Long-term Overall Survival Research Articles

Abstract PS08-08: Updated efficacy and safety of SKB264 (MK-2870) for previously treated metastatic triple negative breast cancer (mTNBC) in Phase 2 study

Abstract Background: Patients (pts) with mTNBC have limited treatment options and poor prognosis. The estimated median overall survival (OS) of pts with mTNBC is 12 to 18 months (mo) after diagnosis. SKB264, an antibody drug conjugate (ADC) composed of an anti-TROP2 antibody coupled to a cytotoxic belotecan-derivative via a novel linker with an average Drug to Antibody Ratio (DAR) of 7.4, has shown promising anti-tumor activity and tolerable safety profile in pts with mTNBC (Yin, Y. et al. SABCS 2022). Here, we report the updated data from a Phase 2 expansion cohort for pts with mTNBC (NCT04152499). Methods: Pts with previously treated mTNBC were enrolled to receive SKB264 at 4 mg/kg Q2W or 5 mg/kg Q2W in a non-randomized manner until disease progression or unacceptable toxicity. Tumor assessment was performed every 8 weeks per RECIST v1.1 assessed by investigator. The primary objective was to assess objective response rate (ORR). Secondary objectives included DoR, PFS, and OS. The TROP2 expression was scored using the semi-quantitative H-score method, and a preliminary cutoff was set as 200. TROP2 expression and its association with anti-tumor activity were retrospectively analyzed. Results: At data cut-off date (May 05, 2023), 59 pts were enrolled (23 in 4 mg/kg, 36 in 5 mg/kg), and 88% (52 pts) had received ≥3 prior lines of therapy for metastatic disease. The median follow-up was 22.8 months (mo; 95% CI, 21.3-25.2). The ORR was 42.4% (25/59, 22 confirmed and 3 unconfirmed) and disease control rate (DCR) was 76.3% (45/59). The median duration of response (DoR) was 11.5 mo (range, 3.7 to 22.1+). Median PFS (mPFS) was 5.7 mo (95% Cl: 3.8, 9.1). Median OS (mOS) was 16.8 mo (95% Cl: 12.7, NE), while 12-mo and 24-mo OS rates were 65.0% and 39.5%, respectively. In the subset of pts with high TROP2 expression (H-score>200, N=32), ORR was 53.1% (including 3 complete response), mDoR was 11.1 mo (range, 3.7 to 22.1+), mPFS was 5.8 mo (95% Cl: 3.7, 13.3), mOS was not reached (95% Cl: 9.7, NE), while 12-mo and 24-mo OS rates were 65.3% and 57.3%, respectively. Treatment-related adverse events (TRAEs) of ≥ Grade 3 severity were reported in 57.6% (34/59) of pts. The most common ≥ Grade 3 TRAEs (≥ 10%) were neutrophil count decreased (25.4%), white blood cell count decreased (23.7%), anemia (22.0%) and platelet count decreased (16.9%). TRAEs leading to dose reduction and dose delay occurred in 13.6% (8/59) and 47.5% (28/59) of pts, respectively. Three pts discontinued treatment due to TRAEs (platelet count decreased, dry eye, anaphylactic shock). No cases of interstitial lung disease (ILD), neuropathy or grade ≥3 diarrhea were observed. Serious TRAEs were reported in 28.8% (17/59) of pts; no deaths associated with TRAEs were observed. Conclusions: The updated data continues to demonstrate that pts with heavily pretreated mTNBC could achieve durable response and a trend of long-term OS benefit from SKB264 treatment, along with a manageable safety profile. Higher response rate was seen in mTNBC pts with high TROP2 expression. A Phase 3 study of SKB264 vs. investigator’s choice of chemotherapy in 3L+ mTNBC (NCT05347134) and a Phase 2 study evaluating SKB264 as monotherapy or combination with anti-PD-L1 antibody in first-line setting (NCT05445908) are ongoing in China. Citation Format: Yongmei Yin, Xinhong Wu, Quchang Ouyang, Min Yan, Lihua Song, YunPeng Liu, Zhongsheng Tong, Cuizhi Geng, Ying Wang, Guohua Yu, Xiang Wang, Ying Cheng, Weihong Zhao, Xiaoping Jin, Yina Diao, Gesha Liu, Mengyu Yang, Yue Yang, Yalan Yang, Lian Lu, Junyou Ge, Jin Li, Qun Li. Updated efficacy and safety of SKB264 (MK-2870) for previously treated metastatic triple negative breast cancer (mTNBC) in Phase 2 study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS08-08.

Long-term outcomes and renal responses following autologous hematopoietic stem cell transplantation for light chain deposition disease: a retrospective study on behalf of the Chronic Malignancies Working Party of the European Society for Blood and Marrow Transplantation.

There is little long-term outcome data on the efficacy of autologous hematopoietic stem cell transplantation (ASCT) in light chain deposition disease (LCDD). We identified 51 LCDD patients in the European Society for Blood and Bone Marrow transplantation registry who had undergone upfront ASCT between 1995 and 2021. The median serum creatinine was 280 μmol/L and 45% required renal replacement therapy (RRT) at time of transplant. The melphalan dose was 100 mg/m2 in 23%, 140 mg/m2 in 55% and 200 mg/m2 in 21%. The rate of very good partial response or better improved from 41% pretransplant to 66% at day +100 post- ASCT. In RRT-independent patients, there was a modest improvement in renal function within the first 3 months; the median estimated glomerular filtration rate increased from 44 to 51 mL/min/1.73 m2. There was no further change between 3 and 12 months post-ASCT. No patient who was RRT-independent at ASCT became RRT dependent by day + 100 post-ASCT. Median follow- up post-ASCT was 84 months (interquartile range [IQR]: 46-122). At 6-years post ASCT, overall survival was 88% (95% confidence interval [CI]: 78-98) and PFS was 44% (95% CI: 28-60). The 2-year cumulative incidence of relapse and non-relapse mortality was 17% (95% CI: 6-27) and 2% (95% CI: 0-6), respectively. The cumulative incidence of renal transplantation at 4 years after ASCT was 27% (95% CI: 13-41) with renal transplantation performed between 6.3 and 52.9 months post-ASCT (median 24.7 months). ASCT represents a feasible option for LCDD patients even if RRT dependent at time of transplant. Outcomes are favorable with low non-relapse mortality and good long-term overall survival.

Long-term outcomes of endoscopic therapy versus surgical resection for 2–5 cm gastric gastrointestinal stromal tumors: A population-based comparative study

BackgroundEndoscopic therapy (ET) of gastrointestinal stromal tumors (GIST) has become a viable treatment. We intended to compare long-term outcomes of ET versus surgical resection for 2–5 cm GIST using the Surveillance, Epidemiology, and End Results (SEER) database. MethodsA multicenter retrospective study was conducted to compare the long-term outcomes of patients treated with ET and surgical resection for GIST. The multivariate Cox proportional hazards models were used to identify predictors for patients survival. To balance the clinicopathologic characteristics, a 1:1 propensity score matching (PSM) was utilized. ResultsA total of 749 patients with 2–5 cm GIST were enrolled, of whom 113 accepted ET and 636 underwent surgical resection. Before PSM, there was no significant difference in long-term outcomes between ET and surgical resection (5-year overall survival (OS): 93.5% vs. 91.6%, P=0.374; 5-year cancer-specific survival (CSS): 99.1% vs. 96.5%, P=0.546; 10-year OS: 71.1% vs. 78.2%, P=0.374; 10-year CSS: 93.6% vs. 92.7%, P=0.546). After adjusting for the relevant variables using the multivariable Cox proportional hazards models, we observed that the ET and surgical resection groups were similar in OS (HR 0.726, 95%CI 0.457-1.153, P=0.175) and CSS (HR 1.286, 95%CI 0.474-3.488, P=0.621). After PSM, the long-term OS and CSS of patients with 2–5 cm GIST after ET and surgical resection were comparable. ConclusionsWe found that the long-term survival of patients with 2–5 cm gastric GIST after ET and surgical resection were comparable. Further high-quality studies are needed to confirm the role of ET in 2–5 cm GIST.

Laparoscopic liver resection is superior to radiofrequency ablation for small hepatocellular carcinoma: a systematic review and meta-analysis of propensity score-matched studies.

The approach in small hepatocellular carcinoma (HCC) is controversial, no prospective randomized trials to compare ablative or surgical approaches. We compared the surgical and oncological outcomes after laparoscopic hepatectomy (LH) and radiofrequency ablation (RFA) in small HCC patients based on matched cohort studies that performed propensity score matching (PSM). We systemically searched the PubMed, Cochrane Library, Embase, Web of Science, and the Chinese BioMedical Literature (CBM) databases. All published propensity score-matched studies that compared LH and RFA for small HCC were included in this study. Eight studies with a total of 1273 small HCC cases were included. The results of the meta-analysis revealed that there was no significant difference in the 1- year overall survival (OS) rate between the two groups, whereas the LH group had significantly higher 3- year overall survival rate (RR = 1.14, 95% CI 1.08-1.20, p < 0.00001) as well as 1- and 3-year disease-free survival (DFS) rates (RR = 1.31, 95% CI 1.22-1.42, p < 0.00001; RR = 1.66, 95% CI 1.46-1.90, p < 0.00001) than the RFA group. Meanwhile, the local recurrence rate and intrahepatic distant recurrence rate were significantly lower in the LH group than in the RFA group (RR = 0.29, 95% CI 0.20-0.42, p < 0.00001; RR = 0.67, 95% CI 0.49-0.92, p = 0.01). In comparison with the LH group, the RFA group had a lower incidence of overall and major postoperative complications (RR = 1.81, 95% CI 1.47-2.24, p < 0.00001; RR = 2.76, 95% CI 1.48-5.12, p = 0.001), but there was no significant difference in postoperative mortality between the two groups. In addition, further comparison of single postoperative complications showed that the incidence of ascites was lower in the RFA group than in the LH group (RR = 3.62, 95% CI 1.64-7.96, p = 0.001), whereas there was no significant difference in the incidence of postoperative bleeding, abdominal infection and bile leakage between the two groups (RR = 3.50, 95% CI 0.74-16.61, p = 0.11; RR = 5.00, 95% CI 0.59-42.23, p = 0.14; RR = 4.00, 95% CI 0.45-35.23, p = 0.21). Besides, the hospital stay was shorter in the RFA group than in the LH group (MD = 4.29, 95% CI 2.06-6.53, p = 0.0002). Our meta-analysis demonstrated that in comparison with RFA in the treatment of small HCC, LH provided superior long-term OS and DFS together with lower rates of local and intrahepatic distant recurrence after surgery. However, RFA was associated with better short-term outcomes.

Transoral Robotic Surgery for Oral Cancer: Evaluating Surgical Outcomes in the Presence of Trismus.

Trismus, defined as restricted mouth opening, is a common complication among Taiwanese oral cancer patients, especially those who chew betel quid. However, the impact of trismus on survival outcomes in oral cancer patients undergoing transoral robotic surgery (TORS) is unclear. This study aimed to investigate the associations between trismus and surgical outcomes in Taiwanese male oral cancer patients treated with TORS. We conducted a retrospective propensity score-matched cohort study of 40 Taiwanese male oral cancer patients who underwent TORS between 2016 and 2022. Overall, 20 patients with trismus were matched to 20 patients without trismus. TORS achieved similar operative and short-term clinical outcomes in trismus patients to non-trismus patients. There were no significant differences between groups in operation time, blood loss, margin status, flap reconstruction rates, duration of nasogastric tube feeding, or length of hospital stay. Kaplan-Meier and Cox proportional hazard regression analyses were performed to compare overall survival (OS) and disease-free survival (DFS) between the two groups. The overall survival (OS) rate at three years was significantly lower in patients with trismus than those without trismus (27.1% vs. 95.0%, log-rank p = 0.02). However, there was no significant difference in disease-free survival (DFS) rates between the trismus and non-trismus groups (36.6% vs. 62.7%, log-rank p = 0.87). After adjusting for confounders, trismus was independently associated with a 13-fold increased risk of mortality (adjusted HR 12.87, 95% CI 1.55-106.50, p < 0.05). In conclusion, trismus appears to be an independent prognostic factor for reduced long-term OS in Taiwanese male oral cancer patients undergoing TORS, though short-term surgical outcomes were non-inferior in the trismus patients. Further research is warranted to clarify the mechanisms linking trismus and survival in this population.

High-Risk Hepatocellular Carcinoma: Hepatic Arterial Infusion Chemotherapy versus Transarterial Chemoembolization.

To compare the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) with transarterial chemoembolization (TACE) for the treatment of high-risk hepatocellular carcinoma (hHCC) patients. Between January 2014 and August 2022, a total of 1765 consecutive patients with hHCC who underwent initial intra-arterial therapies were reviewed and divided into a TACE group (n, 507) and a HAIC group (n, 426). The study used propensity score matching (PSM) to reduce selectivity bias. Overall survival (OS) and progression-free survival (PFS) were compared using Kaplan‒Meier curves with the Log rank test. The objective response rate (ORR), conversion surgery rate (CSR) adverse event (AE) comparison and subgroup analysis were performed between the two groups. After PSM 1:1, 444 patients were divided into two groups. The patients with hHCC who received HAIC had higher median PFS (6.1 vs 3.3 months, P < 0.001) and OS (10.3 vs 8.2 months, P=0.303) than TACE. Higher ORR (24.8% vs 11.7%) and CSR (15.5% vs 8.9%) were found in the HAIC group than in the TACE group (both P < 0.05). The incidence of grade 3/4 AE was 23.9% and 8.1% in the TACE and HAIC groups, respectively. The subgroup analysis suggest that HAIC appeared to particularly benefit patients with tumor diameter of more than 10 centimeters (hazard ratio [HR], 0.6; 95% CI, 0.47-0.77; p, 0.00) and PVTT Vp4 (HR, 0.56; 95% CI, 0.39-0.8; P, 0.01) for PFS outperforming TACE. HAIC can provide better disease control for hHCC than cTACE, with a comparable long-term OS and safety.

Advanced lung cancer inflammation index predicts overall survival of hepatocellular carcinoma after hepatectomy.

Limited data are available regarding ALI's clinical relevance and prognostic value in patients with hepatocellular carcinoma (HCC) after hepatectomy. HCC patients who received hepatectomy at the Meizhou People's Hospital from May 2011 to February 2022 were enrolled in the study cohort. The ALI was calculated as follows: ALI = BMI (kg/m2) × ALB (g/dL)/(absolute neutrophil count/absolute lymphocyte count). The primary outcome was overall survival (OS). The secondary outcome was cancer-specific survival (CSS). Univariate and multivariate Cox regression analyses were performed, followed by nomogram construction and decision curve analysis (DCA). 425 HCC patients were enrolled for analyses. Lower preoperative ALI was significantly correlated with incomplete tumor capsule and advanced tumor stage. Lower preoperative ALI was an adverse independent prognostic factor for OS (HR: 1.512, 95% CI: 1.122-2.039, P 0.007) and CSS (HR: 1.754, 95% CI: 1.262-2.438, P <0.001) in HCC patients. The nomogram plot was built based on three (including age, TNM stage, and ALI) and two (including TNM stage and ALI) independent prognostic factors for OS and CSS, respectively. Further analyses indicated that the nomogram had better predictive value and some net benefit than the traditional TNM stage alone, especially in long-term OS. Our study further indicated that ALI could be a prognostic marker for OS and CSS in HCC patients after hepatectomy, especially in long-term OS.

Impact of pulmonary complications following esophagectomy on long-term survival: multivariate meta-analysis and restricted mean survival time assessment.

Pulmonary complications (PC) are common after esophagectomy and their impact on long-term survival is not defined yet. The present study aimed to assess the effect of postoperative PCs on long-term survival after esophagectomy for cancer. Systematic review of the literature through February 1, 2023, was performed. The included studies evaluated the effect of PC on long-term survival. Primary outcome was long-term overall survival (OS). Cancer-specific survival (CSS) and disease-free survival (DFS) were secondary outcomes. Restricted mean survival time difference (RMSTD), hazard ratio (HR), and 95% confidence intervals (CI) were used as pooled effect size measures. Eleven studies were included (3423 patients). Overall, 674 (19.7%) patients developed PC. The RMSTD analysis shows that at 60-month follow-up, patients not experiencing PC live an average of 8.5 (95% CI 6.2-10.8; p < 0.001) months longer compared with those with PC. Similarly, patients not experiencing postoperative PC seem to have significantly longer CSS (8months; 95% CI 3.7-12.3; p < 0.001) and DFS (5.4months; 95% CI 1.6-9.1; p = 0.005). The time-dependent HRs analysis shows a reduced mortality hazard in patients without PC at 12 (HR 0.6, 95% CI 0.51-0.69), 24 (HR 0.64, 95% CI 0.55-0.73), 36 (HR 0.67, 95% CI 0.55-0.79), and 60months (HR 0.69, 95% CI 0.51-0.89). This study suggests a moderate clinical impact of PC on long-term OS, CSS, and DFS after esophagectomy. Patients not experiencing PC seem to have a significantly reduced mortality hazard up to 5years of follow-up.

Lack of clinical benefit from preoperative short-term parenteral nutrition on the clinical prognosis of patients treated with radical gastrectomy for gastric cancer: a two-center retrospective study based on propensity score matching analysis.

Preoperative nutritional support studies for patients undergoing gastrointestinal (GI) surgery mostly focused on enteral nutrition (EN) or long-term (≥7 days) parenteral nutrition (PN). Some studies also found that preoperative short-term PN could improve the postoperative short-term nutritional status of tumor patients. But whether short-term PN support (1-6 days) before surgery can improve the prognosis of patients undergoing surgery for gastric cancer (GC) remains unclear. Therefore, we focused on assessing the effect of preoperative short-term PN on the outcomes of patients undergoing radical surgery for GC. A retrospective analysis of 1,155 patients who underwent radical gastrectomy for GC between July 2014 and February 2019 was conducted. According to whether patients received short-term (1-6 days) PN support before surgery, patients were divided into non-PN group and PN group. After 1:1 propensity score matching (PSM), two groups of patients with similar baseline clinical characteristics were obtained. The incidence of various complications and overall survival (OS) rate were compared between the two groups, and logistic regression analysis for complications, Cox regression analysis for OS, and subgroup analysis were performed. Each group had 478 patients after PSM, and the clinical characteristics were balanced. There were no significant differences in overall postoperative complications (pre-PSM: P=0.495; post-PSM: P>0.99), postoperative length of stay (LOS; pre-PSM: P=0.092; post-PSM: P=0.460), or readmission rate within 30 days (pre-PSM: P=0.496; post-PSM: P=0.793) between the two groups before and after PSM. The OS of PN group before matching was lower than that of non-PN group (P=0.023), but this difference was not significant after matching (P=0.950), but the PN group's hospitalization expenses were substantially greater than those of the control group (post-PSM: P<0.001). Preoperative short-term PN support was not an independent factor in the incidence of postoperative complications (P>0.99) and OS (P=0.949). Subgroup analyses failed to identify those patients who might benefit from preoperative short-term PN support. Preoperative short-term PN support may have no significant benefit on short-term postoperative complications or the long-term OS of patients with GC but increase hospitalization costs. It thus should not be the first choice of treatment for these patients.

Survival outcomes in patients with resectable gastric cancer treated with total neoadjuvant therapy.

338 Background: Perioperative chemotherapy is the standard of care for patients diagnosed with advanced gastric cancer. However, the use of total neoadjuvant therapy (TNT), which includes both chemotherapy and chemoradiation, is increasing in other malignancies. The purpose of this study is to determine overall survival (OS) in a contemporary cohort of gastric cancer patients treated with TNT and surgical resection. Methods: Patients diagnosed with microsatellite-stable clinical T2+ or N+ gastric adenocarcinoma (January 2012 to June 2022) were identified from a prospectively maintained institutional database. Those who underwent staging laparoscopy and received neoadjuvant chemotherapy and chemoradiation therapy, followed by gastrectomy, were included in the study. OS and variables associated with OS were determined using standard statistical methods. Results: Of 203 study patients, the median (interquartile range) age was 61 (50-69.5) years and 50 (24.6%) had tumor involving the gastroesophageal junction. The most common TNT sequence was chemotherapy followed by chemoradiation, which was utilized in 173 (85.2%) patients. The chemotherapy regimen typically given was fluorouracil and oxaliplatin in 149 (73.4%) patients. The most common radiation dose was 45 Gy in 25 fractions (169 [83.3%] patients), with 18 (8.9%) patients receiving 30 Gy in 10 fractions. One hundred ninety-seven (97.0%) patients completed all their planned neoadjuvant therapy. Surgical resection included total gastrectomy in 108 (53.2%), adjacent organ resection in 24 (11.8%), and extended (D1+/D2) lymphadenectomy in 193 (95.1%) patients. Pathologic complete response was achieved (pCR) in 32 (15.8%) patients. The median OS was 8.4 (95% confidence interval [CI] 6.5-not reached) years, and the 5-year OS rate was 65.2% (95% CI 57.8-73.5%). Patients with pCR had a 5-year OS rate of 89.1% (95% CI 78.1-100.0%). On multivariable analysis, D1+/D2 lymphadenectomy (HR 0.21 [95% CI 0.088-0.51]), post-treatment pathologic (yp) T (ypT3 vs ypT0, HR 3.11 [95% CI 1.09-8.82]; ypT4 vs ypT0, HR 5.51 [95% CI 1.64-18.5]) and N stages (ypN1 vs ypN0, HR 2.41 [95% CI 1.13-5.13]; ypN2 vs ypN0, HR 2.43 [95% CI 1.14-5.20]; ypN3 vs ypN0, HR 4.70 [95% CI 2.09-10.6]), incidental distant metastasis at time of resection (HR 3.75 [95% CI 1.50-9.37]), and postoperative complications (HR 2.06 [95% CI 1.21-3.52]) were associated with OS. Conclusions: TNT is associated with a high rate of treatment completion and promising long-term OS for patients with resectable gastric cancer. Comparative studies with perioperative treatment and predictors of tumor response will be important in identifying patients suitable for TNT.

Follow-up for More than 10 Years of Patients with Peritoneal Metastases Treated with Cytoreductive Surgery + Hyperthermic Intraperitoneal Chemotherapy in a Specialized Unit.

Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have demonstrated their impact on disease-free survival (DFS) and overall survival (OS) of patients with peritoneal metastases (PM). However, prior literature lacks evidence regarding any follow-up beyond 5 years. In this study, we analyse long-term OS and DFS (more than 10 years of follow-up) of patients undergoing CRS + HIPEC in a specialized unit. We conducted a retrospective study that included only patients who underwent CRS + HIPEC from January 2001 to May 2012. Data collection was conducted by reviewing medical records and telephone calls to patients or relatives. A total of 86 patients were included. The mean PCI was nine (range 0-39) and complete cytoreduction (CC-0) was reached in 80% of patients. Postoperative complications Clavien-Dindo III-IV occurred in 27.9% of patients and the 30-day mortality rate was 2.3%. After 10 years of actual follow-up, OS was 33.7% and DFS was 31.4%. Considering the historical context in which the standard of care for patients with PM was palliation, the results obtained show that CRS + HIPEC was a valid option, with morbimortality comparable to other major abdominal surgeries and encouraging survival results, since, after 10 years of follow-up, almost one-third of patients are still alive and disease-free.

Hepatocellular carcinoma in HBsAg seroclearance: clinical features, recurrence, and prognosis following curative hepatectomy.

To explore clinical features and prognosis of hepatocellular carcinoma (HCC) in hepatitis B virus surface antigen (HBsAg)-serocleared patients and identify risk factors associated with postoperative recurrence after curative hepatectomy. Patients who had undergone initial hepatectomy for HCC from January 2010 through December 2022. Clinicopathological data were compared between HBsAg-seropositive and HBsAg-serocleared patients. Furthermore, risk factors associated with early and late postoperative HCC recurrence (early and late recurrences (ER and LR), respectively) were analyzed for HBsAg-serocleared HCC patients treated by curative hepatectomy. A total of 2184 consecutive patients undergoing initial hepatectomy for HCC were enrolled, including 339 (15.5%) HBsAg-serocleared and 1845 (84.5%) HBsAg-seropositive cases. Tumor characteristics were comparable between the two groups. After curative hepatectomy, the ER rate was lower in the HBsAg-serocleared group than in the HBsAg-seropositive group (16.2% vs 26.3%; p = 0.000). LR rates in the HBsAg-seropositive and HBsAg-serocleared groups were similar (8.3% vs 6.9%, respectively, p = 0.418). Multivariate analysis showed that among HBsAg-serocleared patients, Hong Kong Liver Cancer stage and microvascular invasion were risk factors associated with postoperative ER, while γ-glutamyl transferase level and neutrophil-to-lymphocyte ratio were associated with LR. HBsAg-serocleared and HBsAg-seropositive HCC patients exhibited similar tumor characteristics. Curative hepatectomy-treated HBsAg-serocleared HCC patients experienced a lower ER rate and better short-term (⩽3 years) overall survival (OS) rates than their HBsAg-seropositive counterparts. LR, very late recurrence, and long-term (4-, and 5-year) OS rates were similar between the two groups.

Liver transplantation for hepatocellular carcinoma: a proposal for including preoperative serological indicators improves the Milan criteria expanded.

Liver transplantation (LT) is the most effective and radical treatment for hepatocellular carcinoma (HCC). Most LT criteria are based on the morphological characteristics of tumors, which are not enough to predict the risk of tumor recurrence. It is found that some serological biomarkers can predict tumor recurrence and may be a good indicator for selecting suitable HCC patients for LT. This article aims to evaluate the predictive effect of preoperative serological indicators on long-term overall survival (OS) and tumor recurrence-free survival (TFS) of patients with HCC after LT, and to explore its significance for expanding the Milan criteria. Clinical data of 253 patients after LT in HCC were collected retrospectively. The receiver operating characteristic curve was used to calculate the best cut-off value. χ2 test was used to analyze the correlation between preoperative serological indicators and tumor pathological features. Univariate and multivariate analyses were used to analyze the risk factors affecting the OS and TFS rates and the predictive values of different LT criteria were compared. Nomogram model was used to predict the OS and TFS rates of patients exceeding Milan criteria. Independent risk factors for poor OS and TFS rates were alpha-fetoprotein (AFP) >200 ng/mL, gamma-glutamyl transpeptidase (GGT) >80 IU/L, total tumor diameter (TTD) >8 cm and microsatellite lesions. Nomogram model showed patients beyond Milan criteria had better survival when AFP ≤200 ng/mL and GGT ≤80 IU/L or AFP >200 ng/mL, GGT ≤80 IU/L and TTD ≤8 cm. According to Milan criteria, AFP, GGT and TTD, Milan-AFP-GGT-TTD (M-AGT) criteria was established. There was no significant difference in OS and TFS rates among patients in M-AGT, Milan, Hangzhou, Malaya and the University of California at San Francisco (UCSF) criteria. Preoperative serological indicators AFP and GGT can effectively predict long-term OS and TFS in HCC patients after LT. Establishing M-AGT criteria based on serological indicators is helpful to supplement the Milan criteria.

Applicability of SIE/Sies/GITMO Fitness Criteria to Therapy-Related and AML-MRC Receiving CPX-351: Results from a Large, Retrospective, Multicentric, Observational Study

Introduction: Treatment of therapy-related AML (t-AML) and AML evolving from an antecedent myelodysplastic syndrome (AML-MRC) represent a clinical unmet need being characterized by an unfavorable outcome. Among the emerging treatment options, CPX-351 has been approved by Regulatory Authorities for the treatment of fit patients (pts) affected by these AML sub-types. Although patented for the treatment of pts fit for intensive chemotherapy, in real-life CPX-351 is also administered to unfit ones, raising the case of tolerability in these categories. Among scores for fitness definition, SIE/SIES/GITMO criteria were extensively validated in large cohorts of AML pts receiving intensive chemotherapy and are increasingly incorporated into clinical trials. However, since these criteria have not been tested yet in the subset of t-AML and AML-MRC, we investigated their applicability in these pts receiving CPX-351. Methods: Patients classified as t-AML or MRC-AML according to WHO2016 classification receiving at least one cycle of CPX-351 were included in the present analysis. Genetic and cytogenetic data were classified according to ELN2017 risk stratification. SIE/SIES/GITMO criteria were retrospectively applied to the whole series to categorize pts as fit or unfit to intensive chemotherapy (Ferrara et. al, Leukemia 2013), aiming at evaluating early-death rate and overall survival (OS). We also verified if ELN2017 risk-stratification might provide further information about long-term outcome, independently of fitness assessment. Results: This retrospective study includes 398 pts with t-AML (19.3%) or AML-MRC (80.7%) enrolled from 29 Italian Institutions between 2018 and 2023. Median age was 65 years (range 32-79), with a slight male prevalence (56.8%). According to SIE/SIES/GITMO criteria, 323 (81.2%) pts qualified as fit and 75 (18.8%) as unfit. Based on ELN2017 risk stratification, 17 (4.3%) pts were classified as favorable, 162 (40.7%) as intermediate, 217 (54.5%) as adverse risk. Only 2 (0.5%) pts were not classifiable due to incomplete genetic data. No differences were observed in terms of ELN2017 risk distribution among the fit and unfit groups. After first induction, 188 of 323 (58.2%) fit and 42 of 75 (56%) unfit pts achieved a complete remission (CR), for a total of 230 (57.8%) pts entering CR. From CPX-351 start, 18 and 55 deaths at 28 days and at 100 days occurred, respectively. Early death rate at these early timepoints statistically differed between the two groups (3% vs. 10.7% at 28 days and 10% vs. 28% at 100 days for fit and unfit pts respectively; p&amp;lt;0.05). No excess of mortality was observed for unfit patients at any timepoint after 100 days from first CPX-351 induction. Competitive risk analyses showed no differences in terms of early death by relapse between the two groups. With a median follow up of 24 months, unfit pts were characterized by a significantly shorter OS as compared to fit ones (median OS of 8 months [CI 95%: 4.1-11.8] and of 18 months [CI 95%: 14.7-21.1] for unfit and fit pts, respectively; p&amp;lt;0.0001) [Figure 1]. When stratified according to genetic/cytogenetic, median OS of fit pts was commensurate with ELN2017 risk (median OS not reached vs 20 months vs 13 months for favorable vs intermediate vs adverse risk, respectively; p &amp;lt; 0.01), whereas no differences in median OS were observed between favorable, intermediate, and adverse categories in unfit pts (median OS of 20 months vs 11 months vs 7 months, respectively; p=NS). Conclusions: In our real-life analysis, we demonstrated that fitness assessment according to SIE/SIES/GITMO criteria identifies populations with discrete outcome among t-AML and AML-MRC pts receiving CPX-351. In unfit patients, outcome prediction seems independent from ELN 2017 risk stratification. Fit and unfit groups achieved similar CR rates but different long-term OS. Such discrepancy can be justified by the higher early mortality observed among unfit pts that translated into shorter long-term survival. In a future perspective, modulating CPX-351 schedule in this group may be a reasonable option to spare toxicity without giving up the opportunity to deliver curative-intended therapies.

A Propensity Score-Matched Analysis on the Outcomes of Brexucabtagene Autoleucel from Zuma-2 Study and Allogeneic Stem Cell Transplantation from the EBMT Database in Relapsed and Refractory Post-Btki Mantle Cell Lymphoma

Introduction Brexucabtagene autoleucel (brexu-cel), an autologous anti-CD19 CAR T-cell therapy, is approved in the US for the treatment of relapsed/refractory (r/r) mantle cell lymphoma (MCL) and in Europe for r/r MCL after ≥2 prior lines of therapies, including Bruton's tyrosine kinase inhibitor (BTKi). The pivotal ZUMA-2 trial demonstrated very good efficacy of brexu-cel in r/r MCL and tolerable safety including cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (Wang et al. J Clin Oncol. 2022). Allogeneic stem cell transplantation (alloSCT) is potentially curative but is associated with high treatment related mortality (TRM) and clinically significant graft-versus-host disease (GvHD). The optimal choice of treatment between brexu-cel and alloHCTs is unclear. We conducted a propensity score matched (PSM) analysis of brexu-cel and alloSCT in patients (pts) with r/r MCL. Methods Pts from ZUMA-2 were matched with alloSCT pts from the EBMT database. Selection criteria to identify pts in the EBMT registry were: r/r MCL diagnosis and receipt of alloSCT from 2010 to 2020, age ≥18 years, prior treatment with anti-CD20, prior anthracycline- or bendamustine containing regimens, and prior BTKi. We performed a 1:1 nearest neighbor matching without replacement, balanced for 5 baseline parameters: age, sex, number of prior treatment lines, time from diagnosis to cellular immunotherapy, and prior autologous stem cell transplantation (autoSCT). The primary endpoint was overall survival (OS) from cellular immunotherapy. The following secondary endpoints were analyzed: progression-free survival (PFS), TRM, defined as incidence of deaths which are related to the treatment and occurred in absence of disease progression, and rate of GvHD. Competing risks were defined as relapse, progression or treatment-unrelated death for TRM, and death for GvHD. The EBMT registry includes pts who actually underwent alloSCT. To characterize the dropout rate prior to cellular therapy, we conducted a multicenter intent-to-treat (ITT) analysis and identified 77 pts with r/r MCL for whom an unrelated donor search was initiated and an alloSCT was intended. Results Sixty-four of 68 pts from the ZUMA-2 cohort were included in the study; 4 pts were excluded because of inability to anonymize. A total of 270 pts who had undergone alloSCT and met eligibility criteria were identified in the EBMT registry. Patient characteristics between the brexu-cel and the alloSCT cohorts were imbalanced. Brexu-cel pts were older (p&amp;lt;0.001), had more prior lines of treatment (median 3 vs 2, p&amp;lt;0.001), had less prior autoSCT (41% vs 71%, p&amp;lt;0.001), and had longer time between diagnosis and treatment (53 vs 40 months, p=0.01). After 1:1 PSM matching, criteria were well balanced between cohorts. Median follow-up time was 36.5 and 46.4 months for the brexu-cel and the matched alloSCT cohort, respectively. PFS and long-term OS were similar between both cohorts (Fig. 1A). However, the risk of death within the first 12 months was significantly lower in the brexu-cel cohort vs the alloSCT cohort (logistic regression with inverse probability of censoring weighting, risk ratio=0.5, 95% confidence interval [CI] 0.3-0.9, p=0.02). This was mainly attributable to the significantly higher TRM rate in the alloSCT cohort (alloSCT vs brexu-cel: cause specific hazard ratio=7.7, 95% CI 1.9-31.6, p=0.005, Fig. 1B). The cumulative incidence of acute GvHD grade ≥3 at 3 months and chronic GvHD at 24 months was 17.9% (95% CI 9.1-29.0%) and 44.3% (95% CI 30.6-57.2%), respectively. In our ITT analysis, the dropout rate was significantly higher in the cohort intended to receive alloHCT (23%, [18/77]) vs the cohort intended to receive brexu-cel (8% [6/74]; Fisher test, p=0.01). For alloSCT, failure to proceed to cellular therapy was related to progression in 13%, change of patient's preference in 5% and ineligibility in 4%; in the brexu-cel cohort this was due to manufacturing failures in 4% and progression in 3%. Conclusion Brexu-cel is an effective treatment in pts with r/r MCL post-BTKi with a superior safety profile compared with alloSCT, as indicated by lower 12-month mortality, lower TRM, and absence of chronic GVHD-related morbidity. Despite efforts to match pts between the cohorts, the inherent limitations of this study, such as incongruent data sources and case selection bias, have to be considered. Additional analyses will be presented.

Long-Term Outcomes from the Phase 3 OCEAN (OP-103) Study: Melflufen and Dexamethasone (Dex) Versus Pomalidomide (Pom) and Dex in Relapsed Refractory Multiple Myeloma (RRMM)

Background/Introduction: Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases resulting in rapid release of alkylating agents inside tumor cells. Based on the phase 2 HORIZON study and supported by the phase 3, randomized, controlled OCEAN study, melflufen was approved in Europe for use in patients (pts) with triple-class refractory RRMM with ≥3 prior lines of therapy (LoTs) and without prior autologous stem cell transplantation (ASCT) or with a time to progression (TTP) &amp;gt;36 mo after prior ASCT. In the OCEAN study (NCT03151811), melflufen + dex showed superior progression-free survival (PFS) compared with pom + dex (6.8 vs 4.9 mo; hazard ratio [HR]: 0.79; P=0.032); PFS benefit in the melflufen + dex group was mainly driven by pts who had not received prior ASCT. Overall survival (OS) trended in favor of melflufen + dex in pts without prior ASCT and favored pom + dex in pts with prior ASCT (Schjesvold et al. Lancet Haematol. 2022;9:e98). Post-hoc analyses of OCEAN and HORIZON demonstrated that a TTP &amp;lt;36 mo after prior ASCT was a negative prognostic factor for OS with melflufen + dex (Sonneveld et al. Clin Lymphoma Myeloma Leuk. 2023;S2152). Here, we present long-term OS and safety data from the final analysis of the OCEAN study. Methods: Pts with RRMM (2-4 prior LoTs including lenalidomide [len] and a proteasome inhibitor) refractory to len and last LoT were randomized 1:1 (stratified by age, no. of prior LoTs, and International Staging System score) to receive 28-day (d) cycles of melflufen 40 mg intravenously on d1 or pom 4 mg orally (PO) daily on d1 to 21. All pts received dex 40 mg (20 mg for pts ≥75 y) PO on d1, 8, 15, and 22. Pts received therapy until disease progression or unacceptable toxicity. The primary endpoint was PFS, as assessed by independent review committee per IMWG Uniform Response Criteria, and key secondary endpoints were overall response rate, OS, and safety. Results: As of 3 Feb 2023, 495 pts were randomized (246 to melflufen; 249 to pom); median age was 68 y (range, 39-91) and median prior LoTs was 3. In the intent-to-treat (ITT) melflufen and pom populations, median OS was 20.2 mo vs 24.0 mo (HR, 1.09 [95% CI, 0.88-1.35]), at a median follow-up of 40.3 mo and 38.1 mo, respectively. In the target subgroup of the melflufen and pom groups (pts without a prior ASCT or TTP &amp;gt;36 mo after an ASCT), median OS was 23.6 mo vs 19.1 mo (HR, 0.88 [95% CI, 0.67-1.16]); in the non-target population (pts with TTP &amp;lt;36 mo after ASCT), median OS was 15.7 mo vs 27.5 mo (HR, 1.60 [95% CI, 1.15-2.21]), respectively. While any grade hematologic toxicities were more common with melflufen, the occurrence of non-hematologic toxicities was similar in the 2 groups. Grade 3/4 (G3/4) treatment-emergent adverse events (TEAEs) in the safety population (melflufen [n=228] and pom [n=246]) occurred in 90% vs 76% of pts, respectively; most commonly thrombocytopenia (78% vs 13%; occurring with G3/4 hemorrhage in 1% vs 0%), neutropenia (64% vs 50%; occurring with G3/4 infections in 4% vs 7%), anemia (43% vs 19%), and infection and infestations (14% vs 24%). Serious AEs occurred in 43% vs 50% of pts (including pneumonia [6% vs 9%], COVID-19 pneumonia [5% vs 6%], and anemia [4% vs 2%]), and fatal AEs in 14% vs 15% (including COVID-19 pneumonia [4% vs 2%] and pneumonia [2% vs 2%]) in the melflufen and pom groups, respectively. With melflufen and pom, TEAEs led to dose reductions in 52% vs 28% of pts (most frequently thrombocytopenia [32% vs 2%] and neutropenia [12% vs 8%]), and discontinuations in 30% vs 24% of pts, respectively. Deaths occurred in 74% vs 68% of pts in the melflufen and pom groups, with AEs being the primary cause of death ≤30 d after last dose in 8% and 11%, respectively. Conclusion: Long-term results were consistent with those of previous analyses (Schjesvold, et al. Lancet Haematol. 2022;9:e98-e110). While OS trended in favor of pom in the ITT population, OS outcomes continued to be more favorable with melflufen in pts with no prior ASCT or with TTP &amp;gt;36 mo after ASCT. No new safety signals were reported, and AEs were manageable with dose modifications, consistent with previous reports. This long-term follow-up of OCEAN confirms the favorable safety and OS outcomes of melflufen + dex in the target population and supports its continued use as an alternative treatment choice for pts with RRMM who have received ≥2 prior LoT and who have not received ASCT.

Quantum-First Trial: FMS-like Tyrosine Kinase 3-Internal Tandem Duplication ( FLT3-ITD)-Specific Measurable Residual Disease (MRD) Clearance Assessed through Induction (IND) and Consolidation (CONS) Is Associated with Improved Overall Survival (OS) in Newly Diagnosed (nd) FLT3-ITD+ AML Patients (pts)

Background Detection of MRD by flow cytometry or gene fusion transcript quantitation increasingly is used to guide treatment decisions in AML. Molecular monitoring of recurrent gene mutations for MRD detection is an alternative strategy but, other than for nucleophosmin 1 ( NPM1) gene quantitation, remains controversial. FLT3-ITD is among the most common recurrent mutations in AML and confers a worse prognosis vs FLT3-wild-type and FLT3-TKD+ AML. Routine use of FLT3-ITD detection in remission as a predictor of relapse risk or OS has been limited by the low sensitivity of both conventional PCR-based detection methods and broad NGS platforms in clinical practice settings. More recently, FLT3-ITD-specific PCR-NGS assays such as getITD (PMID: 31089248) show greater sensitivity and ease of interpretation that point to eventual routine clinical application. However, the clinical value of these measurements has not been evaluated prospectively in large scale randomized controlled trials of FLT3 inhibitors. The phase 3 QuANTUM-First study (NCT02668653) evaluated the novel, potent, and highly selective type II FLT3 inhibitor quizartinib (Quiz) in nd FLT3-ITD+ AML pts and demonstrated that Quiz added to intensive IND and CONS, ± transplant, followed by single-agent continuation (CONT) therapy (Tx) resulted in a significant improvement in OS (PMID: 37116523). We analyzed if FLT3-ITD-specific MRD in QuANTUM-First pts impacted the clinical outcome or the benefits provided by Quiz in nd FLT3-ITD+ AML pts. Methods Genomic DNA, isolated from bone marrow aspirates or peripheral blood from pts after achievement of remission after 1 or 2 courses of IND and at end of CONS (prior to transplant or CONT cycle 1 day 1 [C1D1] for transplant pts and prior to CONT C1D1 for non-transplant pts), was analyzed with a FLT3-ITD PCR-NGS assay specifically developed for this trial (PMID: 31722002). ITD mutations detected after IND were cross-validated against the ITD detected at enrollment for each patient. Using a custom bioinformatics program, ITD mutations were identified, and variant allele frequencies (VAFs) were calculated with a sensitivity of 10 −5. MRD was classified as undetectable (using the 0 cutoff) or detectable above or below a 10 −4 predefined cutoff (based on lower limit of quantification for the assay). Comparisons of complete response (CR), composite complete response (CRc=CR+CRi), and the rate of pts achieving CRc during IND with no MRD between arms were made using a stratified Cochran-Mantel-Haenszel test. Comparison of FLT3-ITD VAF during IND and during CONS between arms was made using Wilcoxon rank sum test. All P-values were not adjusted for multiplicity. Results In QuANTUM-First, 539 nd FLT3-ITD+ AML pts were randomized to Quiz (n=268) or placebo (PBO; n=271). Of the 539 randomized pts, 368 (68.3%) achieved CRc after 1 or 2 courses of IND, and MRD analysis was performed on 321 (87.2%) of these pts (162 pts in Quiz and 159 pts in PBO) using samples collected at the time of response assessment during IND, before further Tx. MRD was also assessed in 337 pts (172 pts in Quiz and 165 pts in PBO) by end of up to 4 cycles of CONS prior to CONT/maintenance Tx. Of these pts, 166 additionally received transplant (87 in Quiz, 79 in PBO). The % of pts in CRc at end of IND with FLT3-ITD MRD of &amp;lt;10 −4 was similar between study arms (25.4% Quiz vs 21.8% PBO, nominal P = 0.3430), however, a greater % of pts in CRc had undetectable MRD with Quiz than PBO (12.3% vs 7.0%, nominal P = 0.0403). Among pts with CRc at end of IND, the median best FLT3-ITD VAF by end of CONS was lower (0% versus 0.0017%; nominal P = 0.0006) with Quiz vs PBO (Fig 1) and, using the 0 cutoff at end of IND, a longer OS was observed with Quiz vs PBO, regardless of MRD status, with a greater effect with Quiz (HR, 0.789 in MRD− pts; HR, 0.749 in MRD+ pts; Fig 2). In MRD+ pts, the median OS was not reached with Quiz and 35.4 months with PBO (Fig 2). Performing this analysis with an MRD cutoff of 10 ‒4 yielded similar findings (HR, 0.696 in MRD− pts; HR, 0.800 in MRD+ pts). Additional data about MRD impact on pts ± transplant in this trial will be presented. Conclusions These findings demonstrate the potential prognostic utility of FLT3-ITD-specific MRD measurements in the clinical management of pts with FLT3-ITD+ AML. Our data suggest that long-term OS benefits conferred by Quiz in part derive from a deep and sustained reduction of the FLT3-ITD+ leukemia burden.

Favorable Survival Outcomes in AML Patients Undergoing Allogeneic Hematopoietic Cell Transplant with Fludarabine/Melphalan-Conditioning with Tacrolimus/Sirolimus-Based Gvhd Prophylaxis

Introduction: Fludarabine/melphalan (F/M) conditioning is associated with superior disease-free survival (DFS) compared to busulfan-based reduced-intensity conditioning (RIC) regimens in patients with AML/MDS undergoing allogeneic hematopoietic cell transplantation (alloHCT). A recent CIBMTR analysis in AML patients reported 5-year OS, cumulative incidence of Relapse (CIR) and NRM of 29%, 36% and 36% respectively after F/M conditioning when Tac/MTX was used for graft-vs-host disease (GVHD) prophylaxis (Blood Adv 2020). At City of Hope (COH), tacrolimus and sirolimus (T/S)-based GVHD prophylaxis has been used in patients undergoing HLA-matched sibling and unrelated donor alloHCT, based on the results of a phase 2 study by Rodriguez et al (Blood 2010). Here, we retrospectively reviewed clinical outcomes of 409 consecutive AML patients who underwent RIC alloHCT at COH from 2008-2019 with F/M conditioning and T/S-based GVHD prophylaxis. The primary objective was to assess long term survival outcomes and associated risk factors adjusted for secular trends in patient demographics undergoing alloHCT over time. Methods: Descriptive statistics were used to summarize patient demographics, and disease characteristics. Kaplan-Meier curves and log-rank test were used to evaluate OS and LFS. Cumulative incidence curves and Gray test were used to examine differences in relapse and NRM. The assumptions of proportionality for Cox regression and Fine-Gray models were checked by corresponding tests and plots of the scaled Schoenfeld residuals. To study changes in patient demographics, we divided patients into early era of 2008-2012 (n=140; 34%) and late era of 2013-2019 (n=269; 66%). Results: Patient and HCT characteristics are shown in Table 1. Briefly, the median age was 63 years (range: 19-78) and 70% of patients underwent alloHCT in CR-1. Cytogenetics (ELN 2017) were classified as adverse risk in 25% (n=104) and intermediate risk in 65% (n=265) patients. By disease risk index (DRI), patients were categorized as low (32%; n=131), intermediate (47%; n=193), or high/very high risk (20%; n=84). KPS of 80-100 was recorded in 93% of patients and HCT comorbidity index score of ≥3 was seen in 41%. AML-from prior hematologic disorder (secondary AML) or therapy related was documented in 32% (n=133) and data on somatic mutations and measurable residual disease (MRD) were available only in the recent era. Compared to the early era, HCT recipients of the recent era were significantly older(64 vs 60 years; p=0.0001), had higher HCT-CI (median score of 3 vs 1; p&amp;lt;0.0001), and more patients with KPS &amp;lt; 80 (9% vs 2 %; p=0.0024). With the median follow-up duration of 4 years (range: 0.3-12.5) for the whole cohort, the 5-year OS and DFS were 53% (95% CI: 0.48-0.58) and 51% (95% CI: 0.46-0.56), respectively. The cumulative incidence of relapse (CIR) at 5 years was 23% (95% CI: 0.19-0.28). The non-relapse mortality (NRM) at day+100 and 5 years were 5% (95% CI: 0.03-0.08) and 25% (95% CI:0.20-0.29), respectively. Day +100 grade 2-4 acute GVHD was 37% (95% CI: 0.32-0.42) and 2-year chronic GVHD was 70% (95% CI: 0.65-0.74). Overall survival (OS) and disease-free survival (DFS) were not significantly different in the two eras (Figure 1). Despite high incidence of cGVHD, only 21% (n=86) required prednisone at one year with median dose of 10 mg/day (range: 2-60mg/day). In key subgroups of interest, the 5-year OS were: 70% for FLT3-ITD mutation (n=50), 70% for NPM1 mutation (n=47), 83% for IDH 1/2 mutation (n=30), 65% for patients older than ≥70 (n=55), and 55% (95%CI :43-63) for secondary AML (n=102). MRD by multi-color flow cytometry was available in 58 patients in CR of whom 18 were MRD-positive; this was associated with worse 5-year OS (26%: 95% CI: 5.5-53%). Multivariate analyses (MVA) identified DRI high/very high-risk as the only independent variable associated with worse OS (HR=1.62, [95%CI: 1.16-2.27]) and DFS (HR=1.76, [95%CI: 1.28-2.41]), primarily due to increased NRM (HR 1.86, 95%CI [1.21-2.87]), while its impact on relapse was insignificant. Conclusion: Fludarabine-melphalan with T/S associated with favorable long-term OS with good disease control without excessive NRM, even in high-risk patient subgroups and changing demographics of older adults with higher comorbidity. However, cGVHD rates remain high and novel strategies are being explored to realize the OS benefits of the FM backbone while attenuating chronic GVHD and NRM.

Allogeneic Stem Cell Transplantation with Myeloablative Compared with Reduced- Intensity Conditioning for AML and Mds; 20 Years Later

Background. Allogeneic stem cell transplantation (SCT) with both myeloablative (MAC) and reduced intensity conditioning (RIC) regimens is effective therapyin AML and MDS. However, the relative merits of each may differin different settings and at different time-points after SCT. We have previously reported on the role of dose intensity in a group of 112 patients with AML/MDS given SCT with different regimens between 1999 and 2004 (ASH 2004, Leukemia 2005). At that time we showed that MAC was associated with lower relapse rate, higher non-relapse mortality (NRM) and similar overall survival (OS) as RIC. MAC was associated with survival advantage in patients with active leukemia at SCT. There is paucity of data on the comparison of these 2 approaches very late after SCT (beyond 20 years). Methods. We have now updated SCT outcomes in the same cohort with a median follow up of 20 years (range, 15-22) in order to better predict long-term outcome and confirm whether late events may have changed the initial conclusions. Updated follow-up is available for all but one patient. Results. The median age at SCT was50 years (18-70). Eighty-five patients had AML and 17 had MDS (IPSS int2 or high). Fifty-eight hadactive disease at SCT (&amp;gt;10% marrow blasts) and 54 were inremission. The donor was HLA-matched sibling (n=58), 1-Ag mismatchedrelated (n=6) or matched-unrelated (n=48). Twenty-nine patients (26%) had poor risk cytogenetics. Forty-five patients meteligibility criteria for standard MAC and were given intravenous-busulfan (ivBu, 12.8 mg/kg) and cyclophosphamide(BuCy). Sixty-seven patients were considered non-eligible for standardMAC and were given RIC with fludarabineand ivBu (6.4 mg/kg, FB2, n=41) or reduced toxicity conditioning (RTC) with fludarabine and myeloablative dosesof ivBu (12.8 mg/kg, FB4, n=26). The medianage of RIC, RTC and MAC recipients was 57, 51 and 42 years at transplantation, respectively (p=0.001) and a larger proportion of RIC/RTC recipients had unrelateddonors (p=0.01). In all, 31 patientsare alive and 81 have died, 50 of relapse and 31 of NRM.The median age at last follow-up was 66 years (35-81). The 20-year OS rate was 29% (20-37). The rate was 40% (26-54), 19% (7-31) and 19% (7-31) after BuCy, FB4 and FB2, respectively (P=0.19). The 20-year NRM was 29% (18-45), 27% (14-51) and 27% (16-45) respectively (Figure 1, P=0.94). The 20-year relapse mortality was 31% (20-48), 54% (38-77) and 54% (40-71), respectively (Figure 2, P=0.12). Five patients with relapse in the first 5 years are very long-term survivors with no recurrent disease following additional treatments. Forty patients were alive and disease-free 5 years after SCT with a 5-year OS of 42% (33-51). Fourteen patients died beyond 5 years, 3 from late relapse (6.6 -11.8 months after SCT) and 11 due to NRM. The causes of late NRM were second malignancies (n=6), cardiovascular disease (n=3), pulmonary disease (n=1) and liver disease (n=1). The risk of late NRM was 17% (6-47), 25% (7-83) and 44% (24-81) after BuCy, FB4 and FB2, respectively (P=0.29). The risk of late NRM was 14% (4-52) and 35% (21-59) in patients younger and older than 55 years at SCT, respectively (P=0.18). Late relapse mortality was low; 6 (8-37), 13% (2-78) and 7% (1-5), respectively (P=0.81). In all, the subsequent 15-year OS in those who were alive and disease-free 5-years after SCT was 78% (59-97), 63% (29-96) and 49% (22-76), respectively. The small number of events did not allow a meaningful multivariate analysis. Conclusions. With a long-term follow-up of 20 years, RIC/RTC is an acceptable alternative to MAC in ineligible patients. NRM is lower after RIC in the early post SCT period, but late NRM negates this early advantage and at longer follow-up there is no difference between the regimens. Relapse after RIC is higher at the first 5 years after SCT. However, late relapses beyond 5 years from SCT are rare after all regimens. In all, the very long-term OS is better after MAC. However, older age at SCT for RIC may be a major cause of these observations. Longer follow up of randomized studies is needed for more definite conclusions.

The Role of High-Dose Regimens Followed By Autologous Stem Cell Transplantation for Salvage Chemotherapy-Sensitive DLBCL Patients

CONCLUSION INTRODUCTION： It has been reported that lisocabtagene maraleucel improved event-free survival and complete response rate compared with standard care as second -line therapy for early relapsed/refractory diffuse large B-cell lymphoma (rrDLBCL) patients(pts). However, CAR T-cell therapy could not be available for some candidates with rrDLBCL due to socioeconomical issues and manufacturing limitations. High-dose chemotherapy followed by autologous stem cell transplantation (auto-SCT) is a conventional curative treatment for salvage chemotherapy-sensitive DLBCL. We have devised AECC regimen (Usui, Clin Lymph; 2005, and Yano, Clin Lymph and Myeloma; 2007) for auto-SCT. Further, we have also used ranimustine (MCNU) based MEAM regimen due to not availability for carmustine in Japan. In this retrospective study, we compared the efficacy and safety of AECC with MEAM. METHODS： We retrospectively analyzed 68 pts with DLBCL who received AECC or MEAM followed by auto-SCT from January 2006 to December 2021 at the Jikei University Hospital and the Jikei University Kashiwa Hospital. AECC regimen consists of nimustine 200mg/m 2 on day -7 to day -6, etoposide (ETP) 30mg/kg on day -5 to day -4, cyclophosphamide 60mg/kg on day -3 to day -2, carboplatin 700mg/m 2 on day -3 to day -2. MEAM regimen consists of MCNU 300 mg/m 2 on day -7, ETP 200 mg/m 2 on day -6 to day -3, cytarabine 200 mg/m 2 q12 hrs on day -6 to day -3, and melphalan 140 mg/m 2 on day -2. In this study, early relapsed DLBCL (erDLBCL) was defined as DLBCL pts relapsed within 2 years from diagnosis. We retrospectively analyzed overall survival (OS), progression-free survival (PFS) and adverse events (AE). Thirty-five pts received AECC and 33 pts MEAM in DLBCL, respectively. AECC was mainly used from 2006 to 2013, and MEAM was used from 2014 to 2021. The patient characteristics between AECC and MEAM were as bellows; the median follow-up time for survival was 109 (0-193) vs 35(1-83) months ( P &amp;lt;0.01), the median age at auto-SCT was 54(25-65) vs 58 (40-68) years ( P = 0.01), 66% vs 61% were male ( P = 0.80), the median years from diagnosis to auto-SCT was 1.43(0.39-12.79) vs 1.67(0.39-22.40) years ( P = 0.41), the number of pts who receive 2 lines of therapy before auto-SCT were 18 vs 23 ( P = 0.144). Disease status at auto-SCT in the AECC and MEAM groups were 16 vs 12 pts in complete response (CR), 15 vs 21 pts in partial response (PR), and 4 vs 0 pts in stable disease or progressive disease (SD/PD) ( P = 0.06). The 2-year OS and PFS rates in the AECC and MEAM groups were 76.9% vs 68.3% ( P =0.323), and 68.2% vs 59.4% ( P =0.137), respectively. In addition, we focused er DLBCL pts whose disease status at auto-SCT was CR or PR, named as “chemotherapy-sensitive er DLBCL”. Twenty-one pts were treated with AECC and 19 pts were received MEAM. The patient characteristics between AECC and MEAM were as bellows; the median age at auto-SCT in the AECC group was younger than those in the MEAM group (53(25-65) vs 60 (47-68) years, P = 0.01), the number of pts with CR in the AECC group was higher than those in the MEAM group. (10 vs 3, P = 0.046). The OS and PFS in the AECC group were significantly higher than those in the MEAM group (2-year OS 85.4% vs 48.5% ( P = 0.019), and 2-year PFS 75.6% vs 39.0% ( P &amp;lt;0.01), respectively). Additionally, AECC achieved long-term survival with 8-year OS and PFS of 80.4% and 75.6% in the chemotherapy-sensitive er DLBCL, respectively. At the time of data analysis, deaths had been reported in 12 of 35 pts in the AECC and 12 of 33 in the MEAM. The most common cause of death was disease progression (10 pts in the AECC and 8 in the MEAM). Non-relapse mortality (NRM) was observed in 2 pts of the AECC (drug-induced cardiomyopathy (n = 2)), and 4 of the MEAM (liver failure (n = 2), pneumonia (n = 1), and suicide (n = 1)). It should be mentioned that grade 3 or higher heart failure was observed in the AECC group (n = 8) compared to in the MEAM group (n = 0). Treatment related mortality (TRM) within 100 days was 2 pts in the AECC group due to cardiomyopathy and 0 in the MEAM group. AECC followed by auto-SCT achieved both long-term OS and PFS compared to MEAM in chemotherapy-sensitive er DLBCL pts. Further validation for efficacy is needed due to the differences in patient's background and follow-up period in the study. However, AECC was associated with a higher incidence of cardiac toxicity and TRM within 100 days. It was suggested that auto-SCT with AECC may be a treatment option when CAR T-cell therapy was not available.