Probability Of OS Research Articles

A circadian rhythm-related lncRNA signature correlates with prognosis and tumor immune microenvironment in head and neck squamous cell carcinoma

ObjectiveTo investigate circadian rhythm-associated long non-coding RNA (lncRNA) signatures in predicting prognosis, metabolism, and immune infiltration in Head and Neck Squamous Cell Carcinoma (HNSC).MethodsHNSC samples were collected from the TCGA database. A signature was constructed using Cox regression and Least Absolute Shrinkage and Selection Operator (LASSO) methods. The immune cell infiltration was analyzed using CIBERSORT, ssGSEA, and MCPcounter. The RT-qPCR was used to detect the expression of signature lncRNAs.ResultsA signature comprising 8 lncRNAs was constructed. The constructed signature demonstrated good prognostic prediction capability for HNSC. A nomogram encompassing risk score accurately predicted the long-term OS probability of HNSC. The infiltration levels of T cell, B cell and Macrophages were significantly higher in the high-risk group than in the low-risk group. Cluster analysis showed that the signature lncRNAs could classify the HNSC samples into two clusters. The RT-qPCR suggested that the expression of lncRNAs in signature was consistent with the data in TCGA.ConclusionThe circadian rhythm-associated lncRNA signature has potential as a prognostic indicator for HNSC. It exhibits associations with metabolism, immune microenvironment, and drug sensitivity, thereby providing valuable insights for informing the treatment of HNSC.

Single-Cell Analysis Identifies Distinct Populations of Cytotoxic CD4+ T Cells Linked to the Therapeutic Efficacy of Immune Checkpoint Inhibitors in Metastatic Renal Cell Carcinoma.

The involvement of cytotoxic CD4+ T cells (CD4+ CTLs) and their potential role in dictating the response to immune checkpoint inhibitors (ICIs) in patients with metastatic renal cell carcinoma (mRCC) remains an unexplored area of research. Utilizing single-cell RNA sequencing, we analyzed the immunophenotype and expression patterns of CD4+ T lymphocyte subtypes in mRCC patients, followed by preliminary validation via multi-immunofluorescent staining. In addition, we obtained a comprehensive immunotherapy dataset encompassing single-cell RNA sequencing datasets and bulk RNA-seq cohorts from the European Genome-Phenome Archive and ArrayExpress database. Utilizing the CIBERSORTx deconvolution algorithms, we derived a signature score for CD4+ CTLs from the bulk-RNA-seq datasets of the CheckMate 009/025 clinical trials. Single-cell analysis of CD4+ T lymphocytes in mRCC reveals several cancer-specific states, including diverse phenotypes of regulatory T cells. Remarkably, we observe that CD4+ CTLs cells constitute a substantial proportion of all CD4+ T lymphocyte sub-clusters in mRCC patients, highlighting their potential significance in the disease. Furthermore, within mRCC patients, we identify two distinct cytotoxic states of CD4+ T cells: CD4+GZMK+ T cells, which exhibit a weaker cytotoxic potential, and CD4+GZMB+ T cells, which demonstrate robust cytotoxic activity. Both regulatory T cells and CD4+ CTLs originate from proliferating CD4+ T cells within mRCC tissues. Intriguingly, our trajectory analysis indicates that the weakly cytotoxic CD4+GZMK+ T cells differentiate from their more cytotoxic CD4+GZMB+ counterparts. In comparing patients with lower CD4+ CTLs levels to those with higher CD4+ CTLs abundance in the CheckMate 009 and 25 immunotherapy cohorts, the latter group exhibited significantly improved OS and PFS probability. Our study underscores the pivotal role that intratumoral CD4+ CTLs may play in bolstering anti-tumor immunity, suggesting their potential as a promising biomarker for predicting response to ICIs in patients with mRCC.

Baseline tumor-infiltrating lymphocyte patterns and response to immune checkpoint inhibition in metastatic cutaneous melanoma

IntroductionThe presence of tumor-infiltrating lymphocytes (TILs) in melanoma has been linked to survival. Their predictive capability for immune checkpoint inhibition (ICI) response remains uncertain. Therefore, we investigated the association between treatment response and TILs in the largest cohort to date and analyzed if this association was independent of known clinical predictors. MethodsIn this multicenter cohort study, patients who received first-line anti-PD1 ± anti-CTLA4 for advanced melanoma were identified. TILs were scored on hematoxylin and eosin (H&E) slides of primary melanoma and pre-treatment metastases using the validated TILs-WG, Clark and MIA score. The primary outcome was objective response rate (ORR), with progression free survival and overall survival being secondary outcomes. Univariable and multivariable logistic regression and Cox proportional hazard were performed, adjusting for known clinical predictors. ResultsMetastatic melanoma specimens were available for 650 patients and primary specimens for 565 patients. No association was found in primary melanoma specimens. In metastatic specimens, a 10-point increase in the TILs-WG score was associated with a higher probability of response (aOR 1.17, 95 % CI 1.07–1.28), increased PFS (HR 0.93, 95 % CI 0.87–0.996), and OS (HR 0.94, 95 % CI 0.89–0.99). When categorized, patients in the highest tertile TILs-WG score (15–100 %) compared to the lowest tertile (0 %) had a longer median PFS (13.1 vs. 7.3 months, p = 0.04) and OS (49.4 vs. 19.5 months, p = 0.003). Similar results were noted using the MIA and Clark scores. ConclusionIn advanced melanoma patients, TIL patterns on H&E slides of pre-treatment metastases, regardless of measurement method, are independently associated with ICI response. TILs are easily scored on readily available H&Es, facilitating the use of this biomarker in clinical practice.

Outcome of chemo-immunotherapy for extensive-stage small-cell lung cancer according to potential clinical trial eligibility: 3-year outcomes from prospective cohort study.

8087 Background: Chemo-immunotherapy is the standard 1st-line therapy for patients with extensive-stage small-cell lung cancer (ES-SCLC). Our large previous real-world prospective analysis showed outcomes of chemo-immunotherapy for these patients according to potential clinical trial eligibility with a minimum follow-up period of 1 year. However, long-term outcomes have not been studied in the real-world setting. Methods: We conducted a 32-hospital prospective cohort study of consecutive patients with ES-SCLC who received carboplatin and etoposide with atezolizumab as 1st-line therapy between September 2019 and September 2020. Patients who met eligibility criteria for pivotal phase 3 clinical trials were considered “trial-eligible.” We present 3-year outcomes from this study. Results: In total, 207 patients with ES-SCLC were analyzed. The median (range) time from the start of treatment to data cutoff (September 30, 2023) was 42.2 (35.8.-48.2) months. The median age was 72 years, and 64 patients (31%) were elderly (≥75 years). Most patients (89%) had a performance status (PS) of 0 or 1. As a result, 132 (64%) were categorized as trial-eligible patients. The 3-year PFS and OS probability of all patients was 6.1 % (95%CI:3.5-10.4%) and 20.9 % (95%CI:15.6-27.3%), respectively. Patients achieving 3-year OS included significantly higher proportions of trial-eligible patients (30 out of 132 versus 5 out of 75, respectively; p = 0.002). Kaplan-Meier estimates of the 3-year OS rate were 26.7% for the trial-eligible group and 9.5 % for the trial-ineligible group. Conclusions: This is the first real-world study to show the long-term efficacy of chemo-immunotherapy for ES-SCLC by using the largest prospective cohort of its kind. Additionally, this study demonstrated that trial eligibility was associated with long-term efficacy. Our study suggests that long-term clinical outcomes among trial-eligible patients may not translate to ineligible patients.

Treatment outcomes of pediatrics acute myeloid leukemia (AML) and associated factors in the country’s tertiary referral hospital, Ethiopia

BackgroundPediatric Acute Myeloid Leukemia (AML) is a major cause of morbidity and mortality in children with cancer in Africa and other developing continents. Systemic chemotherapy and effective supportive care have significantly contributed to increased survival rates of pediatric AML in developed countries reaching approximately 70%. There is a paucity of contextual data regarding overall and event-free survival outcomes in children with acute myeloid leukemia in developing countries and most centers in Africa provide palliative care. The objective of this study was to assess the overall survival, event-free survival, and associated factors in pediatric AML patients treated in Ethiopia.MethodsThis retrospective study was conducted on Pediatric AML patients treated at Tikur Anbessa Hospital between January 1, 2015, and May 30, 2022. The socio-demographic profile of patients, the clinical characteristics, the biochemical and morphological subtypes of AML were analyzed using SPSS version 25. The Kaplan–Meier survival curve was used to estimate the probabilities of overall and event-free survival. Statistical significance was set at p < 0.05.ResultsA total of 92 children with AML were included in this study. The median age at diagnosis was 7 years (interquartile range: 5–10 years) with a slight male predominance. The median duration of symptoms was one month. Neutropenic fever (56, 86.2%) was the most common complication during treatment. About 29.3% of the patients succumbed to early death. The corresponding 1-year and 3-year OS probabilities were 28.2% and 23% respectively. The median event-free survival time for all pediatric AML patients was one-month (95% CI: 0.77–1.23). The determinants of poorer survival outcomes were FAB subtype, type of protocol used, and signs of CNS involvement (p < 0.05).ConclusionThe survival rates of children from AML were low in the study setting. More than 25% of AML patients succumbed to early death, and febrile neutropenia was the most common complication. Effective supportive and therapeutic measures should be taken to manage febrile neutropenia and to prevent early death in AML patients.

A novel nomogram and prognostic factor for metastatic soft tissue sarcoma survival.

This study represented the inaugural effort to develop predictive survival nomograms for metastatic soft tissue sarcoma (mSTS) patients in the era of immune checkpoint inhibitors. From the Surveillance, Epidemiology, and End Results (SEER) program database, we extracted 3078 eligible patients with mSTS between 2016 and 2022. Kaplan-Meier survival analysis, univariate and multivariable Cox analyses, and univariate and multivariable logistic analyses were conducted. Subsequently, predictive nomograms were constructed. Clinical effectiveness was validated using the area under the curve (AUC), calibration curve, and decision curve analysis (DCA) methods. We used the SEER database to include 3078 eligible patients with mSTS between 2016 and 2022. All the eligible patients were randomly allocated in a ratio of 6:4 and stratified into a training group (n = 1846) and a validation group (n = 1232). In the multivariate Cox analysis, age, race, marital status, pathological grade, histologic subtype, surgery, and chemotherapy were identified as independent prognostic factors. These factors were used to construct the nomogram to predict the 1-, 3-, and 5-year OS of mSTS patients. The C-index for the training cohort and the validation cohort was 0.722(95% confidence interval [CI]: 0.708-0.736), and 0.716(95% CI: 0.698-0.734), respectively. The calibration curves for 1-, 3-, and 5-year OS probability demonstrated excellent calibration between the predicted and the actual survival. The AUC values of the nomogram at 1-, 3-, and 5-year were 0.785, 0.767, and 0.757 in the training cohort, 0.773, 0.754, and 0.751 in the validation cohort, respectively. Furthermore, DCA indicated the favorable clinical utility of the nomogram in both cohorts. The risk stratification system was constructed using the established nomogram, which enhanced prediction accuracy, aided clinicians in identifying high-risk patients and informing treatment decisions. This study marked the inaugural effort in constructing predictive survival nomograms mSTS patients in the era of immune checkpoint inhibitors. The robustly constructed nomograms, alongside actual outcomes, offered valuable insights to inform follow-up management strategies.

Abstract PO1-04-06: Exposure-response analyses of sacituzumab govitecan efficacy and safety in patients with metastatic breast cancer

Abstract Background: Sacituzumab govitecan (SG) is an antibody-drug conjugate that is composed of an anti Trop-2 antibody coupled to the cytotoxic SN-38 payload via a proprietary, hydrolysable CL2A linker. SG (10 mg/kg on D1 and D8 of every 21D cycle) is approved for patients (pts) with metastatic triple-negative breast cancer (mTNBC) who received ≥2 prior systemic therapies (≥1 in the metastatic setting). The relationship between exposure of SG, free SN-38, and total antibody (tAB) following SG administration and its efficacy and safety were evaluated in pts with HR+/HER2‒ metastatic breast cancer (mBC) and all pts with mBC (mTNBC or HR+/HER2‒ mBC), respectively. Methods: Available exposure and efficacy outcomes from HR+/HER2‒ mBC pts from phase 3 study TROPiCS-02 (n=260) and safety outcomes from mBC pts in phase 1/2 study IMMU-132-01, phase 3 study ASCENT and TROPiCS-02 (total n=569) were analyzed. Exposure-response (ER) models were developed to characterize the relationship between exposure and efficacy (complete response [CR], overall response rate [ORR], clinical benefit rate [CBR], overall survival [OS] and progression-free survival [PFS]) and safety (adverse events [AEs] of vomiting, diarrhea, hypersensitivity reactions, nausea, neutropenia, febrile neutropenia, time to first dose reduction and first dose delay) endpoints. Exposure metrics of SG, free SN-38, and tAB were evaluated as predictors and effect of clinically relevant covariates was characterized within the modeling framework. Results: Average SG-related serum exposures over the duration of treatment (until the event) were associated with significantly increased efficacy (probability of CR, ORR, CBR and longer OS and PFS) and safety events (probability of any grade AE). Neutropenia was the only AE where the increase in exposure was significantly associated with the increased probability of Grade ≥3 and Grade 4 events. Baseline Trop-2 expression level was not correlated with assessed efficacy and safety endpoints. Conclusions: Within the exposure range achieved with the 10 mg/kg regimen, higher exposure values were associated with a higher probability of achieving better efficacy. The 10 mg/kg SG dose achieved an acceptable balance between efficacy and safety which supports the appropriateness of this regimen in pts with HR+/HER2‒ mBC. Citation Format: Indrajeet Singh, Abhishek Sathe, Paul Diderichsen, Han Witjes, Arne Van Schanke, John Maringwa, Wendy Verret, Sandhya Girish, Ahmed Othman. Exposure-response analyses of sacituzumab govitecan efficacy and safety in patients with metastatic breast cancer [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 PO1-04-06.

Development of a Novel Lipid Metabolism-related Gene Prognostic Signature for Patients with Colorectal Cancer.

The purpose of this study was to explore the expression profiles of lipid metabolism-related genes in patients with Colorectal Cancer (CRC). The lipid metabolism statuses of CRC patients from The Cancer Genome Atlas (TCGA) were analyzed. Risk characteristics were constructed by univariate Cox regression and minimum Absolute contraction and Selection Operator (LASSO) Cox regression. A histogram was constructed based on factors such as age, sex, TNM stage, T stage, N stage, and risk score to provide a visual tool for clinicians to predict the probability of 1-year, 3-year, and 5-year OS for CRC patients. By determining Area Under Curve (AUC) values, the time-dependent Receiver Operating characteristic Curve (ROC) was used to evaluate the efficiency of our model in predicting prognosis. A novel risk signal based on lipid metabolism-related genes was constructed to predict the survival of CRC patients. Risk characteristics were shown to be an independent prognostic factor in CRC patients (p <0.001). There were significant differences in the abundance and immune characteristics of tumor-filtering immune cells between high-risk and low-risk groups. The nomogram had a high potential for clinical application and the ROC AUC value was 0.827. Moreover, ROC analysis demonstrated that the nomogram model was more accurate to predict the survival of CRC patients than age, gender, stage and risk score. In this study, we demonstrated a lipid metabolism-related genes prognosis biomarker associated with the tumor immune micro-environment in patients with CRC.

Decreasing the steroid rapidly may help to improve the clinical outcomes of patients with intestinal steroid-refractory acute graft-versus-host disease receiving basiliximab treatment.

Intestinal steroid refractory acute graft-versus-host disease (SR-aGVHD) is the major cause of mortality in allogeneic hematopoietic stem cell transplantation (allo-HSCT). This retrospective cohort study aimed to identify the relationship between different steroid decreasing velocity and therapeutic response in patients with intestinal SR-aGVHD receiving basiliximab treatment, and also aimed to propose a reasonable steroid decreasing regimen for these patients. The median time for steroid dose decreasing to the 50% of initial dose and decreasing to the low-dose steroid for patients achieving ORR was 5 days and 12 days, respectively, which was both shorter than patients without achieving ORR. The ORR, NRM and survival in rapid and medium steroid decreasing group were all better than slow group. The cumulative incidence of ORR at any time was 90.4%, 78.1% and 62.3%, respectively, in rapid, medium, and slow group. The cumulative incidence of NRM at 1 year after basiliximab treatment was 18.7% (95% CI 11.3%-26.1%), 22.8% (95% CI 14.2%-31.4%) and 32.8% (95% CI 24.1%-41.5%), respectively, in rapid, medium, and slow group. The probability of OS at 1 year after basiliximab treatment was 76.9% (95% CI 68.9%-84.9%), 72.7% (95% CI 63.7%-81.7%), and 62.3% (95% CI 53.5%-71.1%), respectively, in rapid, medium, and slow group. Hence, it was helpful to decrease steroid to the 50% of initial dose ≤ 5 days and to the low-dose steroid ≤ 12 days after basiliximab treatment for intestinal SR-aGVHD patients, which may also be the reasonable steroid decrease protocol for these patients.

Predicting postoperative prognosis of pancreatic cancer using a computed tomography-based radio-clinical model: exploring biologic functions

Patients with PC who had undergone radical pancreatectomy (R0 resection) were divided into development and external validation sets. Independent predictors of OS were identified using Cox regression analyses and included in the nomogram, which was externally validated. The area under the curve was used to measure the model's accuracy in estimating OS probability. RNA sequencing data from The Cancer Genome Atlas were used for gene expression analysis. In the development and external validation sets, survival was estimated respectively for 132 and 27 patients. Multivariate Cox regression analysis identified 5 independent OS predictors: age (P=.049), sex (P=.001), bilirubin level (P=.005), tumor size (P=.020), and venous invasion (P=.041). These variables were incorporated into the nomogram. Patients were divided into high- and low-risk groups for OS and survival curves showed that all patients in the low-risk group had better OS than that of those in the high-risk group (P<.001). Differentially expressed genes in patients with a poor prognosis were involved in neuroactive ligand-receptor interaction. The radio-clinical model may be clinically useful for successfully predicting PC prognosis.

Nomograms predict survival in elderly women with triple-negative breast cancer: A SEER population-based study.

The effective treatment of breast cancer in elderly patients remains a major challenge. To construct a nomogram affecting the overall survival of triple-negative breast cancer (TNBC) and establish a survival risk prediction model. A total of 5317 TPBC patients with negative expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) who were diagnosed and received systematic treatment from 2010 to 2015 were collected from the American Cancer Surveillance, Epidemiology and End Results (SEER) database. They were randomly divided into training set (n= 3721) and validation set (n= 1596). Univariate and multivariate Cox regression analysis were used to identify prognostic features, and a nomogram was established to predict the probability of 1-year, 3-year and 5-year OS and BCSS. We used consistency index (C-index), calibration curve, area under the curve (AUC) and decision curve analysis (DCA) to evaluate the predictive performance and clinical utility of the nomogram. The C-indices of the nomograms for OS and BCSS in the training cohort were 0.797 and 0.825, respectively, whereas those in the validation cohort were 0.795 and 0.818, respectively. The receiver operating characteristic (ROC) curves had higher sensitivity at all specificity values as compared with the Tumor Node Metastasis (TNM) system. The calibration plot revealed a satisfactory relationship between survival rates and predicted outcomes in both the training and validation cohorts. DCA demonstrated that the nomogram had clinical utility when compared with the TNM staging system. This study provides information on population-based clinical characteristics and prognostic factors for patients with triple-negative breast cancer, and constructs a reliable and accurate prognostic nomogram.

Low- versus standard-dose post-transplant cyclophosphamide as GVHD prophylaxis for haploidentical transplantation.

Haploidentical haematopoietic cell transplantation (haplo-HCT) using post-transplant cyclophosphamide (PTCY) as graft-versus-host disease (GVHD) prophylaxis is the standard of care for various haematological malignancies. The original PTCY dose after haplo-HCT was 100 mg/kg, but no dose-finding studies have been performed to identify the optimal dose. We performed a retrospective analysis to compare standard-dose PTCY (100 mg/kg) with reduced-dose PTCY (80 mg/kg): 969 in the standard-dose group and 538 in the reduced-dose group. As there was a significant difference between the two groups regarding patient and transplant characteristics, we performed propensity score (PS) matching. After PS matching, 425 patients in each group were included. The probabilities of 2-year OS were 55.9% in the standard-dose group and 47.0% in the reduced-dose group (p = 0.36). The cumulative incidences of 2-year non-relapse mortality were 21.3% in the standard-dose group and 20.5% in the reduced-dose group (p = 0.55). There was no significant difference in the incidence of acute (grade II-IV 29.2% [95% CI, 24.9-33.6] vs. 25.3% [95% CI, 21.3-29.6]; grade III-IV 7.3% [95% CI, 5.1-10.0] vs. 6.6% [95% CI, 4.5-9.3]) or chronic GVHD. In conclusion, reduced- and standard-dose PTCY were comparable in terms of major clinical outcomes.

Final Results of the AIEOP (Associazione Italiana Ematologia/Oncologia Pediatrica) AML 2013 Prospective Randomized Trial in Childhood Acute Myeloid Leukemia (AML)

Background: Treatment of children with newly diagnosed AML is based on induction therapy, followed by consolidation approaches which differ according to the group of risk patients (pts) are allocated to. In this respect, most treatment protocols stratify pts into 3 risk groups, namely standard (SR), intermediate (IR) and high-risk (HR), mainly based on the molecular/cytogenetic characterization and values of measurable residual disease (MRD) at the end of induction therapy. We report the outcomes of 371 pts with de novo AML other than acute promyelocytic leukemia (aged 0-18) enrolled in the randomized trial AIEOP AML 2013 (EudraCT:2014-000652-28). Patients and methods: pts were diagnosed and enrolled in the trial from 06/2015 to 06/2022 at 33 Centers affiliated to the AIEOP group. Main pt characteristics and criteria used for stratification are shown in Table 1. A marker of recurrent molecular lesions was detected at diagnosis for 247 cases out of the 371 enrolled (67%). Monitoring of flow-cytometry MRD at the end of the 1 st and 2 nd induction course was centrally performed in all pts but 7. The 1 st induction course was common for all pts (ICE scheme), while, then, SR pts were treated with 4 additional chemotherapy courses, all including high-dose cytarabine (HD-Ara-C). IR and HR pts were randomized to receive either a 2 nd ICE or the FLA-Liposomal Doxorubicin (L-Doxo) scheme as 2 nd induction course. IR pts were given 3 additional consolidation courses including HD-Ara-C with other agents or, in the presence of an HLA-compatible sibling, 1 consolidation course followed by allogeneic hematopoietic stem cell transplantation (HSCT). Pts of the HR group were consolidated with 2 courses of HD-Ara-C combined with other cytotoxic agents and, then, had an indication to receive HSCT from either a donor compatible for &amp;gt; 9/10 HLA loci or from an HLA-partially matched relative. Data cut-off for the analysis was March 31, 2023. Results: The proportion of pts allocated to the SR, IR and HR groups were 19% (72 pts), 23% (81 pts) and 58% (218 pts), respectively. Overall, 92% of pts obtained morphological complete remission (CR) at the end of the 2 induction courses [as compared to 87% of the previous AIEOP AML 2002 study (Pession et al. Blood 2012), p&amp;lt;0.05]. Twenty-five pts (7%) experienced a primary induction failure. Only 3 pts died during or after the 2 induction courses, while the subsequent cumulative incidence of 3-yr non-relapse mortality in continuous CR was 6.8%. Leukemia recurrence occurred in 63 pts, this leading to a 3-yr cumulative incidence of relapse of 18.9%. With a median follow-up of 4.5 yrs (range 0.8-8), the 3-yr probabilities of overall (OS) and event-free survival (EFS) were 83.9% and 68.5% (Figure 1), respectively, both values being significantly better (p&amp;lt;0.01) than those of the AIEOP AML 2002 study. The 3-yr OS of SR, IR and HR pts were 99.2%, 84.2% and 79.4%, respectively (p=0.01). The 3-yr estimate of disease-free survival (DFS) was 74.3%, with no difference among the 3 risk groups. The EFS did not differ in IR and HR randomized to receive either a 2 nd ICE or the FLA-L-Doxo scheme as second induction course. Levels of flow-cytometry MRD after the 2 nd induction course strongly influenced the probability of EFS which was 76% and 48% in pts with an MRD value &amp;lt; or &amp;gt;0.1%, respectively (p&amp;lt;0.01). Allogeneic HSCT was performed in 160 pts; in these pts, the 3-yr probabilities of OS and DFS were 87.7% and 85.1%, respectively, with no difference according to the type of donor employed. The DFS of the 10 IR pts given HSCT was 100% as compared to 72.1% of the 71 not transplanted (p=0.07). The outcome of infants treated in this study was particularly good, since their 3-yr probability of EFS was 78.3%. The 3-yr EFS of the 35 pts with FLT3-ITD and of the 75 with KMT2-A rearrangements were 57.1% and 64.7%, respectively. Conclusions: These results indicate that in children enrolled in the trial AIEOP AML 2013 the 3-yr OS and EFS overcomes 80% and approaches 70%, respectively, with a significant improvement as compared to the previous AIEOP protocol. Disease recurrence/primary resistance were the main cause of treatment failure, while the probability of DFS did not differ among the 3 different risk groups, this finding indicating that tailoring of consolidation therapy according to the risk profile was successful in improving the outcome of pts with worse prognostic characteristics. The use of FLA-L-Doxodid not offer any advantage over repeating a 2 nd ICE.

Moderate Incidence but Striking Correlation with TBI of Secondary Malignancies after HSCT in Children with ALL: Long-Term Follow-up from the Prospective International BFM- and Forum-Trials

Introduction: Total body irradiation (TBI)-based conditioning was found to be associated with superior leukemia-free survival when compared to chemo-based conditioning for children with ALL undergoing allogeneic hematopoietic stem cell transplantation (HSCT) in the prospective, international, randomized FORUM trial (Peters et al, JCO 2021). Nevertheless, TBI is considered as the major risk factor for developing secondary malignancies (SM). We and others have previously reported the incidence, risk factors, and outcomes of SM after HSCT in children with ALL (Eichinger et al, Leukemia 2022), but prospective studies of SM after HSCT in children are limited. Therefore, we analyzed the results of 2151 patients enrolled in the prospective BFM 2003 and the FORUM trial from 2003-2022. Patients and methods: We included data from all 668 patients (pts) treated in the BFM 2003 trial and from all 1483 patients treated in the FORUM trial with HSCT from HLA-identical family donors (MFD, 26% of patients), matched unrelated donors (MUD, 65%), and either related or unrelated mismatched donors (MMD, 9%). In the BFM 2003 trial pts &amp;gt;2 years (y) of age years were offered TBI/VP-16 (12 Gy TBI in 6 fractions of 2 Gy each, given as 2 fractions per day for 3 days; VP-16 60 mg/kg, maximum total dose 3600 mg) as conditioning. Only pts with contraindications for TBI received chemo-conditioning, which consisted of i.v. busulfan, cyclophosphamide and etoposide. In the FORUM trial pts &amp;gt;4y of age were randomized to receive either TBI- or chemo-based conditioning regimens; pts &amp;lt;4y were allocated to the chemo-conditioning arm consisting of fludarabine/thiotepa and either busulfan or treosulfan. Details on the transplant procedure have been previously described (C. Peters, et al. JCO 2015 /2021). Results: Centres from 31 countries on 5 continents contributed to the two studies. The median age was 9.2 (range 0.5-23) y. The majority were male (63%, 1356/2151) and &amp;gt;2 y of age at HSCT (94%, n=2024). TBI-based conditioning was applied in 64% (n=1429), while 34% (n=722) of pts received chemo-conditioning. TBI/VP16 was given in 27% (43/159) of age group 2-4y, and in 76% (1269/1672) of age group &amp;gt;4y. With a median follow-up of 3.29 (range 0.1-16.4) y, a total of 46 SM (33 in BFM 2003, 13 in FORUM) were diagnosed at a median of 5.12 (range 0.4-13.4) y post HSCT, all but one in the TBI group. Four pts experienced ALL relapse prior to the occurrence of the SM leaving 42/2151 cases for further analysis. The 5-, 8-, and 10-y cumulative incidence (CI) of SM, with relapse and non-relapse mortality being competing events, were 0.02 (±0.01), 0.06 (±0.01), and 0.13 (±0.03), respectively. Details of the SM are described in Table 1. Regarding age at HSCT, no SM was observed in the very young age group (&amp;lt;2 years) (0/127), 4 SM in the 2-4 years group (2.2%, 4/181), 20 SM in the 4-10 years group (2.3%, 20/867), and 22 SM in the &amp;gt;10 years group (2.25%, 22/976) (p=n.s.). Six patients developed an additional SM: these were MDS (n=2), and glioblastoma, breast cancer, basal cell carcinoma, and squamous cell carcinoma (one each). The first SM occurred at a median of 5.12 (range 0.4-13.4) y, and the additional SM at 10.7 (range 4.3-12.1) y after HSCT. The probability of OS after SM diagnosis was 0.65 (±0.008) at 5y and 0.32 (±0.17) at 10y. Causes of death were SM in 12/14 cases and 2/14 ALL relapse-associated. All 3 glioblastoma-pts died within 8 months after diagnosis. 17/18 pts (94%) with thyroid cancer were alive at last follow-up (0-10 y after SM diagnosis). As shown in Figure 1, the 8-y CI of SM differed significantly between TBI- and chemo-conditioning (0.08[±0.02] versus 0.04[±0.04], p=0.004) in both age groups (2-4 y and &amp;gt;4 y). No significant correlation was observed with patient characteristics such as age, gender and ALL remission status. In addition, we did not identify other statistically significant transplant-specific risk factors including donor type, stem cell source, grade II-IV and III-IV aGVHD and cGVHD. Conclusions Updated data from two prospective studies using uniform regimens confirmed TBI-based conditioning as a risk factor for SM in pediatric ALL. Further analysis is ongoing regarding the association with immune phenotype of ALL and details of genetic risk factors (e.g. TP53 mutations). Rigorous long-term FU of TBI patients is mandatory.

A Nationwide Clinical Trial ALL-B12: An Optimized Therapy for Pediatric B-Precursor Acute Lymphoblastic Leukemia with Excellent Overall Survival and Minimal Non-Relapse Mortality: A Report from the Japan Children's Cancer Group

Background: Advancements in treatment have significantly improved therapeutic outcomes for pediatric acute lymphoblastic leukemia (ALL) and relapsed ALL. However, there remains a need for therapies that minimize relapse in high-risk groups and avoid long-term complications. To address this gap. we conducted the nationwide clinical trial ALL-B12, aimed at newly diagnosed B-precursor ALL aged 1-18 years. Methods: ALL-B12 enrolled participants from November 2012 to November 2017. Patients were stratified based on the NCI classification (age and WBC count at diagnosis). Those with NCI-SR and NCI-HR were assigned to the standard risk group (SR) and the intermediate group (IR), respectively. Poor steroid responders and those with high-risk genomic abnormalities were assigned to the high risk group (HR). A treatment regimen, including 4-drug remission induction, early consolidation, HD-MTX-containing intensification, re-induction, and maintenance, was implemented. Anthracycline dose in the induction therapy was reduced in SR patients. In contrast, early consolidation was intensified with L-ASP for a part (randomized) of the IR and the entire HR. Patients classified as CNS3 were treated as high risk, receiving 12 Gy cranial irradiation; prophylactic cranial irradiation was avoided in non-CNS3 groups. Allogeneic hematopoietic cell transplantation (allo-HCT) during the first remission was restricted to those in the very high-risk group with specific genomic abnormalities (e.g., hypodiploid &amp;lt;44 and TCF3-HLF) and residual MRD above 10^-3 at the end of early consolidation. A randomized comparison was carried out within each risk group to identify the optimal treatment. We assessed the effectiveness of intensification with VCR/DEX pulses for the SR, the impact of L-ASP intensification for the IR, and compared block-type treatment and HD-MTX intensified with VCR and L-ASP (HD-MTX/VL) for the HR. The primary outcome measure was the 5-year event-free survival (EFS) rate. Results: In total, 1,936 patients were enrolled, with 1,804 patients receiving protocol treatment after excluding ineligible patients such as those with BCR-ABL1 positivity. The percentage of patients achieving remission at the end of early consolidation was 98.9%. The overall 5-year EFS and OS probability were 85.2% (95%CI 83.5-86.8%) and 94.3% (95%CI 93.1-95.3%), respectively. Only 1.7% of patients underwent allo-HCT during the first remission. The mortality rate during induction was just 0.6%, with non-relapse mortality (NRM) after remission at 0.6%. The overall relapse incidence was 13.2%, and the overall CNS relapse rate was 1.9%. Among patients assigned to risk groups, 1,107 (62.7%) were assigned to the SR, 459 (26.0%) to the IR, and 200 (11.3%) to the HR. The 5yEFS for the SR was 89.9%. The post-randomization EFS rates for those with and without VCR/DEX intensification were 90.7% and 90.1%, respectively, indicating nearly identical survival curves (p = 0.73). The EFS for the IR was 79.7%, but L-ASP intensification was expected to be effective, the EFS for groups with and without ASP intensification was 82.1% and 77.9%, respectively, failing to reach statistical significance (p = 0.31). The EFS for the HR was 75.5%, with overlapping survival curves for block treatment (75.7%) and HD-MTX/VL (74.2%) (p = 0.92). MRD dynamics were associated with prognosis, and early consolidation therapy enhanced by ASP resulted in better MRD clearance. MRD of 10^-4 was associated with poor prognosis at both the end of induction and the end of early consolidation. Conclusion: In our multi-center clinical trial, we observed excellent outcomes in a diverse group of patients nationwide. Using the NCI criteria for stratification, a significant number of patients were categorized into the SR. Additionally, introducing L-ASP during early consolidation decreased the number of MRD-positive patients, which subsequently reduced the subset needing allo-HCT. This strategic adjustment in treatment intensity resulted in both high EFS rates and low NRM. Given the rise of immunotherapy and its promising results for recovery even post-relapse, there's a pressing need to enhance overall outcomes while minimizing non-relapse mortality. We anticipate refining our stratification further and integrating immunotherapy and other innovative treatments into our approach.

A Phase II Multicenter Trial of Ruxolitinib to Treat Bronchiolitis Obliterans Syndrome after Allogeneic Hematopoietic Cell Transplantation

Background: Bronchiolitis obliterans syndrome (BOS) occurring after allogeneic HCT is a pulmonary manifestation of chronic GVHD (cGVHD) that is associated with poor outcomes. Ruxolitinib, an oral selective JAK1/2 inhibitor, is approved for the treatment of recurrent/refractory cGVHD. However, efficacy of ruxolitinib for BOS is not well-characterized. Methods: In this prospective, multicenter phase II trial (NCT03674047), adult subjects (age 18-75) with BOS were enrolled at 7 academic centers. BOS was defined by either NIH criteria (Jagasia et al. BBMT. 2015) or atypical (Bergeron et al. BMT. 2013) criteria. Subjects were ≥4 weeks since start of most recent systemic GVHD therapy. Subjects were enrolled into a newly diagnosed cohort (&amp;lt;6 mo since BOS diagnosis, cohort A) or an established BOS cohort (≥6 mo since BOS diagnosis, cohort B), and were treated with ruxolitinib 10 mg BID continuously in 28-d cycles, for up to 12 cycles. A treatment extension up to 36 cycles was allowed for subjects benefiting from treatment. The primary objective was to evaluate the early treatment effect of ruxolitinib on BOS, assessed by % change in FEV1 at 3 months compared to baseline. Secondary objectives included NIH lung-specific ORR, treatment-emergent toxicities and infection, longitudinal changes in corticosteroid dosing, patient-reported outcomes, and exploratory evaluation of GVHD and BOS-associated cytokines. Results: Fifty subjects were enrolled (cohort A, n=37; cohort B, n=13). The median age for the entire cohort was 62 years (range, 21-71). At enrollment, the NIH lung score based on %FEV1 of predicted were 1 (n=19, 38%), 2 (n=23, 46%) or 3 (n=8, 16%). 33 subjects met NIH diagnostic criteria for BOS. At enrollment, 37 subjects were being treated with prednisone (median dose: 20 mg/d). The median follow-up of survivors is 19 months (range, 2-31) at last cutoff (3/31/23). The median number of cycles of treatment is 10 (range, 1-12; treatment extension not included in current analysis). 17 subjects remain on therapy; reasons for discontinuation include: completion therapy (n=7), BOS or GVHD progression (n=6), relapse (n=6), physician discretion (n=4), AEs (n=3), death (n=3), subject withdrawal (n=2), and lost follow-up (n=2). When comparing PFTs after 3 cycles of ruxolitinib to baseline, newly diagnosed BOS (cohort A) experienced more dynamic early changes in FEV1 (11 subjects with ≥10% increase, 8 subjects with ≥5% decrease); in established BOS (cohort B), disease was stable (1 subject with ≥10% increase, no subjects with ≥5% decrease) ( Figure 1). According to the NIH response criteria, the best lung-specific ORR for the entire study is 34% (18% CR, 16% PR). ORR did not differ between cohorts (cohort A: 36%, cohort B: 31%; p=1.0) nor BOS classification (NIH: 29%, atypical: 44%; p=0.2). ORR according to the baseline disease was 44%, 16% and 57% for NIH lung scores of 1, 2, and 3, respectively (p=0.07). In univariate analysis, only the total number of GVHD sites involved at baseline was significantly associated with lung-specific response (OR 4.7 for &amp;lt;3 vs ≥3, 95%CI 1.23-18, p=0.023); however, this did not meet criteria for significance in multivariate analysis (OR 6.3, p=0.06). The most common non-infectious severe (grade ≥3) TEAEs were neutropenia (n=3), anemia (n=2), and hypertension (n=2). There were 8 grade ≥3 infectious events: upper respiratory infection (n=6) and pneumonia (n=2). No fungal infections were observed. The median reduction in steroid dose was 50% by the end of treatment and 14% of subjects were able to discontinue steroids altogether. Clinically meaningful improvement (≥7-point reduction) in mLSS score on consecutive assessments was observed in 45% of subjects (responders: 50%; non-responders: 44%). However, only 3 subjects (7.5%) experienced a clinically meaningful organ-specific change (≥10-point reduction) in mLSS lung scores. The 1-year FFS and OS probabilities are 79% (95%CI, 64-88) and 89% (95%CI, 75-95), respectively. PRO and exploratory correlative studies are being analyzed. Conclusion: Ruxolitinib is associated with clinical responses in BOS, which were observed across all severity of disease. Ruxolitinib was associated with few severe AEs, including severe infections. Most subjects were able to taper or discontinue corticosteroids while on trial treatment. These results support the use of ruxolitinib in the management of BOS after allogeneic HCT.

Efficacy and Safety of AALL0232 Protocol in Adults with Acute Lymphoblastic Leukemia: Single Institution Experience

Background Over the past few decades, the outcomes for children with ALL have significantly improved with current regimens that yield a 5-year complete remission (CR) and event-free survival (EFS) rates of 98% and 70-80%, respectively. In contrast, the adult population has a CR of 85-90%, with a less satisfactory disease-free survival (DFS) rate of only 30-40% at 5-years. The feasibility of Children's Oncology Group (COG) AALL0232 protocol in older patients has not been established, especially adults older than 40 years and whether they will tolerate such unmodified pediatric based regimen. Therefore, we planned to assess our practice's outcomes in terms of the efficacy and safety of the COG AALL0232 protocol in adult ALL patients. Method This was a retrospective observational study that included patients ≥ 14 years with newly diagnosed ALL. Patients were excluded if they have secondary ALL. Our institute has adopted the AALL0232 protocol for both B-cell and T-cell ALL due to the similarities between the AALL0232 and CALGB 10403 protocols. MRD data was not included in our study since the cut-off for detection has been changed over the study period. Patient demographics and treatment-related outcomes will be reported using descriptive statistics. OS and RFS probabilities will be calculated using the Kaplan-Meier product-limit method from the date of pre-phase initiation. All P-values will be two-sided with P &amp;lt;0.05 indicating significance. Results Between 2014 and 2022, a total of 96 patients were included in our study. 74% had B-cell and 26% had T-cell ALL. The majority of the patients had standard risk ALL (23%). 65% of the patients were receiving AALL0232 protocol. Early death with AALL0232 protocol occurred in 11.1% of our population. The 2-year OS rate was 72.6% (95% CI 61.4-81.1) (Figure 1). The OS rate for B-cell ALL was 78.5% compared to 53.8% for T-cell ALL at 2-years (P =0.0912). The use of AALL0232 protocol was comparable to other protocols in terms of survival with a 2-year OS rate of 77% and 62.3%, respectively (P=0.0761). Adults with favorable cytogenetic risk had an OS rate of 100% compared to 67.6% for standard and 49.2% for poor risk (P =0.047). Adults younger than 40 years had a higher OS rate compared to those older than 40 (76.4% vs. 54.7%, P= 0.0187). RFS rate at 2-years was durable in 68.2% of the patients (95% CI 56.8-77.2) (Figure 2). RFS rates were 72.3% for B-cell and 54.8% for T-cell ALL. The AALL0232 Protocol had a significant impact on RFS compared to other protocols (73.6% vs. 56.5%, P= 0.0277) (Figure 3). Those who were younger than 40 had an RFS rate of 73.9%. The 2-year NRM occurred in 21.7% of the population. The AALL0232 protocol did not result in a higher NRM compared to other protocols (P= 0.492). Conclusion Although the use of AALL0232 protocol in the adult population has a remarkable impact on the rate of relapse, its effect on survival remains questionable especially for patients with T-cell ALL and poor cytogenetic risk. Another point of concern is the early death rate that was observed in our study. Further studies are needed to assess the overall impact of COG protocol in the adult population.

CD49d Expression Is Included in a Revised 4-Factor Model Predicting Outcome in Patients with Chronic Lymphocytic Leukemia Treated with Ibrutinib: A Multi-Center Real-World Experience

Introduction. Expression of the CD49d integrin chain has prognostic impact on ibrutinib (IB)-treated CLL patients (Tissino et al, J Exp Med, 2018; Tissino et al, Blood 2020). In addition, a 4-factor (4-f) score, based on TP53 aberration, β2-microglobulin (β2M), lactate dehydrogenase (LDH) and previous therapy lines was proposed to identify patients at a higher risk of treatment failure or death during IB therapy (Ahn et al, J Clin Oncol, 2020; Morabito et al, Am J Hematol, 2021). The clinical impact of TP53 disruption was recently refined by demonstrating that only the co-presence of TP53 deletion and mutations, and not the single aberrations, has prognostic value in the IB setting (Bomben et al, Leukemia 2022). The aim here is to integrate these observations in a comprehensive scoring for the management of IB-treated patients. Methods. This study is a retrospective/multicenter analysis of 410 CLL patients treated with IB in the current clinical practice (December/2013-March/2021). Outcome data were updated as of March/2023. Median follow-up from IB treatment was 29.5 months (95% CI 26.7-33.1 months); 57 patients were treatment naïve (0 previous lines), while 353 had ≥1 previous lines. CLL patients were characterized for CD49d expression and for the 4-f variables, TP53 disruption was evaluated by FISH and TP53 mutational status by NGS (low-VAF mutations included). OS or PFS were measured from the date of IB treatment to the date of death (OS), or progression/death (PFS) or last follow-up. Results. 1) The canonical 4-f was applied as previously described, identifying 111 low-, 163 intermediate (int)-, and 136 high-risk patients. Patients in the low-risk group had a longer OS than patients in the int-, and high-risk groups ( P=0.0115 and P=0.0011), while no difference was found comparing patients in the int- vs. high-risk groups (P=0.3036). 2) We generated a modified version of the 4-f score by considering: i) as TP53 disrupted only patients presenting a concomitant TP53 deletion and mutation (n=93); ii) since no difference in terms of OS was found comparing previously untreated patients (n=57) and patients treated with 1 previous line (n=157; P=0.78), these two groups were combined (n=214) and kept separated from patients who had received &amp;gt;1 previous lines of therapy (n=196). Accordingly, the 4-f-modified identified 218 low-, 109 int-, and 83 high-risk patients, the 3 groups presented different OS, the latter model outperforming the canonical 4-f score (C-indices 0.616 vs 0.639; P&amp;lt;0.0001). 3) CD49d-high CLL cases (i.e. CLL with CD49d expression ≥30% and/or with CD49d-bimodal expression; n=268) had shorter OS and PFS intervals ( P=0.0005 and 0.0194, respectively) than CD49d-low cases (n=142). By combining these observations, CD49d remained an independent prognostic factor for OS ( P=0.004) in a multivariable model, which included the 4-f-modified int-risk ( P=0.0585) and high-risk ( P=0.0011) groups. Driven by these findings, we re-analyzed the single parameters of the 4-f score along with CD49d expression. According to a new multivariable analysis (Fig. A), LDH was not included in the final model, which in turn included CD49d expression as independent OS predictor ( P=0.0011). 4) We then redesigned a novel 4-f model excluding LDH data in favor of CD49d expression data (4-factor-CD49d). Each of the four factors contributed one point and stratified patients (n=407/410) into three groups with a significantly different risk for OS probability, merged on a one-to-one risk group comparison basis: score 0-1, low-risk (n=185); score 2-3, int-risk (n=211); score 4, high-risk (n=11; Fig. B). The inclusion of CD49d into this novel 4-f model improved its prediction capability (C-index=0.663; P&amp;lt;0.0001 versus both the original 4-f and the 4-f-modified). Similar results were obtained when considering PFS as clinical readout. Conclusions. Evidence is provided that in the context of CLL patients treated with IB in a real-world setting, variables like B2M, the number of previous lines of therapy and assessment of TP53 disruption remain important tools for identifying patients at a higher risk of relapse/death. Here we emphasize the need of a comprehensive assessment of TP53 aberrations considering TP53 deletions and mutations simultaneously, and propose to add the assessment CD49d expression, integrating these four variables into a novel 4-f-CD49d scoring system. Further validation in independent cohorts is needed.

Post-Allograft Romidepsin Maintenance Mitigates Relapse Risk and Stimulates the Graft-Versus-Malignancy Effect through Enhanced NK-Cell Cytotoxicity in Patients with T-Cell Malignancies: Final Results of a Phase I/II Trial

Background: For patients with high risk, and relapsed/refractory T-cell malignancies allogeneic stem cell transplant (allo-SCT) is the only available potentially curative therapy. The efficacy of allo-SCT is limited in this population by high rates of relapse, with rates up to 55-60% post-allo-SCT. We designed a phase I/II trial, evaluating the combination of the histone deacetylases inhibitor romidepsin (rom) with busulfan/fludarabine (BuFlu) conditioning, followed by romidepsin maintenance (m-rom) in patients receiving allo-SCT for T-cell malignancies (NCT02512497). Here we present final clinical results of this therapeutic approach, including an evaluation of the stimulatory effects of m-rom on the graft-versus-malignancy effect through NK-cells post-allo-SCT. Methods: This was a phase I/II clinical trial. Eligible patients had: a diagnosis of T-cell leukemia (including T-acute lymphoblastic leukemia) or T-cell lymphoma (TCL, cutaneous or peripheral) in at least a partial remission requiring an allo-SCT, &amp;lt;70 years of age, with a matched sibling/unrelated donor. Patients received myeloablative (20K) or reduced intensity (16K) BuFlu with rom, followed by standard tacrolimus/methotrexate GVHD prophylaxis and anti-thymocyte globulin for unrelated donors (MUD). An expansion cohort of up to 30 patients (total) was included. M-rom was initiated between day +28 and +100 for 1 year (2 nd year optional), with built in dose reductions for toxicity. An efficacy endpoint of 20% reduction in relapse risk at 1-year in the whole cohort or any individual disease cohort was set based upon historical/CIBMTR (Center for Blood and Marrow Transplant Research) controls was pre-specified. The effect of m-rom on NK-cell cytotoxicity was assessed on samples taken pre-transplant, and 1, 3, 6, 12 months post allo-SCT. NK cytotoxicity was assessed by isolating mononuclear cells from patient samples at each timepoint, comparing those on m-rom (n=13) versus those who did BuFlu controls who did not receive m-rom (n=16). Cells were targeted against K562 targets using the calcein-AM assay. K-M and Fine-Gray models were used to estimate PFS, OS, and cumulative incidence, and compare survival across groups. Results: 28 patients were enrolled on this trial (Table). With a median follow-up time of 15 months, the median OS is 3.3 years (95% CI: 0.85-not reached), with a 1 and 3 year OS probability of 68% and 54%. The median PFS is 2.3 years (95% CI: 0.6-not reached), with 1 and 3-year PFS of 61% and 41%. Cumulative incidence (CI) of NRM at day 100 and 1 year were 14.3% and 21.4%. CI of grade II-IV aGHVD and extensive cGVHD were 46.4% and 38%. The CI of relapse (CIR) was 18.1% at 1 year and 33% at 3 -years. There was no difference between PFS among patients with MRD versus those without MRD prior to transplant (p=0.43). The CIR of patients with TCL was 9.3% at 1 and 3 years, whereas the CIR of patients with leukemia was 25% at 1 year and 48% at 3 years. No patients with PTCL relapsed, 1/2 patients with CTCL relapsed, and 4/6 patients with T-PLL are alive, disease free. Pre-specified general CIR was 55% for all patients. With an overall CIR of 18% at 1 year, and 33% at 3-years, this trial met its pre-specified endpoint of decreasing relapse by 20% at 1-year, and performed well compared to published CIBMTR control populations. Matched propensity score analysis across disease subsets with CIBMTR controls will be presented. 18/28 (64%) of patients received m-rom with a median number of 13 cycles (range 1-47). 8 patients experienced grade 3/4 adverse events (AE), and 1 patient discontinued m-rom due to toxicity, unlikely related to romidepsin (loss of CD3 chimerism). When NK-cytotoxicity was assessed between the two groups after starting maintenance, NK-cytotoxicity in the m-rom group was significantly higher than in those without m-rom (p&amp;lt;0.0001) (Figure). Conclusions: BuFluRom with m-rom is effective at decreasing relapse in patients with T-cell malignancies, with 1-year CI relapse below expected relapse rates for this set of diseases, meeting the pre-specified efficacy endpoint. NK-cell cytotoxicity data in a large sample set of trial patients demonstrates that m-rom enhances NK-cell cytotoxicity post allo-SCT, augmenting the GVL effect and likely accounting for at a minimum, some of the decrease in relapse seen on this trial. M-rom should be considered a new option post allo-SCT to mitigate relapse in patients with T-cell malignancies.

A Retrospective Study on Outcomes of Secondary CNS Lymphoma: Pattern of Relapse, Prognostic Factors, and Role of Consolidation Therapy

Introduction Secondary CNS lymphoma (SCNSL) remains a treatment challenge in patients (pts) with aggressive lymphoma. Outcome of SCNSL is poor. Pts are often treated with high dose Methotrexate (HD-MTX) based regimens followed by autologous stem cell transplant (auto SCT). However, the benefit of consolidation therapy is not well established. There is limited data on the treatments and outcomes of SCNSL. In this single institution study, we aim to analyze the role of consolidation therapy and potential prognostic factors of outcomes in SCNSL. Method All pts with a diagnosis SCNSL who presented to Moffitt Cancer Center, FL, USA between 2017 and 2022 were included. The hazard ratios (HRs) were evaluated in the univariate and multivariate analysis using the cox proportional hazard mode. All analyses were done using SAS 9.4. Results A total of 60 pts with SCNSL were identified. The median age was 63 years (range 26-83 years); 27 (45%) were female; 13 (21.7%) had Eastern cooperative oncology group performance status (ECOG) ≥2. Entire cohort was divided in 3 subgroups: pts with concurrent CNS involvement at the time of initial diagnosis with systemic lymphoma (Sys-CNS) [22 (36.7%)]; pts with isolated CNS relapse (R-SCNS) [30 (50.0%)]; and pts with simultaneous CNS and systemic relapse (R-Sys-CNS) [8 (13.3%)]. 31 (51.7%) pts had brain parenchymal involvement, 24 (40%) had leptomeningeal disease, 4 (6.7%) had both leptomeningeal and parenchymal involvement, and 1 (1.7%) had ocular disease. 58(96.6%) pts had diffuse large B cell lymphoma (DLBCL) histology; 9 (15%) had DLBCL with MYC and BCL2 rearrangement; 10 (16.7%) had DLBCL MYC and BCL2 expression. For induction therapy of SCNSL, 53 (88.3%) of pts received HD MTX-based chemotherapy; 2 (3.3%) received Bruton tyrosine kinase inhibitor (BTKi), and 5 (8.3%) with meningeal disease alone received IT chemotherapy and/or rituximab(R). Sys-CNS pts also received R-CHOP or DA-R-EPOCH while R-Sys-CNS pts received R-Polatuzumab or Polatuzumab-R-Bendamustine. 20 (33.3%) received consolidation either by WBRT [13 (21.7%)] or auto SCT [4 (6.7%)]; 3 (5.0%) proceeded with chimeric antigen receptor (CAR-T) therapy. The overall response rate (ORR) for entire cohort was 55.2% (34.5% complete response CR and 20.7% partial response PR). However, improved ORR and CR were observed with 14(73.68%) and 9 (47.37%) respectively in pts who received consolidation. ORR and CR for pts with Sys-CNS, R-SCNS, R-Sys-CNS were 13 (61.9%)/ 10 (47.6%), 14 (48.3%)/9 (31%) and 2 (25%)/ 2 (25%), respectively. After a median follow up of 33.6 months, median OS was 8.3 months with a 2-year survival probability of 33.8% (95% CI: 21.7-46.3%); the PFS was 6.5 months with a 2-year PFS probability of 32.9% (95% CI: 20.7-45.6%). Consolidation therapy with either auto SCT or WBRT had significant survival benefit. In this subgroup, median OS is not reached (NR) and the 2-year OS probability was 59.6% (95% CI: 32.9-78.7%); median PFS was 25.6 months and 2-year PFS probability was 53.3% (95% CI: 27.5-73.6%). After the first-line therapy for CNS disease, 21(35%) pts experienced relapsed. However, relapse rate in consolidation group [7 (36.8%)] was almost similar to those who did not receive consolidation [14 (34.2%)] (table 1). 39 (65%) pts died; 29 (48.33%) from disease progression, 3 (5%) from therapy related side effect and 7(11.7%) from other causes. In the univariate analysis, ECOG PS ≥2 [HR 3.60 (CI:1.80-7.20), p&amp;lt;0.001], lack of consolidation therapy [2.45 (CI:1.12-5.36), p=0.024], &amp;lt;3 cycles of HD-MTX containing regimen [2.85 (CI: 1.47-5.520), p=0.002] and double hit lymphoma [2.27 (CI: 1.02-5.06), p=0.045] were associated with worse OS. In the multivariate analysis, R-SYS-CNS, &amp;lt;3 cycles of HD-MTX, ECOG ≥2 and lack of consolidation remained significant. Lack of consolidation and receiving &amp;lt;3 cycles of HD-MTX were associated with inferior PFS in both univariate and multivariate analysis (figure 1). Conclusion Outcomes of aggressive B cell lymphoma with CNS involvement remain poor. The median OS was 8.3 months in our cohort. After adjusting for confounding factors, receiving &amp;gt;3 cycles of HD-MTX based regimen and consolidation with either WBRT or auto SCT were associated with improved outcomes. Pts with simultaneous CNS and systemic relapse had worse OS. Prospective studies are needed to evaluate optimal treatment for SCNSL.