No abstract

Key Points Routine staging by PET-CT identifies all clinically relevant marrow involvement by DLBCL. Cases with marrow involvement identified by PET-CT have PFS and overall survival similar to stage IV cases without marrow involvement.

Introduction: Hypocellular myelodysplastic syndrome (hMDS) is characterized by decreased marrow cellularity, and is often difficult to distinguish from aplastic anemia (AA) based on standard morphological criteria. It represents around 10-15% of patients diagnosed with MDS, but is not currently considered a separate entity by WHO. Hypocellularity is defined as bone marrow cellularity of less than 30% in patients younger than 70 years or less than 20% in those older than 70 years. Patients and Methods: We retrospectively evaluated the demographic, clinical features, bone marrow aspirate/trephine, treatment characteristics and outcomes of 100 patients with hMDS. The bone marrow aspirates and trephines were also analysed for dysplasia, blast percentage, cellularity, reticulin, p53 by Immunohistochemistry (IHC), CD34 and CD117. An MiSeq based targeted gene panel comprising of 24 frequently mutated MDS genes was used in a subset of patients. Results: The median age was 51 years (18-87), with only a third of patients >60 years. WHO subtypes RA (n=2), MDS 5q- (n=1), RCMD (n=95) and RAEB (n=2), IPSS risk groups low risk (n=20), Int1 (n=61), int2 (n=11) and high risk (n=2). 23% had evolved from previous AA. For the hMDS group IPSS cytogenetic categories comprised good risk 67% (n=62), intermediate 14% (n=13), including 6 cases of trisomy 8, and poor 18% (n=17), with 7 cases of monosomy 7. Of the normal cytogenetics, 15/62 (24%) had positive (moderate to strong) p53 by IHC, 30/62 (48%) with CD117 positivity (1-20%), 48/62 (77%) have fibrosis grade 1-2. Only 2/62 with normal cytogenetics had normal p53, CD34, CD117 and reticulin and these have evidence of dysplasia on morphology. The presence of cytogenetic abnormalities and other features such as p53, CD117 and fibrosis reflect a distinct population differing from the hypocellular marrow of aplastic anemia. A higher incidence (18%) of autoimmune disorders was seen, including ITP (n=2), thyroid dysfunction (n=3), alopecia (n=2), inflammatory bowel disease (n=4), coeliac (n=2), SLE/SjogrenÕs (n=2), others (n=6). Forty percent (n=32) had a PNH clone, all except 2 were subclinical. Progression of disease to AML (n=3), upstaging of disease (RCMD to RAEB, n=6) or cytogenetic evolution (n=3) was seen in 15% of hMDS, including 3 cases with both increase in blasts and karyotypic evolution. A subset (n=33) of hMDS were evaluated for recurrently mutated genes in MDS; 7/33 (21%) of patients harbored somatic mutations in ASXL1 (n=4), DNMT3A (n=2) and BCOR (n=2). All except one patient with somatic mutation had a prior history of aplastic anaemia. As the predominant group was hypocellular RCMD (95%), we compared the clinical features, treatment and prognosis with cellular RCMD cohort during the same time period. Median ages of hMDS and non-hypocellular MDS (nhMDS) were 51 and 60.3 years respectively. Patients with hMDS presented with more significant thrombocytopenia (median platelet count at presentation 43 vs 93), neutropenia (median ANC at presentation 1.13 vs 1.3), anaemia (median Hb 94g/L vs 104g/L), transfusion dependency, and more intermediate-2/high-risk disease than the nhMDS group (p=0.0257). Among hMDS patients, 30% (28/95) had chromosomal abnormalities, an incidence similar to that of nhMDS, 25% (23/94). Treatments received by hMDS cohort were: single agent Cyclosporin (n=27), anti-thymocyte globulin (n=7), erythropoietin and GCSF (n=13), 5-azacytidine (n=6), intensive chemotherapy (n=4), HSCT (n=26), including 9 patients who underwent upfront HSCT. As expected the use of IST was infrequent (8%) in the nhMDS cohort compared to 35% in the hMDS (p<0.03). The rate of progression to acute myeloid leukaemia was lower in hMDS compared to nhMDS group (3% vs 13%, p<0.02). The median overall survival was longer for patients with hMDS compared with the nhMDS (11.1 years vs 4.3 years p<0.001). Conclusion: This large study of hMDS identifies a specific subgroup of MDS with lower median age, severe cytopenia, high risk disease and a good prognosis. The increased incidence of trisomy 8 and autoimmune disorders is indicative of immunological dysfunction in this group of patients. The presence of specific genomic abnormalities (ASXL1, DNMT3A, BCOR), especially in patients with prior history of aplastic anaemia needs further comprehensive evaluation in a prospective study. Figure 1 Figure 1. Hypocellular MDS vs Normo/hypercellular MDS (median OS 11.1 vs 4.3 years, p<0.001) Disclosures No relevant conflicts of interest to declare.

3040 The Polyomavirus hominis 1 BK virus (BKV) is a non-encapsulated DNA virus, which infects up to 90% of the world's population, and may reactivate at times of severe immunosuppression, including post haematopoietic stem cell transplantation (HSCT). The significance of BK virus reactivation post Haematopoietic Stem Cell Transplant (HSCT) remains unclear. We collected retrospective data on viruria, viraemia, haemorrhagic cystitis (HC) and acute/chronic graft versus host disease (a/cGVHD) in patients at our institution over the period 2006 to 2011. We compared with a multivariate matched control group of 38, who did not reactivate BK. The groups were matched for age, sex, donor source and conditioning regimen including use of Alemtuzumab. Global BK reactivation incidence was 32% (38/118) of allogeneic HSCT during this period. 73% (28/38) of those who reactivated received volunteer unrelated donor (VUD) grafts, and 50% (18/38) received Alemtuzumab. Patients were sub-divided into those with high grade viraemia (HGV, VL >104 copies/ml), 47% (18/38) or low grade viraemia (LGV, VL<104 copies/ml), 53% (20/38). HGV was present in 57% of VUD transplants and 20% of sibling recipients, compared to LGV in 29% of VUDs and 70% of siblings. HGV influenced 1 year EFS; 18% versus 55% in LGV. Median OS was 173 days in HGV versus 345 days in LGV. Cumulative mortality rate in the BK group was 71% (27/38) as compared to 55% (21/38) in the control group (not significant). Relapse related mortality in the BK group was 22% (6/27) versus 57% (12/21) in the control group, at a median follow up of 229 days (p=0.088), indicating the high incidence of non-relapse causes of mortality in the BK group. 79% (30/38) of patients reactivating BK developed aGVHD, including 83% (15/18) with HGV, compared to 57% (21/37) in the control group (p=0.039). The number of patients who developed grade II-IV aGVHD in the BK group was 30/38 (79%) and 11/37 (20%) in the control group (p <0.001), figure 1. In 33% of patients BK reactivation preceded aGVHD by a mean of 12 days. 84% (27/32) of patients developed cGVHD, compared to 30% (18/30) in control group (p=0.05). Moderate-severe (NIH grade) cGVHD was more prevalent in patients reactivating BK, compared to control group; 75% (24/32) versus 3% (1/30) (p<0.001), figure 2. This data suggests the association of BK with an increased incidence of acute and chronic GVHD, and significant morbidity. Notably 10 patients developed severe complications including grade 4 HC (5/10), obstructive hydronephrosis and bladder wall dysfunction requiring invasive intervention. 7/10 (70%) of these patients had HGV; 2 patients reactivated early, failed treatment, developed obstructive renal failure and died. These patients had an increased rate of mortality compared to the whole study group (p=0.005), and all failed to achieve an EFS of over 1 year. Of note, 8.5% of all allografts developed grade 4 HC and 90% of these subsequently died. BK reactivation strongly correlates with acute and chronic GVHD and an increase in non relapse mortality. Routine surveillance for BK with risk scoring may allow earlier detection and reduced morbidity of BK and GVHD. Further prospective studies are required to understand the impact of the reactivation of the virus. Figure 1: Cumulative Incidence of acute GVHD Grade II-IV: Figure 1:. Cumulative Incidence of acute GVHD Grade II-IV: p <0.001 Figure 2: Cumulative Incidence of chronic GVHD moderate-severe: Figure 2:. Cumulative Incidence of chronic GVHD moderate-severe: p <0.001 Disclosures: No relevant conflicts of interest to declare.

Despite recent advances in care, central nervous system (CNS) lymphoma remains a disease with very poor long-term outcomes. We reviewed outcomes at our centre following the adoption of autologous stem cell transplant (ASCT) for patients achieving remission. Records for 78 consecutive unselected patients diagnosed with cerebral diffuse large B-cell lymphoma (DLBCL) between 2003-2014 were analyzed. 62 of these patients did not undergo ASCT. The median age for the non-ASCT group was 60 years (range 26-80, 32 males, 30 females). Of these 50 had primary CNS lymphoma (PCNSL) and 12 cases had isolated CNS relapse after systemic lymphoma. 5 patients were HIV positive, and 4 patients had post-transplant lymphoproliferative disease. 30 patients received HD-MTX alone and 3 patients received whole brain radiotherapy (WBRT) alone. 10 patients received HD-MTX with salvage WBRT on relapse and 1 patient with CNS relapse post BEAM autograft for systemic disease received HD-MTX & WBRT. 14 patients received palliative treatment and 2 unknown. The remaining 16 DLBCL patients and an additional 3 with mantle cell (2) or ALK positive anaplastic lymphoma (median age 53, range 27-67, male: female 13:6) who were in remission (VGPR/CR) by MRI with adequate performance status (PS) underwent ASCT after HD-MTX-based induction therapy, conditioned with 400mg/m2 BCNU & 10mg/kg Thiotepa. 4 received WBRT post-ASCT as adjuvant therapy. Of the 19 ASCT patients 16 presented with PCNSL, 2 late relapses confined to the CNS following prior systemic DLBCL, 1 mantle cell showed evidence of low-level disease on bone marrow biopsy and all were HIV negative. Median CD34 cell dose was 4.48 x 106. Median times to neutrophil and platelet engraftment were 12 (range 10-57) and 15.5 (range 7-57) days respectively. No deaths occurred from transplant-related complications, including sepsis. 2 year PFS was 67% and OS was 73%. 4 patients relapsed post-transplant (21%), all within 4 months of transplant; 3 subsequently died. 1 patient developed systemic disease progression at time of ASCT and 1 had evidence of a mixed response on MRI pre-ASCT. No patients in CR pre-ASCT have relapsed and 1/11 PR patients has relapsed. The longest remission is now 64 months without use of WBRT, providing evidence for durable long-term response and possible cure in an unselected group of patients. For the non-ASCT patients, median OS post diagnosis was 2.5 months overall, and 7.5 months, excluding palliative patient. Of those receiving MTX therapy 7 achieved CR, 7 PR and 23 had PD. 3 patients failed to tolerate treatment. Of those who achieved CR/PR reasons for not proceeding to ASCT included inadequate PS or lack of willingness to receive further therapy. Outcomes for those who achieve CR are good, with median PFS & OS for patients achieving CR not reached at a median of 32 months follow-up. 5/7 remain in remission; 1 patient has died. Only 1 of these patients received WBRT. The median PFS & OS for patients achieving PR were 5.5 & 8 months respectively (p= 0.041 & 0.027 vs CR). When comparing the two groups, median OS for patients receiving ASCT was not reached vs 5 months for MTX alone (p<0.001) and 29 months for MTX & WBRT (p=0.013). Overall we conclude MTX therapy alone induces CR in only a small number of patients and outcomes for those not achieving CR are dismal. For patients who are able to proceed to ASCT long-term remissions can be obtained. New strategies are required to enable patients to achieve CR in order to receive ASCT and thus achieve a durable long-term survival from CNS lymphoma. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.