ALBERT

Description: Abstract 1697 There is increasing evidence for the role of KIR genetics in predicting outcome of haematological malignancies. We recently showed that donor (but not recipient) KIR genes 2DS1, 3DS1 and 2DL5a are associated with significantly less relapse in AML patients following matched sibling allogeneic stem cell transplantation. Interestingly, this effect was not seen in patients with AML secondary to MDS but only in de novo AML.1 To explore whether outcome of non-transplant treatment for AML might be affected by KIR genetics we performed KIR genotyping on the DNA sample archive from the Medical Research Council UK AML 10 and 15 trials. All patients underwent four courses of chemotherapy according to MRC protocols. KIR genotyping was performed using Qiagen SSP PCR KIR genotyping kits as previously described.1 We measured KIR gene frequencies in AML samples obtained at diagnosis from 469 de novo AML, and 38 secondary AML and compared the gene distribution with that of a normal control population of 246 individuals. To allow for multiple comparisons, significance was set at p

Description: Abstract 888 Natural killer (NK) cells are expanded in patients with chronic myeloid leukemia (CML) on tyrosine kinase inhibitors (TKI) and exert cytotoxicity against CML cells. NK cytotoxicity is determined by the balance between inhibitory and activating signals from cell surface killer immunoglobulin-like receptors (KIRs). The inherited repertoire of KIR genes may therefore influence susceptibility to treatment and prognosis in CML patients treated with TKI. To determine if innate immunity is associated with CML susceptibility and response to TKI, we investigated the impact of KIR genotype on the outcome of 166 consecutive patients with Philadelphia+ CML in chronic phase (CP) who received imatinib as first line treatment in our institution. The median follow up was 36 months and 75% of the patients were followed for a minimum of 24 months. One hundred and nineteen patients (71.7%) achieved CCyR, 10 (6.0%) progressed to advanced phase disease and 7 (4.2%) died. The 2-year cumulative incidence of CCyR was 72.2% and the 2 year probability of PFS and OS were 95.7% and 97.3% respectively. The presence of 2 KIR genes, namely K2DL5A and KIR2DS1, was associated with a significantly lower 2 year probability of CCyR (78.8% vs 63.2%, p=0.04 and 82.3% and 65.6%, p=0.03) respectively, PFS (98.9% vs 91.5%, p=0.02 and 98.4% vs 91.0%, p=0.01 respectively) and OS (100% vs 93.9%, p=0.02 and 100% vs 92.6% p=0.03 respectively). On multivariate analysis, the presence of KIR2DS1 (RR=0.66, p=0.03) and Sokal risk score (low risk RR=1, intermediate risk RR= 0.65, p= 0.04 and high risk RR= 0.59, p=0.034) were the only independent predictors for the achievement of CCyR. Furthermore, on multivariate analysis, the presence of KIR2DS1 was the only independent predictor for both PFS (P=0.02) and OS (P=0.03). In order to validate our results we explored the influence of the KIR genotype on achievement of CCyR and PFS and OS in a second independent patient group: KIR genotype was determined in 174 patients with CML-CP treated with first line imatinib within the multi-center STI571 Prospective International Randomised Trial (SPIRIT). The 65 patients who were KIR2DL5A positive had a significantly lower 2 year probability of achieving CCyR, PFS and OS than the 106 patients who were negative for this gene, namely 80.4% vs 86.8 (p=0.04), 85.7% vs 98.1% (p=0.01) and 94.3% vs 100% (p=0.02) respectively. Similarly, the 66 patients who were KIR2DS1 positive had a lower probability of achieving CCyR and lower PFS and OS than the 106 patients who did not have the gene (76.9% vs 87.9%, p=0.004, 85.3% vs 98.1% p=0.01 and 94.4% vs 100%, p=0.02 respectively). On multivariate analysis of this patient cohort KIR2DS1 remained the only independent predictor for the three outcomes. When patients were categorized based on their Sokal risk score and KIR2DS1 genotype, the most significant difference in CCyR, PFS and OS was observed in the 77 patients who had a high Sokal risk score and those with an intermediate Sokal risk score who were KIR2DS1 positive compared to the 89 patients who had a low Sokal risk score and those with an intermediate Sokal risk score who were KIR2DS1 negative; namely, 82.4% vs 59.3% (p=0.002), 92.1% vs 98.8% (p=0.03) and 94.2% vs 100% (p=0.03) and respectively (Figure 1). The mechanism by which KIR2DS1 predicts for a sub-optimal response to therapy is unknown. KIR2DS1+ve NK cells have been shown to secrete transforming growth factor-beta (TGF-beta) upon interaction with their ligand. TGF-b was recently shown to inhibit Akt signalling, a suppressor of the forkhead O transcription factor, FOXO3a, in the CML leukaemia-initiating cells (LICs) and may represent an important mechanism for the CML LIC to survive imatinib. Alternatively, KIR2DS1 may be simply a surrogate marker for another neighboring gene that is directly involved in pathogenesis of CML. In conclusion, our data demonstrate that KIR immunogenetics represent a novel prognostic tool for patients with CML-CP on TKI, and that KIR2DS1 positivity may predict response to imatinib and identify patients at greater risk of treatment failure. Functional and phenotypic studies to determine the expression of KIR2DS1 on the surface of NK cells and to assess the role of the cytokine milieu and the NK phenotype on outcome are currently underway. Figure 1 CCyR and OS according to the expression of K2DS1 genotype and Sokal score Figure 1. CCyR and OS according to the expression of K2DS1 genotype and Sokal score Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 677 In 2009 the spread of influenza A (H1N1) satisfied the World Health Organization (WHO) criteria for a global pandemic and led to the initiation of a vaccination campaign to ensure protection for the most vulnerable patients. However, the immunogenicity of the 2009 H1N1 vaccine in immunocompromised patients has not been specifically evaluated. Furthermore, the number of doses of vaccine required for effective immunization against H1N1 has not been established. Whereas the European Medicines Agency (EMEA) and the UK Department of Health (DoH) recommended the injection of two doses of inactivated H1N1 vaccine 3 weeks apart in immunocompromised individuals, the Centers for Disease Control and Prevention recommended immunization with one dose of inactivated H1N1 vaccine for patients with cancer receiving chemotherapy, followed by a booster vaccine after completion of treatment if the pandemic continued. The aim of this study was to determine the safety and efficacy of the 2009 H1N1 vaccine in patients with hematologic malignancies. We prospectively evaluated the humoral and cellular immune responses to monovalent influenza A/California/2009(H1N1)v-like strain surface antigen vaccine in 97 adults with hematologic malignancies and 25 adult controls. Patients received two intramuscular injections of the vaccine 21 days apart and controls received one dose. Antibody titers, expressed as geometric mean, were measured using a hemagglutination-inhibition assay on days 0, 21 and 49 after injection of the first dose. The induction of virus-specific T-cell responses by H1N1 vaccination was assessed directly ex-vivo by flow cytometric enumeration of antigen-specific CD8+ and CD4+ T-lymphocytes using an intracellular cytokine assay for IFN-γ and TNF-α production on days 0 and 49. Of the 97 patients, 32 had chronic myeloid leukemia (CML) in chronic phase in complete cytogenetic response on the tyrosine kinase inhibitors imatinib or dasatinib, 39 had a B-cell malignancy in complete remission (CR) or untreated, and 26 were recipients of allogeneic hematopoietic stem cell transplantation (allo-SCT) in CR at least 6 months beyond transplant and without evidence of graft versus host disease. The vaccine was well tolerated, with no obvious difference in side effects for patients and controls. By day 21 post-vaccination, protective antibody titers of 1:32 or more were seen in 100% of controls compared to 39% of patients with B-cell malignancies (p

Description: Natural killer (NK) cells exert antimyeloma cytotoxicity. The balance between inhibition and activation of NK-cells played by the inherited repertoire of killer immunoglobulin-like receptor (KIR) genes therefore may influence prognosis. One hundred eighty-two patients with multiple myeloma (MM) were analyzed for KIR repertoire. Multivariate analysis showed that progression-free survival (PFS) after autologous stem cell transplantation (ASCT) was significantly shorter for patients who are KIR3DS1+ (P = .01). This was most evident for patients in complete or partial remission (good risk; GR) at ASCT. The relative risk (RR) of progression or death for patients with KIR3DS1+ compared with KIR3DS1− was 1.9 (95% CI, 1.3-3.1; P = .002). The most significant difference in PFS was observed in patients with GR KIR3DS1+ in whom HLA-Bw4, the ligand for the corresponding inhibitory receptor KIR3DL1, was missing. Patients with KIR3DS1+KIR3DL1+HLA-Bw4− had a significantly shorter PFS than patients who were KIR3DS1−, translating to a difference in median PFS of 12 months (12.2 vs 24 months; P = .002). Our data show that KIR–human leukocyte antigen immunogenetics represent a novel prognostic tool for patients with myeloma, shown here in the context of ASCT, and that KIR3DS1 positivity may identify patients at greater risk of progression.