Patients Experienced Disease Progression Research Articles

Abstract CT145: The final results of a phase I study using velcade (bortezomib), cladribine, and rituximab (VCR) in treating elderly patient with mantle cell lymphoma

Abstract Background: Mantle cell lymphoma (MCL) is a moderately aggressive and incurable small to medium size B cell lymphoma. In this phase 1 study, we evaluated the safety and efficiency of Valcade, Cladribine, and Rituximab (VCR) combination treatment in MCL. Patients and Methods: This is a single arm, open label, investigator-initiated Phase 1 study. This study employed a standard 3+3 dose escalation scheme designed to determine the maximum tolerated dose (MTD) of Cladribine in VCR regimen. The treatment scheme and Cladribine dose escalation levels (1, 2, and 3) are as follows: the therapy consisted of 6 28-day cycles. At first cycle of the treatment, Rituximab 375 mg/m2 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 35 mg/m2 (3 mg/m2 for level 1, 4 mg/m2 for level 2, and 5 mg/m2 for level 3) infusion was given on days 1 to 5 for 6 cycles. If the patient was older than 70 years old, Cladribine was only given on days 1 to 3 of each cycle. Velcade 1.6 mg/m2 subcutaneous injection was given on days 12, 19 and 26 for cycles 1 to 3, then Day 5 and 19 during Cycles 4 to 6, then once per month as maintenance therapy until toxicity or progression of the disease. The primary endpoint of this study was to investigate the dose limiting toxicity (DLT), safety, and efficiency of this regimen in patients with MCL. The secondary endpoints included remission rate (RR), progression free survival (PFS) and overall survival (OS). This study is registered with clinicaltrials.gov (NCT01439750). Results: No subject experienced dose limited toxicity (DLT) at either level 1 or 2, one possible DLT (infectious colitis) was observed on a subject during 2nd cycle at level 3. Then no additional DLTs were seen in 3 subjects added to level 3. Overall, this study recruited 13 subjects, with a median age of 64 years old (range from 55 to 83), and a total of 11 male and 2 females. Ten subjects were never previously treated, while 3 either relapsed or failed previous treatments. The majority of subjects tolerated this regimen well. Two relapsed patients experienced disease progression after received two cycles of treatments and died in 5 and 7 months after initiating the treatment. Another patient died 15 months after starting treatment. The overall remission (OR) rate was 77% (10/13) and complete remission (CR) rate was 85% (10/13). In newly diagnosed subject cohort, the RR and OS rates were 90% (9/10), PFR was 80% (8/10), and CR rate was 100% (10/10), 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. However, in relapsed/refractory subject cohort, 1 subject achieved CR for 7 months but then relapsed, 2 subjects had no response. There were 2 blastoid subjects, one was newly diagnosed and achieved CR.No severe systemic toxicity was observed in this study. 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. Conclusions: The VCR combination is a well-tolerated, low toxicity and effective regimen for for untreated MCL. Cladribine 5 mg/m2 is a tolerable dose with manageable toxicity. Citation Format: Jeffrey J. Pu, Kristin Berger, David Claxton, Joseph Drabick, Thomas Loughran, Elliot Epner. The final results of a phase I study using velcade (bortezomib), cladribine, and rituximab (VCR) in treating elderly patient with mantle cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT145.

Case report: Temozolomide induced hypermutation indicates an unfavorable response to immunotherapy in patient with gliomas

BackgroundTemozolomide (TMZ) is a key component in the treatment of gliomas. Hypermutation induced by TMZ can be encountered in routine clinical practice, and its significance is progressively gaining recognition. However, the relationship between TMZ-induced hypermutation and the immunologic response remains controversial.Case presentationWe present the case of a 38-year-old male patient who underwent five surgeries for glioma. Initially diagnosed with IDH-mutant astrocytoma (WHO grade 2) during the first two surgeries, the disease progressed to grade 4 in subsequent interventions. Prior to the fourth surgery, the patient received 3 cycles of standard TMZ chemotherapy and 9 cycles of dose-dense TMZ regimens. Genomic and immunologic analyses of the tumor tissue obtained during the fourth surgery revealed a relatively favorable immune microenvironment, as indicated by an immunophenoscore of 5, suggesting potential benefits from immunotherapy. Consequently, the patient underwent low-dose irradiation combined with immunoadjuvant treatment. After completing 4 cycles of immunotherapy, the tumor significantly shrank, resulting in a partial response. However, after a 6-month duration of response, the patient experienced disease progression. Subsequent analysis of the tumor tissue obtained during the fifth surgery revealed the occurrence of hypermutation, with mutation signature analysis attributing TMZ treatment as the primary cause. Unfortunately, the patient succumbed shortly thereafter, with a survival period of 126 months.ConclusionPatients subjected to a prolonged regimen of TMZ treatment may exhibit heightened vulnerability to hypermutation. This hypermutation induced by TMZ holds the potential to function as an indicator associated with unfavorable response to immunotherapy in gliomas.

Abstract 2882: Investigating mechanisms of radioresistance in TYK2 knockout head and neck cancer cells

Abstract Radiation therapy is the primary form of treatment of head and neck squamous cell carcinoma (HNSCC). However, more than half of patients experience disease progression with standard of care treatment. To investigate novel therapeutic targets, a CRISPR screen was done to identify genes that are associated with radioresistance. The screening results indicated that JAK1 and TYK2 knockout (KO) resulted in radioresistance in HNSCC. Preliminary data suggests that loss of JAK1 causes an enhanced G2/M arrest phenotype and enhanced genome stability that contribute to radioresistance. To investigate whether TYK2 KO caused changes to the cell cycle and genome stability as observed in JAK1 KO, Western blots, cell cycle assays, and micronuclei staining experiments were performed. Cal27, a HNSCC cell line, was used. Cal27 cells were transduced with a non-targeting control (NT2) guide RNA (gRNA) or two different gRNAs targeting TYK2 to generate TYK2 KO cells. Western Blot analysis was performed to determine changes in signaling upon TYK2 KO. Additional conditions included radiation and treatments with Interferon gamma, Interferon alpha and Interleukin-6 to activate the canonical JAK-STAT pathways. Overall, there were minimal changes in downstream signaling between the treatments and the knockouts. Cell cycle analysis via flow cytometry revealed no changes between the NT2 and TYK2 KO cells, potentially corroborating signaling results. Forty percent of TYK2 KO cells were arrested at the G2/M checkpoint at 8 hrs and 24 hrs after radiation treatment, but twenty percent returned to the G1 phase at 24 hrs. This indicates that loss of TYK2 is not responsible for cell cycle arrest. Lastly, micronuclei formation was observed to measure genomic instability. Twenty thousand Cal27 NT2 and TYK2 KO cells were seeded. They were allowed to incubate for 48 hrs before treatment with 4 Gy. Micronuclei staining revealed minimal differences between NT2 and TYK2 KO cell lines, although there were significant differences between the control and the radiation groups. Overall, radioresistance by TYK2 KO is not caused by changes in cell cycle or genomic instability as demonstrated with JAK1 KO. To understand how TYK2 is causing radioresistance in HNSCC, next steps would be to see if there are changes in proliferation. If MTT assays demonstrate significant changes, downstream signaling in growth pathways will be measured. If there is no increased proliferation, we will examine changes in DNA damage repair. Citation Format: Nicole Mayerli Constante, Vanessa Kelley, Joseph Contessa. Investigating mechanisms of radioresistance in TYK2 knockout head and neck cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2882.

Prognostic value of micrometric substaging in pT1 bladder cancer patients treated with en-bloc transurethral resection.

We aimed to assess the oncological impact of micrometric extent of invasion in patients with pT1 bladder cancer (BCa) who underwent en-bloc resection for bladder tumour (ERBT). We retrospectively analysed the records and specimens of 106 pT1 high-grade BCa patients who underwent ERBT. The extent of invasion, such as depth from basal membrane, number of invasive foci, maximum width of invasive focus, muscularis mucosae invasion and infiltration pattern (pattern A: solid sheet-like, nodular or nested growth, pattern B: trabecular, small cluster or single-cell pattern) were evaluated by a single genitourinary pathologist. The end-points were recurrence-free (RFS) and progression-free survival (PFS). Within a median follow-up of 23 months, overall, 36 patients experienced recurrence and 13 patients experienced disease progression. The 2-year PFS differed significantly depending on depth from basal membrane (< 1.3 mm: 94.8% versus ≧ 1.3 mm: 65.2%, P = 0.005), maximum width of invasive focus (< 4 mm: 91.7% versus ≧ 4 mm: 62.3%, P < 0.001), muscularis mucosae (MM) invasion (above MM = 96.1% versus into or beyond MM = 64.8%, P = 0.002) and infiltration pattern (pattern A: 100% versus pattern B: 83.3%, P = 0.037). In a multivariable analysis, MM invasion [hazard ratio (HR) = 4.54, 95% confidence interval (CI) = 1.25-16.5] and maximum width of invasive focus ≧ 4 mm (HR = 4.79, 95% CI = 1.25-16.5) were independent prognostic factors of progression. En-bloc resection facilitates the evaluation of pathologic variables that might be useful in predicting disease recurrence and progression. In particular, not only the MM invasion but also the maximum width of invasion focus, reflecting the invasive volume, appear to be reliable prognosticators for disease progression.

Rates and Risk Factors of Progression in Patients With Nontuberculous Mycobacterial Pulmonary Disease: Secondary Analysis of a Prospective Cohort Study

BackgroundThe clinical course of nontuberculous mycobacterial pulmonary disease (NTM-PD) is varied, and a watchful waiting management strategy is appropriate for a subset of patients. Understanding disease progression and risk factors for progression is essential for deciding on an appropriate follow-up strategy. Research QuestionWhat is the rate of NTM-PD progression, and what are the predictors of progression? Study Design and MethodsPatients with NTM-PD who were enrolled in a prospective observational cohort study between July 1, 2011, and December 31, 2022 were included in this analysis. Clinical, bacterial, laboratory, and radiographic data were collected at enrollment and then regularly during follow-up. NTM-PD progression was defined as either the initiation of treatment or the clinician’s intention to treat. The rate of progression was calculated and the predictors for progression were analyzed. ResultsOf the 477 patients enrolled, NTM-PD progressed in 192 patients over a median follow-up of 5.4 years. The incidence of NTM-PD progression was 11.0 cases per 100 person-years (95% confidence interval [CI] 9.5–12.7). The proportion of patients experiencing disease progression was 21.4% at 1 year, 33.8% at 3 years, and 43.3% at 5 years. The final multivariable analysis model identified female sex (adjusted hazard ratio [aHR] 1.69, 95% CI 1.19–2.39), elevated erythrocyte sedimentation rate (aHR 1.79, 95% CI 1.31–2.43), percent predicted forced expiratory volume in 1 second (aHR 0.89, 95% CI 0.82–0.96), and the presence of a cavity (aHR 2.78, 95% CI 2.03–3.80) as predictors of progression. InterpretationAbout half of patients with NTM-PD experienced progression during an observation period of more than 5 years. Patients with risk factors for progression should be observed closely. Trial registrationClinicalTrials.gov; No.: NCT01616745; URL: www.clinicaltrials.gov

Liquid biopsy utilizing miRNA in patients with advanced breast cancer treated with cyclin‑dependent kinase 4/6 inhibitors.

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6is) are the mainstay of treatment of hormone receptor+/human epidermal growth factor receptor 2-patients with advanced breast cancer (ABC). Despite improvements in overall survival, most patients experience disease progression. Biomarkers derived from a liquid biopsy are appealing for their potential to detect resistance to treatment earlier than computed tomography imaging. However, clinical data concerning microRNAs (miRNAs/miRs) in the context of CDK4/6is are lacking. Thus, the present study assessed the use of miRNAs in patients with ABC treated with CDK4/6is. Patients treated for ABC with CDK4/6is between June and August 2022 were eligible. miRNA expression analyses were performed using a TaqMan™ low-density miRNA array. A total of 80 consecutive patients with ABC treated with CDK4/6is at Maria Sklodowska-Curie National Research Institute of Oncology (Gliwice, Poland) were assessed, with 14 patients diagnosed with progressive disease at the time of sampling, 55 patients exhibited clinical benefit from CDK4/6i treatment and 11 patients were at the beginning of CDK4/6i treatment. Patients with disease progression had significantly higher levels of miR-21 (P=0.027), miR-34a (P=0.011), miR-193b (P=0.032), miR-200a (P=0.027) and miR-200b (P=0.003) compared with patients who benefitted from CDK4/6i treatment. Significantly higher levels of miR-34a expression were observed in patients with progressive disease than in patients beginning treatment (P=0.031). The present study demonstrated the potential innovative role of circulating miRNAs during CDK4/6i treatment. Plasma-based expression of miR-21, -34a, -193b, -200a and -200b effectively distinguished patients with ABC who responded to CDK4/6i treatment from patients who were resistant. However, longitudinal studies are required to verify the predictive and prognostic potential of miRNA.

Management of colorectal large cell neuroendocrine carcinoma: case report and literature review

Large cell neuroendocrine carcinoma (LCNEC) of the colorectum is a rare, aggressive subtype of neuroendocrine cancer with a dismal prognosis. Accounting for a mere 0.25% of colorectal cancers, LCNEC is associated with a median overall survival of 4 to 16 months, and nearly all patients succumb within a year. Pure colorectal LCNEC reports are scarce, and this review and case study presents a 40-year-old male, the youngest reported patient, diagnosed with rectal LCNEC. A comprehensive PubMed search for “large cell neuroendocrine carcinoma” and “colorectal” was conducted. Titles were meticulously screened for relevance to the nuanced management of colorectal LCNEC. Despite aggressive therapeutic interventions, including chemotherapy with carboplatin and etoposide, the patient experienced rapid disease progression, emphasizing the challenging nature of LCNEC. The paper discusses the evolving classification of NEC, morphological features, and immunophenotypic characteristics that differentiate LCNEC from other neuroendocrine tumours. Survival rates underscore the aggressive nature of colorectal NEC, and treatment options, primarily relying on retrospective studies, reveal limited efficacy. While surgery remains the preferred approach for localized disease, the optimal chemotherapy regimen for LCNEC is yet to be established. Current evidence suggests platinum-based therapy as a common first-line treatment, but the demand for more effective options persists. The paper highlights the need for additional research, including prospective trials, to elucidate the genuine benefits of adjuvant chemotherapy and to explore emerging therapies, such as immunotherapy, in the context of LCNEC.

Anaplastic Lymphoma Kinase (ALK) Inhibitors Show Activity in Colorectal Cancer With ALK Rearrangements: Case Series and Literature Review.

Anaplastic lymphoma kinase (ALK) rearrangement is a well-known driver oncogene detected in approximately 5% of non-small cell lung cancer. However, ALK rearrangement is much less frequent in other solid tumors outside the lungs, such as colorectal cancer (CRC); thus, the optimal management of CRC with ALK rearrangements has yet to be established. In this report, we describe 2 cases of ALK-positive CRC, both of which benefited from ALK tyrosine kinase inhibitor (ALK-TKI) therapy. Case 1 was a postoperative patient with poorly differentiated colon adenocarcinoma, who was diagnosed with metastatic relapse shortly after surgery. Both fluorouracil, leucovorin, and oxaliplatin (FOLFOX) and bevacizumab combined with 5-fluorouracil, l-leucovorin, and irinotecan (FOLFIRI) proved ineffective against the disease. The patient was then treated with ensartinib, as the CAD-ALK fusion gene was detected by genomic analysis. The patient was initially treated with ensartinib monotherapy for 9 months, then with ensartinib combined with local radiotherapy and fruquintinib for another 4 months for isolated hilar hepatic lymph node metastasis. The patient experienced disease progression with an acquired ALK G1202R resistance mutation that responded well to lorlatinib. Case 2 involved a 72-year-old man with advanced colon cancer (pT4bN2aM1b, stage IV) harboring an EML4-ALK fusion. The patient underwent resection of the right colon tumor due to intestinal obstruction, but the disease continued to progress after 12 courses of FOLFIRI and bevacizumab chemotherapy. However, the patient responded remarkably well to alectinib. Our report emphasizes the importance of gene detection in the treatment of malignant tumors, and the significance of ALK mutations in CRC.

Prospective study investigating hypofractionated proton beam therapy in patients with inoperable early stage non-small cell lung cancer.

To report the results of hypofractionated proton beam therapy (PBT) for the treatment of early stage lung cancer in patients not suitable for surgical resection. Data from 27 adult patients, who were diagnosed with inoperable cT1-3N0 non-small cell lung cancer (NSCLC) between March 2018 and August 2020, were analyzed. PBT was prescribed as 64 Cobalt Grey equivalents delivered in 8 fractions (Sumitomo, Japan). The primary endpoint was local control; secondary endpoints included overall survival, quality of life, and grade ≥3 toxicity. The median follow-up was 28.9 months (range, 1.1-62.1 months). During follow-up, 13 (48.1%) patients experienced disease progression, including local progression in 7. Two-year local control rates were 73.5%, 85.7% for T1, and 61.4% for T2-3. The worse local control rate was observed in those with large clinical target volumes (≥ 47.5 cc) and heavy smoking history (≥30 pack-years). The two-year overall survival rate was 76.5%. Grade 3 radiation-related toxicities were observed in 2 (7.4%) patients. In the European Organization for Research and Treatment of Cancer Quality of Life Core 30 results, the global score did not change significantly from baseline. However, dyspnea score increased from 19.8 before PBT to 33.3 at 4 months' post-PBT (p=0.047) and was maintained until 13 months (p=0.028). Hypofractionated PBT was a safe treatment option for inoperable early stage NSCLC and appeared to be appropriate for small tumor volumes. However, local control for larger tumors requires further improvement.

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

Outcomes of Venetoclax-Based Therapy in Patients with Daratumumab-Refractory t(11;14) Positive Light Chain Amyloidosis

Background: Light chain (AL) amyloidosis is a rare plasma cell disorder (PCD) characterized by misfolded light chains produced by clonal plasma cells leading to organ dysfunction. Over the past few years, the introduction of daratumumab (dara), a CD38 monoclonal antibody, into clinical practice has markedly improved outcomes, however, relapses still occur with limited available options. Venetoclax (VEN) is a BCL-2 inhibitor that has shown encouraging clinical efficacy in PCDs harboring the translocation between the chromosomes 11 and 14 (t[11;14]). The aim of this study was to evaluate the efficacy of VEN-based therapy (VBT) in patients with dara-refractory AL who were positive for t(11;14). Methods:Of all adult patients with systemic AL amyloidosis evaluated at our center between 1/2016 and 7/2023, we focused on those who had prior refractoriness to dara (dara was given at any time during the disease course, as frontline or salvage treatment) and received VBT (at any time after dara refractoriness). Data was obtained via retrospective chart review. Hematologic responses including complete response (CR), very good partial response (VGPR) and partial response (PR) were according to the AL consensus criteria. No patients had concomitant multiple myeloma. Baseline characteristics were outlined by descriptive analysis. Kaplan-Meier method was used for progression free survival (PFS), time-to-next-treatment (TTNT) and overall survival (OS) calculations. Results: A total of 21 patients who met the above criteria, were included in this analysis. The median age of patients was 65 (range 48-80) years, median number of prior lines of therapy (LOT) was 2 (range 1-5) and median percentage of bone marrow plasma cells prior to VBT initiation was 15 (range 5-40). Fifteen (71%) patients had cardiac involvement, 11 (52%) renal involvement, and 7 (33%) in addition to other organs had bone marrow involvement; 67% of patients had &amp;gt;2 organs involved. Of the entire cohort, 24% had undergone autologous hematopoietic cell transplant (AHCT) as frontline therapy. All patients had t(11;14) and one patient had an additional 1q gain. The baseline characteristics are summarized in Table 1. VEN was given in combination with: dexamethasone (VEN-dex) in 9 patients (43%), daratumumab-dex (VEN-dara-dex) in 6 patients (28.5%) and proteasome inhibitor-dex (VEN-PI-dex) in 6 patients (28.5%). The median duration on VBT was 9 (range 1.5-24.1) months. At data cut-off, 5 patients had discontinued therapy because of ongoing CR/VGPR, 1 due to ongoing fatigue and 6 due to disease progression or death. The hematologic overall response rate (ORR) was 95% with 11 (53%) patients achieving CR or better and 7 achieving (33%) VGPR. Patients responded rapidly, with a median time to best hematologic response being 2 (range1-5) months. Among the 18 (86%) patients who achieved &amp;gt;VGPR, 15 also achieved difference of free light chains (dFLC) &amp;lt;10 mg/l. Of the 15 patients with cardiac involvement, 6 (40%) achieved response to VBT, while 4 (27%) were non-evaluable (3 had maintained response from previous LOT and 1 had undergone heart transplant); the remaining 5 (33%) had stable disease without response. Of the 11 patients with renal involvement, 4 (36%) achieved organ response to VBT, while 2 (18%) were non-evaluable (1 had maintained response from previous LOT and 1 had undergone kidney transplant); the remaining 5 (46%) had stable disease without response. Eventually, 4/21 patients experienced disease progression. The median PFS for the entire cohort was not-reached (NR); the 6 and 12-month PFS rates were 83% and 68% respectively. Median TTNT was also NR. At data cut-off, 3 patients had died (2 from cardiac complications [cardiac arrest and heart failure], and 1 from dialysis complications). The median OS was NR; the 6- and 12-month OS rates were 89% and 83%, respectively. Conclusion: Our findings suggest that VEN is effective in t(11;14) positive relapsed-refractory AL amyloidosis in combination with dexamethasone alone or with other established plasma-cell directed agents. VBT led to deep and rapid overall response rates with more than 80% of patients achieving VGPR after exposure to only 2 cycles of therapy. This is critical in the setting of dara-refractoriness where therapeutic options are very limited. A clinical trial is ongoing to further evaluate the role of VEN in relapsed-refractory AL amyloidosis.

A Phase 1 First-in-Human Monotherapy Study of F182112, a B-Cell Maturation Antigen (BCMA)-CD3 Bispecific Antibody, in Patients with Relapsed or Refractory Multiple Myeloma

Introduction: Outcomes of relapsed or refractory Multiple Myeloma（RRMM） are generally poor after receiving current arsenal of therapies. Several novel kinds of drugs targeting BCMA are being developed to overcome resistance in this heavily treated patient population. F182112 is a BCMA x CD3 bispecific antibody that redirects CD3 + T cells to mediate T-cell activation and subsequently caused lysis of BCMA-expressing myeloma cells. A phase 1 clinical trial, NTP-F182112-001, has been launched to evaluate the safety and efficacy of F182112 in patients with RRMM. Shan Dong New Time Pharmaceutical Co. Ltd provides the funding support for the research. Clinical trial information: NCT04984434. Methods: This is a first-in-human, open-label, multicenter, phase 1 study. It has enrolled patients with RRMM who aged ≥ 18 years and previously received at least 2 prior lines of therapy including at least a proteasome inhibitor and an immunomodulatory agent. F182112 was administered intravenously once a week. First four dose cohorts of F182112 (0.01, 0.1, 0.3 and 1μg/kg) were planned for accelerated titration phase and the following four dose cohorts (3, 10, 20, and 30 μg/kg) were planned for i3+3 dose escalation phase . Primary objectives were to access safety and tolerability by monitoring adverse events (AEs) per CTCAE v5.0, with exception of CRS grading per ASTCT 2018. The target rate of dose-limiting toxicity (DLT) was 25% (equivalence interval± 5%). In addition, soluble BCMA, cytokines and immunophenotyping were analysed in peripheral blood. The pharmacokinetics and immunogenicity of F182112 were also explored. Results : As of July 24, 2023, 22 patients have been treated with F182112 (0.01-30 μg/kg) at eight escalating dose levels. Median age was 64.5 years (range 52-74). All of patients were followed up at least five weeks and the median follow-up was 3 months (range 1-18). Fifteen (68.1%) patients received ≥4 prior lines of therapy and 15 (68.1%) patients were refractory to last lines of therapy. Treatment-related AEs (TRAEs) were reported in 18 (82%) pts, with grade ≥3 and serious AEs occurring in 14 (64%) and 4 (18.2%) pts, respectively. The most common TRAEs(≥20%) were CRS (72.7%), lymphopenia (68.2%), neutropenia (54.6%), leukopenia (50%) and anemia (31.8%). All CRS was grade 1 or 2 and the median duration time was 2 days (1-5). One dose-limiting toxicities (ALT elevation, grade 3) occurred at 10 μg/kg dose level. No patients required F182112 dose reduction due to AEs. As of this date cut-off, 20 of the 22 patients were evaluated for response（Figure 1）. The overall response rate (ORR) was 45% (9/20), 30% (6/20) patients had stable disease (SD) and 25% (5/20) patients experienced disease progression (PD). At dose cohorts of 10ug/kg and 20ug/kg （n=9），ORR was 77.8%（7/9）with very good partial remission or better (≥VGPR) rate of 44% (4/9) and stringent complete remission (sCR) rate of 33% (3/9). At the dose cohort of 30ug/kg (n=4), ORR was 25% (1/4), one patient of this dose cohort with extramedullary mass larger than 5cm in diameter at baseline experienced disease progression due to the mass enlargement, though his serum M protein decreased by 60.27%. F182112 exhibited a favorable PK profile in its target patient population of RR MM, with F182112 exposures increasing in a dose-related manner. Conclusions: F182112 in patients with RRMM is well tolerated with preliminary antitumor activity and a favorable PK profile in patients，supporting further evaluation.