Abstract: Background: Myeloid-derived suppressor cells (MDSC), a heterogeneous group of myeloid cells, have emerged as immune regulators, having a high potential to suppress T cell responses. Although uniform characterization of human MDSC needs to be elucidated, they can be divided into the categories of granulocytic (G-MDSC) and monocytic (M-MDSC). Recent studies have reported that MDSC, generated in vitro or in vivo, alleviated the severity of graft-versus-host disease (GVHD) in murine allogeneic transplant models and in human delayed M-MDSC reconstitution was associated with the occurrence of acute GVHD. However, whether G-MDSC and M-MDSC may have different role on the outcomes after allogeneic stem cell transplantation (SCT) remains obscure. Methods: This prospective study was aimed to identify the clinical implications of early G-MDSC and M-MDSC expansion as a predictor for the occurrence of acute GVHD (aGVHD), infections, CMV reactivation, and survival outcomes after allogeneic SCT. The peripheral blood samples from 130 patients with acute myeloid leukemia and myelodysplastic syndrome-refractory anemia with excess blasts, who underwent allogeneic SCT between Jan. 2013 through Oct. 2014 were taken at engraftment and analyzed by flow cytometry. Results: Seventy-eight men and 52 women were enrolled in this study. The median age was 45.5 years (range, 17-68). To compare the predictive role of MDSC for various transplants, the patients were grouped according to the median values of the frequency of G-MDSC and M-MDSC. High G-MDSC at engraftment was a potential factor promoting the occurrence of ≥ grade 2 aGVHD at 100 days (30.8% vs. 47.7%, P = 0.023), whereas high M-MDSC group had no difference in the occurrence of ≥ grade 2 GVHD compared that of low M-MDSC group. There was no difference in CMV reactivation, infection rate, and TRM according to G-MDSC recovery. In contrast, patients in the high M-MDSC group had a higher cumulative incidence of infection at 100 days (25.1% vs. 48.2%, P = 0.002), and TRM (6.4% vs. 22.6%, P = 0.018), compared with the patients in the low group. Ultimately, multivariate analyses reveal that high G-MDSC had a trend for the occurrence of ≥ grade 2 GVHD at 100 days (RR 1.72, 95%CI (0.95-3.11), P = 0.071) and high M-MDSC could predict a higher infection rate (RR 2.30, 95%CI (1.30-4.07), P = 0.004) and higher transplant related mortality (TRM) (RR 3.30, 95%CI (1.10-9.90), P = 0.033). In addition, high M-MDSC was associated lower event-free survival (P = 0.008). Conclusion: Our data demonstrated that the high G-MDSC in the peripheral blood at engraftment was associated with a trend toward higher incidence of aGVHD and high M-MDSC was an independent factor for infection and TRM. Discrepancy of the role of G-MDSC and M-MDSC after allogeneic SCT suggests that difference of MDSC reconstitution into the more differentiated subset may predict transplant outcomes, including aGVHD, infections, and TRM. Disclosures No relevant conflicts of interest to declare.

Abstract: Background: Lenalidomide combined with low-dose dexamethasone (Len-dex) is an effective treatment for the patients with refractory/relapsed multiple myeloma (RRMM). The anti-myeloma effect of lenalidomide is associated with activation of the immune system, but the exact immunomodulatory mechanisms in vivo and clinical impact of Len/dex in RRMM patients remains unclear. In this study, we analyzed immune cell populations in patients receiving Len-dex for the treatment of RRMM. Methods: Peripheral blood samples from 90 RRMM patients were taken on day 1 of cycles 1 (baseline), 2, 3, and 4 of Len/dex therapy. CD3+, CD4+, CD8+, CD161+ T cells, natural killer (NK) cell (CD16+/CD56+), NKT-like cell (CD3+/CD56+) and myeloid-derived suppressor cell (MDSC) including granulocytic (G-MDSC) and monocytic (M-MDSC) were analyzed by flow cytometry. In addition, response was assessed in 81 patients receiving more than 4 cycles of Len-dex and the comparison of cell populations according to an achievement of ≥very good partial response (VGPR) was performed. Results: Forty-eight men and 42 women were enrolled in this study. The median age was 61 years (range, 29-84 years). At baseline, peripheral blood CD3+ cell frequency was 51.65 ± 1.79% which was significantly decreased to 41.67 ± 2.44% (P=0.001) and 39.72 ± 2.90% (P 〈 0.001) after 2 and 3 cycles of therapy, respectively. Frequency of both CD4+ cell and CD8+ cells was also significantly decreased by 3 cycles of therapy, while NK cell frequency was significantly increased after Len-dex treatment (P 〈 0.05). For the T-cell subset, the frequency of CD8+ CD161high cells was significantly decreased (1.13 ± 0.16% at baseline to 0.65 ± 0.13% at post-3 cycles, P 〈 0.05), while no trend was observed in CD4+ CD161+ cell frequency. No significant change was observed in frequency of G-MDSC and M-MDSC after Len-dex. Among 81 evaluable patients, 36 patients obtained ≥VGPR and 45 ≤ partial response. After adjusting for factors affecting failure of achieving a response of ≥VGPR on univariate analyses, multivariate analyses showed that decrease in CD8+ cell frequency (P=0.043) and increase in M-MDSC frequency (P=0.033) by post-3 cycles of Len-dex treatment were predictors for failure of achieving ≥VGPR. High frequency of NKT-like cell prior to Len-dex treatment could predict a longer time to progression (RR of 0.40, P=0.011). In addition, patients with less decrease in frequency of both CD3+ cell and CD8+ cells by post-3 cycles had a longer time to next treatment (RR of 0.24, P=0.024 and RR of 0.33, P=0.044, respectively). Conclusion: Our data demonstrate that Len-dex therapy in patients with RRMM is associated with decreased frequency of T cells with a trend of increased NK cell frequency. Change in CD8+ cell and M-MDSC frequency can correlate with the quality of response to Len-dex. Baseline NKT-like cell frequency and change in CD3+ and CD8+ cells early after treatment may predict continuation of anti-myeloma effect of Len-dex therapy. Disclosures No relevant conflicts of interest to declare.

Abstract: Background Although the combination of lenalidomide and low-dose dexamethasone (Len-dex) is known to preserve the efficacy with reduced toxicity than lenalidomide plus high-dose dexamethasone (Len-Dex) in patients with refractory/relapsed multiple myeloma (RRMM), infection is still a leading toxicity. Moreover, the patterns and risks for infection in patients with RRMM during Len-dex treatment remain unclear and there is a need to identify contributing factors associated with increased risk for infection. Considering the disease-related and treatment-related immune deficits in patients with RRMM, we explored the predictive implications of the revelation of the immune cell populations prior to Len-dex initiation for the occurrence of infection. In addition, the various clinical and laboratory parameters were analyzed. Methods Clinical and microbiology records of 90 RRMM patients during Len-dex treatment were reviewed and risk factors for infection were analyzed using the logistic regression. In addition, to develop the new immune cell biomarker, we prospectively examined immune cell populations (CD3, CD4CD161, CD8CD161, Lin-HLA-DR-CD11b+CD33+, CD14+HLA-DR-, NK and NKT cells) of the peripheral blood taken on baseline of Len-dex therapy. Results Forty-eight men and 42 women were enrolled in this study. The median age was 61 years (range, 29-84 years). During a median 11 cycles of Len-dex treatment, 52 (57.8%) patients experienced at least 1 infection episode. Of a total of 92 episodes of infection, 58 (63%) episodes were clinically defined, 29 (31.5%) episodes were microbiologically defined, and 5 (5.4%) episodes were fever of unknown focus. Severe episodes were frequently observed during early 3 cycles. In the univariate analyses, lower Hb ( 〈 10 g/dL) and serum albumin ( 〈 3.5 mg/dL), and higher serum creatinine (≥2 mg/dL) were associated with increased risk of infections (≥grade 3) during early 3 cycles. After adjusting for risk factors for infection on univariate analyses, multivariate analyses showed that lower Hb ( 〈 10 g/dL) was an independent factor for the occurrence of infections and lower frequency (P = 0.009) and absolute count (P = 0.072) of CD4+CD161+ cells in peripheral blood prior to Len-dex were associated with the occurrence of infection, especially during early 3 cycles of Len-dex therapy. Conclusions We demonstrated several clinical predictive factors for the occurrence of infection in patients with RRMM receiving Len-dex treatment. And we found that the frequency and absolute count of CD4+CD161+ cells may provide additional information for predicting the occurrence of infection in early period of Len/dex therapy. Disclosures No relevant conflicts of interest to declare.

Abstract: Background: Recently, a high-risk subgroup of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) called Philadelphia chromosome (Ph)-like ALL was identified in adolescents and young adults. However, there are conflicting data regarding the incidence and prognosis of Ph-like ALL in adult patients, and no data have yet been introduced in Asian countries. Aim: We tried to identify the prevalence and genetic characteristics of Ph-like ALL in adult patients with newly diagnosed BCP-ALL. Furthermore, we analyzed the clinical characteristics, long-term outcomes, and prognostic impact of Ph-like ALL compared with non-Ph-like ALL (Ph-positive ALL or BCP-other ALL). Methods: Between December 2008 and March 2016, 334 adult patients with newly diagnosed BCP-ALL who received modified hyper-CVAD chemotherapy and had suitable material for genomic analysis were included in this analysis (median age, 43 years [range, 16-65 years]). Our post-remission therapy was based on allogeneic hematopoietic cell transplantation (HCT) if a donor is available. Ph-like ALL was determined by next generation sequencing using the Archer® FusionPlex® ALL Kit (ArcherDX Inc., CO) which can detect fusions, point mutations, and expression levels in 81 genes associated with ALL and additional FISH analysis was done. Results: Overall, 48 (14.4%) of the 334 patients were Ph-like ALL, and the cohort was divided into patients with ABL1-class rearrangements (n=4), CRLF2 rearrangements (n=11), JAK2 rearrangements (n=4), other JAK-STAT sequence mutations (n=12), and RAS mutations (n=17). The remaining 286 patients had Ph-positive ALL (n=197) and BCP-other ALL (n=89; including 19 patients with KMT2A [MLL] rearrangements). No significant differences in baseline characteristics were observed between the Ph-like ALL and BCP-other ALL subgroups, whereas patients with Ph-positive ALL were older (median age, 47 vs 37 years; p=0.003) and had higher presenting leukocyte counts (median, 33.1 vs 11.4´109/L; p=0.001) compared with Ph-like ALL. The complete remission rate was somewhat different between the 3 disease subgroups (Ph-like ALL, 97.9%; Ph-positive ALL, 95.9%; BCP-other ALL, 88.8%; p=0.027). A higher proportion of patients with Ph-like ALL actually received allogeneic HCT in CR1 than patients with non-Ph-like ALL (Ph-like ALL, 91.6%; Ph-positive ALL, 84.2%; BCP-other ALL, 71.9%; p=0.007). With a median follow-up of 58.1 months (range; 6.0-121.0), outcomes of patients with Ph-like ALL were not inferior compared with outcomes of patients with non-Ph-like ALL. Disease-free survival rates at 5 years were 56.0% for Ph-like ALL, 42.6% for Ph-positive ALL, and 40.6% for BCP-other ALL (p=0.138). The 5-year cumulative incidence of relapse were 19.2% for Ph-like ALL, 35.3% for Ph-positive ALL, and 33.5% for BCP-other ALL (p=0.076). These findings were maintained when only patients receiving HCT were considered. Within the Ph-like ALL subgroup, patients with ABL1-class and CRLF2-rearrangements had worse outcomes than patients with other JAK-STAT sequence and RAS mutations. Also, patients with higher CRLF2 expression had inferior outcomes. Conclusion: Within the limitation of sample size, our data showed a different frequency of subtypes (e.g., lower incidence of CRLF2 rearrangements, higher RAS mutations) and treatment outcomes of adult patients with Ph-like ALL compared with other Western reports. Racial and ethnic differences in the patient population studied may have contributed to these differences. We also suggest that HCT-based post-remission therapy may overcome the poor prognosis of Ph-like ALL. Disclosures Kim: BMS: Research Funding; Ilyang: Research Funding; Pfizer: Research Funding; Novartis: Research Funding. Lee:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding.

Abstract: In western countries, several studies have reported that CMV seronegative acute leukemia (AL) patients might have a beneficial effect from CMV seropositive donor for reduction of relapse. These observations resulted from subclinical CMV viremia with delayed initiation of antiviral therapy which showed a stimulatory effect on natural-killer cells and cytotoxic T-cells that may enhance graft-versus-leukemia (GVL) effect. We tried to evaluate the relationship between CMV reactivation and relapse of AL in Korean population, in which CMV serostatus is mostly positive for both donors and recipients. Three hundred eighty-nine AL patients with AML (n=197), ALL (n=192) who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first remission between 2007 and 2011 were retrospectively analyzed. Most of the donors (95.1%) and recipients (98.7%) were CMV seropositive. After engraftment, we serially measured CMV RQ-PCR once a week for surveillance of CMV reactivation and generally initiated preemptive ganciclovir (GCV) therapy when the titer reaches over 15,000copies/mL. Below 15,000, patients without GVHD were observed with tapering immunosuppressive agents. To evaluate the anti-leukemic activity of CMV viremia, patients with early death ( 〈 150 days) were excluded and subgroup analysis was performed according to the occurrence of chronic GVHD. OS, EFS and relapse incidence was compared between the 3 groups; undetected viremia, GCV-treated viremia with higher-level and untreated viremia with lower-level of CMV RQ-PCR. In the entire group, CMV viremia was an adverse factor for OS (p 〈 0.001) and EFS (p 〈 0.001), and patients with acute-GVHD significantly showed more CMV viremia (91.5% vs. 83.6%, p=0.017). After excluding early death (n=51), 195 patients without chronic-GVHD were finally analyzed. Untreated lower-CMV group (n=93) showed significantly superior OS (p 〈 0.001) and EFS (p 〈 0.001) with lower relapse rate (p=0.003) compared to the treated higher-CMV (n=72) and CMV-undetected group (n=30). Patients with other than untreated lower-CMV viremia and adverse-risk karyotype were independent adverse-risk factor for OS, EFS and relapse by multivariate analyses in subgroup without chronic GVHD. In chronic-GVHD subgroup (n=143), CMV-undetected group showed superior OS (p=0.006) and EFS (p=0.010), but the relapse rate was not significantly different (p=0.238). The results were similar in subgroup analyses for AML and ALL. Our data showed the possible GVL effect associated with CMV reactivation measured by RQ-PCR. This finding should be evaluated by larger validated studies to disclose the role of CMV reactivation in AL in the CMV seropositive population. Disclosures: No relevant conflicts of interest to declare.

Abstract: Core-binding factor (CBF)-positive acute myeloid leukemia (AML) is regarded as a favorable group with good complete remission (CR) rate after induction chemotherapy and is generally treated by repeated high-dose cytarabine consolidation or autologous hematopoietic stem cell transplantation (auto-HSCT). However, emerging molecular studies have recently identified the unfavorable CBF-AML subgroup which should be treated by further intensified treatments. This single center retrospective study enrolled 264 adult CBF-AML patients from 2002 to 2011. Except 15 patients, 217 patients were treated by intensive induction chemotherapy and 32 were treated by reduced intensity treatment. After CR achievement, patients with available donor were treated by allogeneic (allo)-HSCT and the rest were treated by auto-HSCT or chemotherapy alone. We evaluated 206 patients who achieved CR after intensive chemotherapy regarding survival outcomes according to post-remission therapies and prognostic factors which affected the outcomes. The factors included cytogenetic study and subgroup analysis with additional chromosomes and normal karyotype (NK) mosaicism, c-kit mutation, minimal residual disease (MRD) qPCR level, BAALC and WT1 expression. We achieved CR in 94.9% with intensive chemotherapy and 115 patients went on allo-HSCT and 72 were treated by auto-HSCT. There were no significant OS differences between CBF¥â/MYH11 and RUNX1/RUNX1T1 (p=0.173), and auto-HSCT showed favorable EFS (p=0.038) compared to allo-HSCT and chemotherapy alone. For cytogenetic analysis, inv(16) or t(16;16) with NK mosaicism showed the most favorable OS compared to t(8;21) with additional chromosome (¡Ã2) which showed the worst OS. c-kit mutation was a poor prognostic factor with lower reduction rate of post-induction MRD qPCR, however the effect was not definite after HSCT. For HSCT patients, we analyzed post-HSCT MRD qPCR and WT1 expression level. We found that undetected level of post-HSCT MRD qPCR and lower level of WT1 expression ( 〈 0.015) showed the most favorable OS with no relapse cases. For CBF-AML, the role of auto-HSCT and allo-HSCT for selected patients should be re-evaluated by large prospective studies and the values like post-treatment MRD qPCR and WT1 expression level can be used for prediction of patients who might relapse with higher probability. Disclosures: No relevant conflicts of interest to declare.

Abstract: Background Cytomegalovirus (CMV) establishes lifelong latency after primary infection under the control of the immune system because of the numerous virus evasion strategies that interfere with the host immune response at many levels. Human leukocyte antigen (HLA)-restricted cytotoxic T lymphocytes (CTLs) are involved in the early immune response and are an important defense mechanism in CMV infections, reactivation, and related diseases. Furthermore, an assessment of the clonal diversity of T cell responses against CMV infection provides important insight into the molecular basis of T cell immunodominance. In this single-center study, we tried to demonstrate a specific correlation between the donor HLA genotype and cumulative incidence of CMV reactivation and disease. Patients and methods We retrospectively analyzed 613 donors and recipients diagnosed with acute myeloid leukemia (AML) who received allogeneic hematopoietic stem cell transplantation (allo-HSCT) from matched siblings (n=260), matched unrelated donors (n=167), or haploidentical family donors (n=186) from 2012 to 2017. The CMV-related disease was diagnosed with aggressive procedures in suspicious tissues such as the eyes, gastrointestinal tract, or respiratory tract. The cumulative incidence of overall CMV-related diseases was 12.3% (n=71; range, 9.8 - 15.2), and in each matched sibling, matched unrelated, and haploidentical family donor allo-HSCT group were 6.1% (range, 3.6-9.6), 14.4% (9.2-20.7), and 19.4% (14.0-25.5), respectively. Except for seven patients, all 64 patients developed CMV disease in the CMV reactivation state. We determined the genotypes of the HLA-A, B, C, and DRB1 alleles in 613 donors and recipients by sequencing method and further selected 560 (91.4%) CMV IgG seropositive donors to identify the genetic influence of donor HLA according to CMV infection. Results We first analyzed the relationship between entire donor HLA allotypes and the cumulative incidence of CMV-related disease, then subdivided the donor groups by CMV IgG seropositivity. In the CMV IgG seropositive donor group, we conducted subgroup analysis to identify any difference in CMV-related disease incidence according to types of allo-HSCT. As a result, an entire donor CMV serostatus, three genotype alleles, HLA A*3004 (OR 2.8; p-value 0.044), B*5101 (OR 2.3; p-value 0.003), and DRB1*0901 (OR 2.3; p-value 0.004), demonstrated a statistically significant odds ratio (OR) value with the proper number of patients. However, in the donor CMV IgG seropositive subgroup, two allotypes, HLA B*5101 (OR 2.0; p-value 0.003) and DRB1*0901 (OR 2.7; p-value 0.002), remained. Interestingly, the HLA DRB1*0901 allele showed a concrete association (OR 6.0; p-value 〈 0.001, and p(c)-value 0.002) between CMV IgG seropositive donor HLA and the CMV-related disease incidence of the recipient, especially in the haploidentical allo-HSCT setting. The HLA-B*5101 allele showed a statistically significant association in the IgG seropositive donor subgroup with the matched unrelated allo-HSCT recipient and in the IgG seronegative donor subgroup. HLA-DRB1*1302 showed a promising value as the protective marker (OR 0.2; p-value 0.041) only in the IgG seropositive donor subgroup with the matched unrelated allo-HSCT recipient category. HLA-A*2402 (OR 3.6; p-value 0.048) was only significant in the IgG seropositive donor subgroup with the matched sibling and haploidentical allo-HSCT recipient category. HLA-DR*1501 (OR 2.6; p-value 0.039) was only significant in the IgG seropositive donor subgroup with the matched sibling allo-HSCT recipient category. Conclusion This study demonstrated that certain donor alleles, donor CMV IgG serostatus, and types of allo-HSCT, especially the seropositive donor HLA-DR*0901 allele in the haploidentical allo-HSCT setting, significantly correlated with high CMV-related disease incidence and might be considered risk markers for suitable donor selection. Additionally, the specific donor HLA allele showed either protective or aggravated CMV-related disease incidence in a different allo-HSCT setting. For patients receiving various types of allo-HSCT, a strategic approach to donor selection with careful consideration of donor HLA allotype is important and intensive CMV reactivation monitoring may be required, especially in acute GVHD under active steroid pulse treatment. Disclosures Kim: BMS: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Ilyang: Research Funding. Lee:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding.

Abstract: Antihuman T-lymphocyte immune globulin (ATG) was shown to lower the incidence of chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) from an unrelated donor. The type, dose, and duration of ATG treatment is a matter of ongoing controversy in allo-HSCT. Furthermore, there has been no phase 3 study to explore the role of ATG-thymoglobulin for the prevention of cGVHD in allo-HSCT from matched siblings, whereas results from a recent randomized trial of ATG-Fresenius was reported (NEJM 2016). We performed a prospective, single-center, open-label, randomized trial of ATG-thymoglobulin as a part of the conditioning regimen. The primary endpoint was the cumulative incidence (CI) of cGVHD at a 2-year evaluation. A total of 126 patients with acute leukemia were planned to be enrolled and assigned randomly at a 1:1 ratio to receive ATG-thymoglobulin (1.25 mg/kg at three and two days before allo-HSCT) or receive no ATG-thymoglobulin stratified according to the refined Disease Risk Index and conditioning intensity. Both groups were well balanced for NCCN risk, disease type, disease status, and MRD status at HSCT. The current study finally enrolled 120 patients with a median of 560 days of follow-up (range 52 - 1257). The CI of cGVHD in the ATG group (n=60) and non-ATG (n=60) group at 2 years after allo-HSCT was 37.2% and 82.7%, respectively (p & lt;0.001). Moderate-to-severe cGVHD occurred in 11.7% of the ATG group and 47.2% of the non-ATG group (p & lt;0.001). In multivariate analysis, non-AGT group, NCCN favorable to intermediate risk, and reduced intensity conditioning remained significant risk factors for the CI of chronic GVHD. There were no significant between-group differences in the CI of infectious complications, acute GVHD, or other allo-HSCT-related adverse events. In contrast, the ATG group had a significantly increased CI of relapse (CIR) compared with the non-ATG-group (28.8% vs 11.7%, p=0.010), which remained significant in the multivariate analysis. Disease-free survival, overall survival, and GVHD and relapse free survival were similar between the ATG and non-ATG groups. In conclusion, the current study revealed that the use of ATG-thymoglobulin, even at a relatively low dose (2.5 mg/kg), decreases the occurrence of cGVHD at a cost of an increased risk for relapse in the setting of allo-HSCT from matched sibling donors for acute leukemia. The optimal dose, timing, and duration of ATG-thymoglobulin should be investigated further. Disclosures Kim: BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sun Pharma.: Research Funding; ILYANG: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Research Funding. Lee:Alexion Pharmaceuticals Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kim:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AML Global Portal: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Hanmi: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BL & H: Research Funding; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Chugai: Consultancy, Honoraria; Amgen Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Yuhan: Consultancy, Honoraria; SL VaxiGen: Consultancy, Honoraria; AbbVie: Honoraria; Sanofi-Genzyme: Honoraria; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract: Introduction Geriatric assessment (GA) typically refers to a multidimensional evaluation designed to evaluate an older person's functional ability, physical health, cognition, psychological health, nutritional status, and social support. The purpose of GA is to develop time-efficient and straightforward tools to evaluate multiple patient characteristics, which may be predictive of treatment outcomes of elderly acute myeloid leukemia (eAML) patients treated with intensive chemotherapy. Given that there have been few prospective studies with conflicting results, we performed a single-center prospective observational cohort study (#KCT0002172) investigating the prognostic value of multiparameter GA domains for eAML patients' tolerance and survival outcomes after intensive chemotherapy. Patients and methods Newly diagnosed eAML patients aged over 60 years who received intensive chemotherapy (n=105) were prospectively enrolled between November 2016 and December 2019. The median age was 64 years (range, 60-75), and they were all considered fit for intensive chemotherapy, with adequate performance and organ function. All the enrolled patients were administered various questionnaires for pretreatment GA and functional evaluation, which included evaluation for social and nutritional support, cognition, depression, distress, and physical function. Results Of the 105 enrolled patients, 93% had an Eastern Cooperative Oncology Group performance score of 1 and received intensive chemotherapy. Among them, between 32.4% and 69.5% of patients met the criteria for impairment on each GA domain. Physical impairment measured by the Short Physical Performance Battery (SPPB) was significantly associated with non-fatal toxicities of Grade III-IV severe infection (odds ratio (OR) 3.000, 95% confidence interval (CI), 1.159-7.788, p=0.024) and acute renal failure (OR 3.891, 95% CI, 1.329-11.39, p=0.013). Cognitive dysfunction measured by the Mini-Mental Status Examination- Korean version of CERAD Assessment Packet was significantly associated with a higher risk of Grade III-IV infection (OR 2.667, 95% CI, 1.025-6.939, p=0.044) and prolonged hospitalization (OR 4.208, 95% CI, 1.485-4.229, p=0.005). Reduced physical function measured by the SPPB and depressive symptoms measured by the Korean version of Short form Geriatric Depressive Scale (SGDS-K) were predictive of worse overall survival (OS; hazard ratio (HR) 1.917, 95% CI, 1.074-3.420, p=0.027 and HR 1.902, 95% CI, 1.005-3.602, p=0.048). SPPB impairment was also significantly related to higher treatment-related mortality (TRM; HR 2.023, 95% CI, 11.057-3.874, p=0.033). Furthermore, gait or sit-and-stand speed, a component of SPPB, was the single most powerful tool to predict survival outcomes of both OS (HR 2.766, 95% CI, 1.471-5.200, p=0.002 and HR 3.615, 95% CI, 1.868-6.999, p & lt;0.001) and TRM (HR 2.461, 95% CI, 1.233-4.913, p=0.011 and HR 3.814, 95% CI, 1.766-8.237, p & lt;0.001). We reconfirmed the prognostic value of preexisting survival prediction models, Wheatley index scores, and web-based AML scores, contrasting to the lack of significance of Ferrara criteria. The addition of SPPB/SGDS-K or gait (or sit-and-stand) speed/SGDS-K improved the predictability of the Wheatley index and web-based AML scores with 69% and 90% relative increases in predictive power for survival, respectively. Conclusions We prospectively demonstrated the prognostic value of physical and psychological assessment by GA for survival outcomes in intensively treated eAML patients. Gait or sit-and-stand speed was the single most powerful tool to identify frailty and predict survival outcomes. The prognostic value of preexisting survival prediction models, Wheatley index scores, and AML scores was reconfirmed.. The addition of measures for physical function and depression improved the predictability of those prediction models for survival. Cognitive and physical impairment were able to identify non-fatal toxicities during intensive chemotherapy in eAML patients. Our data will facilitate the incorporation of GA measures into validated survival prediction models to determine initial treatment for eAML patients in routine clinical care and clinical trials. Further studies are warranted to determine the best ways to adjust the care provided for frail patients to improve treatment tolerance and outcomes. Disclosures Kim: Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding; ILYANG: Research Funding; Takeda: Research Funding. Lee: Alexion, AstraZeneca Rare Disease: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kim: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AIMS Biosciense: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AML-Hub: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BL & H: Research Funding; BMS & Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Boryung Pharm Co.: Consultancy; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Handok: Consultancy, Honoraria; LG Chem: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria; Pintherapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Honoraria, Speakers Bureau; SL VaxiGen: Consultancy, Honoraria; VigenCell: Consultancy, Honoraria.

Abstract: Background Transplantation-associated thrombotic microangiopathy (TA-TMA) is a significant complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and may affect 20% of recipients on average. A few groups have proposed risk or prognostic factors for TA-TMA, including a recent prospective study in a cohort that included both children and young adults (Jodele et al. Blood 2014), yet there has been no reproduced or validated data for consensus. Furthermore, with rapid advances in transplantation technology such as an increased variety of donors, conditioning regimens, and graft-versus-host disease (GVHD) prophylaxis, currently used diagnostic criteria and risk factors for TA-TMA must be re-evaluated using recent large cohorts. Patients and method The purpose of this study is to investigate risk and prognostic factors for TA-TMA in adult patients with acute myeloid leukemia (AML). TA-TMA was primarily diagnosed with previously published diagnostic criteria proposed by our group (Cho et al. Transplantation 2010). Then, we analyzed TA-TMA incidence, risk, and prognostic factors in two independent cohorts for training (n = 382, 2012-2015, retrospective) and validation (n = 231, 2016-2017, prospective). In particular, predictive factors for TA-TMA in a prospective cohort, including children and young adults as recently suggested by Jodele et al., were evaluated in our adult AML patients. Results In the entire cohort (n = 613), the median TA-TMA onset was 66 (range, 5-511) days from allo-HSCT. Among TA-TMA patients, 33.6% and 32.6% of them suffered from proteinuria and AKI, respectively. Also, 33.2% suffered from preceding or concurrent hemorrhagic cystitis (any grade), and 12.7% suffered from VOD/SOS at the time of TA-TMA diagnosis. Regarding the treatment of TA-TMA, 87.3% of patients discontinued or reduced the calcineurin inhibitor with supportive care, while 12.7%, 5.6%, and 4.2% were treated with total plasma exchange, t-PA, and defibrotide addition to calcineurin inhibitor dose modification, respectively. Thirty percent of patients achieved complete remission, and TA-TMA was related to poor three-year OS. There were no significant clinical characteristic differences between the training and validation cohorts with the exception of more haploidentical allo-HSCT in the validation cohort (training vs. validation; 26.7% vs. 36.4%, p = 0.012), and the cumulative incidence of TA-TMA was significantly (p 〈 0.001) higher among the validation cohort (18.8%) than the training cohort (8.9%). For the risk factors of TA-TMA, univariate and multivariate analyses revealed that LDH 〉 1.5 x upper normal limit (training p = 0.042 and validation p = 0.0042), proteinuria ≥30 mg/dL (training p = 0.0019 and validation p = 0.0012), and ≥Grade I hemorrhagic cystitis (training p = 0.0460 and validation p = 0.0049) were significantly associated with an increased risk of TA-TMA in both the training and validation cohorts. Among patients with TA-TMA, concurrent hemorrhagic cystitis upon diagnosis of TA-TMA was a significant factor for inferior overall survival in the entire cohort (32.3% vs. 5.9%, p = 0.031). Conclusions This study validates the feasibility of diagnostic criteria for TA-TMA proposed by our group with a recent large cohort consisting of training and validation cohorts and points out the role of preceding hemorrhagic cystitis as a risk and prognostic factor for TA-TMA in AML. Of note, proteinuria and elevated LDH prior to the appearance of MAHA proposed by Jodele et al. with a younger population were proven to be useful for predicting the occurrence of TA-TMA among adult populations with AML. Disclosures Kim: Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Hanmi: Consultancy, Honoraria; AGP: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SL VaxiGen: Consultancy, Honoraria; Novartis: Consultancy; Amgen: Honoraria; Chugai: Honoraria; Yuhan: Honoraria; Sanofi-Genzyme: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Handok: Honoraria; Janssen: Honoraria; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka: Honoraria; BL & H: Research Funding. Kim:BMS: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Il-Yang co.: Research Funding; Novartis: Research Funding. Lee:Achillion: Research Funding; Alexion: Consultancy, Honoraria, Research Funding.