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Background: The advent of B-cell-receptor associated kinase inhibition (BCR-KI) inaugurated a novel therapeutic principle in chronic lymphocytic leukemia (CLL). First-in-class Ibrutinib (Ib) and Idelalisib (Id) received marketing authorization from the EMA for the treatment of relapsed/refractory (r/r) CLL in 2012 and 2014, respectively. In spite of ample evidence from trials, real life data are scarce. Methods: Our clinical registry has been previously described in detail [https://doi.org/10.1182/blood-2018-99-110618]. It comprises of 168 unselected CLL patients (pts.), who were observed between 10/2014 and 08/2020. 65 of them required treatment during this period: 39 x 1st line only and 26 x > 2nd line. 18 of these 26 r/r CLL pts were treated either with Ib (11 x) or Id (7 x). Treatment was started according to iwCLL guidelines. The type of BCR-KI was chosen based on an individual's performance status, previous treatment and co-morbidity. Median 1st line-treatment (as a rule immunochemotherapy) started 27.5 months (m) after diagnosis (range: 0.5 m to 87.5 m). Time from 1st line therapy to BCR-KI treatment ('Ctx effected time') was 13.0 to 128.1 m (median 50.5 m), in total (18 pts.) 1052.5 m, i.e. 87.7 years (y). 17 of 18 pts. had received Rituximab (R) as part of a pre-BCR-treatment protocol. Estimated charges per month are 9.000 € in Id + R, 7.000 € in R + chemotherapy (ctx, i.e. Fludara or Bendamustin mostly) and 4.500 € in Ib or Id mono or R + Chlorambucil (Clb) respectively. Results: Patients described herein differed according to age at start of BCR-KI (44.4 to 86.8 y, median 76.0 y), sex (10 m, 8 f), types and lines (1 to 6, median 2) of prior treatment. Indications for BCR-KI were increasing tumor burden (17 x, 1 x combined with pleural effusion) and persistent hemolysis (1 x). Genetic high risk features comprised of at least one of the following: IGHV unmutated status, mutation and/or deletion of TP53 gene, deletion of 11q, and complexe karyotype. These features were present in 17 of 18 pts. (median 3 features). In particular, unmutated IGHV was found in 13/18 r/r pts who received BCR-KI (total cohort of r/r pts, 21/26). Overall response rate was 78% (Ib 8/11; Id 6/7). Time to next therapy or death (`KI effected time`) varies from 1.1 m to 69.1 m - in total 286.9 m until now. 4 pts. continued BCR-KI from 30 to 67 months. This was always the longest period of unchanged therapy in these 4 pts. Shorter `KI effected time` in the other 14 pts. was associated with higher treatment line and treatment interruptions. 2 responding pts. (without side effects) stopped BCR-KI and stayed in ongoing hematological remission for 11 and 25 months after cessation of treatment. Adverse drug reactions occurred in 6 pts. (Ib 4 x, Id 2 x). 5 pts. died on BCR-KI, but there was no therapy related death. Approximate costs per month in Germany are 1700 € in `Ctx effected time` (1.800.000 € per 1052,9 m) and 4.700 € in `KI effected time` (1.350.000 € per 286,9 m). Of note, one pt. on Id showed clinical progression associated with genetic evolution after 67 months of BCR-KI. He promptly responded to venetoclax. Discussion: In real live many r/r CLL pts. are elderly and present a broad spectrum of different clinical features. A clinical registry can reflect this and may add to our knowledge from multicenter studies. Remarkably almost all of our unselected r/r CLL pts. revealed genetic high risk features, in particular unmutated IGHV status, making them ideal candidates for targeted treatment strategies. These strategies take advantage of the fact that BCR-KI has been demonstrated to be well tolerated and effective in elderly and pre-treated pts. Undoubtedly BCR-KI increases the total costs of therapy, but affords a prolongation of overall survival. Remaining open questions include optimal treatment sequences, combination partners for BCR-KI as well as thorough analysis in the quality of molecular remissions. Disclosures Böttcher: Janssen: Honoraria, Research Funding; Celgene: Research Funding; AbbVie: Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Novartis: Honoraria.

Background: Therapy studies yield important insights into clinical features and therapeutic options of CLL. However studies in Germany represent less then 20% of all CLL patients (pts); pts >75 years (yrs) are included in 3% only. Furthermore initial phases are not reflected in multicenter studies and data representing real life situation are scarce. Methods: Out of 1.443 patients consulting our center because of leucocytosis (>10 Gpt/l) between 2003/07/01 and 2018/06/30 we diagnosed CLL consecutively in 234 pts (16,2%): 143 male (m), 91 female (f). Median age at diagnosis is 71,4 yrs. Median leucocyte count is 18,0 Gpt/l. BINET - Stages are: A in 82%, B in 11% and C in 7% of pts. Diagnoses are strictly based on WHO definition: Pts with small lymphocytic lymphomas (sLL, n=11) are included but those with monoclonal lymphocytosis of unknown significance (MLUS) or monoclonal B - lymphocytoses with uncertainly flow cytometry (FC) results are excluded. Histopathology, FC and genetics have been performed by external hematological reference laboratories. All investigations followed the rules of best clinical and laboratory practice. Dates of death are given by the record sections of the involved communities (deadline 2018/06/30). To address different questions we defined 3 groups of pts: A: "collective group", (n=234), i.e. all pts.diagnosed from 2003/07/01 to 2018/06/30. B: "epidemiological group" (n=129), i.e. pts from 3 communities (113.000 inhabitants - inc - in 2009/12/31) in close proximity referred to our center. C: "genetic features group" (n=99), i.e. pts diagnosed continuously between 2012/07/01 and 2018/06/30 with systematically performed genetics, (i.e. at least 80% of pts in this group. Genetics are: Cytogenetic (banding) n=88; FISH (del 6q21/6q, del 11q22.3, +12/+12q, del 13q14/ 13q34, del 17p13.1, 14q32) n=85. PCR (IgVH status - mutated vs. unmutated; TP53, NOTCH1, SF3B1 mutation) n=82. Results: "Collective group" (A): 7,5 years OS is 72% and 15 years OS is 33% respectively (KAPLAN-MEIER). Age of pts acts as a predominant factor for long term OS: 77% in pts < 60 yrs vs. 40% in pts ≥60 to "Epidemiological group" (B): Raw incidence is 7,56/105 inh. (m: 9,13, f: 6,06), age adjusted incidence is 10,3/105 inh (m: 12,5, f: 8,3), with highest rate of age between 75 to < 80 yrs. Standard incidence is calculated as 6,27/105 (BRD 1987), 4,78/105 (Europe) and 5,06/105 (USA 2000). Prevalence could be measured directly (2017-12-31): 79,1/105 inh. "Genetic features group" (C): IgVH mutation status is hypermutated in 48 pts. vs. unmutated in 39 pts. Results of FISH analyses (n = 85) are: del 6: 5,5%, del 11: 17,6%, +12: 3%, del 13q: 70,3%, del 17p: 8,8%; normal status: 13,2%. PCR revealed mutations of NOTCH1 in 7%, of SF3B1 in 10,5% and of TP53 in 8,6% of 82 pts, respectively. Combined del17p by FISH and molecular TP53 mutations at diagnosis are found in 3 of 81 pts (3,7%). Cytogenetic findings different to results of FISH and/or PCR were found in 36 of 82 pts (43,9%). Calculated 5 yrs freedom of therapy is 75% in IgVH hypermutated pts vs. 45% in unmutated pts (p = 0,0005; log rank test); calculated 5 yrs OS is 92% vs. 59% (p=0,023). Special situations in CLL: 13 of 234 pts (5,5%) have one parent or sibling with low grade NHL, mostly CLL. In contrast there is non spouse suffering of CLL / low grade NHL. Deficiency in Immunoglobuline G (Ig G < 4,0 g/l) was found in 17 of 199 pts at diagnose (8,5%), 29 pts (12,4%) were substituted with Ig G's in the Course of CLL. In 14 (6,0%) pts. we diagnosed a 2nd hematologic malignancy (3x cMPN, 1x CML, 3x MDS, 3x AML, 1x FL, 1x MCL, 1x MZL, 1x DLCBL-independent of CLL; monoclonal gammopathies are not considered). RICHTER syndrome was found in 1 case, but progression to plasmocytic/plasmoblastic disease was seen in 3 cases. Li FRAUMENI Syndrome was revealed in 1 male patient, he has been in stable disease for 13 yrs. Conclusion: CLL seems to be more frequent than yet considered. IgVH mutation status seems to be very important as a single prognostic factor concerning time of 1st therapy as well as OS. Clinical features of CLL are very different and impressing. Disclosures Böttcher: Genentech: Research Funding; Janssen: Honoraria; AbbVie: Honoraria, Research Funding; Celgene: Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract 1941 Poster Board I-964 Multiple studies have repeatedly shown that loss of MHC II expression correlates with poor patient prognosis in diffuse large B-cell lymphoma (DLBCL). Major histocompatibility complex class II (MHCII) molecules present peptides for antigen recognition and are important for the adaptive immune response. Loss of MHCII expression is also one of the changes seen during normal B-cell differentiation into plasma cells. Plasmablastic lymphoma (PBL) is another B-cell lymphoma characterized by a proliferation of large B-cells with a plasma cell immunophenotype and very poor prognosis. In this study, we questioned whether DLBCL cases that have low MHCII expression have a similar gene expression pattern to PBL. Unstained cuts from formalin-fixed, paraffin-embedded tissue blocks of 101 DLBCL and 76 PBL cases were analyzed for gene expression using a quantitative nuclease protection assay (qNPA, ArrayPlateR). The 42 genes on the array were previously identified as B-cell lineage-related or prognostically important in DLBCL. DLBCL cases were divided into low [MHCII(-)] and high [MHCII(+)] MHC II expression using a 20% cutoff for expression of HLA-DRB by qNPA, as previously described (L Rimsza et al, Blood 2008). Genes that differed significantly between lymphoma types were determined using the Partek Genomics SuiteR software, using ANOVA tests with a false discovery rate of 0.05. Thirty of the 42 genes on the array (71%) were differentially expressed between DLBCL as a whole and PBL. As expected from the literature, the PBL cases had less expression of B-cell antigen, MHCII, and germinal center-related genes as compared to DLBCL. Of these 30 genes, 29 were also different between MHCII(+) and PBL. In contrast, only 21 genes of the 42 on the array (50%) were differentially expressed between MHCII(-) and PBL, indicating a less dissimilar expression pattern between these two sets of cases. Of the 21 genes, two were uniquely different between MHCII(-) and PBL. Both of these, FN1 and CTGF, are found in the extracellular matrix and were low in the MHCII(-) cases. This finding, that the MHCII(-) cases are similar, but not identical to PBL, agrees with our previous immunohistochemistry studies suggesting MHCII(-) cases may be invoking selected mechanisms of differentiation (S Wilkinson et al, AACR Annual Meeting 2009, #2712). Our findings confirm the hypothesis that MHCII(-) DLBCL have a more plasma cell-like expression pattern than MHCII(+) DLBCL. These findings may have implications for pathogenesis and treatment. Disclosures: Schwartz: High Throughput Genomics: Employment. Gascoyne:Roche Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Rimsza:High Throughput Genomics: Memorandum of understanding with HTG to run qNPA assay at no cost..