Overall Response Rate In Patients Research Articles

Treatment strategies for relapse after CAR T-cell therapy in B cell lymphoma.

Clinical trials of anti-CD19 chimeric antigen receptor T (CART19) cell therapy have shown high overall response rates in patients with relapsed/refractory B-cell malignancies. CART19 cell therapy has been approved by the US Food and Drug Administration for patients who relapsed less than 12 months after initial therapy or who are refractory to first-line therapy. However, durable remission of CART19 cell therapy is still lacking, and 30%-60% of patients will eventually relapse after CART19 infusion. In general, the prognosis of patients who relapse after CART19 cell therapy is poor, and various strategies to treat this patient population have been investigated extensively. CART19 failures can be broadly categorized by the emergence of either CD19-positive or CD19-negative lymphoma cells. If CD19 expression is preserved on the lymphoma cells, a second infusion of CART19 cells or reactivation of previously infused CART19 cells with immune checkpoint inhibitors can be considered. When patients develop CD19-negative relapse, targeting different antigens (e.g., CD20 or CD22) with CAR T cells, investigational chemotherapies, or hematopoietic stem cell transplantation are potential treatment options. However, salvage therapies for relapsed large B-cell lymphoma after CART19 cell therapy have not been fully explored and are conducted based on clinicians' case-by-case decisions. In this review, we will focus on salvage therapies reported to date and discuss the management of relapsed/refractory large B-cell lymphomas after CART19 cell therapy.

Belantamab mafodotin, pomalidomide and dexamethasone in refractory multiple myeloma: a phase 1/2 trial

Due to evolving treatment standards for newly diagnosed multiple myeloma, many patients will be triple-class exposed after initial relapses and have poor survival. Novel therapies and combinations are therefore required to improve outcomes. B cell maturation antigen (BCMA)-targeted biologics have emerged as an important new area of therapeutics for relapsed multiple myeloma. The two-part ALGONQUIN trial evaluated various doses and schedules of the anti-BCMA antibody–drug conjugate belantamab mafodotin plus pomalidomide and dexamethasone for patients who are lenalidomide refractory and proteosome inhibitor exposed. The primary endpoints, including evaluating dose-limiting toxicities, establishing the recommended Part 2 dose (RP2D) and overall response rate for patients treated at the RP2D, were met. Secondary efficacy endpoints included progression-free survival and overall survival. Patients treated on study (N = 87) had a median of three previous regimens and 55.2% were triple-class refractory. At the RP2D the most common adverse events were decrease in best-corrected visual acuity (71.1%), keratopathy (65.8%), fatigue (57.9%), infection (47.4%; 7.9% grade ≥3), neutropenia (39.5%) and thrombocytopenia (39.5%). For RP2D patients (n = 38), the overall response rate was 85.3%, ≥very good partial response 75.7% and estimated two-year progression-free survival 52.8% (95% confidence interval, 33.9% to 82.4%), at a median follow-up of 13.9 months. The RP2D schedule was associated with manageable antibody–drug conjugate-associated corneal adverse events and improved tolerability without compromising efficacy. Belantamab mafodotin plus pomalidomide and dexamethasone induced durable responses with promising overall survival in relapsed multiple myeloma, the results of which are yet to be confirmed in the phase 3 DREAMM-8 study. ClinicalTrials.gov Identifier: NCT03715478.

A systematic review and meta-analysis of moxibustion for chronic prostatitis.

Chronic prostatitis (CP) is a common condition that affects many individuals. Previous clinical trials have explored the use of moxibustion as a potential treatment for CP. However, the evidence on the effectiveness of moxibustion for CP remains limited. Therefore, this study aimed to comprehensively assess the effects of moxibustion for CP. In order to gather relevant and up-to-date information, we conducted a systematic literature search of databases including Cochrane Library, PUBMED, EMBASE, CNKI, and Wangfang from inception until June 30, 2023. Only randomized clinical trials (RCTs) that investigated the use of moxibustion for CP were included in this study. The primary outcomes of interest were the National Institutes of Health-Chronic Prostatitis Symptom Index (NIH-CPSI) scores and the overall response rate. To evaluate the quality of the included studies, we used the Cochrane risk-of-bias tool. After analyzing the data from 8 RCTs involving a total of 664 patients, we found significant differences in NIH-CPSI scores between moxibustion and other treatment modalities. Specifically, when compared with herbal medicine, moxibustion was associated with a mean difference (MD) of -1.78 in NIH-CPSI scores (95% confidence interval [CI] [-2.78, -0.78], P < .001), and when compared with western medicine, moxibustion was associated with a MD of -5.24 in NIH-CPSI scores (95% CI [-7.80, -2.67], P < .08). In terms of the overall response rate, moxibustion was found to be superior to herbal medicine, with a MD of 2.36 (95% [19, 4.67], P = .01). Additionally, when moxibustion was combined with herbal medicine, it yielded a higher overall response rate with a MD of 4.07 (95% CI [1.54, 10.74], P = .005) compared to herbal medicine alone. Moxibustion also outperformed western medicine in terms of the overall response rate, with a MD of 4.56 (95% CI [2.24, 9.26], P < .001). Based on the findings of this study, moxibustion appears to be a potentially efficacious treatment for CP. The results suggest that moxibustion can improve NIH-CPSI scores and overall response rate in patients with CP. However, further high-quality studies are needed to validate these results and establish the long-term effects of moxibustion as a treatment for CP.

Clinical characteristics and outcomes of newly diagnosed patients with human immunodeficiency virus-associated Burkitt lymphoma: the Central and Western China AIDS lymphoma league 002 study (CALL-002 study)

BackgroundDespite the introduction of combined antiretroviral therapy, the clinical outcomes of HIV-associated Burkitt lymphoma (BL) remain poor.MethodsTo evaluate the clinical characteristics, prognostic factors, and outcomes of HIV-associated BL, we conducted a retrospective analysis of patients from multiple centers in China.ResultsThe study included 41 patients from 8 medical centers. Among the included population, male patients accounted for 87.8%, with 75.6% in advanced stages. Notably, 46.3% of cases involved bone marrow, while 19.5% involved the central nervous system (CNS). The most commonly used chemotherapy regimen was DA-EPOCH ± R, accounting for 53.6% of cases. The overall response rates for patients receiving DA-EPOCH ± R and R-Hyper-CVAD were 59% and 58.2%, respectively. Interestingly, patients receiving regimens containing rituximab had similar complete remission rates (25% vs. 23.5%) and overall survival time (45.69 ± 11.58 vs. 47.79 ± 11.72 months, P = 0.907) compared to those without rituximab, but differed in progression rates (33.3% vs. 47.1%). For the entire cohort, the 1-year progression-free survival (PFS) and overall survival (OS) rates were 52% and 67%, respectively. CNS involvement was independent risk factors for survival, with 1-year PFS and OS rates of 0% and 38% for patients with CNS involvement, and PFS and OS rates of 66% and 75% for patients without CNS involvement.ConclusionsHIV-associated BL patients in China have poor prognosis and show limited response to current treatment regimens. The absence of CNS involvement significantly improves clinical outcomes. The use of rituximab is not significantly associated with improved outcomes but can reduce disease progression.

Efficacy and Safety of Human Umbilical Cord-Derived Mesenchymal Stem Cells in the Treatment of Immune Thrombocytopenia: A Prospective, Single Centre, Single Arm, Phase I Trial

Background Patients with refractory immune thrombocytopenia (ITP) often suffer severe bleeding events and have poor responses to various treatments. Umbilical cord-derived mesenchymal stem cells (UC-MSCs) have been used to treat multiple autoimmune diseases due to their low immunogenicity and strong immunomodulatory potential. To explore the safety and efficacy of UC-MSCs in treating refractory ITP, we conducted this phase Ⅰ clinical trial. Methods Patients diagnosed with refractory ITP were screened for the study. The major inclusion criteria included age 18 to 60 years, ITP duration lasting for more than six months, platelet count &amp;lt; 30 × 10 9/L and concomitant bleeding manifestations at enrolment. The study consisted of two parts: a dose-escalation phase for exploring the safety and efficacy of three different dosage groups according to the traditional 3+3 protocol and a dose-expansion phase for further verifying the optimal UC-MSC dosage. UC-MSCs were administered at doses of 0.5×10 6 cells/kg, 1.0×10 6 cells/kg, and 2.0×10 6 cells/kg per week four times in the dose-escalation phase and 2.0×10 6 cells/kg per week four times in the dose-expansion phase. The adverse events, platelet counts, and bleeding symptoms were evaluated and recorded during the administration and follow-up period. The study protocol was approved by the Ethics Committees of the Institute of Hematology and Blood Diseases Hospital, and informed consent was obtained from each participant according to the Declaration of Helsinki (ClinicalTrials.gov ID: NCT04014166). Results Between November 2019 and August 2022, 18 refractory ITP patients hospitalized in our centre were successfully screened and enrolled in the study. Twelve patients were enrolled in the dose-escalation phase (three additional patients were added in the 2.0×10 6 cells/kg group due to the dose-limiting toxicity), and six patients were included in the dose-expansion phase. Thirteen patients (13/18, 72.2%) had one or more TEAEs. SAEs occurred in four patients (4/18, 22.2%), including gastrointestinal haemorrhage (2/4), profuse menstruation (1/4), and acute myocardial infarction (1/4). There were 0.0% (0/3), 66.7% (2/3), and 50.0% (6/12) patients in the 0.5×10 6, 1.0×10 6 and 2.0×10 6 cells/kg cohorts who achieved a response after treatment, respectively. The overall response rate was 44.4% (8/18) in all patients who received UC-MSCs. Conclusion UC-MSC infusion achieved a 44.4% overall response rate in patients with refractory ITP and mild adverse events.

Phase II Study of the Combination of Daratumumab, Ixazomib, Pomalidomide, and Dexamethasone (DIPD) As Salvage Therapy in Early Relapsed/Refractory Multiple Myeloma

Background: The combination of daratumumab (D), pomalidomide (P), and dexamethasone (d) has previously demonstrated high overall response rates in patients with RRMM. Results of the phase 3 APOLLO study of DPd vs Pd in patients with RRMM with at least 1 prior line of therapy showed 69% ORR with a median PFS of 12.4 months in those patients who received the triplet combination (Dimopoulos, et al. Lancet 2021). Quadruplet regimens may further improve results by providing deeper and more durable responses with more intensive regimens. We report results from a phase 2 multicenter trial of the addition of Ixazomib to DPd (DIPd) in patients with early RRMM. Methods: This is a prospective, multi-center, open-label, single arm phase 2 study (NCT03590652) with a primary endpoint of overall response rate (ORR) and safety of DIPd. Secondary endpoints include progression-free survival (PFS), overall survival (OS), and MRD-negativity rate. A Simon's optimal 2-stage design was used, with 14 subjects in stage 1 and 32 patients for stage 2. Eligible patients may not have had prior exposure to daratumumab or Ixazomib, may not have progressed on prior pomalidomide, and must have received ≥1 or ≤3 prior lines of therapy including lenalidomide and a proteasome inhibitor. The first six patients in a safety run-in received daratumumab 16mg/kg IV weekly x 8 doses, biweekly x 8 doses, then monthly, pomalidomide 4mg orally on days 1-21, ixazomib 4mg orally on days 1, 8, 15, and dexamethasone 20-40mg weekly on a 28-day cycle. Grade 3-4 neutropenia was observed in 100% of patients in the safety run-in, prompting starting dose reductions to ixazomib 3 mg and pomalidomide 3 mg by the DSMB for subsequent patients. An amendment allowed for subcutaneous (SC) Daratumumab administration and all active patients transitioned to or started with SC dosing for ongoing therapy. MRD assessments were performed by EuroFlow for patients in suspected CR. Pharmacodynamic changes in patients' tumor microenvironments were established by custom panel mass cytometry to include T-cell memory and activated subpopulations, B-cell content, NK-cell subpopulations as well as MDSCs, Tregs and T-exhaustive markers, monocytes and dendritic cells. Results: The study has completed the planned enrollment of 46 patients. The median age is 61.6 years (range 41-87), with 47% female, 72% White, 17% Asian, and 5% Black patients. Patients had a median of 1 prior line of therapy (range 1-3), and 56% (23/41) of patients had at least one high-risk cytogenetic abnormality including del 17p, +1q, t(14;16), t(14;20), or t(4;14). Grade 3-4 treatment emergent adverse events (AE) include neutropenia (72%), infection (19%), febrile neutropenia (8%), lymphopenia (8%), electrolyte disturbance (6%), leukopenia (3%), thrombocytopenia (3%), respiratory condition (3%), infusion reaction (3%), thrombosis (3%), and psychiatric condition (3%). ORR to date is 83% (38/46) in evaluable patients, and best responses include 12 (26%) sCR, 12 (26%) VGPR, and 14 (30%) PR. The median duration of response (DOR) is 21.1 months for all patients, with 11 patients currently remaining on DIPd therapy, and 9 deaths all unrelated to study treatment (5 progressive disease [PD], 2 sepsis, 1 COVID, 1 unrelated surgical complication). Of the 35 patients off therapy, 20 patients had PD, 6 patients had AEs, 5 patients stopped per physician discretion or withdrew consent, and 4 patients received an autologous stem cell transplant. After a median follow up of 15 months, the median PFS is 16.6mo (95% CI: 8.19-NR ) for all patients, 16.6mo (6.9-NR) for standard risk patients, and 22.3mo (7.6-NR) for high risk patients (p=0.9). The median OS for all patients is 30.3mo (95 CI: 30.3-NR). Data will be updated for the conference to include MRD negativity rates and completed data analysis of the primary endpoint. Conclusion: The quadruplet regimen DIPd shows that the addition of a 4 th agent results in high overall response rates and early PFS rates, with manageable toxicity, and the convenience of a nearly all-oral drug regimen in patients with early RRMM. These data are particularly compelling for high-risk disease as more than half of the patients treated had at least one high-risk cytogenetic abnormality, offering a promising option for the management of early relapse in high-risk patients.

Effect of chemotherapy alone or combined with immunotherapy for locally advanced or metastatic genitourinary small cell carcinoma: a real-world retrospective study

BackgroundGenitourinary small cell carcinoma is rare, and has a poor prognosis. However, effective treatment options for this disease are limited. We present a study to assess the efficacy of chemotherapy alone or combined with immunotherapy for locally advanced or metastatic genitourinary small cell carcinoma (GSCC).MethodsWe performed a retrospective analysis of patients with locally advanced or metastatic GSCC from Jan 2013 to September 2022 at Sun Yat-sen University Cancer Center. The survival and safety profiles were analyzed.ResultsForty-two GSCC patients were enrolled, which included 20 with chemotherapy plus immunotherapy and 22 with chemotherapy alone. The median follow-up time was 15.13 months (95% CI, 8.84–21.42). The addition of immunotherapy to chemotherapy demonstrated no significant difference in median progression-free survival (p = 0.37). However, the median overall survival (OS) was 22.97 and 14.03 months with immunotherapy plus chemotherapy and chemotherapy alone, respectively (HR = 0.69, 95%CI 0.08–0.55, p = 0.017). Two patients with immunotherapy plus chemotherapy achieved clinical complete remission. The overall response rate for patients receiving chemotherapy combined with immunotherapy was 65%, which was higher in comparison to those treated with chemotherapy alone (50%). Univariate and multivariate analyses demonstrated that chemotherapy combined with immunotherapy independently achieved favorable OS. Four patients experienced immunotherapy-related adverse events, with one developing grade 3 hypothyroidism.ConclusionsAmong patients with locally advanced or metastatic GSCC, immunotherapy combined with chemotherapy might be thought of as a potentially effective treatment option for patients with GSCC.

Long-term follow-up of humanized and murine CD19 CAR-T-cell therapy for B-cell acute lymphoblastic leukemia

Objective: Murine CD19 chimeric antigen receptor T-cell (CAR-T) products have been approved for the treatment of refractory/relapsed (R/R) B-cell acute lymphocytic leukemia (B-ALL) ; moreover, humanized products are also undergoing clinical trials. This study aimed to explore the differences in safety and short- and long-term follow-up efficacy between humanized and murine CD19 CAR-T-cells for treating relapsed and refractory B-ALL. Methods: Clinical data of 80 patients with R/R B-ALL treated with CD19-targeted CAR-T-cells at the Union Hospital of Tongji Medical College of Huazhong University of Science and Technology between May 2016 and March 2023 were analyzed, which included 31 patients with murine CAR-T and 49 with humanized products. Results: The proportion of patients with cytokine-release syndrome (CRS) in the murine and humanized groups was 63.1% and 65.3%, respectively. Moreover, a higher proportion of patients suffered from severe CRS in the murine group than in the humanized CAR-T group (19.4% vs 8.2%, P=0.174). Furthermore, one patient per group died of grade 5 CRS. The incidence of grade 1-2 immune effector cell-associated neurotoxicity syndrome (ICANS) was 12.9% and 6.1%, respectively; severe ICANS were not observed. Among patients receiving murine CAR-T-cells, an overall response (OR) was observed in 74.2%. Conversely, the OR rate of patients receiving humanized CAR-T-cells was 87.8%. During the median follow-up time of 10.5 months, the median recurrence-free survival (RFS) of patients with murine CAR-T-cells was 12 months, which was as long as that of patients with humanized CAR-T-cells. The median overall survival (OS) were not reached in both groups. Of the 45 patients with a bone marrow burden over 20% at baseline, humanized CAR-T therapy was associated with a significantly improved RFS (43.25% vs 33.33%, P=0.027). Bridging transplantation was an independent factor in prolonging OS (χ(2)=8.017, P=0.005) and PFS (χ(2)=6.584, P=0.010). Common risk factors, such as age, high proportion of bone marrow blasts, and BCR-ABL fusion gene expression, had no significant effect on patients' long-term follow-up outcomes. Three patients reached complete remission after reinfusion of humanized CAR-T-cells. However, one patient relapsed one month after his second infusion of murine CAR-T-cells. Conclusions: The results indicate that humanized CAR-T therapy showed durable efficacy in patients with a higher tumor burden in the bone marrow without any influence on safety. Moreover, it could overcome immunogenicity-induced CAR-T resistance, providing treatment options for patients who were not treated successfully with CAR-T therapies.

Real-world experience of novel multiple myeloma treatments in a large, single-center cohort in Finland.

In this single-center study, we aimed to describe the characteristics, treatment patterns, and outcomes of patients with multiple myeloma (MM) following treatment with bortezomib, carfilzomib, daratumumab, ixazomib, lenalidomide or pomalidomide-based regimens. Data were collected retrospectively from a study cohort of patients receiving a MM treatment in the Hospital District of Helsinki and Uusimaa (HUS) in Finland between 2016-2020. In total, 472 patients were included in the study. Median age was 68.2 years and nearly 25% had a high cytogenetic risk according to the International Myeloma Working Group categorization. In 2018-2020, the spectrum of regimens used as third- or later-line therapy was notably broader than in 2016-2017. The overall response rates for patients who received the most novel regimens (available ≤5 years) in second or third line of therapy (n=67/430) and fourth line or later (n=78/151) were 53.3% and 25.0%, respectively. In this real-world MM patient cohort, the response rates for these novel agents were lower compared to those reported in clinical trials. Given the higher cytogenetic risk profile and more advanced disease stage at the time when treated with novel agents, patients could have benefited from effective novel therapies earlier in their treatment pathway. What is the NEW aspect of your work? (ONE sentence) This study characterized the treatment of Finnish multiple myeloma patients during the era of most novel therapies (after 2016) and also included information on the cytogenetic risk profile of this real-world population.What is the CENTRAL finding of your work? (ONE sentence) There are clear differences between real-world populations treated with most novel combinations and those of randomized controlled trials (RCTs), which is reflected by the poorer treatment outcomes in the real-world setting.What is (or could be) the SPECIFIC clinical relevance of your work? (ONE sentence) Given the high cytogenetic risk profile and advanced disease stage at the time when treated with novel agents, patients could have benefited from effective novel therapies earlier in their treatment pathway.

Predictive value of tumor mutational burden for PD-1/PD-L1 inhibitors in NSCLC: A meta-analysis.

To investigate the association between tumor mutational burden (TMB) and the therapeutic effect of Programmed Death 1/Programmed Death Ligand 1 inhibitors in non-small cell lung cancer. Four electronic databases, PubMed, Embase, Web of Science, and Cochrane Library, were searched on May 10, 2023, and no time limitation was applied. Analyses were performed using STATA17.0. We assessed the methodological quality of each randomized controlled trial using the Newcastle-Ottawa scale. After exhaustive database search and rigorous screening, 10 studies were included in the meta-analysis. Our findings indicate that high TMB significantly improves progression-free survival but reduces overall response rate. The overall survival was not significantly different between the high and low TMB groups. No significant publication bias was observed. High TMB serves as a potential predictive biomarker for improved progression-free survival and reduced overall response rate in patients with non-small cell lung cancer treated with programmed death 1/programmed death ligand 1 inhibitors. However, its predictive value in overall survival requires further investigation.

Safety and efficacy comparisons of intravenous trastuzumab biosimilars to the reference product medicine in treatment‐naïve and switch‐over patients with breast cancer: a systematic and meta‐analysis

AbstractAimTo compare the efficacy and safety of trastuzumab biosimilars to reference trastuzumab in patients with breast cancer. Trastuzumab, a biologic pharmaceutical product, has improved survival in hormone‐oestrogen receptor 2 positive breast cancer. However, due to its high economic burden, ‘highly similar’ products known as biosimilars have been developed. Yet, concerns remain around the equivalency of efficacy and safety between biosimilars and their reference biologic.Data SourcesA systematic review with meta‐analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines. MEDLINE, EMBASE, and Cochrane Central databases were searched from inception to 26 April 2021 to obtain all randomised control trial data reporting on safety and efficacy outcomes of patients with breast cancer treated with trastuzumab biosimilars.Study SelectionStudies were required to investigate and report on the safety and/or efficacy of trastuzumab. No restrictions were placed on study setting or intervention type and any study which reported at least one efficacy or safety outcome was included. A head‐to‐head comparison between the biosimilar and its reference biologic was not required for inclusion in the results. Only studies using randomised control trials were included. There was no restriction on the language the study was published in, and all abstracts, raw clinical trial data, and full‐text studies were eligible.ResultsForty‐one studies were identified to report on patients treated with trastuzumab. The odds of achieving an overall response rate in patients treated with a trastuzumab biosimilar compared to the reference over at least 24 weeks of treatment was 1.10 (95% confidence interval [CI] 0.94–1.29). The proportion of patients experiencing any treatment emergent adverse events were comparable between the two study arms, 1.07 (95% CI 0.87–1.32). The switching group contained one study with 342 patients in the meta‐analysis.ConclusionTrastuzumab biosimilars have comparable efficacy and safety to reference trastuzumab in treatment‐naïve patients. However, evidence is lacking for switching patients from reference trastuzumab to biosimilars, so further work is required in the switch‐over population.

Anti-GPIb/IX autoantibodies are associated with poor response to dexamethasone combined with rituximab therapy in primary immune thrombocytopenia patients

This retrospective study aimed to evaluate whether anti-glycoproteins (GPs) autoantibodies can be used as predictors of response to high-dose dexamethasone combined with rituximab (DXM-RTX) in the treatment of primary immune thrombocytopenia (ITP) patients. One-hundred twenty-six ITP patients were included and retrospectively analyzed, 66.7% of anti-GPIb/IX and 65.9% of anti-GPIIb/IIIa autoantibodies. Results showed that overall response (OR) and complete response (CR) rates of patients without anti-GPIb/IX autoantibodies to DXM-RTX were significantly higher than those with anti-GPIb/IX autoantibodies at 4 weeks (OR: 73.8% vs. 47.6%, CR: 50.0% vs. 26.2%; P < 0.05) and 6 months (OR: 71.4% vs. 45.2%, CR: 42.9% vs. 25.0%; P < .05). Furthermore, patients with anti-GPIb/IX single-positivity exhibited higher resistance to DXM-RTX than patients with anti-GPIIb/IIIa single-positivity at 4 weeks (OR: 37.5% vs. 78.3%; P < .05) and 6 months (OR: 29.2% vs. 78.3%; P < .05). Multivariable logistic regression analysis revealed that anti-GPIb/IX autoantibodies and megakaryocytes were associated with the OR rate of patients at both 4 weeks and 6 months, and anti-GPIb/IX autoantibodies at 4 weeks represented the only significant factor affecting OR rate with DXM-RTX (F = 9.128, P = .003). Therefore, platelet anti-GPIb/IX autoantibodies might predict poor response to DXM-RTX in ITP patients.

Characteristics and clinical outcomes of patients with myeloid malignancies and DDX41 variants.

DDX41 is the most frequently mutated gene in myeloid neoplasms associated with germline predisposition including myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). We analyzed 3795 patients with myeloid neoplasms and identified 151 (4%) with DDX41 variants and a diagnosis of AML (n = 96), MDS (n = 52), and chronic myelomonocytic leukemia (n = 3). The most frequent DDX41 variants were the somatic variant p.R525H, followed by the germline variants p.M1I and p.D140fs. Most neoplasms had a normal karyotype (59%) and the most frequent co-mutations were TP53 (16%) and ASXL1 (15%). 30% of patients had no concomitant mutations besides DDX41 mutation. Patients with myeloid malignancies and DDX41 variants responded well to therapy, with an overall response rate for patients with treatment naïve AML and MDS of 87% and 84%, respectively. The median overall survival (mOS) of patients with treatment-naïve AML or MDS was 49 and 71 months, respectively. Patients with AML treated with low-intensity regimens including venetoclax had an improved survival (2-year OS 91% vs. 60%, p = .02) and lower cumulative incidence of relapse compared to those treated without venetoclax (10% vs. 56%, p = .03). In the 33% of patients receiving hematopoietic stem cell transplantation, the 2-year OS was 80% and 85% for AML and MDS, respectively.

Predictive and Prognostic Value of TUBB3, RRM1, APE1, and Survivin Expression in Chemotherapy-Receiving Patients with Advanced Non‑Small Cell Lung Cancer.

This study aimed to evaluate the expression of class III β-tubulin (TUBB3), ribonucleoside-diphosphate reductase 1 (RRM1), apurinic/apyrimidinic endonuclease 1 (APE1), and survivin in patients with advanced non-small cell lung cancer (NSCLC) to predict response to chemotherapy. TUBB3, RRM1, APE1, and survivin expression levels were determined using immunohistochemistry. Protein expression was validated in Car/Pac-resistant human H1792 and A549 cells. This study included 86 patients, among whom 34 received cisplatin (Cis)/gemcitabine (Gem) and 52 received carboplatin (Car)/paclitaxel (Pac). Patients with low TUBB3 expression and high RRM1 and survivin expression had higher response rates than those with low RRM1 and survivin expression and high TUBB3 expression in the Car/Pac regimen. The multivariate analysis indicated that TUBB3 and RRM1 were significant independent predictive biomarkers for the Car/Pac regimen; however, there was no association between any protein and overall response in patients treated with this regimen. In the Cis/Gem regimen, only high TUBB3 expression was associated with poor overall survival; however, it did not exhibit a prognostic ability. The expression levels of TUBB3 and RRM1 in NSCLC cells are potential predictive biomarkers, but not prognostic factors, of response to chemotherapy in patients with NSCLC receiving the Car/Pac regimen.

Switching to Dupilumab from Other Biologics without a Treatment Interval in Patients with Severe Asthma: A Multi-Center Retrospective Study.

Dupilumab is a fully humanized monoclonal antibody that blocks interleukin-4 and interleukin-13 signals. Several large clinical trials have demonstrated the efficacy of dupilumab in patients with severe asthma. However, few studies have examined a switch to dupilumab from other biologics. This retrospective, multi-center observational study was conducted by the Okayama Respiratory Disease Study Group. Consecutive patients with severe asthma who were switched to dupilumab from other biologics without a treatment interval between May 2019 and September 2021 were enrolled. Patients with a treatment interval of more than twice the standard dosing interval for the previous biologic prior to dupilumab administration were excluded. The median patient age of the 27 patients enrolled in this study was 57 years (IQR, 45-68 years). Eosinophilic chronic rhinosinusitis (ECRS)/chronic rhinosinusitis with nasal polyp (CRSwNP) was confirmed in 23 patients. Previous biologics consisted of omalizumab (n = 3), mepolizumab (n = 3), and benralizumab (n = 21). Dupilumab significantly improved FEV1 (median improvement: +145 mL) and the asthma control test score (median improvement: +2). The overall response rate in patients receiving dupilumab for asthma as determined using the Global Evaluations of Treatment Effectiveness (GETE) was 77.8%. There were no significant differences in the baseline characteristics of the GETE-improved group vs. the non-GETE-improved group. ECRS/CRSwNP improved in 20 of the 23 patients (87.0%). Overall, 8 of the 27 patients (29.6%) developed transient hypereosinophilia (>1500/μL), but all were asymptomatic and able to continue dupilumab therapy. Dupilumab was highly effective for the treatment of severe asthma and ECRS/CRSwNP, even in patients switched from other biologics without a treatment interval.

Meta-Analysis of Capecitabine versus 5-Fluorouracil in Advanced Gastric Cancer.

To investigate the effect of capecitabine versus 5-fluorouracil in advanced gastric cancer patients. We searched PubMed, Cochrane Library, Embase, and other databases from database establishment to June 2022, containing randomized controlled trials (RCT) on capecitabine and 5-fluorouracil in advanced gastric cancer patients. A meta-analysis was conducted to evaluate the effect of capecitabine versus 5-fluorouracil on overall response rate, neutropenia, thrombocytopenia, stomatitis, hand-foot syndrome, nausea and vomiting, alopecia, and diarrhea. Eight RCTs with a total of 1998 patients with advanced gastric cancer were finally included, including 982 with capecitabine and 1016 with 5-fluorouracil. Compared with 5-fluorouracil, capecitabine use was significantly associated with an improved overall response rate in patients (RR 1.13, 95% CI 1.02-1.25, P=0.02). Compared with 5-fluorouracil, treatment with capecitabine was significantly associated with decreased neutropenia events (RR 0.78, 95% CI 0.62-0.99, I2 = 86%, P=0.04), and a decreased risk of stomatitis (RR 0.73, 95% CI 0.64-0.84, I2 = 40%, P < 0.0001) in patients with advanced gastric cancer. In terms of hand-foot syndrome, capecitabine was associated with increased hand-foot syndrome events than 5-fluorouracil (RR 2.00, 95% CI 1.21-3.31, P=0.007). In terms of thrombocytopenia, nausea and vomiting, alopecia, and diarrhea, the effect of capecitabine and 5-fluorouracil were similar (P > 0.05). Compared with 5-fluorouracil, capecitabine treatment improves the overall response rate and reduces the risk of neutropenia and stomatitis in advanced gastric cancer patients. It should be noted that capecitabine treatment may also increase the occurrence of hand-foot syndrome. Capecitabine is similar to 5-fluorouracil in causing thrombocytopenia, nausea and vomiting, alopecia, and diarrhea.

A Metabolically Optimized, Noncytotoxic Low-Dose Weekly Decitabine/Venetoclax in MDS and AML

Abstract Purpose: Venetoclax (VEN) added to the hypomethylating agents (HMA) decitabine or azacitidine is the new standard of care for elderly patients with acute myeloid leukemia (AML) and is being evaluated in myelodysplastic syndrome (MDS). Current dosing of HMA/VEN relies on leukemia suppression through cytotoxicity which also impacts normal hematopoiesis. A regimen using once-weekly low-dose decitabine (LDDec) has demonstrated activity in myeloid malignancies. To overcome the severe myelosuppression often seen with HMA/VEN, we evaluated a once-weekly dosing regimen of VEN and LDDec in elderly and/or frail patients who were felt less likely to tolerate severe myelosuppression. Patients and Methods: This is a retrospective, single-center analysis of patients with AML, MDS, or chronic myelomonocytic leukemia treated with a once-weekly LDDec/VEN regimen. We also compare this regimen with a cohort treated with standard dosing HMA/VEN. Results: In a retrospective cohort of 39 patients, the overall response rate for patients receiving LDDec/VEN for first-line AML and MDS was 88% and 64%, respectively. In patients with TP53 mutations, the composite complete response rate was 71% and the median overall survival was 10.7 months. When compared with 36 patients receiving standard dose HMA/VEN, the LDDec/VEN patients had a longer time on therapy (175 vs. 78 days; P = 0.014) and a trend toward a higher rate of transfusion independence (47% vs. 26%; P = 0.33). Neutropenic fever occurred in 31% of patients, with a median of one hospitalization at any point during treatment. Conclusions: This preliminary clinical experience, although retrospective, provides proof-of-activity of noncytotoxic DNA methyltransferase 1–targeting by allowing frequent, sustained drug exposure often not possible with standard HMA/VEN regimens.

Personalized [177Lu]Lutetium-PSMA Therapy for Patients with Pre-Treated Castration-Resistant Prostate Cancer: A Single Institution Experience from a Comprehensive Cancer Centre.

Castration resistant prostate cancer (CRPC) is characterized by an aggressive biological behavior with a relatively short survival time, especially in progressive tumors pretreated with new hormonal agents and taxane chemotherapy. [177Lu]-Lutetium-PSMA (Lu-PSMA) treatment has proven efficacy in these patients. However, around 30% of the CRPC patients do not benefit from Lu-PSMA treatment, and little is known about predictive factors for treatment success if Lu-PSMA is offered in an individualized approach based on clinical and laboratory features. In this monocentric retrospective study, 86 CRPC patients receiving Lu-PSMA treatment were evaluated. The focus of the study was to describe clinical factors at baseline and during early treatment that are related to overall survival (OS). In addition, PSMA PET/CT-, PSA-response, and safety and tolerability (CTCAE adverse event reporting) were assessed. Efficacy endpoints were calculated using stratified Kaplan-Meier methods and Cox regression models. Mean applied dose was 17.7 GBq (mean 5.3 ± 1.1 GBq per cycle) with an average of 3.6 (range 1-8) therapy cycles. Patients were followed up for a mean of 12.4 months (range 1-39). The median OS was 15 months (95% CI 12.8-17.2). The best overall response rate in patients assessed with PSMA PET/CT and PSA response was 27.9%, and 50.0% had at least stable disease. Nine patients had a ≥grade 3 adverse event with anemia being the most frequent adverse event. Positive predictors for prolonged OS from baseline parameters were pre-treatment hemoglobin level of ≥10 g/dL and a lower PSA values at treatment start, while the presence of visceral or liver metastases were not significantly associated with worse prognoses in this cohort. With careful patient selection, an individualized Lu-PSMA treatment approach is feasible and patients with dose-limiting factors or visceral metastases should be included in prospective trials.

Glofitamab plus R‐CHOP or polatuzumab vedotin‐R‐CHP is deliverable with high overall response in patients ≤65 years of age with high‐risk DLBCL: Interim analysis of COALITION

Glofitamab plus R‐CHOP or polatuzumab vedotin‐R‐CHP is deliverable with high overall response in patients ≤65 years of age with high‐risk DLBCL: Interim analysis of COALITION

Automating Patient-Reported Outcome Measures Following Hand Surgery

The purpose of this study was to assess the overall response rate of patients receiving electronic patient-reported outcome measures (ePROMs) following hand surgery and to determine the patient characteristics associated with responding. A Health Insurance Portability and Accountability Act-compliant, web-based system was developed to automatically distribute ePROMs to patients undergoing hand surgery at five institutions with 22 surgeons. Patients who were at least 18 years old were eligible. The PROMs used were the visual analog scale (VAS) for pain and the Quick Disabilities of the Arm, Shoulder, and Hand (QuickDASH). After surgery, ePROMs along with a satisfaction questionnaire were electronically sent three, six, 12, 24, and 52 weeks after surgery. A total of 6458 patients were eligible. Of these, 80% were enrolled voluntarily. Among these, 70% completed ePROMs for at least one postoperative time point, whereas 30% did not complete any. Among responders, 28% completed all five time points, whereas 72% completed four or fewer time points. Incomplete responders were more likely to be insured by workers' compensation when compared to complete responders. Incomplete responders exhibited higher baseline QuickDASH scores and similar baseline VAS compared to complete responders. During the follow-up, incomplete responders demonstrated worse VAS and QuickDASH scores at all time points. Finally, in comparison with complete responders, incomplete responders were less likely to be satisfied with their surgery at all time points. This study demonstrates that automated email-based ePROM systems may be an effective method for survey distribution. Particularly for simple, outpatient surgeries, this study illustrates the potential for clinical use of the data obtained from these systems. Patient-reported outcome measures continue to have an expanding role in health care with the rise of valued-based systems. Electronic PROMs are a relatively unexplored medium that may offer a viable alternative to more effectively collecting these valuable patient metrics.