Real-world Data Analysis of Immunotherapy in Advanced Lung Cancer

BackgroundThis study was designed to investigate the clinical application, efficacy, and safety of immune checkpoint inhibitors (ICIs) in the treatment of lung cancer in the real world. MethodsA retrospective, observational analysis was conducted on patients treated with ICIs in four tertiary hospitals in the region from January 2015 to March 2021, to evaluate the clinical efficacy of ICI single-agent or combined chemotherapy and anti-vascular drugs in the first-line or second-line treatment of patients with advanced lung cancer. ResultsThree hundred and fifteen patients were enrolled in this study. The objective response rate (ORR) and disease control rate (DCR) were 36.5% (115/315) and 94.0% (296/315), respectively, the median progression-free survival (PFS) was 10.8 months, and the median overall survival (OS) was not reached. A total of 165 patients received ICI as the first-line treatment, the median treatment cycle was 8 cycles (2-20 cycles), the short-term efficacy ORR was 41.2%, DCR was 94.5%, and the median PFS was 12.0 months. 150 patients received ICI treatment as second-line treatment, the median treatment cycle was five cycles (2-10 cycles), the short-term efficacy ORR was 31.3%, DCR was 93.3%, and the median PFS was 10.0 months. There were no statistically significant differences in ORR, DCR, or median PFS with ICI as the first-line treatment compared with the second-line treatment(P>0.05). The results of subgroup analysis showed that Karnofsky performance status (KPS) score, EGFR mutation status, and number of treatment lines were not correlated with median PFS((P>0.05). However, there were statistically significant differences in programmed death-ligand 1(PD-L1) expression, pathological types, hormone interference, and antibiotic (Abx) treatment among all groups (P< 0.05). In terms of safety, the overall incidence of adverse reactions in 315 patients was 62.5%, and the incidence of immune-related adverse events(irAEs) was 13.7%. Grade 1-2 and 3-4 incidence of adverse events were 34.9% and 27.65%, respectively. There were four patients who experienced fatal irAEs, two cases were liver damage leading to liver failure, one case was immune related pneumonia, and one case was immune related myocarditis. ConclusionIn the real world, immunotherapy has a good effect on patients with advanced lung cancer and significantly improves ORR and PFS.

Oral hypomethylating agents: beyond convenience in MDS

Oral hypomethylating agents (HMAs) represent a substantial potential boon for patients with myelodysplastic syndrome (MDS) who have previously required between 5 and 7 visits per month to an infusion clinic to receive therapy. For patients who respond to treatment, ongoing monthly maintenance visits represent a considerable burden to quality of life, and for those who are early in therapy, these sequential visits may tax transportation and financial resources that would be optimally distributed over the treatment cycle to facilitate transfusion support. The availability of oral HMAs may support the optimal application of these agents by contributing to adherence and lessening the burden of therapy, potentially encouraging patients to stay on longer-term treatment. Distinct pharmacokinetic profiles for the recently approved oral HMAs (oral azacitidine and decitabine-cedazuridine) result in differential toxicity profiles and have prompted their clinical trial development in lower- and higher-risk MDS, respectively.

Using artificial intelligence to predict the intrauterine insemination success rate among infertile couples

Background To evaluate the use of artificial intelligence (AI) in predicting the success rate of intrauterine insemination (IUI) treatment among infertile couples and also to determine the importance of each of the parameters affecting IUI success. This study was a retrospective cohort study in which information from 380 infertile couples undergoing IUI treatment (190 cases resulting in positive pregnancy test and 190 cases of failed IUI) including underlying factors, female factors, sperm parameters at the beginning of the treatment cycle, and fertility results were collected from 2013 to 2019 and evaluated to determine the effectiveness of AI in predicting IUI success. Results We used the most important factors influencing the success of IUI as a neural network input. With the help of a three-layer neural network, the accuracy of the AI to predict the success rate of IUI was 71.92% and the sensitivity and specificity were 76.19% and 66.67%, respectively. The effect of each of the predictive factors was obtained by calculating the ROC curve and determining the cut-off point. Conclusions The morphology, total motility, and progressive motility of the sperm were found to be the most important predictive factors for IUI success. In this study, we concluded that by predicting IUI success rate, artificial intelligence can help clinicians choose individualized treatment for infertile couples and to shorten the time to pregnancy.

Effect of Bevacizumab Combined with Neoadjuvant Chemotherapy in Advanced Ovarian Cancer and the Occurrence of Adverse Reactions

Objective: To explore the effect of bevacizumab combined with neoadjuvant chemotherapy in advanced ovarian cancer and the occurrence of adverse reactions. Methods: A total of 80 patients with advanced ovarian cancer, treated in Affiliated People’s Hospital of Inner Mongolia Medical University from June 2019 to December 2020, were randomly divided into two groups. In the chemotherapy group, 40 patients were treated with neoadjuvant chemotherapy, while in the combined group, another 40 patients were treated with bevacizumab combined with neoadjuvant chemotherapy. The therapeutic effects were compared at the end of the treatment cycle. Results: There was no significant difference in the levels of CA125, CEA, and VEGF between the two groups before treatment. However, after the treatment cycle, the levels of CA125, CEA, and VEGF in the combined group were significantly better than those in the chemotherapy group (P < 0.05). At the same time, the incidence of adverse reactions of the chemotherapy group was 67.50%, which was significantly higher than that of the combined group (35.00%; P < 0.05). Conclusion: Bevacizumab combined with neoadjuvant chemotherapy for patients with advanced ovarian cancer has significant curative effect. The combined therapy reduces the levels of tumor markers and inflammatory factors, improves patients’ quality of life, as well as reduces adverse reactions. It has high clinical promotion value.

Analysis of IVF live birth outcomes with and without preimplantation genetic testing for aneuploidy (PGT-A): UK Human Fertilisation and Embryology Authority data collection 2016–2018

Purpose To examine the live birth and other outcomes reported with and without preimplantation genetic testing for aneuploidy (PGT-A) in the United Kingdom (UK) Human Embryology and Fertilization Authority (HFEA) data collection. Methods A retrospective cohort analysis was conducted following freedom of information (FoI) requests to the HFEA for the PGT-A and non-PGT-A cycle outcomes for 2016–2018. Statistical analysis of differences between PGT-A and non-PGT-A cycles was performed. Other than grouping by maternal age, no further confounders were controlled for; fresh and frozen transfers were included. Results Outcomes collected between 2016 and 2018 included total number of cycles, cycles with no embryo transfer, total number of embryos transferred, live birth rate (LBR) per embryo transferred and live birth rate per treatment cycle. Data was available for 2464 PGT-A out of a total 190,010 cycles. LBR per embryo transferred and LBR per treatment cycle (including cycles with no transfer) were significantly higher for all PGT-A vs non-PGT-A age groups (including under 35), with nearly all single embryo transfers (SET) after PGT-A (significantly more in non-PGT-A) and a reduced number of transfers per live birth particularly for cycles with maternal age over 40 years. Conclusion The retrospective study provides strong evidence for the benefits of PGT-A in terms of live births per embryo transferred and per cycle started but is limited in terms of matching PGT-A and non-PGT-A cohorts (e.g. in future studies, other confounders could be controlled for). This data challenges the HFEA “red traffic light” guidance that states there is “no evidence that PGT-A is effective or safe” and hence suggests the statement be revisited in the light of this and other new data.

Combination Treatment of Venetoclax and Hypomethylating Agents (HMA) or Low-Dose Cytarabine (LDAC) for Patients with Acute Myeloid Leukemia (AML) - Real-World Data from Two German Academic Centers

Introduction Treatment with the BCL-2 inhibitor Venetoclax (VEN) in combination with hypomethylating agents (HMA) or low-dose cytarabine (LDAC) has shown encouraging results in patients with acute myeloid leukemia (AML). In contrast to the FDA, EMA approval for unfit AML patients was given only recently, and VEN combinations have therefore often been used as off-label treatment for relapsed/refractory (r/r) AML patients. We conducted a retrospective study of 73 unfit or r/r AML patients treated with a VEN combination between 2017 and 2021 at two German university hospitals. Methods Data was collected by medical chart review and included genetics, ELN2017 risk classification, previous treatment lines, courses of VEN treatment as well as outcome. All statistical tests were performed with GraphPad Prism. The median time of follow-up was 8.3 months. Results At beginning of VEN treatment, the median age was 73 (20-85) years (Table 1). The majority of patients had a secondary (s) AML [n=34 (47%)] and was assigned to the adverse ELN2017 risk group [n=32 (44%)]. Mutations in isocitrate-dehydrogenase 1/2 genes (IDH1/2) were the most frequent alteration [n=19 (26%)]. Before VEN treatment, a total of n=58 (79%) patients had received prior treatment including intensive chemotherapy [n=36 (49%)] and allogeneic stem cell transplantation (allo-HSCT) [n=26 (36%)]. Twenty-five (34%) patients were treated with &gt;4 cycles HMA or LDAC before VEN initiation. VEN was given as first-line treatment in n=15 (21%) patients and started during the first or second treatment cycle of HMA/LDAC. The initial VEN dosage after ramp-up during cycle 1 was in median 400mg (50-800mg). Patients received VEN in combination with azacytidine [n=34 (47%)], decitabine [n=18 (25%)] or LDAC [n=20 (28%)]. In median, patients had received 3 (1-17) VEN cycles at data cut-off. VEN was initiated after progression on HMA/LDAC treatment (&gt;2 cycles) in n=35 (48%) patients. In most patients VEN was discontinued or dose-adjusted during treatment [cycle 1 n=37 (51%), after cycle 1 n=43 (59%)]. Response assessment was available for n=58 (79%) patients, of which n=18 (25%) achieved complete remission (CR) or CR with incomplete hematologic recovery (CRi), n=24 (33%) a partial remission (PR) or stable disease (SD), and n=16 (22%) were refractory to VEN combination treatment. The overall response rate (ORR) including CR/CRi/PR patients was 47% and not influenced by age or previous treatments including allo-HSCT and HMA pretreatment. Achievement of CR/CRi was significantly better in patients with IDH1/2 and/or NPM1 mutations (Figure 1). The median overall survival (OS) of the entire cohort was 6.5 months. OS was significantly better in patients achieving a CR/CRi (20.3 months) as compared to patients with PR/SD/RD. (p&lt;0.0001; Figure 2 A). OS was shorter in patients with more than two prior treatment lines (p=0.01, Figure 2 B) and in patients who had received allo-HSCT (p=0.05, Figure 2 C). There was no significant impact on OS with respect to age (&gt;=65 years), ELN2017 risk group or previous HMA treatment. OS was however significantly longer in patients harboring NPM1 and/or IDH1/2 mutations (p=0.016; Figure 2 D). Conclusions Our real-world analysis demonstrates that VEN combination treatment is feasible and effective also in r/r AML patients. Response rates and survival were lower than in patients treated with VEN combinations in first line (DiNardo, NEJM 2020) and in our cohort highly influenced by the number of previous treatment lines. As in patients treated with VEN combinations at fist line, the NPM1 and IDH1/2 genotype was associated with better response and survival. Further studies with larger cohorts are needed to investigate the role of VEN combinations in r/r AML. Figure 1 Figure 1. Disclosures Westermann: Abbvie: Consultancy, Honoraria; Astellas: Honoraria; Novartis: Consultancy, Honoraria; BMS: Honoraria; Amgen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Stem Cell Line: Consultancy, Honoraria. Bullinger: Seattle Genetics: Honoraria; Bayer: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Astellas: Honoraria; Amgen: Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Gilead: Consultancy; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Menarini: Consultancy; Sanofi: Honoraria; Celgene: Consultancy, Honoraria; Hexal: Consultancy. Keller: Abbvie: Other: Advisory Role. Krönke: BMS/Celgene: Other: Advisory board; Abbvie: Other: Advisory board. Goetze: Abbvie: Other: Advisory Board; BMS/Celgene: Other: Advisory Board, Research Funding. OffLabel Disclosure: Venetoclax was used "off-lable" in unfit and relapsed/refractory AML patients in combination with HMA/LDAC.

Disease Kinetics Measured By Circulating Tumor DNA Correlates with Treatment Response after Tafasitamab in Combination with R-CHOP with or without Lenalidomide in First Line Treatment of DLBCL

Background Currently available clinical and biological prognostic factors do not adequately identify first-line DLBCL patients at risk for treatment failure. In DLBCL, circulating tumor DNA (ctDNA) can be utilized as a for molecular disease classification, detect minimal residual disease (MRD) or predict disease progression. We hypothesized that ctDNA detected by the EuroClonality immunoglobulin-based next generation sequencing (IG-NGS) assay correlates with treatment response and outcome. Patients and methods Overall, 451 samples (41 diagnostic fresh frozen paraffin embedded (FFPE) biopsies, 64 peripheral blood mononuclear cells (PBMC) and 346 plasma samples) from patients from a Phase Ib study in de novo DLBCL treated with tafasitamab and R-CHOP or tafasitamab and R-CHOP in combination with Lenalidomide (First-MIND; MOR208C107) were analyzed. DNA from FFPE or diagnostic PBMC was sequenced by using a 2-step PCR approach with the Euroclonality NGS IGH-VJ, IGH-DJ and IGK primer sets (euroclonality.org) (Brüggemann, Leukemia, 2019) with a number of primers adapted for usage in short fragment cfDNA. IG markers were identified at abundance level ≥5% of annotated IG reads and a &gt;1 log higher abundance to the next most frequent clonotype. Disease related clonotypes were traced in plasma during (C2D1 and C4D1 n=34) and at end of treatment (EOT n=32) by a 1-step PCR approach and sequencing of at least 5000 human genome equivalents (hGE) of cell free (cf)DNA. ctDNA levels were determined as the number of specific clonotype molecules per input genome equivalents normalized by a reference standard DNA spiked into each sample as cIT-QC (Knecht, Leukemia, 2019) and reported per plasma volume. Data were analysed by ARResT/Interrogate (Bystry, Bioinformatics, 2017). Patients were reported MRD positive if ≥1 clonal IG rearrangement was detected. Results From 41 patients with available diagnostic FFPE and sufficient DNA quality for marker screening, 34 (89%) had at least 1 detectable clonal marker (IGH-VJ, IGH-DJ or IGK). One clonal IG marker was identified in 20/34 (59%) patients, whereas two or three markers were identified in 9 (27%) and 5 (14%) patients, respectively. Disease specific clonotypes identified in FFPE were recovered in 11/34 PBMC samples (32%) with a median abundance of 0,29% (range 0.006-21.9%) demonstrating a peripheral blood involvement. In 32/33 (97%) pretreatment plasma samples, ctDNA was detected with a median copy number of 172.5/ml plasma. cfDNA and ctDNA levels prior to treatment correlated with IPI and LDH (Fig1). ctDNA dynamics during treatment demonstrated rapid treatment response at C2D1. 23/34 samples were either MRD neg (n=19) or showed a ctDNA reduction ≥ 2 log levels (Fig2). At C4D1 7/34 (20%) samples had low-level detectable MRD and at EOT 29/32 (91%) patients achieved MRD negativity after treatment with tafasitamab and R-CHOP +/- lenalidomide (LOD 2 x 10 -4 for follow-up samples). Early ctDNA dynamics predicted metabolic response when applying a threshold of ctDNA reduction to &lt;1% after the first treatment cycle. 25/28 (89%) patients completing treatment and achieving PET-response could be identified early during treatment by ctDNA assessment. Conclusion Baseline ctDNA levels determined by the EuroClonality IG-NGS assay and absolute cfDNA amounts correlated with pre-treatment risk factors. ctDNA dynamics after the 1 st treatment cycle demonstrated rapid treatment response to tafasitamab + RCHOP +/- lenalidomide and correlated with metabolic response. Assessment of ctDNA dynamics allows early response assessment and might be useful for risk stratification in patients with DLBCL. Figure 1 Figure 1. Disclosures Kuffer: Morphosys AG: Current Employment. Blair: Morphosys AG: Current Employment.

Optimizing Adaptive Therapy Based on the Reachability to Tumor Resistant Subpopulation

Adaptive therapy exploits the self-organization of tumor cells to delay the outgrowth of resistant subpopulations successfully. When the tumor has aggressive resistant subpopulations, the outcome of adaptive therapy was not superior to maximum tolerated dose therapy (MTD). To explore methods to improve the adaptive therapy's performance of this case, the tumor system was constructed by osimertinib-sensitive and resistant cell lines and illustrated by the Lotka-Volterra model in this study. Restore index proposed to assess the system reachability can predict the duration of each treatment cycle. Then the threshold of the restore index was estimated to evaluate the timing of interrupting the treatment cycle and switching to high-frequency administration. The introduced reachability-based adaptive therapy and classic adaptive therapy were compared through simulation and animal experiments. The results suggested that reachability-based adaptive therapy showed advantages when the tumor has an aggressive resistant subpopulation. This study provides a feasible method for evaluating whether to continue the adaptive therapy treatment cycle or switch to high-frequency administration. This method improves the gain of adaptive therapy by taking into account the benefits of tumor intra-competition and the tumor control of killing sensitive subpopulation.

The Soluble Urokinase-Type Plasminogen Activator Receptor as a Biomarker for Survival and Early Treatment Effect in Metastatic Colorectal Cancer

The soluble urokinase-type plasminogen activator receptor (suPAR) is prognostic for overall survival (OS) in colorectal cancer (CRC). Our study explored the association between baseline suPAR and OS and progression-free survival (PFS) in metastatic CRC (mCRC). It is also the first study to explore the association between the initial change in suPAR level and OS, PFS and the first CT response evaluation. The study included 132 patients with mCRC treated with chemotherapy (FOLFIRI) with or without an EGFR-inhibitor. Blood samples were drawn before the first treatment cycle and in between the first and second treatment cycle. suPAR levels were determined using an ELISA assay. Using the Kaplan-Meyer method, we demonstrated a significantly shorter OS for patients with suPAR levels above the median (HR = 1.79, 95%CI = 1.10–2.92, p = 0.01). We also showed association between plasma suPAR level, gender and performance status (PS). However, we could not show any association with PFS, and analysis on the change in suPAR level provided no significant results. The results showing association between baseline suPAR and OS are in line with previous findings.

Extended Injection Intervals of Gonadotropins by Intradermal Administration in IVF Treatment

Context Gonadotropins can be administered every five days under intradermal injection in in vitro fertilization (IVF) treatment. Objective To explore the effectiveness of intradermal injection of recombinant human FSH (rhFSH) for women undergoing IVF. Materials and Methods Women who received their first time IVF enrolled in this prospective intervention in 2018. All women received a bolus of 900 IU rhFSH intradermally at day 2 of the treatment cycle followed by additional dosage of rhFSH at day 7 and/or day 10. The main outcome measures included the total dose of rhFSH and number of injections required, sequential serum FSH level detected, and number of mature oocytes retrieved. Results Seventy women completed the study. On average, 2.31±0.73 injections and 1662±397 IU of rhFSH were administered. While the baseline FSH level was 5.6±2.2 IU/L, the serum concentrations of FSH after rhFSH administration were 35.3±7.0 on the first day (24 hours) and 10.7±3.7 IU/L on the fifth day (120 hours). A total of 10.5±6.6 mature oocytes were retrieved, resulting in 7.3±5.1 pronuclear embryos; and 1.8±0.6 embryos were transferred to the uterus. Our findings resulted in 72% fertilization, 91% cleavage, 31% implantation, and 36% live birth rates. Although less larger follicles were found, non-inferiority results were noted in the mature oocytes retrieved, good embryos available and clinical pregnancy rate compared to those received conventional daily subcutaneous rhFSH administration. Conclusion Intradermal administration of rhFSH, with less dose of rhFSH and numbers of injection, may achieve the goal of a cost-effective and more patient-friendly regimen.