ALBERT

Description: Background: Iron overload is common after allogeneic hematopoietic stem cell transplantation and may cause liver damage. High pre-transplantation serum ferritin levels have been reported to be associated with impaired survival post transplantation in patients with acute myeloid leukemia or myelodysplastic syndrome. Design and Methods: We performed a retrospective study of 309 adult patients with haematological malignancies who underwent allogeneic hematopoietic stem cell transplantation after myeloablative (51%) or non-myeloablative conditioning (49%). The aim was to determine the incidence of hyperferritinemia and iron overload and the effects of these conditions on graft versus host disease, relapse and survival in patients with blood disorders who receive allogeneic stem cell grafts. Results: For overall survival and for relapse-free survival, only high pretransplantation ferritin (〉400ug/l) and advanced stage of disease were significant in multivariable analysis. High pretransplantation ferritin and advanced stage of disease were also significant for relapse risk at 3 years, but ferritin was not significant for non-relapse mortality. In multivariate analysis, ferritin, age, type of donor, and previous transplantation were significant factors for cGVHD at one year. Conclusions: Hyperferritinemia was associated with lower risk of cGVHD and increased risk of relapse and death, but not with increased non-relapse mortality. The lower rate of cGVHD among patients with high ferritin levels can be explained by an immunosuppressive effect of ferritin, reducing graft versus host disease and graft versus leukaemia effect, resulting in increased risk of relapse and impaired chance of survival. Therefore, these conditions might be best explained by an immunosuppressive effect of ferritin and not by a direct toxic effect.

Description: Abstract The Getz Ice Shelf is one of the largest sources of fresh water from ice shelf basal melt in Antarctica. We present new observations from three moorings west of Siple Island 2016–2018. All moorings show a persistent flow of modified Circumpolar Deep Water toward the western Getz Ice Shelf. Unmodified Circumpolar Deep Water with temperatures up to 1.5 °C reaches the ice shelf front in frequent episodes. These represent the warmest water observed at any ice shelf front in the Amundsen Sea. Mean currents within the warm bottom layer of 18–20 cm/s imply an advection time scale of 7 days from shelf break to ice shelf front. Zonal wind stress at the shelf break affects heat content at the ice shelf front on weekly to monthly time scales. Our 2‐year mooring records also evince that upwelling over the shelf break controls thermocline depth on subannual to annual time scales.

Description: Introduction: We here report from an ongoing phase I/II study of HLA-haploidentical NK cell therapy to patients with high-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) not eligible for standard therapies. The preparative regimen consisted of intermediate doses of Cyklophosphamide (Cy), Fludarabin (Flu) and titrated doses of total lymphoid irradiation (TLI). The trial design excluded systemic IL-2 treatment to avoid expansion of regulatory T cells and to test if in vivo expansion could be obtained without IL-2 support. Patients:The first 12 patients were treated with Cy/Flu and an escalating dose of TLI (2 Gy and 4 Gy), followed by infusion of short-term IL-2 activated (16 hours) NK cells. Three patients received daily cyclosporine A after the conditioning. Three had relapsed, chemotherapy-refractory, primary AML, seven had secondary relapsed or refractory MDS-AML and two had high risk MDS with fibrosis. Results: The treatment was well tolerated and no severe non-infectious toxicity could be observed in the patients. The endpoint of expansion (〉100 donor NK cells/ul at day 14) was not reached, but six patients had positive microchimerism, NK cells of donor origin detectable by RT-PCR at day 7-14, that thereafter became undetectable within 7-14 days. Four of these six patients achieved complete remission (CR) whereafter they become eligible for and could proceed to allogeneic stem cell transplantation. None of the patients with negative microchimerism obtained CR. Four patients died from progressive disease and three patients, with minor response and progressive disease, died in infections within three months of therapy. Discussion: Although the long-term efficacy needs to be evaluated, the results suggest that a combined regimen with mild conditioning followed by NK cell therapy may induce remission in patients with chemo-refractory disease and provide a bridge to allogeneic stem cell transplantation. Notably, clinical responses were observed after only a minimal in vivo NK cell expansion and were independent on KIR-ligand mismatch. Disclosures Blomberg: VECURA: Employment. Hellström-Lindberg:Celgene: Research Funding.

Description: Background. Evidence from multiply affected families, case-control and population-based registry studies implicate a role for genetic factors in multiple myeloma (MM). Previous studies based on small numbers have suggested excess risk of MGUS in relatives of MM patients. Aims of this large nationwide MGUS study were to quantify risks of developing MGUS and lymphoproliferative malignancies in first-degree relatives and to define characteristics of familial aggregation. Methods. We identified 4488 MGUS patients diagnosed in all major hematology/oncology outpatient units in Sweden (1967–2005), with linkable relatives. Using the population-based central Multigenerational Registry, we obtained 17628 frequency-matched controls and first-degree relatives of cases (n=14689) and controls (n=58698). Relatives of MGUS cases and controls were linked with hospital-based outpatient registries and the central Swedish Cancer Registry to define occurrence of MGUS and lymphoproliferative tumors. Measures of familial aggregation were calculated by a marginal survival model using relatives as the cohort. Results. Compared with controls, relative risk (RR) of MGUS was significantly increased (RR=2.84; 95% CI 1.45–5.57) in relatives of MGUS cases. Relatives of MGUS cases (vs. controls) also had excess risk of MM (RR=2.87; 95% CI 1.92–4.27), Waldenstrom’s macroglobulinemia (WM) (RR=4.94; 95% CI 1.32–18.46), and chronic lymphocytic leukemia (CLL) (RR=2.05; 95% CI 1.22–3.43). Risk-estimates were similar for various types of first-degree relatives (parents, siblings, offspring); the same was true when we estimated risks by age at MGUS of cases (above vs. below 65 yrs), and sex of relatives. Age at onset of MGUS and lymphoproliferative tumors was virtually the same for case and control relatives. There was no increased risk (RR∼1) of NHL or HL among relatives of MGUS cases. Conclusions. Among first-degree relatives of a large nationwide MGUS cohort in Sweden, we found 2- to 3-fold elevated risks of developing MGUS, MM, WM, and CLL. These results suggest the operation of shared common germ line susceptibility genes in the pathway to MGUS and certain lymphoproliferative tumors. Better characterization of early genetic lesions mediating monoclonal plasma-cell proliferation, survival, and migration in the bone marrow microenvironment will ultimately enhance our understanding of MGUS, MM, WM, and CLL pathophysiology, provide clues to etiology, and allow identification of novel molecular targets.

Description: According to WHO’s current criteria, follicular lymphoma is morphologically divided into grades 1, 2, and 3, and grade 3 is further subdivided into 3a and 3b, depending on the presence of centrocytes and solid sheets of centroblasts. The clinical relevance of this grading system is unclear. Although there is consensus that grades 1 and 2 share clinical characteristics of indolent lymphoma, it is debated whether grade 3 should be treated intensively with anthracycline-containing regimens. Furthermore, the 3a/3b subdivision is not universally implemented. We wanted to investigate the clinical relevance of the grading system with respect to clinical characteristics, treatment and survival. Totally, 186 cases were diagnosed between January 1994 and January 2004 in South Stockholm County with de novo follicular lymphoma and without concomitant transformation. The biopsies were re-graded according to the current WHO criteria by two experienced hematopathologists. 129 cases were grade 1 or 2, 44 grade 3a, and 13 grade 3b. Clinical characteristics in the patients with follicular lymphoma grade 1–2 and 3a are shown in Table 1. The local policy has been to treat all patients with grade 3 disease aggressively. In grade 3a disease, front-line anthracyclines did not seem to improve overall survival (Figure 1). Grades 1–2 and 3a show similar overall survival curves of indolent and incurable lymphoma, while the 13 patients with grade 3b disease (of whom 12 received aggressive front-line therapy) seem to reach a plateau after four years (Figure 2). We conclude that follicular lymphoma grade 3a is not clinically different from grade 1 and 2 disease, and that patients with grade 3a do not seem to benefit from front-line anthracyclines. Although our findings are limited by the few cases of grade 3b, it seems that grade 3b is another disease entity and, when treated aggressively, it is maybe curable with chemotherapy. The histopathological distinction between grade 3a and 3b is clinically of great importance. Table 1 Grade 1–2 Grade 3a P Clinical characteristics in patients with follicular lymphoma grade 1-2 and 3a. Age 〉60 years 50% 61% NS Elevated LDH 32% 49% 0.046 Stage III or IV 68% 80% NS Front-line anthracyclines 41% 73% 0.0004 Subsequent transformation 21% 19% NS Figure Figure Figure Figure