ALBERT

Description: Mantle cell lymphoma is a non-Hodgkin lymphoma with, in general, a poor prognosis. A minor subset of patients with an indolent disease course has however been recognized (1,2). The various growth patterns of MCL, i.e. mantle zone (MZ), nodular (N) or diffuse (D) is assumed to correlate to stage and to disease course. The genetic aberrations underlying the pathogenesis are well defined and correlate to high tumour cell proliferation and poor prognosis. However, the effect of the lymphoma microenvironment in disease development and sustainability is largely unknown. We have used flow cytometry to investigate the non-malignant cell composition of the lymph node microenvironment in a population-based cohort of 154 MCL cases diagnosed from January 1, 1998 to December 31, 2012. Flow cytometry analyses of lymph nodes, performed as part of the diagnostic process, were used to evaluate percentages of tumour cells, remaining non-malignant B-cells and T-cell subsets (CD3+, CD3+CD4+, CD3+CD8+). As lymph node T-cell numbers reflect a high tumor load in the lymph node we also investigated the CD4/CD8 ratio, which is not dependent on T-cell percentage. Data from 26 non-malignant lymph nodes were used for comparison. T-cell percentages are shown in Table 1. Clinical and other pathological parameters of the MCL cases, including MIPI, cell morphology, tumor growth pattern and cell proliferation were also evaluated. Indolent disease (n=15), defined here as requirement of treatment 〉 two years from diagnosis, was associated with higher amount of CD3, CD3+CD4+ and higher CD4/CD8 ratio (p=0.0429, p=0.0211 and p= 0.0032 respectively). Higher tumor cell proliferation correlated negatively with the CD4/CD8 ratio (p= 0.0007). There was a significant difference in CD3 percentages between reactive lymph nodes and MCL irrespective of growth pattern (all p

Description: The prognostic role of the transcription factor SOX11 in mantle cell lymphoma (MCL) is controversial. We investigated prognostic markers in a population-based cohort of 186 MCL cases. Seventeen patients (9%) did not require any therapy within the first 2 years after diagnosis and were retrospectively defined as having an indolent disease. As expected, indolent MCL had less frequent B symptoms and extensive nodal involvement and 88% of these cases expressed SOX11. In our cohort 13 cases (7.5%) lacked nuclear SOX11 at diagnosis. SOX11− MCL had a higher frequency of lymphocytosis, elevated level of lactate dehydrogenase (LDH), and p53 positivity. The overall survival in the whole cohort, excluding 37 patients receiving autologous stem cell transplantation, was 3.1 year and in patients with indolent or nonindolent disease, 5.9 and 2.8 years, respectively (P = .004). SOX11− cases had a shorter overall survival, compared with SOX11+ cases, 1.5 and 3.2 years, respectively (P = .014). In multivariate analysis of overall survival, age 〉 65 (P = .001), Eastern Cooperative Oncology Group score ≥ 2 (P = .022), elevated LDH level (P = .001), and p53 expression (P = .001) remained significant, and SOX11 lost significance. We conclude that most indolent MCLs are SOX11+ and that SOX11 cannot be used for predicting an indolent disease course.

Description: Epidemiological studies have demonstrated an increased incidence of MDS in patients with plasma cell disorder (PCD) i.e. multiple myeloma (MM) or MGUS and several case reports / series of co-occurring MDS and PCD have been published. The underlying pathogenesis for this condition, and if the two diseases share a common genetic lesion remains unknown. Here, we describe a cohort of 27 consecutive patients with co-occurring MDS and MM (n=6), MGUS (n=20) or plasmocytoma (n=1), diagnosed at the Karolinska University Hospital. In 5 patients, the diagnosis of MGUS preceded the diagnosis of MDS , in one patient the MDS diagnosis preceded PCD, and in 21 patients MDS and PCD were diagnosed at the same time. There was a preponderance for lower-risk MDS subgroups with only 3 patients belonging to the IPSS-R high / very high risk groups. Median overall survival for the whole cohort was 44 months. The most common mutations were TET2, SRSF2 and SF3B1. To identify potential common founder clones, we performed whole exome sequencing on isolated bone marrow myeloid-, plasma- and T-cells from 9 patients. In none of the patients, we could detect a common founder mutation and the two diseases have likely emerged from separate clones.

Description: Abstract 1592 Introduction: Mantle cell lymphoma (MCL) constitutes 3–10% of non-Hodgkin lymphomas and affects predominantly middle-aged to elderly men. The median survival is 3–5 years and seems to improve with new therapeutic regimens. The MCL International Prognostic Index (MIPI) has been proven useful for predicting survival in MCL patients included in clinical trials, but its value in unselected population based MCL cohorts is less well known. Biological markers are increasingly used for prognostication of MCL patients, especially for defining indolent cases. Material and Methods: All 186 patients diagnosed with MCL, confirmed by IHC for cyclinD1 and/or by FISH for t(11;14), between January 1998 and June 2010 in the Stockholm region, were included in a retrospective analysis. Clinical data from patient files, diagnostic biopsies and flow cytometry data were reviewed. Last follow-up was in May 2011. The prognostic value of the following variables, evaluated at the time of diagnosis, were analyzed: age, sex, Ann Arbor stage, ECOG, B-symptoms, Hb, LDH, albumin, lymphocytosis, leukocytosis, splenomegaly, nodal, extranodal and bone marrow involvement, blastoid morphology, expression of CD23, light chain, Ki 67, p53 and nuclear SOX11. Results: The median age at diagnosis was 68.8 years (range 36.2 – 89.9); 67.4 in males and 72.1 in females, respectively. The male: female ratio was 2. Thirty patients had a known malignancy of other type before the MCL diagnosis and 12 acquired a cancer later. In 13 patients the other malignancy was the cause of death. Median overall survival (OS) time was 43 months in the whole cohort and 38 months, when excluding 39 patients receiving ASCT as part of first-line therapy. No statistically significant difference in OS was seen with respect to whether the lymphoma was diagnosed before or after 2005. In the non-transplanted patients (n=149), univariate analysis showed the following clinical variables to be negatively correlated to overall survival: age 〉65 years, B-symptoms, splenomegaly, ECOG 〉2, low albumin, and high LDH. The median survival was not reached in the low risk MIPI group, and was 79 and 34 months, in the middle and high risk MIPI group, respectively. Blastoid morphology and p53 positivity (〉20%), were negatively correlated to overall survival (both with p50%, both with with p30% (p=0.061), while SOX11 positivity was related to a prolonged survival (p=0.015). Multivariate analyses showed that age 〉65 (HR 6.1, p2 (HR 63, p30%, in one 〉50%, two had a p53 expression 〉20% and two were SOX11 negative. Therapy was never required in 9 of these initially indolent patients and only one had an autologous transplantion later in the disease course. The median OS was 72 months for the 17 indolent MCL compared with 34 months in patients requiring treatment earlier in their disease (p=0.003). The follow-up time did not differ significantly between the two groups. Conclusions: Compared to data from published clinical trials of advanced MCL, our population-based cohort of 186 cyclin D1 positive MCL patients were diagnosed at an older age, which may contribute to a shorter overall survival. Certain well-established prognostic variables seem to loose significance outside study populations. In the group of 147 non-transplanted patients multivariate analysis showed that only age, ECOG, LDH and p53 positivity were independently associated with overall survival. Leukocytosis as a variable of MIPI had no impact. Neither SOX11, CD23 or other biological markers applied at the time of diagnosis could predict for clinically indolent disease. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction Gaucher disease (GD), caused by deficient activity of lysosomal glucocerebrosidase, results in tissue infiltration by transformed macrophages (Gaucher cells, GC), loaded with undigested glycolipids. Ensuing clinical signs and symptoms include skeletal lesions and cytopenias, and seem to be due to both local tissue replacement by pathological infiltrates but also to accompanying inflammatory response, elicited by engorged macrophages. Bone marrow GC infiltration coincides with increased microvascular density and skewed angiogenic profiles. The basis for increased risk of plasma cell (PC) dyscrasia in GD remains however still unexplained. The presented study aimed to investigate patterns of PC distribution in bone marrow of untreated GD patients, potential their clinical correlates and evolution during treatment. Methods Study material includes BM samples from 11 previously untreated GD1 patients (7 males, 4 females), followed at the Hematology Center, Karolinska University Hospital, Stockholm, Sweden. Diagnosis of GD was previously confirmed with proven deficient glucocerebrosidase activity in PB, and demonstrated GBA1 mutation. The study was performed in accordance with Declaration of Helsinki, and institutional ethical permit was obtained. Clinical data were retrieved from patient journals. After BM sampling, 10 patients began disease specific therapy, with 9 subjects receiving enzyme replacement therapy (ERT), and one treated with substrate reduction therapy (SRT). Bone marrow samples (trephine biopsies or fine needle aspirates) were taken as part of routine hematologic work-up, at baseline and, if needed, during follow-up. Samples were routinely processed at the Department of Clinical Pathology and Cytology at the same hospital. Plasma cell burden and distribution were studied in immunohistochemically stained sections (CD138), scanned at 40x magnification using the NanoZoomer S360 Digital slide scanner (Hamamatsu Photonics, Hamamatsu, Japan). NDPI.view2 Viewing software was used for scan evaluation, and image saving (JPEG format, 461 nm/pix resolution). For each sample, 5 fields with prominent Gaucher cell infiltrates (≥50% field area; GC-rich areas ), and 5 with

Description: Abstract 3651 Introduction: Mantle cell lymphoma (MCL) constitutes 3–10% of non-Hodgkin lymphomas and has a median survival of 3–5 years. A small number of patients are characterized by a clinically indolent disease and may not require treatment for several years. However, these are difficult to identify at the time of diagnosis due to lack of reliable predictive markers. Recently, the nuclear expression of the transcription factor SOX11 has been suggested to be of prognostic value in MCL. Materials and Methods: All 186 patients diagnosed with MCL in the Stockholm region between January 1998 and June 2010 were included. Diagnosis was according to the WHO criteria and all cases were cyclin D1 positive by IHC and/or for t(11;14) by FISH. Clinical data from patient files, diagnostic biopsies and flow cytometry data were reviewed. Patients not requiring treatment within the first two years after diagnosis were retrospectively defined as indolent disease. Patients were further categorized in nuclear SOX11 negative (n=13) and nuclear SOX11 positive (n=160) cases and in cases with indolent (n=17) versus non-indolent disease course (n=169). The following variables were evaluated at the time of diagnosis: age, sex, Ann Arbor stage, ECOG, B-symptoms, Hb, LDH, albumin, lymphocytosis, leukocytosis, splenomegaly, nodal and bone marrow involvement, MIPI, indolent disease, blastoid morphology, expression of CD23, light chain, Ki 67, SOX11 and p53. Overall survival was analyzed, excluding patients receiving ASCT (n=37). Baumgartner, S. et al presents further data on the entire cohort in the accompanying abstract. Results: The following variables were significantly more common in SOX11 negative cases (Table 1): Lymphocytosis (p=0,045), high LDH (p=0,029) and p53 positivity (p

Description: Introduction Autologous stem cell transplantation (ASCT) combined with novel agents is considered as the standard treatment for eligible patients 〈 70(-75) years of age with multiple myeloma (MM). The number of induction cycles is usually 4-6 followed by ASCT, consolidation and maintenance. The role of consolidation is still under debate especially if complete response has been achieved and maintenance will follow. To improve the quality of life and avoid the frequent visits at hospital an all-oral treatment would be a preferred choice. Despite novel drugs, the outcome of high-risk (HR) patients is poor. We designed a phase 2 Nordic Myeloma Study Group (NMSG) trial (NCT03376672) to explore the response of ixazomib, lenalidomide and dexamethasone (IRd) induction, followed by single ASCT, IRd consolidation and risk-based maintenance either with IR or R. Here we present the response rates and safety after IRd x 4 induction in all patients and in 87% of patients before consolidation. Patients and methods This study included 120 patients in 22 NMSG sites. Patients received 4 IRd cycles as induction, ixazomib 4 mg on days 1, 8, 15, lenalidomide 25 mg on days 1-21, dexamethasone 40 mg weekly in 28-day cycles. Mobilization and ASCT were performed according to standard practice. Three months post-ASCT all patients will receive 2 IRd as consolidation followed by maintenance. Thereafter patients will be stratified to HR if any of the following FISH aberrations were found at inclusion: del17p at least 60%, t(4;14), t(14;16), t(14;20) or +1q and they receive ixazomib 4 mg on days 1, 8, 15 and lenalidomide 10 mg on days 1-21. Non-HR patients receive lenalidomide 10 mg on days 1-21. Maintenance will continue until progression (PD). Lenalidomide dose will increase to 15 mg after 3 cycles. The primary endpoint of the study is minimal residual disease (MRD) by 8-color Euroflow 〈 0.01%. The secondary endpoints include flow-MRD negativity by 10-5, overall response, safety and progression-free survival. Serological responses were assessed before cycles and if sCR or CR is achieved flow-MRD sampling will be performed and repeated every 6 months. Samples were taken concomitantly for later comparison with BM- molecular-MRD, blood cell-free DNA, blood heavy-light chain assay and blood mass spectrometry. Results Within 21 months 120 patients were included, 46 % of them belong to the HR group. Mobilization is by July 2020 performed for 101 (84%) patients with cyclophosphamide (Cy) + G-CSF in 74% and G-CSF alone in 26%. Plerixafor was needed in 32 (32%) patients. The median number of harvesting days was 2 (0-4) and the median number of collected CD34+ cells was 6.4 (0-19.2) x 106/kg. Four patients (4%) failed to mobilize during 1st attempt. Eighty-six (72%) patients have so far received ASCT with the median number of 3.4 x 106/kg CD34+ cells in graft. Overall response rate is 93%. The responses after IRD x 4 induction and before consolidation are presented in Table 1. Before consolidation 10 patients (8%) are out of study due to PD and 4 (3%) have been withdrawn due to toxicity. Toxicity events included hypersensitivity with hepatorenal failure, grade 3 cytopenia with liver toxicity and one unexplained encephalitis. One patient was withdrawn due to Cy toxicity. Eight additional patients are withdrawn from study, 7 by physician´s decision and 1 by patient´s decision. All these 7 patients had high tumor burden based on paraprotein level either in serum (53 - 102 g/L) or in 24h urine (7.8 - 23.2 g/24h) and achieved only stable disease (SD) during induction. Fifty-eight grade 3-4 SAE reports from 39 (33%) patients have been received and 57% of these were infections. Three patients had grade 3 liver problems and 2 patients grade 3 peripheral neuropathy. Seventeen (14%) patients have reported skin reactions, only 4 of them grade 3 events. Conclusion We present here data on response and safety after observation of all patients until post-induction phase and of 87 % of the patients until start of the consolidation phase. The ORR is 93% when all patients have received induction treatment. Nine patients achieved only SD and seven of them with high tumor burden were withdrawn before mobilization. At least VGPR after ASCT was achieved in 37%. Toxicity caused the withdrawal of 4 (3%) patients and 39 (33%) patients have reported grade 3-4 non-hematological SAEs. In all, 98/120 (82%) patients continue in the study including 80% of the HR patients. Disclosures Silvennoinen: BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Cancer patients Finland: Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Waage:Janssen: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy; Shire: Honoraria. Schjesvold:Celgene, Amgen, Janssen, Oncopeptides: Research Funding; Amgen, Celgene, Janssen, MSD, Novartis, Oncopeptides, Sanofi, SkyliteDX, Takeda: Honoraria; Amgen, Celgene, Janssen, MSD, Novartis, Oncopeptides, Sanofi, Takeda: Consultancy. Anttila:Sanofi: Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Research Funding; Janssen: Honoraria, Other: Advisory Board; Takeda: Honoraria, Research Funding. Säily:Amgen: Honoraria; Abbvie: Honoraria; Celgene: Honoraria; Roche: Honoraria; Sanofi: Honoraria; Pfizer: Honoraria; Takeda: Honoraria; Janssen Cilag: Honoraria; Boehringer Ingelheim: Honoraria. Sankelo:Celgene, Amgen, Sanofi: Other: Congress travel support. Partanen:Abbvie: Honoraria, Other: Scientific Advisory Board Meeting; Behring: Honoraria; Takeda: Other: Scientific Advisory Board Meeting.