Lower Complete Response Rate Research Articles

Prognostic significance of PET/CT and its association with immuno-genomic profiling in oesophageal squamous cell carcinoma treated with immunotherapy plus chemoradiotherapy: results from a phase II study.

A phase II trial (EC-CRT-001) demonstrated the promising efficacy of combining toripalimab (an anti-PD-1 antibody) with definitive chemoradiotherapy (CRT) for locally advanced oesophageal squamous cell carcinoma (ESCC). Biomarkers are key to identifying patients who may benefit from this therapeutic approach. Of the 42 patients with ESCC who received toripalimab combined with definitive CRT, 37 were included in this analysis. Baseline assessments included PET/CT metabolic parameters (SUVmax, SUVmean, SUVpeak, MTV, and TLG), RNA sequencing of tumour biopsies to quantify the tissue mutational burden (TMB), and multiplex immunofluorescence staining to estimate immune cell infiltration in the tumour microenvironment (TME). Frozen neoplastic samples were procured for RNA sequencing to further explore the immune-related TME. Among the 37 patients, high baseline SUVmax (≥12.0; OR = 6.5, 95% CI 1.4-48.2, p = 0.032) and TLG (≥121.8; OR = 6.8, 95% CI 1.6-33.5, p = 0.012) were significantly correlated with lower complete response rates. All five PET/CT parameters were notably associated with overall survival; only SUVmax and TLG were associated with a significantly worse progression-free survival. A trend towards an inverse correlation was observed between SUVmax and TMB (R = -0.33, p = 0.062). PD-1 + CD8 + T cell infiltration was negatively correlated with MTV (R = -0.355, p = 0.034) and TLG (R = -0.385, p = 0.021). Moreover, RNA sequencing revealed that the high TLG subgroup exhibited low immune cell infiltration, indicating an immunosuppressive landscape. High baseline SUVmax and TLG might predict poorer treatment response and worse survival in patients with ESCC undergoing immunotherapy combined with CRT. In addition, high PET/CT metabolic parameters, particularly TLG, were correlated with an immunosuppressive TME, which warrants further exploration.

Prediction of response to neoadjuvant chemotherapy by MammaTyper® across breast cancer subtypes: A retrospective cross-sectional study

BackgroundNeoadjuvant chemotherapy (NACT) is widely used in the treatment of triple-negative and HER2-positive breast cancer (BC), but its use in estrogen receptor (ER) and/or progesterone receptor (PR) positive/HER2-negative BC is questioned because of the low pathologic complete response (pCR) rates. This retrospective study assessed the mRNA-based MammaTyper® assay's capability of predicting pCR with NACT, and ER, PR, Ki67, and HER2 status at immunohistochemical (IHC) through transcriptomics. MethodsDiagnostic biopsies from 76 BC patients treated at the Cremona Hospital between 2012-2018 were analyzed. Relative mRNA expression levels of ERBB2, ESR1, PGR, and MKI67 were measured using the MammaTyper® kit and integrated into a pCR score. Predicting capability of pCR and standard IHC biomarkers could be assessed with ROC curves in 75 and 76 patients, respectively. ResultsOverall, 68.0% patients obtained a MammaTyper® high-score and 32.0% a MammaTyper® low-score. Among high-score patients, 62.7% achieved pCR, compared to 16.7% in the low-score group (p = 0.0003). The binary MammaTyper® score showed good prediction of pCR in the overall cohort (area under curve [AUC] = 0.756) and in HR+/HER2-negative cases (AUC = 0.774). In cases with residual disease, the continuous MammaTyper® score correlated moderately with residual tumor size and decrease in tumor size. MammaTyper® showed substantial agreement with IHC for ESR1/ER and ERBB2/HER2, and moderate agreement for PGR/PR and MKI67/Ki67. ConclusionOverall, MammaTyper® pCR score may serve as a standardized tool for predicting NACT response in HR+/HER2-negative BC, potentially guiding treatment strategies. Additionally, it could provide a more standardized and reproducible assessment of ER, PR, HER2, and Ki67 status.

Abstract PO5-15-04: MammaPrint index predicts neoadjuvant chemosensitivity in patients with HR+HER2- early-stage breast cancer in the real-world evidence FLEX study

Abstract Background: Neoadjuvant chemotherapy (NCT) yields low pathologic complete response (pCR, ypT0/is ypN0) rates in hormone receptor positive (HR+), HER2- early-stage breast cancer (ESBC). Genomic signatures may predict chemosensitivity and treatment benefit better than receptor status based clinical subtyping. The 70-gene expression signature, MammaPrint (MP), classifies patients with ESBC as having a High or Low Risk of distant recurrence. In the NBRST and ISPY2 trials, further stratification of MammaPrint High Risk into High 1 (H1) or High 2 (H2) showed significantly higher pCR rates to NCT or targeted agents in MP H2 cancers compared to MP H1 tumors. We evaluated MammaPrint H1 and H2 status as a biomarker for neoadjuvant chemosensitivity in patients with HR+HER2- ESBC enrolled in the real-world evidence FLEX study. Methods: FLEX (NCT03053193) is an ongoing prospective, observational trial that has currently enrolled 12,328 patients with ESBC who were tested with MammaPrint as standard of care, with or without molecular subtyping signature, BluePrint (BP), and consented to clinically annotated full genome data collection (data locked Feb. 2023). Patients with HR+HER2-, MP High Risk tumors who received NCT (majority received AC-T) and had pCR data available were included in this analysis (n = 214). Patients were stratified into MP H1 (index 0.000 to -0.569) and H2 (index -0.570 to -1.000) groups. BP classified MP High Risk tumors into Luminal B-, HER2-, or Basal-Type. Differences in clinical characteristics and pCR rates between H1 and H2 tumors was assessed by Chi-Squared test and two-sided proportional z-test, respectively. The association between MP H1 and H2, BP subtype, and pCR was assessed using logistic regression and was adjusted for age, race, grade, T stage, N stage, and NCT regimen. Results: MammaPrint classified 142 (66%) cancers as H1 and 72 (34%) as H2 tumors. Age, menopausal status, race, tumor stage, and lymph node status were comparable between both groups. Although most H2 tumors (78%) were Grade 3, only 59% of all Grade 3 tumors were H2. Nearly all (98%) H1 tumors were Luminal B whereas for H2 tumors, 51% were Luminal B and 49% were Basal by BP classification. pCR rate was significantly higher in H2 tumors (29.2%) compared to H1 tumors (6.3%, p < 0.01) (Table). Basal-Type, H2 tumors (n=35) exhibited the highest pCR rate of 37.1%. Among BP Luminal B tumors, those with MP H2 tumors had a significantly higher pCR rate (21.6%) vs. MP H1 tumors (5.8%, p = 0.003). Multivariate analysis revealed MP H2 (OR=4.91, p=0.003) and BP Basal-Type (OR=3.54, p=0.03) were significantly associated with likelihood of pCR, whereas clinical variables were not associated with pCR. Conclusion: These data demonstrate MammaPrint and BluePrint utility to predict the likelihood of achieving pCR after NCT in HR+HER2- ESBC. Although both MP High Risk groups exhibit chemosensitivity, High 2 tumors have higher chemosensitivity than High 1 tumors. MP High 2 status can be utilized to identify ER+ patients who are the most likely to experience pathologic downstaging and pCR after NCT. Also, patients with High 2 tumors treated with PD-L1 or PARP inhibitors in the ISPY2 trial exhibited significantly higher pCR rates than those observed for High 2 tumors treated with NCT alone. These data suggest that for patients with MP High 2 tumors, neoadjuvant use of chemotherapy is appropriate and these patients may further benefit from the addition of targeted agents to standard NCT. Table: Distribution of pCR rates among MammaPrint H1 and H2 and BluePrint molecular subgroups Data presented as # of patients with pCR/(total # patients in subgroup) and as percentage Citation Format: Joyce O'Shaughnessy, Lajos Pusztai, Cathy Graham, Pat Whitworth, Peter Beitsch, Cynthia Osborne, Rakhshanda Rahman, Andrea Menicucci, William Audeh, FLEX Investigators' Group. MammaPrint index predicts neoadjuvant chemosensitivity in patients with HR+HER2- early-stage breast cancer in the real-world evidence FLEX study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-15-04.

Real-world and clinical trial outcomes in large B-cell lymphoma with axicabtagene ciloleucel across race and ethnicity

AbstractAxicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Despite extensive data supporting its use, outcomes stratified by race and ethnicity groups are limited. Here, we report clinical outcomes with axi-cel in patients with R/R LBCL by race and ethnicity in both real-world and clinical trial settings. In the real-world setting, 1290 patients who received axi-cel between 2017 and 2020 were identified from the Center for International Blood and Marrow Transplant Research database; 106 and 169 patients were included from the ZUMA-1 and ZUMA-7 trials, respectively. Overall survival was consistent across race/ethnicity groups. However, non-Hispanic (NH) Black patients had lower overall response rate (OR, 0.37; 95% CI, 0.22-0.63) and lower complete response rate (OR, 0.57; 95% CI, 0.33-0.97) than NH White patients. NH Black patients also had a shorter progression-free survival vs NH White (HR, 1.41; 95% CI, 1.04-1.90) and NH Asian patients (HR, 1.67; 95% CI, 1.08-2.59). NH Asian patients had a longer duration of response than NH White (HR, 0.56; 95% CI, 0.33-0.94) and Hispanic patients (HR, 0.54; 95% CI, 0.30-0.97). There was no difference in cytokine release syndrome by race/ethnicity; however, higher rates of any-grade immune effector cell–associated neurotoxicity syndrome were observed in NH White patients than in other patients. These results provide important context when treating patients with R/R LBCL with CAR T-cell therapy across different racial and ethnic groups. ZUMA-1 and ZUMA-7 (ClinicalTrials.gov identifiers: #NCT02348216 and #NCT03391466, respectively) are registered on ClinicalTrials.gov.

A multicenter study of venetoclax-based treatment for patients with Richter transformation of chronic lymphocytic leukemia

AbstractPatients with chronic lymphocytic leukemia (CLL) who develop Richter transformation (RT) have a poor prognosis when treated with chemoimmunotherapy regimens used for de novo diffuse large B-cell lymphoma. Venetoclax, a BCL2 inhibitor, has single-agent efficacy in patients with RT and is potentially synergistic with chemoimmunotherapy. In this multicenter, retrospective study, we evaluated 62 patients with RT who received venetoclax-based treatment outside of a clinical trial, in combination with a Bruton tyrosine kinase inhibitor (BTKi; n=28), rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) (n=13), or intensive chemoimmunotherapy other than R-CHOP (n=21). The best overall and complete response rates were 36%/25%, 54%/46%, and 52%/38%, respectively. The median progression-free and overall survival estimates for the same treatment groups were 4.9/14.3 months, 14.9 months/not reached, and 3.3/9 months, respectively. CLL with del(17p) was associated with a lower complete response rate in the total cohort (odds ratio [OR] 0.15; 95% confidence interval [CI] 0.04-0.6; p=0.01) and venetoclax-naïve subgroup (OR 0.13; 95%CI 0.02-0.66; p=0.01). TP53 mutated CLL was associated with a lower complete response rate (OR 0.15; 95%CI 0.03-0.74; p=0.02) and shorter progression-free survival (hazard ratio 3.1; 95%CI 1.21-7.95; p=0.02) only in venetoclax-naïve subgroup. No other clinical or baseline characteristics, including prior venetoclax treatment for CLL, showed statistically significant association with outcomes. Grade 3-4 neutropenia and thrombocytopenia events were most frequent with intensive chemoimmunotherapy + venetoclax; grade 3-4 infection rates were similar across treatment groups. In this difficult-to-treat RT patient population, venetoclax-based combination regimens achieved high response rates, with durable remission and survival observed in a subset of patients.

Staphylococcus lugdunensis Peritoneal Dialysis-Related Peritonitis: A Matched Comparative Analysis

Staphylococcus lugdunensis (S lugdunensis) is a coagulase-negative staphylococcus species that has been increasingly recognized to cause serious infections with virulence resembling Staphylococcus aureus (S aureus). No studies have evaluated the characteristics and outcomes of patients with S lugdunensis peritoneal dialysis-related peritonitis compared with those with S aureus peritonitis. We aim to evaluate the clinical course of peritonitis as caused by these organisms. A retrospective matched comparative analysis involving a single tertiary center from July 2000 to July2020. Forty-eight episodes of S aureus peritonitis were matched to 19 cases of S lugdunensis peritonitis. The cases were individually matched for year of peritonitis, sex, age (±10 years), and Charlson Comorbidity Index (±3). A comparative analysis was performed between the 2 organisms. The outcome includes responses at day 5 of peritonitis and the rate of complete response. There is a higher predilection of diabetes in those with S aureus peritonitis than in those with S lugdunensis (64.6% vs 31.6%; P=0.03). Patients with S aureus peritonitis also have a much higher total cell count at presentation (4,463.9±5,479.5 vs 1,807.9±3,322.7; P=0.05); a higher prevalence of poor response at day 5 (50.0% vs 15.8%; P=0.03); a lower rate of complete response (64.6% vs 94.7%; P=0.01) and are more prone to relapse with the same organism (29.2% vs 0%, respectively; P=0.01) as compared to those with S lugdunensis. The result of this small retrospective study involving a single center may not be generalizable to other centers. There is also no data for comparative analysis on other coagulase-negative staphylococci such as Staphylococcus epidermidis, which belongs to the same family as S lugdunensis. Although S aureus peritonitis is more virulent with significant morbidity, S lugdunensis can cause similarly serious peritonitis. This largest case series of S lugdunensis peritonitis enabled better characterization of clinical features and outcomes of patients with S lugdunensis peritonitis.

Lower uromodulin serum levels are associated with poorer prognosis in patients with cirrhosis and hepatorenal syndrome type 2.

Hepatorenal syndrome (HRS) is associated with a dismal prognosis in patients with cirrhosis, and therapeutic options are limited. Biomarkers to identify patients with poor response to therapy are urgently needed. This study aimed to evaluate the predictive value of serum levels of uromodulin (sUMOD) in patients with cirrhosis and HRS treated with terlipressin and albumin (T/A). In total, 156 patients [81 patients with HRS treated with T/A, 42 patients with cirrhosis without kidney injury, and 33 patients with cirrhosis with prerenal acute kidney injury (AKI)] were included. sUMOD levels were analyzed by ELISA. Patients with HRS were prospectively followed for the composite endpoint of hemodialysis-/liver transplantation-free survival (HD/LTx-free survival). Of the 81 patients with HRS, 40 had HRS type 1 and 41 type 2. In the cohort of patients with HRS treated with T/A, median sUMOD level was 100 ng/mL (IQR 64; 144). sUMOD differed significantly between patients with HRS compared with patients without AKI (P = 0.001) but not between patients with HRS and prerenal AKI (P = 0.9). In multivariable analyses, sUMOD levels in the lowest quartile were independently associated with a lower rate of complete response to T/A (OR 0.042, P = 0.008) and a higher risk for reaching the composite endpoint of HD/LTX-free survival (HR 2.706, P = 0.013) in patients with HRS type 2 treated with T/A. In contrast, sUMOD was not significantly associated with these outcomes in patients with HRS type 1. sUMOD may be a valuable biomarker for identifying patients with HRS type 2 treated with T/A to predict response and prognosis.NEW & NOTEWORTHY Biomarkers identifying patients with hepatorenal syndrome (HRS) and poor response to therapy are urgently needed. In this study, lower serum uromodulin (sUMOD) levels were associated with poorer response to therapy with terlipressin and albumin and consequently with poorer prognosis in patients with HRS type 2. In patients with HRS type 1, there was no association between sUMOD and poorer prognosis.

Do Tumor SURVIVIN and MDM2 Expression Levels Correlate with Treatment Response and Clinical Outcome in Isolated Limb Perfusion for In-Transit Cutaneous Melanoma Metastases?

Isolated limb perfusion (ILP) involves the local administration of high doses of anticancer drugs into a limb affected by unresectable locally advanced tumors (with special regard to in-transit melanoma metastases), minimizing systemic side effects. Tumor response to anticancer drugs may depend on the expression of apoptosis-related genes, such as SURVIVIN and MDM2. This retrospective cohort study investigated the association between tumor SURVIVIN and MDM2 expression levels and treatment response or clinical outcomes in patients undergoing ILP for in-transit melanoma metastases. The study cohort consisted of 62 patients with in-transit metastases who underwent ILP with tumor necrosis factor (TNF) and melphalan. Tissue samples were taken from the in-transit metastases, and RNA was extracted for gene expression analysis. Patients' response to treatment was assessed using clinical and radiological criteria two months after ILP, and disease response was classified as complete, partial, or stable/progressive disease. Disease-free survival (DFS) and overall survival (OS) were also analyzed. Expression of SURVIVIN and/or MDM2 was observed in 48% of patients; in these cases, complete response to ILP occurred in 40% of cases, with the overall response rate (complete + partial) being 85%. Patients with expression of MDM2 alone had a lower complete response rate (28%), while patients with expression of SURVIVIN alone had a higher complete response rate (50%). The combined expression of MDM2 and SURVIVIN resulted in a complete response rate of 30%. Patients without expression (of SURVIVIN or MDM2) had the highest complete response rate (58%). Survival analysis showed that high MDM2 expression was independently associated with a lower probability of a complete response to ILP. In addition, patients with MDM2 expression were three times more likely to have an incomplete response to ILP. This study highlights the importance of considering SURVIVIN and MDM2 expression in patients undergoing ILP for in-transit cutaneous melanoma metastases. High MDM2 expression was found to be an independent factor associated with a reduced likelihood of achieving a complete response to ILP, suggesting potential mechanisms of chemoresistance. These data support further research to explore the role of already available targeted therapies (i.e., MDM2 inhibitors) in improving tumor response to ILP in patients with in-transit melanoma metastases.

Prognostic impact of pretreatment skeletal muscle index and CONUT score in diffuse large B-cell Lymphoma

BackgroundAlthough the prognostic value of the Controlling Nutritional Status (CONUT) score in diffuse large B-cell lymphoma (DLBCL) has been reported in several previous studies, its clinical relevance for the presence of sarcopenia has not been assessed.MethodsIn this study, 305 DLBCL patients were reviewed. They were categorized into normal/mild (n = 219) and moderate/severe (n = 86) CONUT groups. Sarcopenia was assessed using the L3-skeletal muscle index measured by baseline computed tomography imaging. Based on CONUT score and sarcopenia, patients were grouped: A (normal/mild CONUT and no sarcopenia), B (either moderate/severe CONUT or sarcopenia, but not both), and C (both moderate/severe CONUT and sarcopenia).ResultsThe moderate/severe CONUT group showed higher rates of ≥ grade 3 febrile neutropenia, thrombocytopenia, non-hematologic toxicities, and early treatment discontinuation not related to disease progression, compared to the normal/mild CONUT group. The moderate/severe CONUT group had a lower complete response rate (58.1% vs. 80.8%) and shorter median overall survival (18.5 vs. 162.6 months) than the normal/mild group. Group C had the poorest prognosis with a median survival of 8.6 months, while groups A and B showed better outcomes (not reached and 60.1 months, respectively). Combining CONUT score and sarcopenia improved the predictive accuracy of the Cox regression model (C-index: 0.763), compared to the performance of using either CONUT score (C-index: 0.754) or sarcopenia alone (C-index: 0.755).ConclusionsIn conclusion, the moderate/severe CONUT group exhibited treatment intolerance, lower response, and poor prognosis. Additionally, combining CONUT score and sarcopenia enhanced predictive accuracy for survival outcomes compared to individual variables.

Evaluation of Treatment Outcomes in Adults with Blastic Plasmacytoid Dendritic Cell Neoplasm: A Systematic Review and Meta-Analysis

Introduction: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare neoplasm with a poor prognosis. Treatment options include CD123 directed agents (tagraxofusp) or intensive chemotherapy, followed by allogenic stem cell transplant (allo-HSCT). Sufficient evidence comparing them is lacking and there is no consensus on the best first line treatment. With the aim to compare the efficacy of the various treatment modalities in BPDCN, we performed a meta-analysis from the available literature. Objectives: Our primary objective was to evaluate the treatment outcomes in patients with BPDCN receiving tagraxofusp compared to various chemotherapeutic regimes, in terms of response rates, mortality, and patients proceeding to allo-HSCT. Population: Adult patients (age ≥ 18 years) with BPDCN who received treatment. Outcomes: Our primary outcome was complete response (CR), as designated by the investigators in the respective studies. Secondary outcomes included partial response (PR), no response (NR), overall survival (OS), and proportion of patients receiving allo-HSCT after therapy. Methods: Controlled vocabulary encompassing BPDCN and tagraxofusp or SL-401 was used to perform a systematic search in PubMed, Embase, Scopus and Cochrane from inception to June 2023. No restrictions on date, language, status, or outcomes were applied. 1291 records were identified after duplicates were removed using Mendeley. 2 reviewers independently screened titles and abstracts. We only included studies pertaining to treatment modalities in BPDCN and excluded reviews, opinions, and case reports. 36 studies (clinical trials=9, retrospective studies=20, case series=7) were identified for the final analysis. 3 studies had tagraxofusp and chemotherapy arms. They were used for Odds Ratio (OR) estimates for achieving CR using the random effects model with Mantel-Haenszel method, using RevMan. Single arm studies were utilized to determine proportions from random effects model for CR, PR, NR, mortality rate and allo-HSCT rate using OpenMeta. Results: We identified 818 total patients: 36% (292/818) received tagraxofusp, 60% (494/818) received intensive chemotherapy (HyperCVAD, AML and ALL-like, and CHOP), 3% (22/818) received less intensive chemotherapy (azacytidine, venetoclax, or other mild regimes), 1% received pivekimab (10/818). The median age was 61 (range 36-80). Most patients were male and had extensive systemic disease (97%). The OR of CR for tagraxofusp versus intensive chemotherapy using the random effects model was 0.46 (confidence interval(CI)=0.21-1.02, p=0.06, I 2=0%), shown in figure 1. Proportions calculated using random effects model (figure 2) were used to determine CR (tagraxofusp 71%, intensive chemotherapy 64%, less intensive chemotherapy 25%), PR (17%, 8%, 31%), NR (23%, 21%, 40%), mortality rate (43%, 30%, 71%), and allo-HSCT rate (51%, 50%, 6%). Conclusion: From our analysis, the OR of attaining CR between tagraxofusp and chemotherapy was not significant and did not answer the question of which modality has a higher chance of CR. Although it is not possible to draw a direct comparison between the pooled single arm trials, the trend of proportions favored tagraxofusp for obtaining both CR (71% vs 64%) and PR (17% vs 8%). While the mortality rate was higher for tagraxofusp compared to intensive chemotherapy (43% vs 30%), the NR rate (~21%) and the allo-HSCT rate (~50%) were similar. What is clearly seen is that less intensive therapy had a lower rate of CR (25%) and allo-HSCT (6%), and higher mortality (71%) and failure rates (PR 32%, NR 40%). This may be attributed to the baseline poor functional status of these patients, leading to the selection of less intensive therapy. We can conclude that whenever possible, either tagraxofusp or intensive chemotherapy needs to be used. While our study does not answer the question of whether tagraxofusp or intensive chemotherapy is better as first line therapy for BPDCN, it highlights the fact that controlled data in the literature is sparse and emphasizes the need for further research in this space. Heterogeneity between the studies is a limitation of our analysis. Also, there were only a few studies directly comparing tagraxofusp and chemotherapy. Further research in a prospective, controlled setting will enable performing a more robust systematic review and meta-analysis that may help determine the best initial treatment for this rare disease.

Gemcitabine and Liposomal Doxorubicin (GemDox) for the Treatment of Relapsed and Refractory T-Cell Lymphomas

Introduction: Aggressive T-cell lymphomas (TCL) account for 10-15% of non-Hodgkin's lymphomas and have lower rates of complete response (CR), overall response (OR), and shorter duration of response (DOR) to chemotherapy than other types of NHL, particularly in the relapsed setting. Cutaneous T-Cell lymphoma (CTCL) is treated initially with skin directed therapies, but systemic therapy or cytotoxic chemotherapy may become necessary to control disease. Second-line chemotherapy benefits only a small minority of TCL patients and more effective treatment regimens are needed. Gemcitabine and liposomal doxorubicin have both shown single agent activity in TCL and have been used in combination in patients with relapsed B-cell lymphomas (BCL) and Hodgkin lymphomas (HL), though responses are typically not durable. Therefore, we evaluated a combination of gemcitabine and liposomal doxorubicin (GemDox) for patients with relapsed/refractory (r/r) TCL. Methods: In this single-center, retrospective study, we evaluated the safety, efficacy, and survival (PFS/OS using Kaplan-Meier method) of GemDox in TCL. Patients either received gemcitabine 1000 mg/m 2 and liposomal doxorubicin 15 mg/m 2 either on days 1 and 8 every 21 days (21-day regimen) or gemcitabine 1000 mg/m 2 and liposomal doxorubicin 15 mg/m 2 on days 1 and 15 every 28 days (28-day regimen). Results: 18 patients (13 CTCL, 5 PTCL) with r/r aggressive TCL were treated with GemDox, with 16 evaluable for treatment response. Patients were heavily pre-treated with a median number of 4 prior therapies (range 2-7). This included 62% of CTCL patients with nodal involvement. The overall response rate (ORR) was 50% (19% CR and 31% PR) with a median PFS and OS of 5 and 15 months respectively. In patients that had a response to treatment, the median PFS was 11 months while median OS was not reached. The clinical benefit rate [CR/Partial response (PR)/stable disease (SD)] for CTCL and PTCL was 82% and 40% respectively. The median PFS and OS for CTCL patients was 6 months and 14 months respectively, with an ORR of 55% (18% CR and 36% PR). For PTCL , the median PFS and OS were 4 and 21 months respectively, with an ORR of 40% (20% CR and 20% PR). The clinical benefit (CR/PR/SD) rate for the 21-day vs 28-day regimen was 71% and 67%, respectively, with similar PFS and OS, and no significant difference in toxicities. The median duration of response (DOR) for patients that obtained a response (CR/PR) in evaluable patients was 13 months; 17 months for CTCL, and 5 months for PTCL. We observed a substantial decrease in CTCL skin manifestations, as patients that had a CR/PR had a mean decrease of 76% in mSWAT BSA of 70%. Further, six patients (38%) (5 CTCL, 1 PTCL) were able to proceed to allogeneic stem cell transplant (allo-HSCT). Interestingly, 4 CD30+ CTCL patients were previously treated with brentuximab vedotin (BV). Of those, three (75%) had a response to GemDox, while only one achieved a response (PR) to BV. This demonstrates that GemDox is a potentially effective regimen in heavily refractory CD30+ CTCL patients that fail treatment with BV. 11 patients (61%) experienced any grade 3/4 toxicity and hematologic toxicities were the most common including: anemia (33%), neutropenia (22%), lymphopenia (17%) and thrombocytopenia (17%)., GemDox was very well tolerated with the most common grade 3/4 non-hematologic toxicity being fatigue (17%). 11% of patients discontinued therapy due to adverse events. Conclusion: GemDox produced an excellent ORR of 50%, with an impressive ORR of 82% in CTCL, suggesting this is an effective regimen for heavily pre-treated TCL patients. Additionally, a large number of patients with CTCL with heavy skin burden, including those refractory to BV, were able to achieve remarkable skin responses. Importantly, in this study, 75% of patients who responded to GemDox were able to proceed to allo-HSCT, with 66% experiencing a sustained response. Based on these findings, GemDox should be further investigated as a therapeutic option in relapsed aggressive TCL, particularly in CTCL and considered as a potential bridging therapy patients with a treatment goal of obtaining allo-HSCT and providing a long-term benefit.

Clonal Hematopoiesis in Patients with Immune Thrombocytopenia: Preliminary Results of a Cross-Sectional Study

Immune thrombocytopenia (ITP) is an acquired disorder marked by immune-mediated attack to platelets. However, the borders between ITP and clonal cytopenias, such as low risk myelodysplastic syndromes, may be difficult to establish. Detection of somatic mutations on peripheral blood leukocytes (PBL) through next generation sequencing (NGS) is gaining diagnostic and prognostic power in myeloid disorders and may be found also in individuals without blood malignancies, namely clonal hematopoiesis with indeterminate potential (CHIP). The prevalence and significance of CHIP in immune-mediated hematological diseases, such as ITP, is not clearly known. Here we present the preliminary results of a cross-sectional study on adult ITP patients followed at our clinics from 2019 until March 2023. History of any hematological malignancy was an exclusion criterion. An NGS study on PBL was performed by Ion Torrents5, Ion Reporters software 5.2, evaluating mutations in 69 potentially oncogenic genes present in the Oncomine Myeloid Research Assay diagnostic panel. Only mutations with a variant allele frequency (VAF) of 2% were considered, while mutations with VAF > 40% were regarded as potentially germline and discarded. To correlate mutational status with clinical features, a two-tailed Fisher's exact test was used for analysis of dichotomic variables, while a two-sided student's t was used for continuous ones. We included 37 ITP patients (Table 1), 14 of which (38%) had at least one mutation. After exclusion of 4 mutations with VAF > 40%, a total of 17 mutations were considered, affecting 11/37 (30%) patients (NGS-positive). Mutated genes were TET2 (7/17, 41%), DNMT3A (4/17, 18%), SRSF2 (2/17, 12%), and SF3B1, MPL, ASXL1 and NF1 in 1/17 (6%) case each. All patients, except two, had received at least one treatment line (steroids +/- intravenous immunoglobulins), 32 (86%) and 14 (38%) subjects 2 or 3 lines, respectively. Median age of NGS-positive was significantly higher than NGS-negative patients: 73 years, interquartile range (IQR) 68 - 76 vs 62 years, IQR 52 - 70 (p = 0.02). NGS-positive had a slightly lower rate of complete response (CR; PLT > 100 x 10 9/L) after steroid treatment, compared with NGS-negative patients (40% vs 60%, respectively). Among the 9 NGS-positive patients who received thrombopoietin receptor agonists (TPO-RA), only 2 were evaluated before, and the remaining after a median of 2.6 years from TPO-RA start. Considering the 9 patients treated with TPO-RA, NGS-positive had a slightly lower rate of CR than NGS-negative patients (44% vs 79%, respectively). In this respect, we did not find substantial disparities in distribution or VAF of gene mutations between patients who fully responded to TPO-RA and those failing to achieve CR. With the caveat of a cross-sectional analysis in a limited number of cases, these data show the presence of CHIP in 1/3 of multi-treated ITP patients, a frequency similar to that of a much more elderly Italian population >80-year-old (Rossi et al, Blood. 2021), suggesting a possible role of autoimmunity/inflammation and treatment in clonal selection.

Venetoclax Plus Azacitidine, Low Dose Cytarabine, Aclarubicin and G-CSF (VA-CAG Regimen) for Newly Diagnosed Young Patients with Acute Myeloid Leukemia: A Prospective, Multicenter, Single-Arm Phase 2 Clinical Trial

Background: Venetoclax, in combination with hypomethylating agents or low-dose cytarabine, is approved for newly diagnosed acute myeloid leukemia (AML) patients who are over 75 years of age or not eligible for intensive chemotherapy, while the efficacy of venetoclax-based regimens in young fit AML patients still needs to be further explored. Although the combination of anthracycline and cytarabine has achieved a remission rate of about 70% in these patients, the low complete response rate in adverse-risk patients, strong adverse reactions, and long duration of myelosuppression limited the clinical benefit. We presumed that venetoclax plus azacitidine in combination with low-intensity regimens CAG (G-CSF priming, low dose cytarabine, and aclarubicin) could have a better composite complete remission with an acceptable safety profile. Methods: Patients who were newly diagnosed with AML aged from 18 to 65 years without active infection, bleeding and severe cardiopulmonary insufficiency were enrolled. Participants received induction as azacitidine 75 mg/m 2 subcutaneously once daily on days 1-7, cytarabine 10mg/m 2 subcutaneously q12h on days 1-7, aclacinomycin 12 mg/m 2 on days 1,3,5,7, granulocyte colony-stimulating factor 5µg/kg on days 1-7, and venetoclax orally once daily (100 mg d1, 200 mg d2, 400 mg d3-21). Venetoclax dose was adjusted based on concomitant CYP3A inhibitors. The efficacy were evaluated by bone marrow morphology and flow cytometry on day 28 cycle 1. The primary endpoints were safety and the composite complete remission rate. This study was approved for ethical review and registered with ClinicalTrials.gov (NCT05662956). Results: Twenty-six patients from eight sites were enrolled between January 1, 2023, and June 20, 2023. The median age was 52 years (range, 18-63years). Thirteen patients (50.0%) had adverse risk, 7 patients (26.9%) had intermediate risk, and 6 patients (23.1%) had favorable risk. All 26 patients (100%) achieved complete remission after cycle 1, and 21 patients (80.8%) was MRD negative by flow cytometry. Two patients (7.7%) were treated with venetoclax for 14 days due to ineffective platelet transfusion and severe infection during treatment. Twenty-two patients (84%) used azole drugs to prevent fungal infection. The median myelosuppression time was 13 days (range, 5-22days), and the median red blood cell and platelet transfusions were 5.5u (range, 0-11.5u) and 30u (range, 0-170u), respectively. Eleven patients (42.3%) experienced infection (including pulmonary fungal infection, oral cold herpes, novel coronavirus infection, etc.), and two of them (7.7%) had a breakthrough invasive fungal infection, but with good management. The most common grade 3/4 adverse events included bone marrow suppression (92.3%), liver injury (19.2%), gastrointestinal reaction (11.5%) and coagulation dysfunction (3.8%).No treatment-related death occurred. Conclusion: VA-CAG regimen achieved high rates of complete remission and MRD negative in young adult fit patients with newly diagnosed AML. This combined regimen has an acceptable safety profile, with low incidence of infection and transfusion dependence.

Nodal pCR and overall survival following neoadjuvant chemotherapy for node positive ER+/Her2- breast cancer.

The role of neoadjuvant chemotherapy (NAC) in node-positive (N+) ER+/HER2- breast cancer (BC) is debated, given low total pathologic complete response (pCR) rates. However, the rate and impact of nodal pCR is unknown. We sought to evaluate nodal pCR rates and the impact on overall survival (OS). Further, we sought to validate the association between nodal pCR with age and Ki67. We queried the National Cancer Database for cN + ER+/HER2- BC patients treated with NAC and surgery. Data from 2010 to 2018 were used to evaluate nodal pCR and OS, with multivariable Cox proportional hazards modeling for OS, as well as Ki67 for the years 2018-2019. From 2010 to 2018, we identified 19,611 cN + ER+/HER2- BC patients treated with NAC. While total pCR occurred in only 7.4%, nodal pCR rates were nearly double (14.3%). Nodal pCR (+/- breast pCR) was seen in 21.7% and associated with 5-year OS rate of 86.1% (95% CI: 84.9-87.4%) versus 77.1% (95% CI: 76.3-77.9%) in patients without nodal pCR (p < 0.001). On multivariable analysis, nodal pCR had better OS (adjusted HR 0.57, 95%CI 0.52-0.63, p < 0.001) across all age groups. Of 2,444 patients with available Ki67, those with age < 50 and Ki67 ≥ 20% had the highest nodal pCR at 31.6%. In cN + ER+/HER2- BC treated with NAC, nodal pCR is common, associated with age and Ki67, and prognostic for OS. These data strongly suggest that for cN + patients, eradication of nodal disease is critical for OS, and total pCR may not be the optimal measure of NAC benefit.

The Role of Radiation Therapy in the Management of Gray Zone Lymphoma.

Gray zone lymphoma (GZL) is a relatively rare disease predominantly affecting young adults with purportedly poor outcomes with current treatment approaches. The role of radiation therapy (RT) in the management of GZL is not well established. This is the largest study to report on the outcomes of GZL patients treated with and without RT. A retrospective review of 30 patients with GZL treated across 3 institutions from 2009 to 2021 was performed. Event-free survival (EFS) was defined from initiation of frontline chemotherapy (CHT) to disease progression/relapse, initiation of salvage therapy, or death. Local control (LC) was defined from RT start date to in-field recurrence. The median age was 32 (range: 18-86) years, and 16 (53%) patients had early stage (I-II) disease. Bulky mediastinal disease was present in 63% of patients, and the median tumor diameter was 10 (range: 1.5-18) cm. Patients received ABVD (20%), RCHOP (33%), or REPOCH (47%) as frontline CHT. Among 25 patients with interim PET/CT scan, there were 6 rapid early responders and 14 slow early responders (SER), with 2-year EFS of 33% and 24%, respectively (p = 0.13). After the completion of CHT, 15 (50%) patients achieved complete response (CR) and 10 (33%) achieved partial response (PR), with 2-year EFS of 46% and 10%, respectively (p = 0.004). RT was given to 9 patients in CR (n = 3) or in PR (n = 6). The median RT dose was 36 (30.6-48.6) Gy, at 1.8-2 Gy/fraction. Those receiving RT had bulkier disease at diagnosis (p = 0.049) and lower rates of CR following CHT (p = 0.03). After RT, 3/6 (50%) PR patients converted to CR. At a median follow-up of 4 years, the 2-year EFS was 26% for all patients, 33% for RT and 23% for noRT (p = 0.44). Among patients who did not receive upfront RT and experienced progression (n = 17), 16 (94%) relapsed in pre-existing sites. The 5-year OS was 80% for all patients, 88% for RT and 78% for no RT (p = 0.63). Patients who achieved PR to CHT and received RT had better 2-year EFS (17% vs 0%, p = 0.007) compared to patients who did not receive RT. Similarly, patients with SER who received RT had superior 2-year EFS (33% vs 13%, p = 0.038). Patients with bulky mediastinal disease had a 2-year EFS of 43% with RT and 11% without RT (p = 0.08). After 1st line treatment, 22 (73%) patients relapsed and 18 were successfully salvaged with a sustained CR. The most common salvage regimen involved high dose CHT followed by hematopoietic cell transplantation (HCT) (n = 15). RT was given for 7 patients in the relapsed/refractory setting (consolidative peri-HCT n = 4; definitive salvage n = 3) and 5 (71%) achieved a sustained CR. Among the 16 patients who received RT in the upfront (n = 9) or salvage (n = 7) setting, 3 patients experienced in-field recurrence translating to 2-year LC of 79%. GZL patients have high risk of relapse and maximal upfront combined modality therapy should be considered. RT provides good local control and improves EFS particularly for SER, PR, and bulky mediastinal disease.

Complete pathological response in patients with HER2 positive breast cancer treated with neoadjuvant therapy in Colombia

Breast cancer is the most common type of cancer and the leading cause of death by cancer in women in Colombia. Approximately 15 to 20% of breast cancers overexpress HER2. To analyze the relationship between multiple clinical and histological variables and pathological complete response in patients with HER2-positive breast cancer undergoing neoadjuvant therapy in a specialized cancer center in Colombia. We performed a retrospective analysis of non-metastatic HER2-positive breast cancer patients who received neoadjuvant therapy between 2007 and 2020 at the Instituto de Cancerología Las Americas Auna (Medellín, Colombia). Assessed parameters were tumor grade, proliferation index, estrogen receptor, progesterone receptor, HER2 status, type of neoadjuvant therapy, pathologic complete response rates, and overall survival. Variables associated with low pathologic complete response rates were tumor grades 1-2 (OR = 0.55; 95% CI = 0.37-0.81; p = 0.03), estrogen receptor positivity (OR =0.65; 95%; CI = 0.43-0.97; p=0.04), and progesterone receptor positivity (OR = 0.44; 95% CI = 0.29-0.65; p = 0.0001). HER2 strong positivity (score 3+) was associated with high pathological complete response rates (OR = 3.3; 95% CI = 1.3-8.35; p=0.013). Five-year overall survival was 91.5% (95% CI = 82.6-95.9) in patients with pathological complete response and 73.6% (95% CI = 66.4-79.6) in patients who did not achieve pathological complete response (p = 0.001). Additionally, the pathological complete response rate was three times higher in patients receiving combined neoadjuvant chemotherapy with anti-HER2 therapy than in those with chemotherapy alone (48% versus 16%). In patients with HER2-positive breast cancer, tumor grade 3, estrogen receptor negativity, progesterone receptor negativity, strong HER2 positivity (score 3+), and the use of the neoadjuvant trastuzumab are associated with higher pathological complete response rates.

Chemoradiotherapy effcacy in squamous cell rectal cancer: a propensity score matched analysis

Introduction. Sporadic cases of squamous cell carcinoma of the rectum (rSCC) do not allow a comparative characterization of tumor aggressiveness and its response to chemoradiotherapy in relation to more common squamous cell entities, in particular, anal squamous cell carcinoma (aSCC). Objective: comparative evaluation of the short- and long-term results of chemoradiation therapy in patients with rSCC and aSCC. Material and Methods. In this retrospective study we included patients with nonmetastatic squamous cell carcinoma of the rectum (rSCC) and anal canal squamous cell carcinoma (aSCC) who received chemoradiotherapy and compared them in a 1:1 ratio using propensity-score matching. The dynamics of tumor response to treatment were compared by Kaplan-Meier survival analysis (OS and RFS) followed by Log-Rank verifcation, rate of complete response after 6 months. Results. A total of 15 pairs of matched patients were evaluated. Patients in both groups had reliably similar sex, age, histological grade, initial primary tumor size, differing only in tumor histological subtype. In the aSCC group, 60 % of patients had metastases to pelvic lymph nodes, while in the rSCC group metastases had 46.67 % (p=1). The median follow-up was 44 months. The 3-year OS in the aSCC group of patients was 76.9 %, and 71.4 % in the rSCC group (p=0.567). The 3-year DFS in the aSCC group was 66.7 %, and in the rSCC group 34.7 % (p=0.406). The rate of achieving complete clinical response to CRT after 6 months was 86.7 % for the aSCC group and only 46.7 % for the rSCC group (p=0.05). Organ-saving treatment was achieved in 93.3 % of aSCC patients and 73.3 % of rSCC patients (p=0.33). Conclusion. Overall and recurrence-free survival rates were not signifcantly decreased for rSCC patients relative to aSCC patients. This indicates a similar course and prognosis in the two diseases, but rSCC is characterized by a signifcantly lower rate of complete response to treatment.

Pituitary adenomas with multiple cell lineage combinations: clinicopathological features and short-term prognosis.

There are few published data concerning pituitary adenomas (PAs) derived from multiple lineages. In this study the authors aimed to determine the clinicopathological characteristics and prognostic profiles of PAs with multiple cell lineage combinations (PAwMCs). The authors reviewed data on 723 patients with PAs who had undergone surgery between 2018 and 2021 and identified 93 cases (12.9%) of PAwMC. They collected detailed data on these cases, including clinical information, pathological features, and prognosis. From among 589 cases of PAs with only one cell lineage (PAwOCs), they randomly selected 100 cases to investigate differences between the two tumors. To enable investigation of the characteristics of different subgroups, they further subclassified PAwMCs into 4 groups according to the following specified combinations of pituitary-associated transcription factors: group A, immunopositive for pituitary-specific positive transcription factor 1 (Pit1) and steroidogenic factor 1 (SF1); group B, immunopositive for Pit1 and T-box transcription factor (Tpit); group C, immunopositive for SF1 and Tpit; and group D, immunopositive for Pit1, SF1, and Tpit. Compared with PAwOC, PAwMC was more often associated with hormone hypersecretion (31.0% vs 50.0%, p = 0.037) and had worse short-term prognoses with lower complete response rates (58.7% vs 30.0%, p = 0.026) and more postoperative complications (19.4% vs 35.9%, p = 0.041). Each of the 4 PAwMC subgroups had its own clinical features. Overall, PAwMCs displayed more neurological manifestations than evidence of hypersecretion, which may be attributable to a disparity between pituitary-associated transcription factors and endocrine-related manifestations. Moreover, multiple cell lineages, tumor size (p = 0.011), and Knosp grade (p = 0.013) were all found to be critical predictors of the prognosis of PAwMC. The authors described a special subtype of PAs, which derived from multiple lineages. They found a unique effect of the combination of distinct cell lineages on PAs and present detailed clinicopathological and prognostic profiles of these special PAs. These data will contribute to a more comprehensive view of PAs and assist in the selection of treatment.

Multiparametric Flow Cytometry in Newly Diagnosed Multiple Myeloma Patients: An Italian Monocentric Experience.

Multiple myeloma (MM) is a heterogeneous malignancy characterized by the proliferation of abnormal plasma cells in the bone marrow. Multiparametric flow cytometry (MFC) plays a role in the work-up of the disease in view of the aberrant expression of surface antigens. Our study aimed at describing the antigenic profile detected by MFC in a series of newly diagnosed MM patients to correlate the level of expression with other features of the disease. Between April 2018 and June 2022, 84 consecutive MM patients were studied at presentation. CD56 and CD117 were commonly detected, while CD45, CD28, CD20, CD19, CD13 and CD33 were less recurrent. CD20 expression was associated with the type of secretory MM (p=0.041) and with a higher disease burden (p=0.038). CD28 positivity correlated with a lower platelet count at baseline (p=0.005) and with a lower rate of complete response (p=0.038). Furthermore, CD28 positivity and a lower CD138 expression tended to associate with the high-risk chromosomal translocations t(14;16) and t(4;14). The results of this study indicate that in the diagnostic work-up of MM, MFC may help to identify different patient subsets and improve risk stratification. These observations need to be validated in larger series of patients with a longer follow-up.

LSC17 score complements genetics and measurable residual disease in acute myeloid leukemia: an ALFA study

AbstractWhether the LSC17 gene expression can improve risk stratification in the context of next generation sequencing–based risk stratification and measurable residual disease (MRD) in patients with intensively treated AML has not been explored. We analyzed LSC17 in 504 adult patients prospectively treated in the ALFA-0702 trial. RUNX1 or TP53 mutations were associated with higher LSC1 scores while CEBPA and NPM1 mutations were associated with lower scores. Patients with high LSC17 scores had a lower rate of complete response (CR) in a multivariable analysis (odds ratio, 0.41; P = .0007), accounting for European LeukemiaNet 2022 (ELN22), age, and white blood cell count (WBC). LSC17-high status was associated with shorter overall survival (OS) (3-year OS: 70.0% vs 52.7% in patients with LSC17-low status; P < .0001). In a multivariable analysis considering ELN22, age, and WBC, patients with LSC17-high status had shorter disease-free survival (DFS) (hazard ratio [HR], 1.36; P = .048) than those with LSC17-low status. In 123 patients with NPM1-mutated AML in CR, LSC17-high status predicted poorer DFS (HR, 2.34; P = .01), independent of age, WBC, ELN22 risk, and NPM1-MRD. LSC-low status and negative NPM1-MRD identified a subset comprising 48% of patients with mutated NPM1 with a 3-year OS from CR of 93.1% compared with 60.7% in those with LSC17-high status and/or positive NPM1-MRD (P = .0001). Overall, LSC17 assessment refines genetic risk stratification in adult patients with AML treated intensively. Combined with MRD, LSC17 identifies a subset of patients with NPM1-mutated AML with excellent clinical outcome.