseline PET/CT tumor assessments and 2 pts discontinued early due to AE. Two out of 35 pts are still on study therapy in the optional extension phase after Cycle 6. Up to now 33 pts were evaluated centrally for tumor response. Of those, 11 pts qualified as responders (ORR=33%). Responders included 1 complete response (CR), 3 partial responses (PR) and 7 partial metabolic responses (PMR). Median time to response was 3 cycles. Additional 7 patients achieved stabilization of the disease. Thus, in total 18 pts (55%) obtained a clinical benefit from resminostat monotherapy. Conclusion: Results of the SAPHIRE study demonstrated substantial anti-tumor activity of the HDAC inhibitor resminostat in heavily pre-treated HL patients. Resminostat can be safely administered as oral monotherapy up to 800 mg once daily in a 5+9 day treatment schedule. Disclosures: Walewski: 4SC AG: Consultancy. Hauns:4SC AG: Employment. Mais:4SC: Employment. Henning:4SC AG: Employment. Hentsch:4SC AG: Employment.

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Excessive apoptosis has a central role in ineffective hematopoiesis in myelodysplastic syndrome (MDS). The aim of the study was to quantify apoptosis and Bcl‐2 expression in patients with MDS and to use these parameters in the evaluation of treatment efficacy with compounds modulating proapoptotic cytokines. Bone marrow (BM) samples from eight MDS patients were studied: four with refractory anemia and four with refractory anemia with ringed sideroblasts. Two patients with Hodgkin disease without BM determination were studied for control. Therapy consisted in administration of pentoxyphylline, dexamethasone and ciprofloxacin. Biochemical assay of apoptosis and Bcl‐2 was performed using annexin V‐biotin conjugate antibody and anti‐human Bcl‐2 antibody respectively, followed by streptavidine‐peroxidase conjugate, and peroxidase substrate. Ultrastructural investigation of BM samples was performed with standard electron microscopy techniques. Most of BM hematopoietic cells in the MDS patients had ultrastructural features of various stages of apoptosis including chromatin condensation and margination, cytoplasm condensation and budding of nuclear and plasma membranes to produce apoptotic bodies. Bcl‐2 expression showed an inverse correlation with the rate of the apoptotic process. Periodic evaluation of these two parameters has shown an increase of Bcl‐2 expression and a decrease of apoptotic rate in patients who had responded to the treatment. Response to the treatment was appreciated in accordance with their transfusion needs. Treatment efficiency diminished in time. The rate of apoptosis was inversely correlated with the level of Bcl‐2 expression. These results confirm the importance of the apoptotic process evaluation in monitoring MDS treatment.