Patients Experienced Disease Progression Research Articles

An assessment of survival outcomes among ovarian cancer patients at the National and Referral Hospital in Kenya.

Ovarian cancer has been shown to have poor survival outcomes attributed to late presentation. In Kenya, information on the survival outcomes of ovarian cancer patients is scarce. Therefore, the objective of this study was to examine the survival outcomes among patients with ovarian cancer treated at Kenyatta National Hospital (KNH). A hospital-based retrospective cohort study was performed at KNH to examine the survival outcomes of 112 ovarian cancer patients. The study employed a structured data abstraction tool to acquire patients' relevant socio-demographic and clinical characteristics from the patient's medical records. The data obtained were analyzed using SPSS version 29.0 statistical software. Kaplan-Meier and Cox regression analyses were used to determine the survival outcome and predictors of mortality among ovarian cancer patients, respectively. The mean age of the patients in this study was 51.28 ± 14.24 years. Most patients (59.8%) had evidence of distant metastasis during the follow-up period. One-third (33%) of patients were deceased. The mean-cancer-specific survival time among the study participants was 40.0 ± 3.0 months. The 5-year survival rate was 44%, with most patients experiencing disease progression during the last follow-up. Combination therapy (p < .001) was the only statistically significant predictor of mortality in ovarian cancer patients. The study found that the 5-year survival rate among ovarian cancer patients was poor, with most patients experiencing disease progression during the last follow-up period.

Enhanced clinical outcomes with radiotherapy in diagnostically challenging intracranial plasmacytomas: Analysis of 190 cases.

Intracranial plasmacytomas are rare tumors arising from plasma cells with approximately half of the cases progressing to multiple myeloma (MM). However, there is a lack of comprehensive clinical cohort analysis on the clinical and pathological features, progression, and outcomes of intracranial plasmacytomas. A retrospective analysis of 190 cases was conducted, combining data from 38 cases in a single institution and 152 cases from the literature. Patient demographics, clinical presentations, tumor locations, imaging features, surgical treatments, and follow-up outcomes were collected and analyzed. Survival analysis and Cox regression analysis were performed to identify prognostic factors. A total of 190 intracranial plasmacytoma patients with an average age of 55.4 years were included in the study. The preoperative misdiagnosis ratio was high at 55.3%, and 59.7% of the tumors affected the calvaria convexity, compared to 40.3% located at the skull base. Resection and biopsy were achieved in 72.4% and 27.6% patients, respectively. Among them, 34.2% (65/190) of patients were initially diagnosed with MM with intracranial plasmacytoma as their first presentation (MM-IPFP), while 63.2% (120/190) of patients were diagnosed with solitary intracranial plasmacytoma (SIP), including 61 extramedullary plasmacytomas and 59 solitary bone plasmacytomas. In the SIP group, 22.4% (24/107) of patients experienced disease progression leading to the development of MM during a median follow-up time of 42.6 months (range 1-230 months). Multivariate analysis unveiled that radiotherapy (HR, 0.05; 95% CI, 0.00-0.87; p = 0.04), not surgery, was a protective prognostic factor for overall survival in MM-IPFP patients. Comparison between the SIP progression group and non-progression group revealed a significant difference of Ki-67 index (non-progression vs. SIP progression, 8.82% ± 7.03 vs. 16.5% ± 10.5, p < 0.05). AUC analysis determined that a cutoff value of 9.0% was the best predictor of SIP progression, with an area under the curve of 0.712. This retrospective clinical analysis highlights the potential role of radiotherapy, rather than surgical resection, in improving the outcomes of intracranial plasmacytoma. Additionally, the Ki-67 index is identified as a valuable marker for predicting disease progression. This would provide some evidence for the paradigm of diagnosis and treatment modalities for intracranial plasmacytomas from the large cohort.

Efficacies of anlotinib monotherapy versus gemcitabine-based chemotherapy for patients with advanced soft tissue sarcoma after the failure of anthracycline-based chemotherapy

ObjectiveThe purpose of this study was to compare the antitumor efficacy of anlotinib with gemcitabine-based chemotherapy as subsequent treatment regimens in patients with advanced non-specific soft tissue sarcoma (STS) after the failure of anthracycline-based chemotherapy.MethodsPatients diagnosed with advanced STS who were treated with either anlotinib or gemcitabine-based chemotherapy between May 2009 and May 2023 in our center were eligible. All patients experienced disease progression or recurrence after the anthracycline-based chemotherapy. The primary endpoint was progression-free survival (PFS). Secondary endpoints were disease control rate (DCR), overall survival (OS) and safety.ResultsWe included 49 patients receiving anlotinib and 45 patients receiving gemcitabine-based chemotherapy. The median follow-up time was 76.9 weeks (range 2.9–678.9 weeks). The DCR (65.3% vs. 57.8%; p = 0.610), PFS (24.0 weeks vs. 18.6 weeks; p = 0.669) and OS (79.4 weeks vs. 87.0 weeks; p = 0.471) of anlotinib and gemcitabine-based chemotherapy indicated similar clinical efficacy. Moreover, exploratory subgroup analyses showed that patients with STS originating from limbs and trunk were inclined to benefit from anlotinib treatment (median PFS: 31.3 weeks vs. 12.4 weeks; p = 0.045). ECOG PS was an independent predictor of the PFS [Hazard Ratio (HR) 0.31; 95% confidence interval (CI) 0.11–0.85; p = 0.023] and OS (HR 0.26, 95%CI 0.10–0.70; p = 0.008) in the anlotinib group. While neutrophil-to-lymphocyte ratio (NLR) was an independent prognostic factor of the PFS (HR 0.33, 95%CI 0.11–0.98; p = 0.045) in the gemcitabine-based chemotherapy group. The incidence of grade 3 or higher related AEs in anlotinib and gemcitabine-based chemotherapy was 20.4% (n = 10) and 20.0% (n = 9), respectively.ConclusionOur research suggested that anlotinib and gemcitabine-based chemotherapy showed similar clinical efficacy and safety in the subsequent treatment of advanced STS after the failure of anthracycline-based chemotherapy.

Hypofractionated radiotherapy for refractory or relapsed aggressive B-cell lymphoma in the rituximab era

BackgroundRadiotherapy (RT) is an effective and available local treatment for patients with refractory or relapsed (R/R) aggressive B-cell lymphomas. However, the value of hypofractionated RT in this setting has not been confirmed.MethodsWe retrospectively analyzed patients with R/R aggressive B-cell lymphoma who received hypofractionated RT between January 2020 and August 2022 at a single institution. The objective response rate (ORR), overall survival (OS), progression-free survival (PFS) and acute side effects were analyzed.ResultsA total of 30 patients were included. The median dose for residual disease was 36 Gy, at a dose per fraction of 2.3–5 Gy. After RT, the ORR and complete response (CR) rates were 90% and 80%, respectively. With a median follow-up of 10 months (range, 2–27 months), 10 patients (33.3%) experienced disease progression and three died. The 1-year OS and PFS rates for all patients were 81.8% and 66.3%, respectively. The majority (8/10) of post-RT progressions involved out-of-field relapses. Patients with relapsed diseases, no response to systemic therapy, multiple lesions at the time of RT, and no response to RT were associated with out-of-field relapses. PFS was associated with response to RT (P = 0.001) and numbers of residual sites (P < 0.001). No serious non-hematological adverse effects (≥ grade 3) associated with RT were reported.ConclusionThese data suggest that hypofractionated RT was effective and tolerable for patients with R/R aggressive B-cell lymphoma, especially for those that exhibited localized residual disease.

Clinical study of camrelizumab combined with docetaxel and carboplatin as a neoadjuvant treatment for locally advanced oesophageal squamous cell carcinoma.

Herein, we aimed to evaluate the efficacy and safety of camrelizumab combined with docetaxel and carboplatin as a neoadjuvant treatment for locally advanced oesophageal squamous cell carcinoma (OSCC). Fifty-one patients with OSCC, treated from July 2020 to October 2022, were analyzed. Of them, 41 patients underwent surgery 4-8weeks after undergoing twocycles of camrelizumab (200mg IV Q3W) combined with docetaxel (75mg/m2 IV Q3W) and carboplatin (area under the curve = 5-6 IV Q3W). The primary endpoint was the pathological complete response rate. All 51 patients (100%) experienced treatment-related grades 1-2 adverse events, and 2 patients (3.9%) experienced grade 4 events (including elevated alanine transaminase/aspartate transferase levels and Guillain-Barre syndrome). Fifty patients were evaluated for the treatment efficacy. Of them, 13 achieved complete response, and the objective response rate was 74%. Only 41 patients underwent surgical treatment. The pathological complete response rate was 17.1%, the major pathological response rate was 63.4%, and the R0 resection rate was 100%. Approximately 22% of the patients had tumor regression grades 0. Eight patients (19.5%) developed surgery-related complications. The median follow-up time was 18months (range: 3-29months). Four patients experienced disease progression, while four died. The median disease-free survival and overall survival were not reached. Camrelizumab combined with docetaxel and carboplatin is an effective and safe neoadjuvant treatment for locally advanced OSCC. This regimen may afford a potential strategy to treat patients with locally advanced OSCC.

Oncological Outcomes of Thulium–Yttrium–Aluminum–Garnet (Tm:YAG) Laser Ablation for Penile Cancer

ObjectivesTo report oncological outcomes after Thulium–yttrium–aluminium–garnet (Tm:YAG) laser ablation for penile cancer patients. Materials and MethodsWe retrospectively analysed 71 patients with ≤cT1 penile cancer (2013-2022). All patients underwent Tm:YAG ablation with a RevoLix 200 W continuous-wave laser. First, Kaplan-Meier plots and multivariable Cox regression models tested local tumor recurrence rates. Second, Kaplan-Meier plots tested progression-free survival (≥T3 and/or N1-3 and/or M1). ResultsMedian (IQR) follow-up time was 38 (22-58) months. Overall, 33 (50.5%) patients experienced local tumor recurrence. Specifically, 19 (29%) vs. 9 (14%) vs. 5 (7.5%) patients had 1 vs. 2 vs. 3 recurrences over time. In multivariable Cox regression models, a trend for higher recurrence rates was observed for G3 tumors (HR:6.1; p=0.05), relative to G1. During follow-up, 12 (18.5%) vs. 4 (6.0%) vs. 2 (3.0%) men were re-treated with 1 vs. 2 vs. 3 Tm:YAG laser ablations. Moreover, 11 (17.0%) and 3 (4.5%) patients underwent glansectomy and partial/total penile amputation. Last, 5 (7.5%) patients experienced disease progression. Specifically, TNM stage at the time of disease progression was: 1) pT3N0; 2) pT2N2; 3) pTxN3; 4) pT1N1 and 5) pT3N3, respectively. ConclusionTm:YAG laser ablation provides similar oncological results as those observed by other PSS procedures. In consequence, Tm:YAG laser ablation should be considered a valid alternative for treating selected penile cancer patients.

A Retrospective Study on the Efficacy and Safety of Chidamide As a Maintenance Therapy for Peripheral T-Cell Lymphoma

Background: Peripheral T-cell lymphomas (PTCLs) are a set of rare and highly heterogeneous tumors of non-Hodgkin's lymphoma (NHL) with inferior outcomes. Chidamide is a novel benzamide class of histone deacetylase (HDAC) inhibitor (HDACi) that was approved by the Chinese Food and Drug Administration in 2014 for the treatment of relapsed or refractory (R/R) PTCL patients. This study aimed to assess the efficacy and safety of chidamide as a maintenance therapy after induction or salvage treatment in patients with PTCLs. Methods: The clinical data of 58 patients with different PTCL subtypes who received chidamide as a maintenance therapy after first-line or salvage treatment were collected. Progression-free survival (PFS), overall survival (OS), and safety were analyzed. Results: Fifty-eight patients enrolled in our study between January 2015 and July 2022, of whom 39 patients received chidamide as a maintenance therapy after first-line treatment and 19 patients after salvage treatment. All patients started chidamide maintenance after reaching at least partial response (PR). The median age was 66 (29-83) years. Patients with angioimmunoblastic T-cell lymphoma (AITL) represented the largest subgroup (34, 58.6%), followed by PTCL, not otherwise specified (PTCL-NOS) (10, 17.2%), anaplastic large cell lymphoma (ALCL) (8, 13.8%), NK/T cell lymphoma (NKTCL) (5, 8.6%) and monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) (1, 1.7%). Thirty-four (58.6%) patients were stage III-IV, and 38 (65.5%) patients had intermediate or high risk (prognostic index for T-cell lymphoma (PIT) 2-4). Among the 39 patients who underwent chidamide maintenance after first-line treatment, 30/39 (76.9%) patients began maintenance after reaching complete response (CR) and 9/39 (23.1%) after achieving PR. Notably, 8/9 (88.9%) patients achieved CR from PR during maintenance treatment, with a median time of 6 (3-12) months. A total of 11/39 (28.2%) patients experienced disease progression during the maintenance treatment, and their median duration of remission was 6 (3-13) months. Among them, 2 patients experienced disease progression 2 to 3 months after drug withdrawal due to COVID-19 infection. A total of 19 patients who received maintenance treatment after salvage therapy, 9 (47.4%) received maintenance therapy after CR and 10 (52.6%) received maintenance therapy after PR. Among them, 9/19 (47.4%)had disease progression and their median duration of remission was 16 (2-25) months. The remaining 10 patients (8 CR and 2 PR) were still undergoing maintenance treatment and follow-up. The median maintenance treatment time for all patients was 16 (1-72) months, and the median maintenance dose was 20 (15-30) mg twice weekly. The median follow-up time was 39 (2-79) months, the median PFS was 33 months, and the median OS had not been reached (Figure 1 a, b) for all patients. The median PFS and OS of the patients who received first-line maintenance therapy were not reached, which were significantly better compared to patients who received chidamide as salvage treatment maintenance (the median PFS and OS were 7 and 67 months, P &amp;lt; 0.001, P = 0.009, respectively) (Figure 1 c, d). There was no statistical difference in PFS and OS among the different pathological subtypes, but AITL seemed to achieve better PFS (Figure 1 e, f). The most common toxicities were hematologic toxicities, including neutropenia (42, 72.4%), anemia (23, 39.7%), and thrombocytopenia (29, 50.0%), followed by fatigue (35, 60.3%), anorexia (31, 53.4%), liver dysfunction (10, 17.2%), and pneumonia (4, 6.9%). Most adverse events were grade 1 or 2, and the grade 3‒4 adverse events were neutropenia (15/42), thrombocytopenia (7/29), fatigue (1/35), and pneumonia (2/4). Twelve (20.7%) patients underwent a dose reduction and three patients discontinued treatment (two patients with severe pulmonary infections, and one patient had intolerable fatigue) due to adverse events. One patient stopped maintenance treatment after taking chidamide for 10 months for financial reasons and he is still in follow-up. Conclusion: The findings of this study showed that patients with chidamide maintenance therapy had a better PFS and OS with a manageable safety profile, especially as the first-line maintenance therapy. We conclude that chidamide can be used as a maintenance treatment to improve the survival of patients with PTCLs.

Efficacy Analysis of Ixazomib-Based Regimens Based on Dynamic Frailty Assessment in Elderly and Frail Patients with Newly Diagnosed Multiple Myeloma

Background: Elderly frail MM patients often lack evidence-based basis due to many comorbidities and poor treatment tolerance, and are often excluded by new drug clinical trials. There are many unsolved problems in clinical practice.There is still variation in the prognosis of frail patients identified using current frailty assessment tools. A potential treatment approach to improve outcomes in this heterogeneous population could involve starting with a well-tolerated low-intensity regimen and adjusting treatment based on ongoing dynamic frailty assessments.Therefore, our center conducted a retrospective study to explore the efficacy and safety of real-world isazomib-based two-drug regimen in the treatment of newly diagnosed elderly frail MM patients by adjusting treatment intensity based on dynamic frailty assessment. Methods: Patients with NDMM who received 2 or more courses of ixazomib-based regimens at the Department of Hematology, Affiliated Hospital of Hebei University from January 1, 2018 to April 1, 2023. All patients were assessed for frailty using the IMWG Geriatric Assessment (IMWG-GA) tool, and a total of 21 patients with frailty assessed as Frail were included, including 11 patients (52.4%) aged 75 years and older and 17 patients (81.0%) with ECOG score ≥ 2.A two-drug regimen of ixazomib combined with dexamethasone (ID) was initiated, and dynamic frailty assessment and efficacy evaluation were performed during the 3-4 courses of treatment. After the frailty status improved, the third drug was used in the following cases: 1) R-ISS high-risk group, and 2) R-ISS intermediate-low risk group with efficacy &amp;lt; PR. The combination of the two drugs was continued in the following cases: 1) R-ISS intermediate-low risk group with improved frailty status with efficacy ≥ PR, and 2) no improvement in frailty status with efficacy ≥ SD. The effectiveness of treatment, discontinuation rate, early death and related adverse effects were assessed. Results: A total of 21 patients were included in this study, of whom 12 patients increased the intensity of treatment after improvement of frail status , the third drug was added with Cyclophosphamide (8 patients) or Lenalidomide (3 patients) or Daratumumab (1 patient) in courses 3-4. 9 patients continued to be treated with ID regimen. The median duration of treatment was 10 (2-19).The ORR was 85.7% (18/21), and the efficacy above MR was 95.2% (20/21). Two patients died, both over 80 years of age, with many underlying complications, including one patient who abandoned treatment and died (17 months), one patient who died (24 months) due to gastrointestinal bleeding, without early death. Four patients experienced disease progression after self-interruption of treatment, 15 patients were still using ixazomib-based therapy, and none discontinued due to adverse reactions. After a follow-up time of 9.0 (2.6-37.0) months, the PFS and OS were not reached. All patients overall tolerated well, mainly grade 1-2 adverse reactions (CTCAE 5.0). Conclusion: This study is a single-center retrospective study that included 21 frail patients with newly diagnosed multiple myeloma and achieved good efficacy with a low discontinuation rate, no serious adverse effects, and no early deaths. This study confirmed that the frail state of the patient was dynamically altered over time and treatment during the remedy period. For elderly frail patients, the two-drug regimen for ID was initiated, the treatment regimen was dynamically adjusted based on frailty assessment, cytogenetic-based stratification (R-ISS) was introduced after frailty assessment was improved, the treatment intensity was increased in patients, and the third drug was added to make up for the lack of treatment; for intermediate-low risk patients with better efficacy, continuous two-drug treatment was performed to avoid adverse reactions caused by excessive treatment, early drug withdrawal and early death. For the heterogeneous population of frail MM in the elderly, the treatment was dynamically adjusted according to frailty assessment and an individualized treatment plan was developed, which achieved the combination of efficacy and safety. However, the benefit of dynamically adjusting treatment regimens according to frailty stratification and the optimal regimen suitable for frailty MM in the elderly still need to be confirmed by evidence-based medical data.

Efficacy and Safety of Selinexor-Based Combination Therapy in CNS Lymphoma: A Retrospective Experience

Introduction ： Primary central nervous system lymphoma (PCNSL) is a rare diffuse large B-cell lymphoma (DLBCL) with distinct clinical and biological features, characterized by an aggressive course and poor prognosis. Patients with relapsed/refractory (R/R) disease have an unmet medical need due to a median overall survival (OS) of only 6.8 months. Novel therapies are urgently required for patients with R/R CNSL. In June 2020, the U.S. Food and Drug Administration granted accelerated approval to selinexor for the treatment of adult patients with R/R DLBCL. Selinexor has demonstrated central nervous system (CNS) penetration and activity in secondary CNS lymphoma (SCNSL) patients. Thus, we conducted a retrospective review of PCNSL/SCNSL cases treated with a selinexor-based regimen to preliminarily evaluate its effectiveness and safety. Methods: We retrospectively analyzed the medical records of 13 patients with CNSL who received selinexor-based combination therapy between June 2021 and June 2023 at three research centers in China. Among these cases, 2 were previously untreated, and 11 were relapsed or refractory patients. All patients had histopathologically confirmed DLBCL at the time of initial diagnosis. Data collection included baseline characteristics, treatment efficacy and safety evaluation. Results: A total of 13 patients (10 PCNSL and 3 SCNSL) were included in the study, with a median age of 62 years (range, 28-73), including three male patients. The median international extranodal lymphoma study group (IELSG) score for PCNSL cases was 3 (range, 1-3). The median International Prognosis Index (IPI) score for the three systemic DLBCL cases was 5 (range, 3-5), and three cases were at Ann Arbor stage IV. Among the patients, 11 had relapsed or refractory disease with a median of 2 prior treatments (range, 1-4), and 10 of them were refractory to previous treatments. The main patient characteristics, responses, and toxicities of the selinexor-based combination regimen are summarized in Table 1. Figure 1 presents the response of all evaluable patients. The overall response rate (ORR) of the patients was 84.6% (11 /13), with a complete response (CR) rate of 76.9% (10/13). Both treatment-naïve patients achieved CR after four and six cycles of the selinexor-containing first-line regimen, respectively. They are currently experiencing sustained remission, with the longest duration reaching 13 months. For relapsed/refractory CNSL, the ORR and CR rate were 81.8% (9/11) and 72.7% (8/11), respectively. Two patients had stable disease (SD). Among the 9 patients who achieved remission, 4 patients are still in remission, with the longest duration reaching 20 months, 2 patients received CART bridging therapy, one received radiation therapy, and 2 patients experienced disease progression after 5 months, but all are currently still alive. These patients are currently under continuous observation. Due to the heterogeneity of the selinexor-based regimens, the categories and severity of adverse events (AEs) varied greatly among the different regimens. The median treatment cycle number was six (range, 2-22). One patient died due to pneumonia infection, one patient was lost to follow-up, three patients successfully bridged to CART/RT, and eight patients completed the treatment as planned. The common AEs included thrombocytopenia, infection, nausea, vomiting, and gastrointestinal bleeding(Table 1). Conclusion: This report provides encouraging evidence of the efficacy and tolerable safety of the selinexor-based regimen in the treatment of CNSL. However, further prospective studies with a larger sample size are needed to provide more comprehensive evidence regarding the efficacy of selinexor in central nervous system lymphoma and to determine the appropriate dosage and optimal combination strategies.v

A Prospective, Exploratory, Phase II Study of the Xpo-1 Inhibitor Selinexor in Combination with RCHOP in Double/Triple-Hit Large B-Cell Lymphoma

Background Double-hit (DH) lymphoma or triple-hit (TH) lymphoma, according to 2016 WHO Classification Criteria, is recognized as a distinct subset of non-Hodgkin lymphoma. The optimal treatment for DH/TH lymphoma remains unclear, although outcomes are inadequate with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP) alone. Selinexor is a first-in-class, oral therapeutic that forms a slowly reversible covalent bond with cytoplasm by exportin 1 (XPO1/CRM1), leading to its inactivation. The U.S. Food and Drug Administration has approved selinexor monotherapy for relapsed/refractory DLBCL. Previous studies also suggested that selinexor was used to treat 5 patients with relapsed/refractory DH lymphoma, and 1 patient achieved CR and 2 achieved PR. Here, we report on the efficacy and safety of selinexor in combination with RCHOP as first-line treatment in patients with DH or TH lymphoma. Methods This prospective, phase 2, exploratory study was conducted in Zhejiang Cancer Hospital. The primary endpoint of the study was to evaluate the objective response rate (ORR), including complete remission (CR) rate and partial remission (PR) rate. In addition, diagnostic tumor tissue was prepared to conduct NGS analysis, and dynamic peripheral blood samples were collected before treatment, after 4 cycles when achieving CR from first-line chemotherapy, and progression of disease, to conduct ctDNA analysis. The initial dose of each drug in this regimen is as follows (repeat every 21 days, 6 cycles in total): rituximab: 375mg/m 2, d0; vindesine 4mg, d1; epirubicin 75mg/m 2, d1 (or liposomal doxubicin 35mg/m 2, d1); cyclophosphamide: 750mg/m 2, d1; prednisone: 100mg, d1-5; selinexor 60mg orally once a week. AEs were assessed according to the National Cancer Institute Common Terminology Criteria (CTCAE, version 4.0). Results From May, 2022, 8 patients were enrolled in the study, including 5 females and 3 males. All patients had received at least 2 cycles of selinexor with RCHOP. A full summary of patient baseline characteristics and response to chemotherapy was shown in Table 1. Four patients have completed full cycles of chemotherapy, while 2 patients are still undergoing treatment, and 2 patients suspended subsequent chemotherapy due to rejection of antitumor treatment. A total of 34 cycles of chemotherapy have been completed. Best responses after induction as assessed by positron emission tomography/CT were 5 CRs and 3 PRs. Two patients received ASCT as consolidation therapy after achieving CR. CNS prophylaxis with intrathecal methotrexate was administered to all patients for 2-6 cycles. No patient experienced disease progression, and no patient had CNS involvement during follow-up period (Figure 1A). All patients were assessable for toxicity. All patients in the study received prophylactic granulocyte colony-stimulating factor after each cycle of chemotherapy. The most common hematologic toxicities included anemia (15/34, 44.1%), neutropenia (20/34, 58.8%), thrombocytopenia (13/34, 38.2%), leukopenia (10/34, 29.4%). Other nonhematologic toxicities included fever (6/34, 17.6%), nausea (16/34, 47.1%), vomiting (13/34, 38.2%), fatigue (20/34, 58.9%), and infection (5/34, 14.7%). NGS was conducted successfully in 3 patients, while another 5 patients could not provide NGS data due to insufficient tumor tissue. 139 somatic alterations were detected in 3 patients, with a median of 30 mutations per sample. BCL6/IGLL5/TMSB4X were the most frequently mutated gene in 100% of patients followed by 66.7% who had BTG2/ETS1/EZH2/MYC/NFKBIE/OSBPL10/SOCS1/TNFRSF14 mutations. TP53 mutations were detected in 33.3% of the patient (Figure 1B). In 71.4% (5/7) of the cases, we were able to detect a total of 143 variants in the ctDNA from pretreatment serum samples. 80 variants were detected in both tumor tissue and peripheral blood samples. 4 variants were detected only in the ctDNA, and 59 were detected only in the tissue biopsy. Serial ctDNA monitoring results showed that 100% (8/8) reduction to zero in ctDNA after 4 cycles of chemotherapy. Conclusions Selinexor combined with RCHOP may be an effective first-line regimen for patients with DH/TH lymphoma. Dynamic testing of ctDNA demonstrated deep remission to chemotherapy. Based on the encouraging results of the current study, a large scale, multicenter trial is needed to further investigate this promising regimen.

Hypofractionated Radiotherapy in Aggressive B-Cell Lymphoma

Background and purpose: Radiotherapy (RT) is an effective and available local treatment for patients with refractory or relapsed (R/R) aggressive B-cell lymphomas. However, the value of comprehensive hypofractionated RT in this setting has not been confirmed. Materials and methods : We retrospectively analyzed patients with R/R aggressive B-cell lymphoma who received comprehensive hypofractionated RT between January 2020 and August 2022 at a single institution. The objective response rate (ORR), overall survival (OS), progression-free survival (PFS) and acute side effects were analyzed. Results : A total of 30 patients were included. The median dose for residual disease was 36 Gy, at a dose per fraction of 2.3-5 Gy. After RT, the ORR and complete response (CR) rates were 90% and 80%, respectively. With a median follow-up of 10 months (range, 2-27 months), 10 patients (33.3%) experienced disease progression and three died. The 1-year OS and PFS rates for all patients were 81.8% and 66.3%, respectively. The majority (8/10) of post-RT progressions involved out-field relapses. Patients with relapsed diseases, no response to systemic therapy, multiple lesions at the time of RT, and no response to RT were associated with out-field relapses. PFS was associated with response to RT (P=0.001) and numbers of residual sites (P&amp;lt;0.001). No serious non-hematological adverse effects (≥grade 3) associated with RT were reported. Conclusion: These data suggest that comprehensive hypofractionated RT was effective and tolerable for patients with R/R aggressive B-cell lymphoma, especially for those that exhibited localized residual disease.

Upfront Allogeneic Hematopoietic Stem Cell Transplantation Can Provide Survival Benefit Versus Hypomethylating Agent in Myelodysplastic Syndrome with Increased Blasts I (MDS-IB I)

Introduction Myelodysplastic syndrome (MDS) is a group of clonal disorders of hematopoietic stem cell. Survival would be significantly shortened if excessive blasts appear in marrow or the periphery. As disease progression accelerating, about 25% of MDS-IB1 and 33% of MDS-IB2 patients were reported to finally transformed into leukemia. Currently, allogeneic stem-cell transplantation (Allo-HSCT) still remains the only curable treatment accompanied with risk of therapy related mortality and decline of life quality. Decitabine (DAC), an of DNA methylation, was also reported to exhibit benefit in treatment of MDS. Thus, comparative studies with allo-HSCT are needed. Objective To retrospectively compare response of upfront allogeneic HSCT with hypomethylating agent (DAC in 87.5% of the group) therapy according to stem-cell donor availability in patients with MDS-IB1. Methods We retrospectively reviewed 103 patients with primary MDS patients who were evaluated and received treatment in our center between August 2011 and August 2020.Overall survival (OS) , event-free survival (EFS), non-relapse mortality (NRM) and cumulative rate of relapse or progression (CIR) at 1 year was calculated according to treatment arm.Cox regression analyses with allo-HSCT as time-dependent covariate (Mantel-Byar approach) were performed. Results According to the International Prognostic Scoring System (IPSS), 55 patients (55%) were stratified into lower-risk and 46 patients (45%) were stratified into higher-risk (IPSS intermediate 2 or high risk). Allogeneic HSCT was performed in 61.2% (n=63) and the rest 38.8% (n=40) received continuous HMA. In the no-donor group, 28 patients (70%) experienced disease progression or relapse after remission and leukemia transformation was noted in 14 patients (35%). The median follow-up time for surviving patients was 30.4months (range: 3.2-122.1 months). In the entire cohort, non-relapse mortality rate at 1 year was significantly higher in the allo-HSCT group compared with HMA group (14.3% vs. 2.5%, P=0.008), and the cumulative incidence of relapse and progression at 1 year was significantly lower (1.6% vs. 45.5%, P&amp;lt;0.001). After matching with propensity-score, the overall survival rate at 3 years was 77.8% in the allo-HSCT group compared with 43.5% in the HMA group with a significant difference by Cox-regression considered allo-HSCT as time-dependent covariate ( P=0.045), and event-free survival rate at 3 years was higher in allo-HSCT patients (73.4%) compared with HMA group (20.6%; P=0.001). The advantage of allo-HSCT was seen in those who aged &amp;gt; 50 years, male, those with ineffective erythropoiesis and without iron overload. Conclusion We concluded that patients with MDS-EB1 significantly benefited from receiving allo-HSCT with prolonged OS and EFS compared with continuous HMA (DAC) therapy. The advantage of allo-HSCT has been seen in subgroups of patients who age &amp;gt;50 years, male, those with ineffective erythropoiesis and without iron overload. Even earlier myeloablative allo-HSCT prevents further progression of MDS-EB1 at risk of higher non-relapse mortality, upfront allo-HSCT should be considered in a donor available scenario.

Retrospective Analysis of Clinical Outcomes of Utilizing R-CHOP Plus Zanubrutinib for High-Risk Diffuse Large B Cell Lymphoma Patients with Extranodal Involvement or MYC/BCL2 Double Expression

Background: Diffuse large B-cell lymphoma (DLBCL) patients with extranodal involvement and double expression of MYC and BCL2 often have a poorer prognosis when treated with the standard first-line R-CHOP regimen. The 5-year progression-free survival (PFS) and overall survival (OS) rates are both below 40% for these high-risk DLBCL cases. In this study, we perform a retrospective analysis of the clinical outcomes and adverse events of the high-risk DLBCL patients with extranodal involvement and double expression, who were admitted to our center and used Bruton's tyrosine kinase inhibitor (BTKi) zanubrutinib on the basis of R-CHOP regimen. Methods: We conducted a retrospective analysis of 26 DLBCL patients with extranodal involvement or MYC/BCL2 double expression who were admitted to our center and used R-CHOP regimen in combination with zanubrutinib between 1 st January 2021 and 30 th April 2023 (Figure A). Of these patients, 19 had extranodal involvement, and 7 were identified as double expression cases. The patients had a median age of 70 years, ranging from 34 to 87. Among them, 20 cases (77%) were aged over 60, and 8 cases (30%) were aged over 75. Moreover, 20 cases (76.9%) exhibited an Eastern Cooperative Oncology Group (ECOG) performance status score higher than 2 points. All the patients received an induction regimen consisting of zanubrutinib in combination with R-CHOP for a total of 4 cycles. After the fourth cycle, treatment efficacy was assessed using 18FDG-PET/CT scans. Patients achieving partial response (PR) or better continued with rituximab in combination with zanubrutinib for consolidation maintenance therapy, lasting for 1 year. For patients at risk of central nervous system involvement, oral administration of zanubrutinib continued for 2 years. During the treatment period, imaging evaluations were performed every 3 months to assess treatment response (Figure B). Results: After the induction therapy, a mid-term PET/CT evaluation showed that all patients achieved PR or above, resulting in an overall response rate (ORR) of 100%. Among them, 19 patients (73.1%) achieved complete response (CR), while 7 patients (26.9%) achieved PR. During the consolidation and maintenance therapy, 7 patients who were initially in PR converted to CR. As of the latest follow-up, with a median follow-up duration of 11 months (ranging from 4.1 to 30.0 months), 2 patients (7.7%) were lost to follow-up, and 2 patients (7.7%) experienced disease progression. The median PFS and OS were not reached. The 2-year PFS was 69.7±13.4% (Figure C), and the 2-year OS was 77.4±12.2% (Figure D). Non-hematological adverse events included fatigue (38.5%), hypertension (15.38%), neurological symptoms (7.7%), and infections (100%). Among the infections, 3 cases (11.5%) were of &amp;gt;3-grade and led to treatment discontinuation. Additionally, one patient experienced immune encephalitis and went into a coma. Hematological adverse events included granulocytopenia (55%), anemia (26%), thrombocytopenia (42.3%), and bleeding (38.5%). Among them, &amp;gt;3-grade granulocytopenia occurred in 4.5% of the patients. Five patients who were on long-term anticoagulant therapy due to concurrent cardiovascular diseases experienced a reduction in zanubrutinib dosage during the follow-up period, resulting in an improvement in bleeding symptoms. Conclusions: The combination of 4 cycles of R-CHOP regimen with zanubrutinib in the induction treatment of DLBCL patients with high-risk factors, such as extranodal involvement or MYC/BCL2 double expression, has shown promising clinical outcomes especially in older or unfit/frail patients. This approach allows for a reduction in the number of cytotoxic drug cycles, thereby improving the patients' tolerance to the treatment. Moreover, the efficacy of this regimen is superior to the traditional 6-8 cycles of R-CHOP induction therapy. Furthermore, the consolidation and maintenance therapy with rituximab in combination with zanubrutinib has demonstrated good safety and manageable adverse effects. This approach exhibits hope for further enhancing the prognosis of high-risk DLBCL patients.

Evaluating the Effectiveness of Risk Adjustment Using Dynamic Frailty Assessment in Treating Newly Diagnosed Multiple Myeloma in Elderly Patients

Background: The treatment of newly diagnosed multiple myeloma (NDMM) in elderly patients is challenging due to various problems. To address these challenges, the European Myeloma Network (EMN) recommends conducting a frailty assessment before NDMM treatment in elderly patients. If the assessment identifies an intermediate fit or frail group, dosage reduction is recommended to avoid excessive treatment. However, as frailty status improves, there may be a risk of insufficient treatment leading to poor outcomes. In order to explore the optimal treatment approach for elderly NDMM patients in real-world settings, a retrospective analysis was conducted on the effectiveness of dynamically adjusting treatments based on frailty assessment in intermediate-fit and frail groups of elderly NDMM patients. Methods: Patients who were initially diagnosed with multiple myeloma and assessed as intermediate fit or frail patients by IMWG-GA frailty assessment at the Department of Hematology, Affiliated Hospital of Hebei University from January 1, 2018 to April 1, 2023 were included in this study.The initial treatment regimen for all patients in this group consisted of a combination of Bortezomib with dexamethasone (BD) or Ixazomib with dexamethasone (ID) .Frailty assessment and efficacy evaluation were conducted every 2-3 courses during the treatment period. In the frail group, treatment in those frailty status improved was adjusted based on prognosis stratification by adding a third drug to high-risk R-ISS patients and subsequently adjusting it according to efficacy evaluation; additionally, a third drug was added to patients who did not reach partial response (&amp;lt;PR). For the intermediate fit group, sequential addition of a third drug occurred during courses 2-3.The options for the third drug included cyclophosphamide, lenalidomide, and thalidomide，and common regimens used were ICD, IRD, VRD, VCD, and VTD.The response rate, discontinuation rate, early death, and adverse drug reactions were observed. Results: A total of 45 patients with newly diagnosed NDMM were included in this study. Among them, 37 patients were assessed as frail .24 /45 patients were treated with the BD regimen and 21/45 patients with the ID regimen. During treatment, dynamic frailty assessment showed significant improvement in frail status during courses 3-4 (see Table 1). Following dynamically adjusted principles, additional drugs were administered to certain patients: 24 /37 frail patients received a third drug; among the intermediate fit patients, all received a third drug. The best ORR achieved throughout the study was at an impressive rate of 82.2% (37/45), with a corresponding best efficacy above VGPR seen in 51.1% (23/45) of cases. Twenty-one patients experienced disease progression for various reasons during treatment, with a median PFS of 14.0 (3.0-96.0) months. During the follow-up period, a total of 17 patients died, while none died within 6 months. The median overall survival (OS) was found to be 18.0 months (ranging from 3.0 to 115.5 months). Safety evaluation was conducted on all 45 patients within the first year and they tolerated the treatment well. Most adverse reactions reported were of grade 1-2 according to CTCAE version 5.0. Conclusion: This study is a retrospective study that the initial treatment involved administering a low-intensity regimen consisting of either BD or ID two-drug combination. Serious adverse reactions, drug withdrawal, and early death decreased in both groups. The treatment intensity was increased for high-risk patients or those with poor efficacy in the frail group after the improvement of frailty status. This new therapeutic strategy which integrates dynamic changes of frailty status, cytogenetic risk factors, efficacy evaluation and dynamic adjustment of treatment, has shown improved efficacy for patients with two different levels of frailty. Additionally, it has been found to reduce early mortality rates. These promising results warrant further investigation through prospective studies.

Long-Term Follow-up of the AST Trial of Treatment-Free Remission in Chronic Myeloid Leukemia Patients

Background: Treatment-free remission (TFR) is a new goal for chronic myeloid leukemia (CML) patients who achieved a long deep molecular response (DMR) with better quality of life, reduced adverse events and high economic impact. The primary objective of the AST trial was to estimate molecular relapse rate at 24 month in CP-CML patients who discontinued TKI. Secondary objective to explore predictive markers for sustained TFR through clinical and immunological analysis ( innate inmune response). This update provides longer follow-up data and includes a new cohort of patients. Patients and Methods: AST-Argentina Stop Trial (NCT05926128) is a multicenter prospective study that included patients from 15 centers. Recruited patients ≥ 18 years, treated with TKI for at least 4 years, sustained MR 4.0 for ≥ 2 years and confirmed typical BCR-ABL1 b3a2 and/or b2a2 transcripts. Molecular studies were centralized in 2 internationally standardized laboratories and were performed monthly during the first 6 months, every 2 months until the first year, and every 3 months during the second year. TKI was restarted due to loss of major molecular response (MMR). Expression of multiple NK cell immunophenotypic markers(CD3-CD56+) was analyzed by flow cytometry at discontinuation time and 3 months later. The nonparametric Mann-Whitney test was used to compare the differences between relapsed and responding patients. Molecular relapse-free survival was estimated using the Kaplan-Meier method and optimal cut-off points were obtained using ROC curves. Comparisons between survival curves were made using the Log rank test method. The differences were considered statistically significant with p-values less than 0.05. Multivariate analysis was performed using the COX regression model. Results: A total of 81 patients divided into 2 cohorts were evaluated: 46 patients recruited between February 2018 and July 2020 (1st cohort) and 35 patients recruited between July 2022 and April 2023. Between these two periods, recruitment was stopped due to the COVID19 pandemic. This analysis focuses on the 1st cohort that has completed 24 months in the study. The median age was 57.5 years (24-86), median duration of treatment before discontinuation was 10.5 years (4.2-20). TKI treatment prior to discontinuation was as follows: Imatinib in 34 (73%) patients, Dasatinib 8 (17%), and Nilotinib 4 (9%). According to Sokal risk score: 22 (48%) were low risk, 14 (30%) intermediate, and 10 (22%) high risk. Seventeen patients (37%) lost MMR, leading to a 63% molecular relapse-free survival rate with a median follow-up of 47 months (41-52). All patients who lost MMR recovered it after restarting the same TKI, with a median time to response of 2.8 months (1-7). With a prolonged follow-up, 2 late relapses were observed (18 and 42 months) (Fig 1). For a univariate analysis, the continuous variables were dichotomized seeking to maximize the difference between the different cohorts. The differences were significant in the variables time in DMR (cut-off point: 51 months, p=0.0166)(HR=0.97 (0.94 - 0.99); p=0.013). Two of the NK cell markers showed significant differences between groups at month 3 after starting treatment, PD1 (Mann-Whitney p=0.035; Log-Rank test p=0.033) and NK-p44 (Mann-Whitney p=0.015; Log -Rank test p=0.020). Multivariate analysis using the Cox model that included variables as gender, age at diagnosis, time in DMR, time in TKI prior to discontinuation, Sokal score, and type of inhibitor, the clinical predictor of time in DMR was the only predictor, significantly associated with a higher rate of TFR, (HR = 0.97 (0.95 - 0.99); p=0.020). No patient experienced disease progression to advanced stages or death for any reason. Conclusion:This is the first multicenter study of TKI discontinuation in CML patients in Argentina showing that TKI can be safely discontinued in those who achieve and maintain a DMR before discontinuation. Molecular relapse-free survival rate was slightly higher than that reported in the international literature, and longer follow-up confirmed the sustained response. DMR before discontinuation showed to be a robust predictor of TFR. Although the sample size was increased, longer follow-up is needed to validate these findings in the second cohort. Potential advantages of TFR will not only impact in patients' quality of life but also show considerable reduction in the use of economic resources.

Preliminary Outcomes of Orelabrutinib Plus R-CHOP in Treatment-Naive Patients with Double-Expression Diffuse Large B-Cell Lymphoma

Background Double-expression lymphoma (DEL), a type of diffuse large B cell lymphoma (DLBCL) with co-expression of MYC and BCL2 proteins without gene rearrangements, is associated with poor prognosis for patients. The double expression of MYC and BCL2 may result in the activation of the B cell receptor (BCR) signaling pathway. Bruton tyrosine kinase (BTK) serves as a rational therapeutic target for DEL due to its crucial role in BCR signaling. The Phoenix study demonstrated that ibrutinib (first generation of BTK inhibitor) plus R-CHOP could improve event-free survival (EFS) and overall survival (OS) in younger patients with DEL. Orelabrutinib is a novel BTK inhibitor with high selectivity to BTK. Orelabrutinib has been shown in a preclinical study that it could preserve the NK-cell-mediated antibody-dependent cellular cytotoxicity induced by rituximab, and combination with R-CHOP (O-RCHOP) displayed higher anti-tumor activity than either alone in vivo or in vitro. This study aimed to evaluate the efficacy and safety of the O-RCHOP regimen in the treatment of naive patients with DEL DLBCL. Methods This was a prospective, single-arm, phase II study recruiting treatment-naive patients with DEL DLBCL. DEL was defined as≥40% positive rate for MYC and ≥50% for BCL2 by immunohistochemistry. The double-hit cases (with gene rearrangement) were excluded. All patients were treated for 6-8 cycles with 21 days per cycle. They received 150 mg of orelabrutinib once daily on days 1-14 combined with R-CHOP (Rituximab 375 mg/m 2, cyclophosphamide 750 mg/m 2, liposome doxorubicin 30 mg/m 2, vincristine 1.4 mg on day 1, and prednisone 100 mg daily on days 1-5). The primary endpoint was EFS. The response was assessed after 4 or 6 cycles using PET-CT. Adverse events (AEs) were assessed according to the Common Terminology Criteria for Adverse Events v 5.0. Results From March 27, 2021 to June 7, 2023, 15 patients with DEL were enrolled. All patients received an O-RCHOP regimen and 13 patients . The baseline characteristics of the patients were listed in Table 1. Thirteen patients who had received at least 4 cycles of treatment achieved CR (100.0%; Figure 1). After a median follow-up of 14.6 months (1.5-27.1 months), the estimated 12-month EFS rate was 100.0%. None of the 13 patients experienced disease progression or death at the cutoff date. Three of the 15 patients had the mutation of TP53 with or without other cytogenetic abnormalities tested by NGS. Grade 3/4 AEs were mainly hematological toxicity including febrile neutropenia (20%; 3/15), neutropenia (66.7%; 10/15), anemia (13.3%; 2/15), and thrombocytopenia (6.6%; 1/15), which were manageable. Neutropenia mainly occurred after the first cycle of chemotherapy, which improved after prophylaxis of PEG-rhG-CSF. The incidence of all-cause infection was 13.3% (2/15) . No atrial fibrillation, tumor lysis syndrome, or hemorrhage were observed. No patients discontinued treatment due to toxicity. Conclusion The combination of orelabrutinib and RCHOP showed encouraging efficacy and a tolerable safety profile in DEL DLBCL in this preliminary analysis. More updated data from this ongoing study will be provided in the future.

The Final Results of a Phase I Study Using Bortezomib (Velcade), Cladribine, and Rituximab (VCR) in Treating Mantle Cell Lymphoma

Background: Mantle cell lymphoma (MCL) is a moderately aggressive and incurable small to medium sized B cell lymphoma. No standardized treatment exists for this disease. Cladribine is a hypomethylating agent that indirectly down-regulate DNA methylation to suppress tumorigenesis. Combination of Cladribine and Rituximab showed a synergetic effect in treating B cell lymphomas. Bortezomib (Velcade) is an FDA approved proteasome inhibitor to treat relapsed/refractory MCL. In this study, we evaluated the safety and efficacy of Valcade, Cladribine, and Rituximab (VCR) combination treatment in newly diagnosed and relapsed/refractory MCL. Patients and Methods: This is a single arm open label phase I trial. This study employed a standard 3+3 dose escalation scheme designed to determine the maximum tolerated dose (MTD) of Cladribine in VCR regimen. Briefly, the treatment scheme was consisted of 6 28-day cycles. At first cycle of the treatment, Rituximab 375 mg/m 2 infusion started on day 5 of the first week and then given weekly for 3 weeks; in the next 5 cycles Rituximab was given on day 5 of each cycle, and then every 2 months as the maintenance therapy. Cladribine 3 to 5 mg/m 2 (3 mg/m 2 for level 1, 4 mg/m 2 for level 2, and 5 mg/m 2 for level 3) infusion was given on days 1 to 5 for 6 cycles. For patient older than 70 years old, Cladribine was only given on days 1 to 3 of each cycle. Velcade 1.6 mg/m 2 subcutaneous injection was given on days 12, 19 and 26 for cycles 1 to 3, Days 5 and 19 for Cycles 4 to 6, then once per month as maintenance therapy. The primary endpoint of this study was the dose limiting toxicity (DLT), safety, and efficacy of this regimen in patients with MCL. The secondary endpoints included remission rate (RR), progression free survival (PFS) and overall survival (OS) (Figure 1). The analysis was done by intent to treat. Differentially methylated region (DMR) analysis and cytokine assay were performed to explore biomarkers differentiating good-responders from poor-responders. Results: This study recruited 13 patients, with a median age of 64 years old (range from 55 to 83) and including 11 males and 2 females. Ten patients were never previously treated, other 3 either relapsed or failed from previous treatments. Most patients tolerated this regimen well. No patient experienced DLT at either level 1 or 2, one possible DLT (infectious colitis) was observed during 2nd cycle at level 3. Two relapsed patients experienced disease progression after received two cycles of treatment and died in 5 and 7 months. Another patient died in 15 months after receiving treatment. The overall remission (OR) rate was 85% (11/13) and complete remission (CR) rate was 77% (10/13). In newly diagnosed patient cohort, CR rate was 100% (10/10), OS rates were 90% (9/10), and PFS was 80% (8/10), of which 3 patients have been followed for more than 4 years, 3 other patients for more than 3 years, and 3 others for over 2 years (Fig.1). In relapsed/refractory patient cohort, 1 achieved CR for 7 months but then relapsed, 2 had no response. There were 2 blastoid patients, 1 of these 2 patients was newly diagnosed and achieved CR. Bone marrow suppression caused prolonged anemia and thrombocytopenia were the most common toxicity (3/13 with ≤grade 2). Low grade peripheral neuropathies (≤grade 2) were observed in 15% (2/13). Mild fatigue was a frequent complaint. Cytokine assay showed decreased CXCL12 level in the good responders. Though global methylation pattern showed no difference, DMRs were identified in the good responders and the poor responders. DMRs-related genes involved in CXCL2 pathways were further extracted and enriched biological process analysis revealed the pathway profile difference between good responders and poor responders. Good responders exhibited alternation of apoptotic and Wnt signaling pathways (Fig.2). Conclusions: The VCR combination is a well-tolerated, low toxicity and effective regimen for MCL, especially for untreated MCL. Cladribine 5 mg/m 2 is a tolerable dose with manageable toxicity. Individual patient methylation profile may affect response to VCR therapy.

Combining PET/CT and Ctdna Assessments at 6 Months from Induction Treatment Better Predicts Outcome in Previously Untreated Patients with Follicular Lymphoma: A Relevance Ancillary Lysa Study

Background Most patients with follicular lymphoma (FL) have long-term disease control resulting in a prolonged overall survival (OS), beyond 20 years. However, approximately 20% of patients experience disease progression within two years after treatment initiation (POD24) which is associated with a shorter OS but early prediction of POD24 remains challenging. Positron emission tomography computed tomography (PET/CT) positivity after induction therapy has been associated with shortened progression-free survival (PFS). Also, minimal residual disease (MRD) positivity in peripheral blood using BCL2-JH translocation predicts outcome but barely 50% of patients are informative with this tumor marker. Circulating tumor DNA (ctDNA) may increase the proportion of MRD informative patients up to 80%. Our objective was to evaluate the predictive value of ctDNA for PFS and POD24, either alone or coupled with PET/CT response in first-line patients enrolled in the RELEVANCE trial. Methods This ancillary study was carried out on patients included by French LYSA centers in RELEVANCE, a randomized phase III trial comparing the chemotherapy-free regimen R2 versus standard R-chemo followed by Rituximab maintenance in previously untreated patients with FL. All patients who had a PET/CT at diagnosis and at week 24 (W24, end of induction treatment) and for whom serum was stored at these 2 time points were eligible. Cell-free DNA (cfDNA) was extracted from a median of 2.8 mL of serum (range 0.35 to 4.1). Libraries were generated from 129kb captured-DNA custom panel (Agilent, XTHS2). Variant calling and phased variant annotation were performed using Unique Molecular Identifiers (UMI). Libraries were sequenced with a median coverage of 3257 UMI. Concentrations of ctDNA were calculated from TapeStation migration system (Agilent) using 50 bp to 600 bp limits and expressed as log hGE/mL. To ensure maximum specificity in a context of non-optimal serum samples, only patients with phased variants in ctDNA at diagnosis were studied for MRD at W24. Total metabolic tumor volume (TMTV) was computed using the 41% SUVmax method and PET/CT response assessed with Lugano criteria. Results As PET/CT at W24 was optional in RELEVANCE, only 141 out of 581 patients enrolled were eligible. Compared to the overall RELEVANCE population, baseline characteristics were similar except for FLIPI (7.1% FLIPI 0-1 versus 15.9% respectively, p=0.013) and PFS event (29.3% versus 39.5% respectively, p=0.035). At time of diagnosis, with a median of 81 variants per patient (range 1 to 659), a mutational profile could be identified from cfDNA in 99% (140/141) of patients. A significant correlation was found between ctDNA load (median 2.39 log hGE/mL (range 1.01 to 4.20) and TMTV (median 298 mL, range 5 to 3100) (p=0.023). Phased variants were detected in 124 patients (87.9%) at diagnosis and were used for MRD analyses. At W24, ctDNA remained detectable (ctDNA+) in 15 patients, 9/69 (13%) in the R2 arm and 6/55 (11%) in the R-chemo arm (p=0.787). PET/CT remained positive (Deauville 4 and 5) in 20 patients, 11/72 (15.2%) in the R2 arm and 9/56 (16.1%) in the R-chemo arm. With a median follow-up of 6.4 years, ctDNA+ patients exhibited a median PFS of 37 months versus not reached for ctDNA- patients, p=0.0096. Similarly, PET/CT+ patients had a median PFS of 34 months versus not reached for PET/CT- patients (p&amp;lt;0.001). When adjusting on FLIPI in a multivariate Cox model, ctDNA remains statistically significant (HR=2.63 [1.20; 5.77], p=0.0163). Among PET/CT+ patients, 13/20 (65%) patients showed discrepant PET/CT and ctDNA responses and double positive patients (7/20, 35%) presented a shorter median PFS of 8.6 months (versus not reached, p=0.0147; Figure 1). Regarding POD24, negative predictive value (NPV) and positive predictive value (PPV) were respectively 91.7% and 46.7% for ctDNA MRD and 93.3% and 45.0% for PET/CT. When combined, PET+/MRD+ identified POD24 patients with a NPV and PPV of 91.5% and 85.7% respectively. Conclusion Combining the results of ctDNA and PET/CT at W24 post induction improves early prediction of POD24 in previously untreated patients with follicular lymphoma.

Clinical and molecular biological characterization of patients with accelerated chronic lymphocytic leukemia

Objective: To investigate the clinical and molecular biological characteristics of patients with accelerated chronic lymphocytic leukemia (aCLL) . Methods: From January 2020 to October 2022, the data of 13 patients diagnosed with aCLL at The First Affiliated Hospital of Nanjing Medical University were retrospectively analyzed to explore the clinical and molecular biological characteristics of aCLL. Results: The median age of the patients was 54 (35-72) years. Prior to aCLL, five patients received no treatment for CLL/small lymphocytic lymphoma (SLL), while the other patients received treatment, predominantly with BTK inhibitors. The patients were diagnosed with aCLL through pathological confirmation upon disease progression. Six patients exhibited bulky disease (lesions with a maximum diameter ≥5 cm). Positron emission tomography (PET) -computed tomography (CT) images revealed metabolic heterogeneity, both between and within lesions, and the median maximum standardized uptake value (SUVmax) of the lesion with the most elevated metabolic activity was 6.96 (2.51-11.90). Patients with unmutated IGHV CLL accounted for 76.9% (10/13), and the most frequent genetic and molecular aberrations included +12 [3/7 (42.9% ) ], ATM mutation [6/12 (50% ) ], and NOTCH1 mutation [6/12 (50% ) ]. Twelve patients received subsequent treatment. The overall response rate was 91.7%, and the complete response rate was 58.3%. Five patients experienced disease progression, among which two patients developed Richter transformation. Patients with aCLL with KRAS mutation had worse progression-free survival (7.0 month vs 26.3 months, P=0.015) . Conclusion: Patients with aCLL exhibited a clinically aggressive course, often accompanied by unfavorable prognostic factors, including unmutated IGHV, +12, ATM mutation, and NOTCH1 mutation. Patients with CLL/SLL with clinical suspicion of disease progression, especially those with bulky disease and PET-CT SUVmax ≥5, should undergo biopsy at the site of highest metabolic uptake to establish a definitive pathological diagnosis.

RADT-18. PROTON CRANIOSPINAL IRRADIATION WITH CHECKPOINT INHIBITOR THERAPY FOR PATIENTS WITH LEPTOMENINGEAL DISEASE FROM SOLID TUMORS – A SINGLE INSTITUTION CASE SERIES

Abstract BACKGROUND Leptomeningeal disease (LMD) is a devastating complication of cancer with median overall survival (OS) of 3-6 months following diagnosis. Proton craniospinal irradiation (pCSI) is a novel treatment option for LMD, permitting whole neuroaxis treatment with tolerable toxicity and improved efficacy compared to conventional photon whole brain radiation therapy and as needed focal spine radiotherapy. Despite this, patients experience progression and succumb to LMD. Addition of systemic therapy to pCSI may improve outcomes. METHODS In this single institution retrospective case series, we report feasibility of combination treatment with pCSI and immune checkpoint inhibitor (ICI) in patients with LMD from solid tumors. RESULTS Three patients were treated with pCSI (30 Gy in 10 fractions) and ICI. The first patient developed LMD related to large cell neuroendocrine carcinoma of lung primary, diagnosed by imaging and cytology, having previously undergone resection and stereotactic radiosurgery for brain metastases. Clinical and radiographic improvement was noted following pCSI, bevacizumab, and pembrolizumab therapy. Patient experienced disease progression and passed away only after ICI was held due to hypophysitis, with 6-month OS. The second patient developed LMD related to BRAF V600E mutant melanoma, diagnosed by imaging and cytology, having previously undergone ICI and BRAF-targeted therapy. Following pCSI, relatlimab, nivolumab, and BRAF-targeted therapy, the patient remains alive 7 months after LMD diagnosis despite radiographic progression treated with carboplatin, paclitaxel, intrathecal IL-2, ipilimumab, and bevacizumab. The third developed LMD related to BRAF-wildtype melanoma, diagnosed by imaging, having previously received ICI. Patient underwent pCSI followed by ipilimumab and nivolumab, progression-free 5 months after LMD diagnosis. CONCLUSION Addition of systemic therapy to pCSI is feasible for patients with LMD. Combination of ICI and pCSI may confer additional survival benefit, even among patients with prior exposure to ICI. These initial promising results warrant prospective evaluation.