Abstract: Introduction: Venetoclax (VEN) combined regimen received FDA approval for newly diagnosed elderly or unfit acute myeloid leukemia (AML) patients. Recently, with increasing use as off-label for relapsed or refractory setting in real practice, the evidence that the regimen is potentially effective in R/R AML is emerging. However, there is no answer to the question how VEN combined treatment compares to intensive chemotherapy (IC) in R/R AML when the patients were intended to be cured with bridging to stem cell transplantation (SCT) after either of these treatments. Methods: Adult AML patients (age ≥18 years) who were refractory to or relapsed after anthracycline plus cytarabine induction were subjected to this analysis. As a group of interest, R/R AML patients who received VEN combined regimen were screened first, and we found a total of 54 corresponding patients between Feb 2020 and Jan 2021. As a comparison, we searched historical controls who were treated with salvage IC during the past two years, revealing a total of 89 patients between Jan 2018 and Jan 2020. Patients analyzed here received VEN-combination or IC as their first or second-line salvage therapy. Results: Overall, the median age was 49 years (range, 18 to 72), and the patients of first line salvage (n=125, 87.4%) were more included. When comparing IC and VEN-combination groups, there were no differences in age, sex, ELN risk groups, cytogenetics, disease type or mutation status. However, more patients in VEN-combination group were in their second line salvage setting (IC vs VEN-combination; 5.6% vs 24.1%, p & lt;0.001) and had received prior SCT (13.5% vs 38.5%, p & lt;0.001). The percentage of patients who had CR, CRi and MLFS were 39.3%, 6.0%, and 0.0% in IC group, and were 40.7%, 11.1%, and 7.4% in VEN group, yielding an overall response rate of 45.2% and 59.3%, respectively (p=0.108). Regarding the bridging to SCT, patients who underwent allo-SCT after salvage therapy were 69.7% in IC and 68.5% in VEN-combination group (p=0.886), of whom 62.9% (IC) and 86.5% (VEN-combination) of patients achieved either CR, CRi or MLFS at SCT (p=0.012). Of note, the median time to SCT were shorter in patients who received VEN-combined regimen (median, 103 days) compared to patients receiving IC (median, 139 days) (p=0.012). The median OS without censoring at the time of SCT were 334 days (95% CI, 198-469) and 381 days (95% CI, 345-416) in IC and VEN-combination group, respectively (p=0.592), after a median follow up period of 685 days and 345 days. VEN-combined regimen was significantly superior to IC in achieving response (p=0.031, OR=2.980 [95% CI 1.105-8.033]) and showed trend towards better survival (p=0.059, HR=0.454 [95% CI 0.200-1.030] ) among the patients of fist-line salvage setting only, although significant differences were not shown in overall patients. Conclusion: These findings suggest that VEN-combined treatment is a feasible option for R/R AML and could be chosen over salvage IC in R/R AML based on its anti-leukemic response, bridging to SCT with disease control and survival, which were comparable to IC in overall patients and were tended to be superior in patients of first salvage setting only. Disclosures 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. Lee: Alexion, AstraZeneca Rare Disease: Honoraria, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: venetoclax use in R/R AML: off label use

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: 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.