Single-nucleotide polymorphisms (SNPs) of the programmed cell death protein-1 (PDCD1), programmed cell death protein-1 ligand-1 (PDCD1LG1), and cytotoxic T lymphocyte-associated antigen-4 (CTLA4) genes are implicated in the pathogenesis of some cancers. We investigated the role of PDCD1, PDCD1LG1, and CTLA4 SNPs in MM pathogenesis and the susceptibility to and clinical features of multiple myeloma (MM). We obtained genomic DNA from 124 patients with MM and 211 healthy controls and detected PDCD1 (rs36084323, rs41386349, and rs2227982), PDCD1LG1 (rs2297136 and rs4143815), and CTLA4 (rs733618, rs11571316, rs231775, and rs3087243) genotypes using the polymerase chain reaction-restriction fragment length polymorphism method or the TaqMan allelic discrimination real-time PCR method. The patients with MM had a significantly higher frequency of the PDCD1 GCC/GCC haplotype (rs36084323/rs41386349/rs2227982) compared with the healthy controls. PDCD1 rs2227982 CC genotype was associated significantly with a higher frequency of bone lesions. Patients with PDCD1LG1 rs2297136 TT and TC types (high-expression types) showed lower albumin level than those with CC genotype. In addition, the PDCD1LG1 rs4143815 CC and CG types (high-expression types) were associated significantly with higher frequency of patients who were treated with thalidomide and/or bortezomib. However, there was no statistical significance between CTLA4 polymorphisms and clinical variables of patients with MM. There were no significant differences between all the polymorphisms and OS. Our study indicates that the PDCD1 haplotype is associated with a susceptibility to MM. The PDCD1 rs2227982 and PDCD1LG1 rs2297136 affect the clinical features of multiple myeloma patients.

Background: Acute myeloid leukemia (AML) is a hematological malignancy characterized by the autonomous growth of immature myeloid cells with impaired differentiation and maturation. Cytokines are low-molecular-weight proteins that play a basic and fundamental role in communication within the immune system. Cytokines induce various effects such as differentiation, proliferation, hematopoiesis, and inflammation of target cells. AML is also closely associated with cytokine networks in terms of proliferation, apoptosis, and differentiation of leukemic cells. Cytokines produced by Th1 involved in cell-mediated immunity are called Th1 cytokines. Th1 cytokine includes TNF-α and IL-2. Several studies have reported that TNF-α is highly expressed in leukemia cells with AML patients. Other studies have also reported that high serum level of TNF-α of AML patients is associated with poor survival outcome. However, the association between Th1 cytokine polymorphisms: TNF-α -857C/T and IL-2-330T/G and the pathogenesis of AML is unclear. Therefore, we investigated the role of these polymorphisms in AML. Materials and Methods: This study included 101 patients with AML [male/female, 56/45; age, 15-86 years; median age, 58 years; MRC classification favorable (n = 38), intermediate (n =56), and adverse (n = 7)] and 202 healthy race-matched controls. All participants provided written informed consent. This study was approved by the Institutional Review Board of Gunma University Hospital. Genotyping was performed by the polymerase chain reaction (PCR)-restriction fragment length polymorphism method. Genotype and allele frequency were compared between patient group and control group by χ2-test. Clinical features were compared using Student's t and χ2 tests. Overall survival (OS) and leukemia free survival (LFS) were calculated using the Kaplan-Meier method. Survival curves were compared using the log-rank test. Analyses were performed using the SPSS software package ver. 25 (IBM, Armonk, NY, USA). P < 0.05 was considered to represent statistical significance. Results: TNF-α -857 C/T nonCC genotype (higher producer type) increases the risk of AML (AML vs. controls = 39.6% vs. 28.2%, OR = 1.67, 95% CI = 1.01-2.75, p = 0.045). Moreover, the frequency of TNF-α -857 C/T T allele (higher producer type) was higher in AML patients compared to controls (AML vs. controls = 24.8% vs. 16.8%, OR = 1.625, 95%CI = 1.078-2.451 p = 0.02). There was no significant difference between AML patients and controls in genotype and allele frequencies of IL-2 -330 T/G. In the analysis of clinical features, the average platelet count was significantly lower in TNF-α -857 C/T TT genotype (higher producer type) (TT vs. nonTT = 2.4±1.4 vs. 4.4±5.9, p < 0.01). TT genotype (higher producer type) was also significantly higher in frequency of MRC classification adverse (TT vs. nonTT = 30.0% vs. 4.4%, p = 0.02) and history of tumor (TT vs. nonTT = 30.0% vs. 6.6%. p =0.04). Moreover, in survival time analysis, patients with TNF-α -857 C/T TT genotype (higher producer type) had significantly shortened OS compared with patients with nonTT genotype (lower producer type) (TT vs. nonTT = 17.2 months vs not reached, p < 0.01). Patients with TT genotype (high producer type) also experienced significantly shortened LFS (TT vs. nonTT = 24.0 months vs not reached, p = 0.04). Furthermore, multivariate analysis of OS revealed TNF-α -857 C/T TT genotype (higher producer type) as an independent prognostic factor (HR = 3.01, 95% CI = 1.04-8.69, p = 0.04), like age and white blood cell count. Conclusion: These results suggest that TNF-α-857 C/T T allele (higher producer type) increases the risk of AML. Furthermore, TNF-α-857 C/T TT genotype (higher producer type) affects the poor prognosis. Therefore, these data suggest the new role of TNF-α polymorphism in AML leukemogenesis. Figure Disclosures Handa: Ono: Research Funding.

eculizumab, with subsequent close monitoring, was offered to all patients achieving complete haematological response (platelets >150 x10 9 /L and normal LDH) and complete renal recovery (eGFR back to baseline without significant proteinuria), with discussion of risks/benefits.Results: 22 patients (68% female, median age 32 years (range 16-67), all with native kidneys and no known chronic kidney disease (CKD), were identified. 21/22 were de novo presentations. Median nadir platelet count was 23 x10 9 /L (range 7-85), and median nadir eGFR was 11.5 ml/min/1.73m 2 (range 3-57), with a high incidence of nephrotic range proteinuria (47%). 14/22 (64%) of patients required renal replacement therapy (RRT). GI (64%) and neurological (41%) symptoms were common. 77% had elevated cardiac troponin T (median 64.5 ng/L, range 17-397, NR 0-14), suggesting subclinical cardiac involvement. 41% had an associated complement genetic abnormality but mutation status did not affect severity of clinical presentation. Eculizumab followed a median of 6 days (range 2-38) of plasma exchange (PEX). After a median duration of therapy of 11 weeks (range 1-227), haematological recovery was seen in 100%, while 81% achieved at least partial renal recovery (median increase in eGFR 49 ml/min/1.73m 2 (range 22-80)). At median duration of follow up of 85 weeks (range 4-255), 54.5% had eGFR >60 ml/min/1.73m 2 , 27% had CKD, 14% were on RRT, and 4.5% had died. Eculizumab was withdrawn in 13/22 (59%) following complete haematological and renal recovery, after a median 10 weeks (range 1-26). 10/13 remained in remission at median 66 weeks (range 14-238) since withdrawal. 3/13 (23%) subsequently relapsed, all within 1 year of withdrawal, with defined triggers in 2/3. All made a full recovery with rapid resumption of eculizumab without need for PEX or RRT. Those who relapsed were more likely to have a complement genetic abnormality, with a trend for a shorter duration of initial therapy (Table 1). Summary/Conclusion: The cohort demonstrates the multisystem nature of aHUS, and reiterates that severe thrombocytopenia and mild renal impairment, although classically associated with TTP, can also be seen in aHUS. Haematological and renal outcomes in the cohort compare favourably with the existing prospective and retrospective literature, demonstrating a positive outlook for aHUS in the eculizumab era. Our withdrawal strategy led to no long term adverse effects, with undeniable benefits (including drug cost savings of over £11 million), and as such adds to the growing body of evidence in favour of such an approach.

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