Inferior Progression-free Survival Research Articles

Real-World Analysis of Teclistamab in 115 RRMM Patients from Germany

Background Bispecific antibodies and CAR-T cells are currently changing the treatment landscape of relapsed and refractory multiple myeloma (RRMM), having shown high response rates and durable remissions of more than a year in clinical trials. However, some discrepancies to these results have been observed lately, with lower median progression free survival (PFS) and overall survival (OS) in the real-world setting for idecabtagene vicleucel (ide-cel), possibly related to strict entry criteria of the study and known general benefits for patients participating in clinical trials regardless of study arm allocation. Whether this also holds true for Teclistamab, a B-cell maturation antigen (BCMA) x CD3 bispecific antibody approved for treatment of RRMM in 2022 in several countries, has yet to be determined. Therefore, we thought to assess Teclistamab efficacy and tolerability in the real-world setting. Methods Data of 115 patients with RRMM treated with Teclistamab at 18 different German centers from July 2022 to July 2023 were retrospectively collected and analyzed. The patients had received at least one full treatment dose of Teclistamab. Responses were evaluated in accordance with the IMWG response criteria; in addition, near complete response was defined as serological complete remission lacking bone marrow assessment, as this was not always part of clinical routine. In non-secretory disease, response evaluation was based on radiological criteria. Kaplan-Meier methods were applied for time-to-event-analyses. For comparison of survival among groups, the log-rank test and Cox regression analysis were used. For comparison of response rates among groups, the Chi square test was applied. Results The included 115 patients (49 female, 66 male with a median age of 66.0 years) had a median history of MM diagnosis of 6.5 years and were heavily pretreated with a median of 6 (range 3-14) prior lines of therapy. The majority of patients had triple-class (91.3%) or even penta-drug (58.3%) refractory disease. 35.6% (41/115) had received BCMA-directed pretreatment, among them 20 with ide-cel, 21 with belantamab mafodotin and single patients with both or a BCMA-directed study medication. Cytogenetic high-risk features defined as del(17p), t(4;14) and/or t(14;16) and extramedullary disease (EMD) were present in 38.0% and 37.2% of patients, respectively. Around one third of patients had high disease burden with bone marrow infiltration ≥60% (37.0%) or ISS 3 (35.2%) in the latest assessment before initiation of Teclistamab. Overall, a substantial proportion of 40.9% of the treated patients would not have met selected inclusion criteria of the MAJESTEC-1 trial like measurable disease, stable hematopoiesis and kidney function. With median times to response and best response of 4.3 weeks and 8.0 weeks, we observed an ORR, defined as partial remission or better, of 56.8%. 20.9% of all patients reached a near complete or complete response. With a median follow-up of 3.9 months, median PFS was 8.7 months. Median duration of response and median OS were not reached. In the group of patients with BCMA-directed pretreatment, the ORR of belantamab-pretreated patients (70%) was comparable to that in anti-BCMA naïve patients (60.0%), whereas ide-cel pretreated patients showed a significantly lower ORR of 27.8%. Interestingly, PFS did not differ significantly between ide-cel pretreated and ide-cel naïve patients. In further subgroup analyses, the presence of EMD and an ISS of 3 were associated with inferior ORR and PFS in univariable and multivariable analysis. Safety was similar to the experience in MAJESTEC-1. 60.0% of patients developed CRS and 6.9% neurotoxicity with grade 3 or 4 events in 1.7% and 0.9% of patients, respectively. Tocilizumab was administered in 25.2% and dexamethasone in 15.7% of patients. Infections occurred in 49.6% of patients, nearly half of them requiring hospitalization. 53.9% experienced grade 3 or 4 cytopenia according to CTCAE during treatment. Conclusions With an ORR of 56.8% in all patients and 60.0% in anti-BCMA naive patients, Teclistamab showed a similar ORR in the real-world setting to that observed in the MAJESTEC-1 trial. PFS was slightly lower, but our patient collective comprised higher proportions of patients with high risk disease, extramedullary disease, high disease burden, hematopoietic or renal impairment.

Development of a Modified Prognostic Index for Adult Patients with Acute Lymphoblastic Leukemia

Background:Acute lymphoblastic leukemia (ALL) is associated with inferior overall survival (OS) and progression-free survival (PFS) in adults due to biologic factors and lower tolerance to chemotherapy 1,2. Prognostic stratification is essential to guide therapy intensification and indication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Recently, a prognostic index 2 integrating measurable residual disease (MRD), white blood count (WBC) and cytogenetic/molecular subtypes has been validated in children and young adults with ALL. However, in adult patients, age, allo-HSCT, other genetic subtypes 3 and center reality, may also play role in prognosis. To incorporate new variables to the pre-established prognostic index 2, a multicenter PFS analysis was performed to develop a modified/adpated risk score. Material and Methods: a multicenter (three Brazilian centers and the Spanish PETHEMA AR-03 trial cohort), retrospective study, reviewed medical charts and database of 398 adult patients with Ph-negative ALL (treated between 2003 and 2022), including risk variables: age, WBC count, cytogenetic/molecular classification, MRD, allo-HSCT, clinical outcomes and follow-up. The prognostic index 2 was calculated individually, then through multivariate analysis the coefficients (HR/OR) to incorporate age and allo-HSCT to the model have been determined. The methods of logistic regression, Cox model, Kaplan-Meier, log rank, ROC analysis and competitive risk regression were used in the statistical analysis. Subsequently, patients were stratified into 3 prognostic risk categories. Results: A total of 398 patients, 77% from the PETHEMA protocol and 23% Brazilian centers; 55.2% males; mean age 38.1 years (range 18-60; 67.4% (268) B-ALL; 31.4% (125) T-ALL; 1.2% (5) biphenotypic ALL. median WBC 22.4x10 9/L; 8.9% with central nervous system involvement; 22.9% high risk cytogenetics. Regarding treatment, 93.9% (373) received pediatric-inspired protocols (AR-03, GRAALL, CALGB, St. Jude TOTALXVI), 6.1% (26) (Hypercvad and others). Regarding the response, 83.3% (309/371) achieved complete remission (CR); CR rate was higher in pediatric inspired versus other protocols: 84.6% vs 57.9% (p 0.006). 45.6% (127/278) reached MRD-neg status after induction and 71.4% (125/175) after consolidation; 21.7% (67/309) underwent allo-HSCT in first remission. After a median follow-up of 3.9 years, 4-year-OS was 42.1% (95%CI 47.2-36.8%) and PFS was 33.4% (95%CI 38.5-28.4%). Cumulative incidences of relapse and non-relapse mortality were: 38.0% and 27.6%, respectively. In multivariate analysis, both allo-HSCT (OR:0.36 95%CI 0.19-0.66 p<0.001) and original 2 prognostic index (OR:2.47 95%CI:1.71-3.55 p <0.001) predicted significantly PFS, so allo-HSCT coefficient has been determined and incorporated to the model. According to this modified prognostic index, patients were stratified into 3 risk groups: low (100/285, 35.1%), intermediate (93/285, 32.6%) and high (92/285, 32.3%) high. At 4-years, PFS was significantly superior in low-risk group (55.9% - 95% CI 65.8-44.5%) compared to the intermediate-risk group (37.3% - 95%CI 47.5-27.1%) and high-risk group (182% - 95%CI 27.0-10.8%), p <0.001. Conclusion: The incorporation of the main risk factors in ALL and the role of allo-HSCT into prognostic index for adults can adequately stratify the PFS of patients into 3 risk categories and could assist in clinical decision-making. Reference 1. Fernandes da Silva Junior W, Medina AB, Yamakawa PE, Buccheri V, Velloso EDRP, Rocha V. Treating Adult Acute Lymphoblastic Leukemia in Brazil-Increased Early Mortality Using a German Multicenter Acute Lymphoblastic Leukemia-based regimen. Clin Lymphoma Myeloma Leuk. 2018 Jun;18(6):e255-e259. doi: 10.1016/j.clml.2018.03.001. Epub 2018 Mar 14. PMID: 29605423. 2. Amir Enshaei , David O'Connor , Jack Bartram , Jeremy Hancock , Christine J. Harrison , Rachael Hough , Sujith Samarasinghe , Monique L. den Boer , Judith M. Boer , Hester A. de Groot-Kruseman , Hanne V. Marquart , Ulrika Noren-Nystrom , Kjeld Schmiegelow , Claire Schwab , Martin A. Horstmann , Gabriele Escherich , Mats Heyman , Rob Pieters , Ajay Vora , John Moppett, Anthony V. Moorman; A validated novel continuous prognostic index to deliver stratified medicine in pediatric acute lymphoblastic leukemia. Blood 2020; 135 (17): 1438-1446. doi: https://doi.org/10.1182/blood.2019003191

Non-Invasive MRD Monitoring in Multiple Myeloma Patients By Heavy/Light Chain Analysis

Introduction The majority of multiple myeloma (MM) patients are now achieving very deep responses. The most sensitive disease detection techniques are currently bone marrow assays. However, as bone marrow sampling is invasive and unpleasant for patients it is important to investigate whether blood-based assays could be equally or more informative of disease status. The heavy/light chain assay (Hevylite TM, The Binding Site, UK) evaluates serum heavy/light chains (HLC) for IgG, IgA and IgM M-proteins. This study assessed whether the HLC assay could act as an effective marker for disease in the bone marrow of treated MM patients and evaluated the prognostic utility of HLC measurements at best response and relapse time points. Methods 104 IgG and IgA MM patients were recruited either prior to transplant or during chemotherapy. Median follow up was 18 months. Routine M-protein tests were performed alongside HLC testing with parameters including involved HLC (iHLC), uninvolved HLC (uHLC) and kappa/lambda HLC ratio (HLCr). A bone marrow flow cytometry (NGF) assay was performed up to a sensitivity of 10 -6 and was considered to be the gold standard assay. Disease response was determined according to the IMWG criteria. Results and Discussion At pre- and post-transplant time points there was significant agreement between HLC measurements and NGF, with uHLC being the most sensitive measurement (86%) and HLCr the most specific (100%). Both uHLC and HLCr show substantial agreement with the bone marrow NGF method whilst iHLC cannot be used to indicate bone marrow status. Survival analysis showed significantly inferior progression free survival (PFS) in patients with an abnormal uHLC (p=0.01) (Figure A) or HLCr (p=0.02) result post-transplant but no survival difference based on iHLC status (p=0.78) (Figure B). Interestingly, performing survival analysis on these same samples using serum immunofixation (IFE) status (positive or negative) did not produce a significant PFS difference between participants (p=0.21). During long term follow up, HLC values showed a correlation with depth of response, with uHLC being abnormal in 60% of complete response (CR) patients. This suggests that those participants currently grouped as CR may be able to be further subdivided according to uHLC level and this could have a prognostic value in the monitoring and treatment of these patients. At best response uHLC was the only HLC or free light chain (FLC) measurement which gave a significant difference in PFS for all patients in partial response (PR) or better (p=0.005), remaining true when analysing patients in ≥CR only (p=0.002). The addition of free light chain measurements into the HLC analysis did not improve the significance of these survival differences. In relapsed patients, paired comparisons of M-protein and disease activity markers at best response vs. prior to clinical relapse were performed. uHLC was the only marker which was significantly different between the two time points in IgG and IgA patients. The significance of this was confirmed by showing that those patients in stable disease did not experience a significant change in uHLC levels. For other M-protein variables such as total immunoglobulin, IFE status and FLC values there was an increase in levels or abnormality between best response and pre-relapse but these were not significant. The paired comparison suggests that monitoring an individual using HLC could help to detect relapse earlier than conventional methods. In all analyses performed the HLC assay showed increased sensitivity and utility over the IFE technique. Conclusion This study suggests that the HLC assay can be used prior to bone marrow analysis to help influence decisions and improve the patient and laboratory experience. These results can be put into practice during patient follow up post initial treatment in the following ways: At deepest response an abnormal uHLC or HLCr suggests a positive MRD status, meaning a possible reduction or delay in the requirement for bone marrow assessment.All patients in ≥VGPR should have HLC performed alongside conventional assays during follow up.If uHLC values become abnormal during follow up then it should be assumed that the patient is about to undergo relapse. The measurement of HLC values have been shown to be a significant marker in this study, for sensitively detecting the M-protein, giving further clarification of response status and predicting early relapse.

The Temporal Evolution of Chromosome 1q Gain and Hyperdiploidy and Its Impact on Clinical Outcomes in Multiple Myeloma

INTRODUCTION: Multiple myeloma (MM) evolution is shaped by the acquisition and selection of distinct genomic events over time. While various temporal patterns have been identified, the precise chronological order in which key clonal genomic defining events are acquired, and their specific impact on clinical outcomes remain to be fully elucidated. METHODS: To decipher the genomic life history of MM and its impact on clinical outcomes, we interrogated the high coverage (80X) whole genome sequencing (WGS) of 378 MM patients. Overall, 319 and 59 WGS were generated from samples collected at diagnosis and at relapse, respectively. Newly diagnosed MM (NDMM) patients were treated upfront with proteosome inhibitors, lenalidomide, dexamethasone, +/- monoclonal antibodies. To estimate the relative and absolute temporal relationship among clonal events, we leveraged the molecular time approach, based on the corrected ratio between duplicated and non-duplicated single nucleotide variants (SNV). RESULTS: Overall, 300/378 (79%) patients had at least one large chromosomal gain defined as >1Mb with >50 clonal SNV eligible for molecular time analysis, for a total of 1493 events tested. Consistent with recent findings, using clock-like mutational signatures SBS1-SBS5, we estimated that the first gain in MM is typically acquired around the second or third decade of life, with a median time lag of approximately 33 years between acquisition and diagnosis. In 158/178 (89%) of hyperdiploid (HRD) patients, all trisomies of odd-numbered chromosomes were acquired simultaneously. Among patients with canonical IGH translocations and HRD, the molecular time when trisomies were acquired was usually late compared to HRD without canonical IGH translocations (p<0.0001). Next, we examined the temporal relationship between IGH canonical translocations and gains linked to the same IGH canonical translocation in 29 patients. We consistently observed that when IGH canonical translocations co-occurred with HRD (n=7), and/or 1q gain (n=8) in the same patient, the canonical IGH translocation was always found to be the initiating event, occurring earlier than the chromosomal gains. Interestingly, in 104/178 (58.4%) HRD patients, the earliest multi-gain event was not always restricted to odd chromosomes, but in involved other non-HRD chromosomes such as: 6p (n=43) and 1q (n=32), demonstrating that gain 1q, which is assumed to occur at progression, can also be acquired very early in disease life history. A total of 92 and 21 patients with 1q gain and 1q amp (>3 copies) were identified, respectively. In 14/21 (66%) with 1q amp, the first and second 1q extra copies were acquired in two distinct and independent time windows. Interestingly, patients with early 1q gain showed the same clinical outcomes as 1q amp, and inferior progression free survival outcomes compared to late 1q gain (p=0.01; Figure 1). In 18/21 1q amp the first 1q duplication was acquired early, suggesting that the adverse prognostic effect of 1q gain/amp in NDMM may be more dependent on the timing of its acquisition rather than the number of extra copies gained. To investigate late temporal patterns and differentiate selection versus acquisition of large gains at relapse after autologous stem cell transplant (ASCT), we interrogated 25/59 (42%) RRMM patients exposed to melphalan with detectable SBS-MM1. To establish the temporal order of events, we employed the melphalan mutational signature, SBS-MM1, as a unique temporal barcode (Diamond et al. Blood 2023). Overall, we observed that 21% of all loss of heterozygosity (LOH) events and 15% of all gains were acquired after ASCT (i.e., SBS-MM1 mutations were only detectable in the pre-gain/duplicated SNV). Notably, among these events, 1q gain was acquired after ASCT in 3/4 patients, indicating that the acquisition of 1q gain can occur even after administration of first-line therapy. CONCLUSIONS: In our study, we have uncovered distinct temporal patterns in the acquisition of early genomic drivers in MM. These patterns contribute to the reconstruction and better understanding of the life history of MM and may hold potential clinical and prognostic implications.

Recombinant Human Adenovirus Type 5 (H101) Intra-Tumor Therapy in Patients with Persistent, Recurrent, or Metastatic Cervical Cancer: Genomic Profiling Relating to Clinical Efficacy.

Genomic profiles relating to H101 treatment-induced alterations are yet to be achieved. Here, we evaluated the impact of H101 via exome-sequencing approaches aiming to probe for potential biomarkers that are actionable in the treatment of persistent/recurrent/metastatic (P/R/M) cervical cancer. Whole exome sequencing (WES) was performd on paired pre- and post-H101 samples from 17 P/R/M cervical cancer patients who received serial intra-tumor injections of H101. Somatic mutations, including high-frequency mutations, microsatellite instability (MSI) status, tumor mutation burden (TMB), clonal evolution, and mutational signature were analyzed. The median follow-up time after the H101 treatment was 14 months. Complete response was achieved in 9 patients, 3 patients achieved partial response, and 2 patients had stable disease, resulting in an objective response rate (ORR) of 70.6% (95% CI: 46.4%-96.7%). WES analysis showed no difference in treatment-related mutation characteristics, including non-synonymous-SNVs and TMB status. Patients with lower TMB were correlated with improved H101 response rates (P=0.044), whereas the same was not evident in high MSI (MSI-H) versus non-MSI-H patients (P=0.528). We observed a few high-frequency mutation genes (TTN, KMT2D, ALDOA, DNAH7, ADAP1, PTPN23, and THEMIS2) that probably carry functional importance in response to H101 treatment, among which KMT2D and ADAP1 mutations were associated with inferior progression-free survival (PFS) and/or overall survival (OS) (P<0.05). Notably, H101 treatment-induced accumulating subclones or clusters in primary tumors and some (Signature 2) were associated with shorter PFS. We conducted an unprecedented work via a WES-based approach and provided preliminary insights into H101 treatment-induced genetic aberrations in which some genes (TTN, KMT2D, ALDOA, DNAH7, ADAP1, PTPN23, and THEMIS2) could be considered potential therapeutic targets of H101-containing treatment in cervical carcinoma. Moreover, the therapy-associated characteristics such as clonal evolution and a mutational signature may warrant further evaluation of H101 in clinical settings for treating cervical carcinoma.

The Prognostic Value of Preoperative Naples Prognostic Score in Upper Tract Urothelial Carcinoma Patients after Radical Nephroureterectomy

This study aims to determine the prognostic value of preoperative Naples prognostic score (NPS) on survival outcomes in upper tract urothelial carcinoma (UTUC) patients after radical nephroureterectomy (RNU). We conducted a retrospective study about UTUC patients at West China Hospital from January 2015 to June 2019. The X-Tile program was used to identify the optimal cutoff value of NPS. Overall survival (OS), cancer-specific survival (CSS) and progression-free survival (PFS) were the endpoints of interest. Kaplan-Meier curves were used to estimate survival and Cox proportional hazard model was used for risk assessment. A total of 237 UTUC patients after RNU were identified and the threshold of NPS was determined to be 2. Preoperative high-NPS was associated with inferior OS (p = 0.004), CSS (p = 0.002) and PFS (p = 0.008), especially in locally advanced UTUC patients. Preoperative NPS was an independent predictor for OS (HR: 1.78; 95% CI: 1.08, 2.93), CSS (HR: 1.87; 95% CI: 1.11, 3.14) and PFS (HR: 1.60; 95% CI: 1.02, 2.50). The addition of NPS into the predictive model consisting of predictors from multivariate Cox regression resulted in better prediction performance. Preoperative NPS was a novel and reliable predictor for survival in UTUC patients after RNU, and should be further explored.

Impact of Folinic Acid Dosing on Efficacy and Toxicity of High-Dose Methotrexate in Central Nervous System Lymphoma

IntroductionHigh-dose methotrexate (HDMTX)-based regimens are the treatment of choice in primary central nervous system lymphoma (PCNSL). Folinic acid (FA) rescue is used to mitigate the toxic effects of MTX on normal cells. However, the optimal dosing of FA in PCNSL remains uncertain. MethodsWe analyzed the relationship between FA dosing and treatment efficacy and toxicity in a cohort of 36 PCNSL patients treated at our institute between the years 2014 and 2022. A combination of univariate and multivariate analyses using known prognostic factors were used to determine the association between FA dosing and treatment outcomes. ResultsWe found that higher per-treatment cumulative FA doses were associated with inferior progression-free survival (PFS), with a hazard ratio (HR) of 2.2 for each 100 mg/m2 increase in FA dose. We identified a threshold of 350 mg/m2/treatment, above which there was a significant reduction in PFS. Notably, lower FA doses did not result in increased toxicity. ConclusionOur findings suggest that optimizing FA dosing to avoid very high rescue doses may improve treatment outcomes in PCNSL patients receiving HDMTX. Further prospective studies are warranted to validate these findings.

Metabolic tumor volume predicts outcome in patients with advanced stage follicular lymphoma from the RELEVANCE trial

We investigated the prognostic value of baseline positron emission tomography (PET) parameters for patients with treatment-naïve follicular lymphoma (FL) in the phase III RELEVANCE trial, comparing the immunomodulatory combination of lenalidomide and rituximab (R2) versus R-chemotherapy (R-chemo), with both regimens followed by R maintenance therapy. Baseline characteristics of the entire PET-evaluable population (n= 406/1032) were well balanced between treatment arms. The maximal standard uptake value (SUVmax) and the standardized maximal distance between tow lesions (SDmax) were extracted, the standardized distance between two lesions the furthest apart, were extracted. The total metabolic tumor volume (TMTV) was computed using the 41% SUVmax method. With a median follow-up of 6.5 years, the 6-year progression-free survival (PFS) was 57.8%, the median TMTV was 284 cm3, SUVmax was 11.3 and SDmax was 0.32 m-1, with no significant difference between arms. High TMTV (>510 cm3) and FLIPI were associated with an inferior PFS (P= 0.013 and P= 0.006, respectively), whereas SUVmax and SDmax were not (P= 0.08 and P= 0.12, respectively). In multivariable analysis, follicular lymphoma international prognostic index (FLIPI) and TMTV remained significantly associated with PFS (P= 0.0119 and P= 0.0379, respectively). These two adverse factors combined stratified the overall population into three risk groups: patients with no risk factors (40%), with one factor (44%), or with both (16%), with a 6-year PFS of 67.7%, 54.5%, and 41.0%, respectively. No significant interaction between treatment arms and TMTV or FLIPI (P=0.31 or P= 0.59, respectively) was observed. The high-risk group (high TMTV and FLIPI 3-5) had a similar PFS in both arms (P= 0.45) with a median PFS of 68.4% in the R-chemo arm versus 71.4% in the R2 arm. Baseline TMTV is predictive of PFS, independently of FLIPI, in patients with advanced FL even in the context of antibody maintenance.

Exploring the cell-free total RNA transcriptome in diffuse large B-cell lymphoma and primary mediastinal B-cell lymphoma patients as biomarker source in blood plasma liquid biopsies.

Diffuse large B-cell lymphoma (DLBCL) and primary mediastinal B-cell lymphoma (PMBCL) are aggressive histological subtypes of non-Hodgkin's lymphoma. Improved understanding of the underlying molecular pathogenesis has led to new classification and risk stratification tools, including the development of cell-free biomarkers through liquid biopsies. The goal of this study was to investigate cell-free RNA (cfRNA) biomarkers in DLBCL and PMBCL patients. Blood plasma samples (n=168) and matched diagnostic formalin-fixed paraffin-embedded (FFPE) tissue samples (n=69) of DLBCL patients, PMBCL patients and healthy controls were collected between 2016-2021. Plasma samples were collected at diagnosis, at interim evaluation, after treatment, and in case of refractory or relapsed disease. RNA was extracted from 200 µl plasma using the miRNeasy serum/plasma kit and from FFPE tissue using the miRNeasy FFPE kit. RNA was subsequently sequenced on a NovaSeq 6000 instrument using the SMARTer Stranded Total RNA-seq pico v3 library preparation kit. Higher cfRNA concentrations were demonstrated in lymphoma patients compared to healthy controls. A large number of differentially abundant genes were identified between the cell-free transcriptomes of DLBCL patients, PMBCL patients, and healthy controls. Overlap analyses with matched FFPE samples showed that blood plasma has a unique transcriptomic profile that significantly differs from that of the tumor tissue. As a good concordance between tissue-derived gene expression and the immunohistochemistry Hans algorithm for cell-of-origin (COO) classification was demonstrated in the FFPE samples, but not in the plasma samples, a 64-gene cfRNA classifier was developed that can accurately determine COO in plasma. High plasma levels of a 9-gene signature (BECN1, PRKCB, COPA, TSC22D3, MAP2K3, UQCRHL, PTMAP4, EHD1, NAP1L1 pseudogene) and a 5-gene signature (FTH1P7, PTMAP4, ATF4, FTH1P8, ARMC7) were significantly associated with inferior progression-free and overall survival in DLBCL patients, respectively, independent of the NCCN-IPI score. Total RNA sequencing of blood plasma samples allows the analysis of the cell-free transcriptome in DLBCL and PMBCL patients and demonstrates its unexplored potential in identifying diagnostic, cell-of-origin, and prognostic cfRNA biomarkers.

Residual plasma Epstein–Barr virus DNA after intensity-modulated radiation therapy is associated with poor outcomes in nasopharyngeal carcinoma

Aim: To investigate the effects of residual plasma Epstein-Barr virus (EBV) DNA levels after 3 months of intensity-modulated radiation therapy (IMRT) (postIMRT-EBV DNA) on prognosis in patients with nasopharyngeal carcinoma. Methods: Data from 300 patients were retrospectively collected for analysis. Results: Of these patients, 25 (8.3%) and 275 (91.7%) had positive and negative postIMRT-EBV DNA, respectively. Multivariate survival analysis showed that EBV DNA &gt;688 IU/ml was independently associated with inferior distant metastasis-free survival (p = 0.003) and progression-free survival (p = 0.002). Moreover, postIMRT-EBV DNA was independently associated with inferior locoregional recurrence-free survival (hazard ratio: 4.325; p = 0.018), distant metastasis-free survival (hazard ratio: 10.226; p &lt; 0.001) and progression-free survival (hazard ratio: 10.520; p &lt; 0.001). Conclusion: Positive postIMRT-EBV DNA is a prognostic biomarker for nasopharyngeal carcinoma.

Baseline Serum Albumin Levels for Predicting Progression-free Survival in Patients with Non-Hodgkin Lymphoma: A Single-center Prospective Study in Syria

Abstract BACKGROUND AND AIMS: A low baseline serum albumin (SA) level is considered an adverse prognostic indicator of various solid tumors and hematological malignancies. However, studies evaluating the relationship between SA levels and survival in non-Hodgkin lymphoma (NHL) patients are limited in Syria. Thus, this is the first study to assess the impact of baseline SA as an independent prognostic factor on progression-free survival (PFS) over 18 months (1.5 years) in Syrian NHL patients. METHODS: We prospectively analyzed patients diagnosed with de novo NHL who met the inclusion criteria and were admitted to the Chemotherapy and Radiotherapy Center at Tishreen University Hospital (TUH) in Latakia, Syria, between January 2021 and December 2021. The baseline SA concentration was measured. The PFS rate was estimated using the Kaplan–Meier method. Univariate and multivariate Cox proportional hazard regression analyses were carried out. RESULTS: Sixty patients in total were included. SA’s optimal cutoff value for survival analysis was 3.95 g/dL, according to the receiver operating characteristic (ROC) curve. Patients were categorized into two groups based on that value, 25 (41.7%) had low (≤3.95 g/dL) and 35 (58.3%) had high SA levels (&gt;3.95 g/dL). The PFS rate for 18 months was 56.7%. Kaplan–Meier curves showed that patients with low SA had a significantly inferior PFS rate (28% vs. 77.1%, P &lt; .001). The independent prognostic significance of SA was verified by multivariate analysis. CONCLUSION: Low baseline SA levels (≤3.95 g/dL) could be a simple and effective factor in predicting poor 18-month PFS in Syrian NHL patients. To verify our findings, more extensive research is advised.

Clinical Validation of HPV ctDNA for Early Detection of Residual Disease Following Chemoradiation in Cervical Cancer

Despite chemoradiation (CRT), 30-40% of patients with locally advanced cervical cancer relapse. Most cases are caused by human papilloma virus (HPV), and HPV circulating tumor DNA (ctDNA) may identify patients at highest risk of relapse. Our previous pilot study showed that detectable HPV ctDNA at the end of CRT is associated with inferior progression-free survival (PFS) using digital polymerase chain reaction (dPCR), and that a next generation sequencing approach (HPV-seq) may outperform dPCR. We hypothesized that HPV ctDNA may identify cervical cancer patients at increased risk of relapse following CRT and aimed to prospectively validate HPV ctDNA as a tool for early detection of residual disease. This prospective, multicenter validation study accrued 70 patients with HPV+ stage IB-IVA cervical cancer treated with definitive CRT from 2017-2022. Patients underwent phlebotomy at baseline, end of, 4-6 weeks and 3 months post CRT for HPV ctDNA levels. HPV genotyping was performed on the baseline plasma sample using HPV-seq. HPV genotype-specific DNA levels in plasma were quantified using both dPCR and HPV-seq. PFS was estimated using the Kaplan-Meier method and compared using the log rank test. Multivariable Cox regression analyses incorporating stage and HPV ctDNA detectability assessed independent prognostic factors associated with PFS. At the time of abstract, results for 67 patients were available. The majority had squamous histology (84%) and stage IIB (36%) or IIIC1 (25%) disease. HPV genotyping using HPV-seq revealed 54% (36/67) of cases harboring HPV-16, and 46% harboring other HPV types: 15 HPV-18; 5 HPV-59; 2 HPV-31; 2 HPV-33; 2 HPV-52; 1 each HPV-39, HPV-45, HPV-53, HPV-58, and HPV-82. With a median follow up of 2.2 (range 0.4 - 5.2) years, there were 21 PFS events. Most recurrences (14/21) were distant and/or paraaortic; 4 local and nodal/distant; 2 pelvic nodal; and 1 local. Patients with detectable HPV ctDNA on dPCR at the end of, 4-6 weeks and 3 months post CRT had significantly worse 2-year PFS compared to those with undetectable HPV ctDNA (78 vs 52%, p = 0.04; 82 vs 26%, p < 0.001; and 80 vs 23%, p = < 0.001, respectively). HPV-seq showed similar results (87 vs 55%, p = 0.02; 81 vs 45%, p = 0.003; and 84 vs 31%, p = < 0.001, respectively). On multivariable analyses, detectable HPV ctDNA on dPCR and HPV-seq remained independently associated with inferior PFS (see table). HPV-seq enables HPV genotyping directly from plasma in locally advanced cervical cancer. Persistent HPV ctDNA following CRT is independently associated with inferior PFS in this prospective validation study. HPV ctDNA testing can be used to identify, as early as at the end of CRT, patients at high risk of recurrence in future treatment intensification trials.

Prognostic model using 18F-FDG PET radiomics predicts progression-free survival in relapsed/refractory Hodgkin lymphoma

AbstractInvestigating prognostic factors in patients with relapsed or primary refractory classical Hodgkin lymphoma (R/R cHL) is essential to optimize risk-adapted treatment strategies. We built a prognostic model using baseline quantitative 18F-fluorodeoxyglucose positron emission tomography (PET) radiomics features and clinical characteristics to predict the progression-free survival (PFS) among patients with R/R cHL treated with salvage chemotherapy followed by autologous stem cell transplantation. Metabolic tumor volume and several novel radiomics dissemination features, representing interlesional differences in distance, volume, and standard uptake value, were extracted from the baseline PET. Machine learning using backward selection and logistic regression were applied to develop and train the model on a total of 113 patients from 2 clinical trials. The model was validated on an independent external cohort of 69 patients. In addition, we validated 4 different PET segmentation methods to calculate radiomics features. We identified a subset of patients at high risk for progression with significant inferior 3-year PFS outcomes of 38.1% vs 88.4% for patients in the low-risk group in the training cohort (P < .001) and 38.5% vs 75.0% in the validation cohort (P = .015), respectively. The overall survival was also significantly better in the low-risk group (P = .022 and P < .001). We provide a formula to calculate a risk score for individual patients based on the model. In conclusion, we developed a prognostic model for PFS combining radiomics and clinical features in a large cohort of patients with R/R cHL. This model calculates a PET-based risk profile and can be applied to develop risk-stratified treatment strategies for patients with R/R cHL. These trials were registered at www.clinicaltrials.gov as #NCT02280993, #NCT00255723, and #NCT01508312.

Use of concomitant proton pump inhibitors, statins or metformin in patients treated with pembrolizumab for metastatic urothelial carcinoma: data from the ARON-2 retrospective study.

Concomitant medications may potentially affect the outcome of cancer patients. In this sub-analysis of the ARON-2 real-world study (NCT05290038), we aimed to assess the impact of concomitant use of proton pump inhibitors (PPI), statins, or metformin on outcome of patients with metastatic urothelial cancer (mUC) receiving second-line pembrolizumab. We collected data from the hospital medical records of patients with mUC treated with pembrolizumab as second-line therapy at 87 institutions from 22 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS), and overall response rate. We carried out a survival analysis by a Cox regression model. A total of 802 patients were eligible for this retrospective study; the median follow-up time was 15.3months. PPI users compared to non-users showed inferior PFS (4.5 vs. 7.2months, p = 0.002) and OS (8.7 vs. 14.1months, p < 0.001). Concomitant PPI use remained a significant predictor of PFS and OS after multivariate Cox analysis. The use of statins or metformin was not associated with response or survival. Our study results suggest a significant prognostic impact of concomitant PPI use in mUC patients receiving pembrolizumab in the real-world context. The mechanism of this interaction warrants further elucidation.

TP53 mutations identify high-risk events for peripheral T-cell lymphoma treated with CHOP-based chemotherapy.

Nodal peripheral T-cell lymphomas (PTCL), the most common PTCLs, are generally treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-based curative-intent chemotherapy. Recent molecular data have assisted in prognosticating these PTCLs, but most reports lack detailed baseline clinical characteristics and treatment courses. We retrospectively evaluated cases of PTCL treated with CHOP-based chemotherapy that had tumors sequenced by the Memorial Sloan Kettering Integrated Mutational Profiling of Actionable Cancer Targets next-generation sequencing panel to identify variables correlating with inferior survival. We identified 132 patients who met these criteria. Clinical factors correlating with an increased risk of progression (by multivariate analysis) included advanced-stage disease and bone marrow involvement. The only somatic genetic aberrancies correlating with inferior progression-free survival (PFS) were TP53 mutations and TP53/17p deletions. PFS remained inferior when stratifying by TP53 mutation status, with a median PFS of 4.5months for PTCL with a TP53 mutation (n= 21) vs 10.5months for PTCL without a TP53 mutation (n= 111). No TP53 aberrancy correlated with inferior overall survival (OS). Although rare (n= 9), CDKN2A-deleted PTCL correlated with inferior OS, witha median of 17.6months vs 56.7months for patients without CDKN2A deletions. This retrospective study suggests that patients with PTCL with TP53 mutations experience inferior PFS when treated with curative-intent chemotherapy, warranting prospective confirmation.

MYC protein is a high-risk factor in mantle cell lymphoma and identifies cases beyond morphology, proliferation and TP53/p53 - a Nordic Lymphoma Group study.

The transcription factor MYC is a well-described oncogene with an important role in lymphomagenesis, but its significance for clinical outcome in mantle cell lymphoma (MCL) remains to be determined. We performed an investigation of the expression of MYC protein in a cohort of 251 MCL patients complemented by analyses of structural aberrations and mRNA, in a sub-cohort of patients. Fourteen percent (n=35) of patients showed high MYC protein expression with >20% positive cells (MYChigh), among whom only one translocation was identified, and 86% (n=216) of patients showed low MYC protein expression. Low copy number gains of MYC were detected in ten patients, but with no correlation to MYC protein levels. However, MYC mRNA levels correlated significantly to MYC protein levels with a R2 value of 0.76. Patients with a MYChigh tumor had both an independent inferior overall survival and an inferior progression-free survival (hazard ratio [HR]=2.03, 95% confidence interval [95% CI]: 1.2-3.4 and HR=2.2, 95% CI: 1.04-4.6, respectively) when adjusted for additional high-risk features. Patients with MYChigh tumors also tended to have additional high-risk features and to be older at diagnosis. A subgroup of 13 patients had concomitant MYChigh expression and TP53/p53 alterations and a substantially increased risk of progression (HR=16.9, 95% CI: 7.4-38.3) and death (HR=7.8, 95% CI: 4.4-14.1) with an average overall survival of only 0.9 years. In summary, we found that at diagnosis a subset of MCL patients (14%) overexpressed MYC protein, and had a poor prognosis but that MYC rearrangements were rare. Tumors with concurrent MYC overexpression and TP53/p53 alterations pinpointed MCL patients with a dismal prognosis with a median overall survival of less than 3 years. We propose that MYC needs to be assessed beyond the current high-risk factors in MCL in order to identify cases in need of alternative treatment.

Baseline serum tumor markers predict the survival of patients with advanced non-small cell lung cancer receiving first-line immunotherapy: a multicenter retrospective study

BackgroundThis study aimed to investigate the association between baseline serum tumor markers (STMs) (carcinoembryonic antigen [CEA], neuron-specific enolase [NSE], cytokeratin-19 fragment [CYFRA21-1], carbohydrate antigen 19–9 [CA19-9], and carbohydrate antigen 125 [CA125]) and the efficacy of first-line immunotherapy in patients with advanced non-small cell lung cancer.MethodsThis multicenter retrospective study evaluated patients who received first-line immunotherapy between July 2017 and July 2022. The endpoints were progression-free survival (PFS) and overall survival (OS), as defined by the Response Evaluation Criteria in Solid Tumors version 1.1. We divided the patients into three groups based on STM levels: Group A ≥ threefold upper limit of normal, threefold upper limit of normal > Group B > upper limit of normal, and Group C ≤ upper limit of normal.ResultsIn total, 716 patients were included in this study. In Cox proportional hazards analyses, the STM levels in Group C were independently associated with superior PFS and OS in patients with lung adenocarcinoma (LUAD). Except for CA19-9 level, the STM levels in Group C were independently associated with superior PFS and OS in patients with lung squamous carcinoma (LUSC). Except for CEA and CA19-9 levels, the levels in Group A were independently associated with inferior PFS and OS in patients with LUAD and LUSC.ConclusionsSerum CEA, NSE, CYFRA21-1, and CA125 levels can predict PFS and OS in patients with LUAD and LUSC, and serum CA19-9 levels can predict PFS and OS in patients with LUAD. The higher the serum NSE, CYFRA21-1, and CA125 levels, the worse the PFS and OS in patients with LUAD and LUSC. In addition, the higher the serum CA19-9 level, the worse the OS in patients with LUAD.

Minimal residual disease in patients with diffuse large B-cell lymphoma undergoing autologous stem cell transplantation.

Improved biomarkers are required to guide the optimal use of autologous stem cell transplantation (ASCT) in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). We hypothesized that minimal residual disease (MRD) identified using immunoglobulin high-throughput sequencing in apheresis stem cell (ASC) samples, post-ASCT peripheral blood mononuclear cell (PBMC), and plasma samples could predict relapse. We studied 159 patients with R/R DLBCL who underwent ASCT, of whom 98 had an ASC sample and 60 had post-ASCT surveillance samples. After a median post-ASCT follow-up of 60 months, the 5-year progression-free survival (PFS) was 48%. MRD was detected in of 23/98 (23%) ASC samples and was associated with very poor PFS (5-year PFS 13% vs 53%, P<.001) and inferior overall survival (52% vs 68%, P= .05). The sensitivity and specificity of ASC MRD positivity for progression and death were 36% and 93%, respectively. Positive ASC MRD remained a significant predictor of PFS in multivariable analysis (hazard ratio [HR], 3.7; P< .001). Post-ASCT surveillance MRD testing of plasma, but not PBMC samples, reliably identified patients with an impending relapse. A positive plasma MRD result was associated with inferior PFS (HR, 3.0; P= .016) in a multivariable analysis. The median lead time from MRD detection to relapse was 62 days (range, 0-518 days). In conclusion, the detection of MRD in ASC samples is associated with a very high risk of relapse, justifying alternative treatment strategies or trials of novel consolidation options in these patients. Furthermore, post-ASCT MRD monitoring may facilitate the evaluation of the early initiation of treatment at molecular relapse. This trial has been registered at www.clinicaltrials.gov as #NCT02362997.

Exploring the Role of Immunotherapy-Based Treatments for Advanced Non–Small-Cell Lung Cancer With Novel Driver Alterations

BackgroundImmunotherapy (IO) single agent or combined with chemotherapy (CT-IO) is the standard treatment for advanced non–small-cell lung cancer (aNSCLC) without driver alterations. IO efficacy in patients with novel driver alterations is not well reported. Materials and MethodsData of aNSCLC patients treated with IO or CT-IO in any line from January 2016 to September 2022 were retrospectively collected. Patients harboring novel driver alterations (m-cohort), including MET exon 14 skipping, BRAF (V600E or atypical), RET rearrangements, HER2 point mutations/exon 20 insertions or uncommon EGFR mutations/EGFR exon 20 insertions, and wild type patients (wt-cohort) were eligible. Clinico-pathological data were extracted from Institutional databases and compared through chi square or Fisher's exact test. Survivals were estimated through Kaplan-Meier method and compared by log-rank test. Resultsm-cohort and wt-cohort included 84 and 444 patients, respectively. Progression free survival (PFS) was 5.53 vs. 4.57 months (P= .846) and overall survival (OS) was 25.1 vs. 9.37 months, (P < .0001) for m-cohort compared to wt-cohort. Within the m-cohort, BRAF atypical mutations had the better outcomes (Overall Response Rate [ORR], PFS), targeted agents timing did not affect response to IO and CT-IO had better ORR and disease control rate (DCR) compared to IO single agent (P = .0160 and P = .0152). In the PD-L1≥50% group, first line IO single agent resulted in inferior ORR (P = .027) and PFS (P = .022) in m-cohort compared to wt-cohort. ConclusionIO based treatments seem not detrimental for patients harboring novel driver alteration. Adding CT could improve modest responses to IO alone. Confirmation on larger datasets is required.

The impact of insurance status on progression-free survival (PFS) and overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC)

Abstract Background In addition to the previously studied socioeconomic factors associated with health disparities, insurance status can serve as a prognostic factor associated with overall survival in RCC patients (Zhang et al., Future Oncol 2019). Moreover, within this population, having access to health insurance has been reported to result in earlier detection of disease (Javier-DesLoges et al., JAMA Netw Open 2021). In this study, we explored the impact of primary and secondary insurance status on PFS and OS in patients receiving first line systemic therapy for mRCC. Methods Patients with mRCC from two NCI-designated comprehensive cancer centers diagnosed between 1990 and 2022 with available insurance information were retrospectively identified using institutional databases. Primary insurance information was categorized into three groups—Medicare, private insurance, and Medicaid/no insurance—while secondary insurance was defined by the presence or absence of secondary coverage. PFS and OS were estimated by Kaplan-Meier method and compared based on insurance status using log-rank tests. Univariate and multivariate Cox proportional hazard regression models were used to examine the impact of insurance status on PFS and OS. Results In total, 645 patients with mRCC had accessible information and were included in our analysis. Of these, 344 (53.3%), 250 (38.8%), and 51 (7.9%) had primary Medicare, private insurance, and Medicaid/no insurance, respectively. Overall, most patients were male (73.0%), with a median age of 60.0 (22.0-94.0) at time of diagnosis. The most commonly rendered first-line treatments were monotherapy with targeted agents (66.4%), dual immunotherapy (13.6%), and targeted/immunotherapy combinations (10.2%). Median PFS for the entire cohort was 6.6 months (95% CI, 5.9-7.7). Median PFS for patients with primary Medicare was 7.7 months (95%, CI 7.0-9.0), 5.5 months (95% CI, 4.0-7.0) for patients with private insurance, and 4.9 months (95% CI, 3.8-8.1) for Medicaid/uninsured patients. Using an overall log-rank test, a significant difference in PFS among the three groups with different primary insurance was observed (p&amp;lt;0.0001). The median PFS for patients with secondary insurance was 8.1 months (95% CI, 6.6-11.3) compared to 6.1 months (95% CI, 5.5-7.4) for patients without secondary insurance. A multivariate Cox model with adjustment for other factors (such as age, gender, and ethnicity) revealed a statistically significant difference in PFS between patients with and without secondary insurance (p=0.0281). Median OS for the entire cohort was 36.8 months (95% CI, 32.4-44.3). Median OS for patients with primary Medicare, private insurance, and Medicaid/no insurance was 49.0 months (95%, CI 41.8-55.3), 28.5 months (95% CI, 24.1-35.7), and 21.6 months (95% CI, 17.5-42.3), respectively. By an overall log-rank test, a significant difference in OS across the three groups of primary insurance was observed (p=0.0003). No statistically significant differences in OS were observed between patients with and without secondary insurance. Overall, patients with primary Medicare had superior median PFS (p=0.0327) and OS (p=0.0004) compared to those with Medicaid/no insurance; although patients with private insurance had a lower risk of progression and death compared to those with Medicaid/no insurance, the result was not statistically significant. Conclusions In this real-world study, we investigated the impact of insurance status on clinical outcomes in patients with mRCC receiving systemic therapy. mRCC patients with primary Medicaid/no insurance or private insurance had inferior median PFS and OS compared to those with primary Medicare. Moreover, patients with secondary insurance had superior PFS over those with primary insurance alone. Overall, our findings suggest that insurance status may serve as a determinant of clinical outcomes. These hypothesis-generating data warrant external validation in prospective studies.