Early Indicator Of Response Research Articles

Plasma ctDNA as a treatment response biomarker in metastatic cancers: evaluation by the RECIST working group.

Early indicators of metastatic cancer response to therapy are important for evaluating new drugs and stopping ineffective treatment. The Response Evaluation Criteria in Solid Tumors (RECIST) based on repeat cancer imaging are widely adopted in clinical trials, are used to identify active regimens that may change practice, and contribute to regulatory approvals. However, these criteria do not provide insight before 6 - 12 weeks of treatment and typically require that patients have measurable disease. Recent data suggests that measuring on-treatment changes in the amount or proportion of circulating tumor DNA (ctDNA) in peripheral blood plasma may accurately identify responding and non-responding cancers at earlier time points. Over the past year, the RECIST working group has evaluated current evidence for plasma ctDNA kinetics as a treatment response biomarker in metastatic cancers and early endpoint in clinical trials, to identify areas of focus for future research and validation. Here, we outline the requirement for large standardized trial datasets, greater scrutiny of optimal ctDNA collection time points and assay thresholds, and consideration of regulatory body guidelines and patient opinions. In particular, clinically-meaningful changes in plasma ctDNA abundance are likely to differ by cancer type and therapy class, and must be assessed before ctDNA can be considered as a potential pan-cancer response evaluation biomarker. Despite the need for additional data, minimally-invasive on-treatment ctDNA measurements hold promise to build upon existing response assessments such as RECIST, and offer opportunities for developing novel early endpoints for modern clinical trials.

Role of interleukin 6 polymorphism and inflammatory markers in outcome of pediatric Covid- 19 patients

BackgroundIL-6 polymorphisms were associated to viral infection outcomes through affection of IL-6 production and it is an early indicator of tissue injury and systemic inflammatory response. The study aimed to determine whether genetic IL-6 polymorphisms, serum interleukin-6 level and inflammatory markers (Presepsin, CXCL-10, C3, and C4) are associated with the prediction of disease severity in pediatric COVID-19 patients and its possible use as a prognostic tool in pediatric patients admitted to hospital.MethodsThis prospective cohort study was conducted on 150 children with COVID-19. Patients were divided according to the severity of infection into four groups: group I (mild) 67 cases; group II (moderate) 53 cases, group III (severe) 17 cases and group IV (critical) 14 cases. Serum Interleukin 6, CXCL-10, Presepsin, renal and liver functions, electrolytes, C3, C4, ferritin, and D dimer serum levels were assessed in all patients. The Kruskal Wallis test used to compare parametric quantitative data between studied groups and Mann Whitney test for each pair of groups. Non-parametric quantitative data was compared between studied groups using a one-way ANOVA test and post-hoc Bonferroni analysis for each pair of groups.ResultsGroup I: 35 males and 32 females with a median age of 16 months. Group II: 17 males and 35 females with a median age of 13 months. Group III: 6 males and 11 females with a median age of 12 months and group IV: 3 males and 11 females with a median age of 12 months. There was no statistical difference between the studied groups regarding gender and age. Serum levels of IL- 6, serum ferritin; D-dimer, Presepsin and CXCL 10 were significantly higher in both severe and critical groups than the other 2 groups (mild and moderate). ROC curve analysis showed that interleukin-6 and Presepsin were good markers for prediction of severity of COVID-19 among the diseased children. For severe cases, the sensitivity of interleukin-6 was 76.47% and specificity was 92.31%. For critical cases, the sensitivity of interleukin-6 was 71.43% and specificity was 82.35%. The sensitivity of Presepsin was 76.47% and specificity was 88.46% in severe cases. For critical cases, the sensitivity of Presepsin was 78.57% and specificity of 91.2%. There was significant difference in IL-6 572 allelic among moderate cases with the most frequent 42.3% for genotype (GC) and allelic among severe cases with the most frequent 47.1% for genotype (GC). Significant difference in IL-6 174 allelic among critical cases with the most frequent 78.6% for genotype (CC).ConclusionsChildren whom expressed GC genotypes of IL6 (-572G > C) polymorphism are at a considerably higher risk of developing a severe disease. This risk is significantly larger in the severe group of children than in children in critical condition who have GC genotypes of IL6 (-174 G > C) polymorphism. While IL6 (-597G > A) polymorphism has no role in COVID 19 severity in children.

A novel metric-based approach of scoring early host immune response from oro-nasopharyngeal swabs predicts COVID-19 outcome

Unpredictable fatal outcome of COVID-19 is attributed to dysregulated inflammation. Impaired early adaptive immune response leads to late-stage inflammatory outcome. The purpose of this study was to develop biomarkers for early detection of host immune impairment at first diagnosis from leftover RNA samples, which may in turn identify high risk patients. Leftover RNA samples of COVID-19 patients at first diagnosis were stored. Following prospective follow-up, the samples were shorted and categorized into outcome groups. Impaired adaptive T cell response (severity score) and Impaired IL-10 response (undetectable IL-10 in the presence of high expression of a representative interferon response gene) were determined by RT-PCR based assay. We demonstrate that a T cell response based ‘severity score’ comprising rational combination of Ct values of a target genes’ signature can predict high risk noncomorbid potentially critical COVID-19 patients with a sensitivity of 91% (95% CI 58.7–99.8) and specificity of 92.6% (95% CI 75.7–99) (AUC:0.88). Although inclusion of comorbid patients reduced sensitivity to 77% (95% CI 54.6–92.2), the specificity was still 94% (95% CI 79.8–99.3) (AUC:0.82). The same for ‘impaired IL-10 response’ were little lower to predict high risk noncomorbid patients 64.2% (95% CI 35.1–87.2) and 82% (95% CI 65.5–93.2) respectively. Inclusion of comorbid patients drastically reduce sensitivity and specificity51.6% (95% CI 33.1–69.8) and 80.5% (95% CI 64.0–91.8) respectively. As best of our knowledge this is the first demonstration of a metric-based approach showing the ‘severity score’ as an indicator of early adoptive immune response, could be used as predictor of severe COVID-19 outcome at the time of first diagnosis using the same leftover swab RNA. The work flow could reduce expenditure and reporting time of the prognostic test for an earliest clinical decision ensuring possibility of early rational management.

Fast itch relief during dupilumab predicts clinical efficacy in bullous pemphigoid, a retrospective cohort study.

Dupilumab has emerged as a promising treatment option for bullous pemphigoid (BP). Rapid identification of responders could avoid the need of additional immunosuppressive treatments that are associated with increased morbidity and mortality. To investigate the course of itch as an early indicator of treatment response, data of 12 BP patients treated with dupilumab at the University Hospital of Zurich were retrospectively evaluated. Disease severity was assessed by bullous pemphigoid disease area index (BPDAI) and pruritus by a numeric rating scale (NRS, 0-10) at baseline, day 1, 3, 14, month 1, 2 and last follow-up. 8/12 patients (67%) had complete, and 4/12 patients (33%) had partial response during dupilumab treatment. Notably, a highly significant reduction of pruritus (p < 0.0001) was observed already on day 1 with further improvement at later time points. Moreover, fast relief of itch could predict treatment response with a significant correlation to clinical response on day 14 (Spearman correlation R 0.70, p-value 0.025), with a positive but non-significant trend on day 3 (R 0.63, p-value 0.091). Additionally, 92% (11/12 patients) were on dupilumab monotherapy at last follow-up without any concomitant systemic or topical treatment for BP. The rapid and significant decline in BP-associated pruritus observed with dupilumab correlated significantly with disease remission. Early evaluation of pruritus response could change how bullous pemphigoid is treated in the future and avoid additional immunosuppressive treatment in BP.

Tumor biomechanics as a novel imaging biomarker to assess response to immunotherapy in a murine glioma model

Glioblastoma is the most common and aggressive primary malignant brain tumor with poor prognosis. Novel immunotherapeutic approaches are currently under investigation. Even though magnetic resonance imaging (MRI) is the most important imaging tool for treatment monitoring, response assessment is often hampered by therapy-related tissue changes. As tumor and therapy-associated tissue reactions differ structurally, we hypothesize that biomechanics could be a pertinent imaging proxy for differentiation. Longitudinal MRI and magnetic resonance elastography (MRE) were performed to monitor response to immunotherapy with a toll-like receptor 7/8 agonist in orthotopic syngeneic experimental glioma. Imaging results were correlated to histology and light sheet microscopy data. Here, we identify MRE as a promising non-invasive imaging method for immunotherapy-monitoring by quantifying changes in response-related tumor mechanics. Specifically, we show that a relative softening of treated compared to untreated tumors is linked to the inflammatory processes following therapy-induced re-education of tumor-associated myeloid cells. Mechanistically, combined effects of myeloid influx and inflammation including extracellular matrix degradation following immunotherapy form the basis of treated tumors being softer than untreated glioma. This is a very early indicator of therapy response outperforming established imaging metrics such as tumor volume. The overall anti-tumor inflammatory processes likely have similar effects on human brain tissue biomechanics, making MRE a promising tool for gauging response to immunotherapy in glioma patients early, thereby strongly impacting patient pathway.

A Pilot Study Investigating the Use of Serum Glial Fibrillary Acidic Protein to Monitor Changes in Brain White Matter Integrity After Repetitive Head Hits During a Single Collegiate Football Game.

Repetitive head hits (RHHs) in sports and military settings are increasingly recognized as a risk factor for adverse neurological outcomes, but they are not currently tracked. Blood-based biomarkers of concussion have recently been shown to increase after nonconcussive RHHs during a single sporting contest, raising the possibility that they could be used in real time to monitor the brain's early response to repeated asymptomatic head hits. To test this hypothesis, we measured GFAP in serum immediately before (T0), immediately after (T1) and 45 min (T2) after a single collegiate football game in 30 athletes. Glial fibrillary acidic protein (GFAP) changes were correlated with three measures of head impact exposure (number of hits, total linear acceleration, and total rotational acceleration captured by helmet impact sensors) and to changes in brain white matter (WM) integrity, estimated by regional changes in fractional anisotropy (FA) and mean diffusivity (MD) on diffusion tensor imaging from 24 h before (T1) to 48 h after (T3) the game. To account for the potentially confounding effects of physical exertion on GFAP, correlations were adjusted for kilocalories of energy expended during the game measured by wearable body sensors. All 30 participants were male with a mean age of 19.5 ± 1.2 years. No participant had a concussion during the index game. We observed a significant increase in GFAP from T0 to T1 (mean 79.69 vs. 91.95 pg/mL, p = 0.008) and from T0 to T2 (mean 79.69 vs. 99.21 pg/mL, p < 0.001). WM integrity decreased in multiple WM regions but was statistically significant in the right fornix (mean % FA change -1.43, 95% confidence interval [CI]: -2.20, -0.66). T0 to T2 increases in GFAP correlated with reduced FA in the left fornix, right fornix, and right medical meniscus and with increased MD in the right fornix (r-values ranged from 0.59 to 0.61). Adjustment for exertion had minimal effect on these correlations. GFAP changes did not correlate to head hit exposure, but after adjustment for exertion, T0 to T2 increases correlated with all three hit metrics (r-values ranged from 0.69 to 0.74). Thus, acute elevations in GFAP after a single collegiate football game of RHHs correlated with in-game head hit exposure and with reduced WM integrity 2 days later. These results suggest that GFAP may be a biologically relevant indicator of the brain's early response to RHHs during a single sporting event. Developing tools to measure the neurological response to RHHs on an individual level has the potential to provide insight into the heterogeneity in adverse outcomes after RHH exposure and for developing effective and personalized countermeasures. Owing to the small sample size, these findings should be considered preliminary; validation in a larger, independent cohort is necessary.

Predicting response to neoadjuvant therapy (NAT) in patients (pts) with early-stage breast cancer (BC) using circulating tumor DNA (ctDNA) testing.

569 Background: Recent studies have shown the utility of ctDNA testing for monitoring response and predicting long term outcomes in pts with BC receiving NAT. This pilot, single institution study (CIPHER, NCT05333874) evaluated whether trend of ctDNA during NAT can serve as an early indicator of treatment response and inform disease management in the adjuvant setting. Methods: This study included 35 pts with stage II-III triple negative (TN) and HER2+ BC and longitudinal ctDNA testing performed during standard of care NAT. A clinically validated, personalized, tumor-informed 16-plex PCR assay (Signatera) was used for the detection and quantification of ctDNA in blood samples collected at diagnosis (pre-treatment), every 3 weeks on NAT, and post-surgery. ctDNA status and dynamics were correlated with clinicopathological features and surgical outcomes. Results: At diagnosis (N=30), ctDNA was detected in 95% (18/19) of pts with TNBC [median 8.89 (0.09-180.01) mean tumor molecules (MTM)/mL] and 91% (10/11) of pts with HER2+ BC [median 1.55 (0.29-453.86) MTM/mL], including 73% (8/11) pts with HR+/HER2+ BC. ctDNA detection rate was higher in pts with clinical T3-4 disease compared to T1-2 (TNBC: 4/4, 100% vs 14/15, 93%; HER2+ BC: 4/4, 100% vs 6/7, 86%). Similarly, higher median pre-treatment ctDNA levels were observed in pts with clinical T3-4 compared to T1-2 (TNBC 61.49 vs 9.28 MTM/mL; HER2+ BC 14.94 vs 1.18 MTM/mL). Pts with early ctDNA clearance (&lt;6 weeks of NAT) had a higher proportion of favorable surgical outcomes (pCR or &lt;1 cm, node negative) compared to pts with late (&gt;6 weeks) or no clearance during NAT (17/20, 85% vs 4/6, 67%). Post-surgical ctDNA-positivity was observed in 5% (1/19) vs 67% (4/6) pts with early vs late/no clearance during NAT, respectively. Post-surgery ctDNA detection rate was higher in pts with stage III disease compared to stage II (4/12, 33% vs 1/13, 8%). Interestingly, 20% (2/10) pts with stage III disease vs 9% (1/11) with stage II disease had detectable ctDNA after surgery despite favorable surgical findings. Higher pre-treatment ctDNA levels were associated with higher likelihood of ctDNA positivity post-surgery: &lt;1 MTM/mL: 0/4, 0%; 1-10 MTM/mL: 1/9; 11%; &gt;10 MTM/mL: 3/11, 27% (p=0.0025 χ2). ctDNA positivity post-surgery led to change in disease management for two pts. The first pt (inflammatory HR-HER2+ BC), despite achieving pCR, remained ctDNA positive after NAT and surgery, which informed a change in adjuvant treatment. For the second pt (TNBC), ctDNA positivity post-surgery led to detection of radiographically confirmed asymptomatic metastatic relapse and treatment change. Conclusions: ctDNA dynamics during NAT can facilitate real-time assessment of treatment response and can serve as an early indicator of pathologic response, predict ctDNA status after surgery, and inform disease management for BC pts at high risk of recurrence. Clinical trial information: NCT05333874 .

Abstract PO4-15-12: Personalized circulating tumor DNA monitoring to predict response to neoadjuvant therapy in patients with early-stage breast cancer

Abstract Introduction Longitudinal ctDNA testing offers a minimally invasive approach for monitoring treatment response in patients with breast cancer (BC). In this study, we evaluated whether serial ctDNA testing during neoadjuvant therapy (NAT) can provide an early indication of treatment response or resistance and disease progression. Methods In this real world study, longitudinal blood samples collected from 159 patients with stage I-III BC were analyzed using a personalized, tumor-informed ctDNA assay (SignateraTM bespoke mPCR-NGS assay). Of the 159 patients, 157 received standard of care NAT; the remaining 2 patients were treated with endocrine therapy only in the neoadjuvant setting. Blood samples were collected at the time of diagnosis from 71 patients (baseline) and longitudinally during treatment from 159 patients (median time between time points: 1.5 months). ctDNA status and dynamics were correlated with clinicopathological features and surgical outcomes available at the time of data cut off. Results At baseline, ctDNA was detected in 72% (51/71) of patients. Baseline ctDNA detection rates varied based on histologic subtypes: 82% (28/34) in patients with triple negative breast cancer, 88% (15/17) in patients with HER2+ disease and 40% (8/20) in patients with ER+HER2- BC. ctDNA was detectable at baseline in 72% (26/36) of patients with clinical T1-2 disease and 92% (11/12) of patients with T3-4 disease. ctDNA was detected in 64% (16/25) of patients with clinical N0, whereas among patients with at least one positive lymph node, ctDNA was detected in 92% (22/24). At baseline, 65% (31/48) of patients with low/intermediate-grade disease were ctDNA-positive, while 81% (25/31) of patients with high-grade disease were ctDNA-positive. Similarly, 83% (24/29) of patients with high levels (&amp;gt;20%) of Ki67 expression had detectable ctDNA prior to treatment initiation, while only 22% (2/9) of those with low level (&amp;lt; 20%) of Ki67 expression had ctDNA detected. Surgical outcomes were available for 22 patients of whom 16 had achieved pathologic complete response (pCR). While 3/16 pts were ctDNA negative at baseline, all of the remaining cases except one patient with baseline ctDNA detection and serial measurements (11/12) became ctDNA negative by the end of two months of treatment. Despite achieving pCR, one patient with inflammatory ER+HER2+ BC remained ctDNA positive before and after the surgery, which informed a change in the adjuvant treatment strategy. Among those with residual disease (pT1c-T3), 28% (7/25) remained ctDNA positive after two months of NAT. Association between ctDNA dynamics and surgical outcomes of the remaining 137 patients will be presented at the time of the conference. Conclusions This real world study demonstrates the prevalence of ctDNA detection and dynamics in patients with eBC treated with NAT. ctDNA monitoring during NAT can facilitate real-time assessment of treatment response and serve as an early indicator of subsequent pCR to NAT. Citation Format: Mridula George, Trishala Meghal, Coral Omene, Ekaterina Kalashnikova, Janie Fielder, Nisha Ohri, Shicha Kumar, Valeria Burkovskaya, Preena Patel, Ashley Young, Melanie Racenstein, Tinamarie Bauman, Wassim Mchayleh, Deborah Toppmeyer, Shridar Ganesan, Barry Rosen, Angel Rodriguez, Minetta Liu. Personalized circulating tumor DNA monitoring to predict response to neoadjuvant therapy in patients with early-stage breast cancer [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 PO4-15-12.

Liquid biopsy for improving diagnosis and monitoring of CNS lymphomas: A RANO review.

The utility of liquid biopsies is well documented in several extracranial and intracranial (brain/leptomeningeal metastases, gliomas) tumors. The RANO (Response Assessment in Neuro-Oncology) group has set up a multidisciplinary Task Force to critically review the role of blood and cerebrospinal fluid (CSF)-liquid biopsy in CNS lymphomas, with a main focus on primary central nervous system lymphomas (PCNSL). Several clinical applications are suggested: diagnosis of PCNSL in critical settings (elderly or frail patients, deep locations, and steroid responsiveness), definition of minimal residual disease, early indication of tumor response or relapse following treatments, and prediction of outcome. Thus far, no clinically validated circulating biomarkers for managing both primary and secondary CNS lymphomas exist. There is need of standardization of biofluid collection, choice of analytes, and type of technique to perform the molecular analysis. The various assays should be evaluated through well-organized central testing within clinical trials.

The role of serum thymidine kinase 1 activity in neoadjuvant-treated HER2-positive breast cancer: biomarker analysis from the Swedish phase II randomized PREDIX HER2 trial

BackgroundThymidine kinase 1 (TK1) plays a pivotal role in DNA synthesis and cellular proliferation. TK1 has been studied as a prognostic marker and as an early indicator of treatment response in human epidermal growth factor 2 (HER2)-negative early and metastatic breast cancer (BC). However, the prognostic and predictive value of serial TK1 activity in HER2-positive BC remains unknown.MethodsIn the PREDIX HER2 trial, 197 HER2-positive BC patients were randomized to neoadjuvant trastuzumab, pertuzumab, and docetaxel (DPH) or trastuzumab emtansine (T-DM1), followed by surgery and adjuvant epirubicin and cyclophosphamide. Serum samples were prospectively collected from all participants at multiple timepoints: at baseline, after cycle 1, 2, 4, and 6, at end of adjuvant therapy, annually for a total period of 5 years and/or at the time of recurrence. The associations of sTK1 activity with baseline characteristics, pathologic complete response (pCR), event-free survival (EFS), and disease-free survival (DFS) were evaluated.ResultsNo association was detected between baseline sTK1 levels and all the baseline clinicopathologic characteristics. An increase of TK1 activity from baseline to cycle 2 was seen in all cases. sTK1 level at baseline, after 2 and 4 cycles was not associated with pCR status. After a median follow-up of 58 months, 23 patients had EFS events. There was no significant effect between baseline or cycle 2 sTK1 activity and time to event. A non-significant trend was noted among patents with residual disease (non-pCR) and high sTK1 activity at the end of treatment visit, indicating a potentially worse long-term prognosis.ConclusionsTK1 activity increased following neoadjuvant therapy for HER2-positive BC but was not associated with patient outcomes or treatment benefit. However, the post-surgery prognostic value in patients that have not attained pCR warrants further investigation.Trial registrationClinicalTrials.gov, NCT02568839. Registered on 6 October 2015.

Clarithromycin for early anti-inflammatory responses in community-acquired pneumonia in Greece (ACCESS): a randomised, double-blind, placebo-controlled trial

Addition of macrolide antibiotics to β-lactam antibiotics for the treatment of patients in hospital with community-acquired pneumonia is based on results from observational studies and meta-analyses rather than randomised clinical trials. We investigated if addition of the macrolide clarithromycin to treatment with a β-lactam antibiotic in this population could improve early clinical response-the new regulatory endpoint for community-acquired pneumonia-and explored the possible contribution of modulation of the inflammatory host response to that outcome. The ACCESS trial was a phase 3 prospective, double-blind, randomised controlled trial, in which adults in hospital with community-acquired pneumonia who had systemic inflammatory response syndrome, Sequential Organ Failure Assessment (SOFA) score of 2 or more, and procalcitonin 0·25 ng/mL or more were enrolled in 18 internal medicine departments of public Greek hospitals. Patients were randomly assigned (1:1) by computer-generated block randomisation to standard of care medication (including intravenous administration of a third-generation cephalosporin or intravenous administration of β-lactam plus β-lactamase inhibitor combination) plus either oral placebo or oral clarithromycin 500 mg twice daily for 7 days. Investigators, staff, and patients were masked to group allocation. The primary composite endpoint required that patients fulfilled both of the following conditions after 72 hours (ie, day 4 of treatment): (1) decrease in respiratory symptom severity score of 50% or more as an indicator of early clinical response and (2) decrease in SOFA score of at least 30% or favourable procalcitonin kinetics (defined as ≥80% decrease from baseline or procalcitonin <0·25 ng/mL), or both, as an indicator of early inflammatory response. Participants who were randomly assigned and received allocated treatment were included in the primary analysis population. This trial is complete and is registered with the EU Clinical Trials Register (2020-004452-15) and ClinicalTrials.gov (NCT04724044). Patients were enrolled between Jan 25, 2021, and April 11, 2023, and 278 individuals were randomly allocated to receive standard of care in combination with either clarithromycin (n=139) or placebo (n=139). 134 patients in the clarithromycin group (five withdrew consent) and 133 patients in the placebo group (six withdrew consent) were included in the analysis of the primary endpoint. The primary endpoint was met in 91 (68%) patients in the clarithromycin group and 51 (38%) patients in the placebo group (difference 29·6% [95% CI 17·7-40·3]; odds ratio [OR] 3·40 [95% CI 2·06-5·63]; p<0·0001). Serious treatment-emergent adverse events (TEAEs) occurred in 58 (43%) patients in the clarithromycin group and 70 (53%) patients in the placebo group (difference 9·4% [95% CI -2·6 to 20·9]; OR 0·67 [95% CI 0·42 to 1·11]; p=0·14). None of the serious TEAEs was judged to be related to treatment assignment. Addition of clarithromycin to standard of care enhances early clinical response and attenuates the inflammatory burden of community-acquired pneumonia. The mechanism of benefit is associated with changes in the immune response. These findings suggest the importance of adding clarithromycin to β-lactams for treatment of patients in hospital with community-acquired pneumonia to achieve early clinical response and early decrease of the inflammatory burden. Hellenic Institute for the Study of Sepsis and Abbott Products Operations.

Early Peripheral Blood Blast Clearance As a Prognostic Marker for Early Treatment Response in Pediatric Acute Myeloid Leukemia

Background and Significance The cure rate of pediatric acute myeloid leukemia (AML) has improved significantly; however, relapses still occur in up to 30% of the total patient population in high-income countries (HICs), and in an even higher percentage of patients in low- and middle-income countries (LMICs). Early treatment response, cytogenetics and minimal residual disease (MRD) are well-known prognostic factors for treatment outcome; however, sophisticated techniques for identifying prognostic factors are often lacking in LMICs, and are sometimes unsuccessful in HICs. Early treatment response assessed by a bone marrow (BM) aspirate on day 15 or day 22 (D22) (depending on the applicable protocol) after initiation of chemotherapy is a known prognostic factor for outcome in patients with pediatric AML, but does not allow modifications of the first induction chemotherapy course (Creutzig 2014, Abrahamsson 2011, Kern 2003). In both pediatric acute lymphoid leukemia (ALL) and adult AML, early peripheral blood blast clearance (PBBC) is a known early indicator of treatment response (Manabe 2008, Arellano 2012), whereas to the best of our knowledge, this has not yet been reported in pediatric AML. In this study, we evaluated the significance of time to complete PBBC, and rate of PBBC after initiation of chemotherapy, in relation to disease status in BM D22, as measure of early treatment response that has prognostic significance. Study Design and Methods Pediatric patients with AML, aged 0-18 years, that were treated according to the NOPHO-DBH AML-2012 protocol were included. The first 5 days of induction therapy consisted of etoposide, followed by 7 days of low-dose cytarabine and mitoxantrone or liposomal daunorubicin. Peripheral blood (PB) was assessed by morphology at the time of diagnosis, daily in the first week, and thrice weekly until D22 or until occurrence of complete clearance of blasts. BM D22 was assessed by morphology and flow cytometry. A receiver operating characteristic (ROC) analysis was performed to evaluate the predictive power of days from starting chemotherapy to complete PBBC. The correlation between time to complete PBBC and BM D22 results was analyzed using a logistic regression model. Multivariable logistic regression models were applied for the association after adjusting for effects of other covariates. Rate of PBBC was defined as the percentage of the absolute PB blast count on the day of diagnosis that cleared with each day of therapy, on average, until D22 or the day of complete PBBC. Results In total, 319 patients were included, out of whom 241 were eligible for analysis, and 78 not eligible due to missing or incomplete data. Day 9 after initiation of chemotherapy was identified as the most discriminating cut-off point for predicting BM D22 response. Patients were categorized into early PBBC (≤9 days; n=159) and delayed PBBC (&amp;gt;9 days; n=82) groups. Early PBBC was associated with having &amp;lt;5% AML cells in BM D22 as assessed by both morphology (OR 3.11; P=0.005) and flow cytometry (OR 2.73; P=0.041). Early PBBC also showed a much lower likelihood of having &amp;gt;15% AML cells in BM D22 by morphology (OR 0.08; P=0.002). None of the early PBBC patients had &amp;gt;15% AML cells in BM D22 by flow cytometry. For 217 patients (selection due to missing data [n=24]), the rate of PBBC could be calculated, and a discriminative cut-off value of 11% was identified. Patients were categorized into high rate of PBBC (&amp;gt;11%; n=132) and low rate of PBBC (≤11%; n=85). High rate of PBBC was associated with having &amp;lt;5% AML cells in BM D22 by flow cytometry (OR 4.30; P=0.007) and negative MRD status (OR 2.02; P=0.004), while also showing a strong association with a lower likelihood of &amp;gt;15% AML cells in BM D22 (OR 0.11; P=0.007) by morphology. None of the high rate PBBC patients had &amp;gt;15% AML cells in BM D22 by flow cytometry. Conclusion Both early complete PBBC and rate of PBBC after initiation of chemotherapy holds promise as prognostic marker for clinical outcome in pediatric AML, as it correlates significantly with BM D22 response. These findings may offer an early and easily accessible prognostic factor, particularly beneficial for LMICs, as well as for patients with unsuccessful MRD analyses.

Optimization of Idarubicin and Cytarabine Induction Regimen with Homoharringtonine for Newly Diagnosed AML Based on the Peripheral Blast Clearance Rate: First Result of the Multicenter, Randomized, Phase 3 Trial (RJ-AML 2016)

Background: Combination of idarubicin and cytarabine (IA) is still the basis of induction treatment for acute myeloid leukemia (AML). As previous reported in RJ-AML 2014 trial [1], day 5 peripheral blast clearance rate (D5-PBCR) can be used as an indicator of early treatment response, and for patients in the D5-PBCR (+) group, addition of homoharringtonine (HHT) to traditional IA induction showed good efficacy and safety. To further verify the efficacy in long-term outcome, we designed the RJ-AML 2016 trial. Here we report the latest response and survival results. Patients and Methods: The RJ-AML 2016 trial is a multicenter, randomized, phase 3 clinical trial, conducted to evaluate the efficacy of HHT in newly diagnosed young AML. Patients in D5-PBCR(+) group was eligible for addition of HHT, and were assigned in a 1:1 ratio, either to the intervention or control group. The primary end point was event-free survival (EFS). The secondary end points were composite complete remission (CR or CR with incomplete hematologic recovery), early death rate, measurable residual disease, drug toxicity, and safety. We hypothesized the 3-year EFS rate may increase from 30% to 50%, therefore the sample size of patients who enter randomization should be 250. Based on historical data, the rate of D5-PRCR(+) was 43%. Assume that 10% of patients may lost to follow-up, at least 638 eligible patients were needed. All patients enrolled in this study received induction regimen same as the RJ-AML 2014 trial. D5-PRCR(+) patients who assigned to the intervention group received additional chemotherapy (HHT 2 mg/m 2 on days 6-10). Favorable cytogenetic/molecular risks group received four courses of the HiDAC for consolidation. Patients with intermediate and unfavorable risks were recommended for allogeneic hematopoietic stem-cell transplantation. The trial is registered in the Chinese Clinical Trial Register, number ChiCTR-OIC-16007764. Results: From December 7, 2016, through April 29, 2023, a total of 747 patients underwent screening, 649 were included in the intention-to-treat (ITT) population and received IA induction from 6 sites in China. D5-PBCR were analyzed in 647 patients and 275 (42.5%) had D5-PBCR (+). Of the 275 D5-PBCR (+) patients, 145 were allocated to the intervention group, while 20 patients withdraw, of which 4 patients received additional FLT3 inhibitor and 16 cases continued IA induction; of the 130 patients allocated to the control group, 5 discontinued the IA regimen on day 6 or 7. Of the 372 D5-PBCR (-) patients, 2 patients discontinued IA. Baseline characteristics, including age, sex, blast counts in bone marrow, and cytogenetic parameters, were similar between two groups. While patients in D5-PBCR (-) group had higher white blood cell counts before treatment. Patients with CBFβ- MYH11 fusion, NPM1 and CEBPA bZIP mutations were more sensitive to IA induction. Meanwhile, high-risk gene mutations including ASXL1, RUNX1, TP53 and U2AF1 were more common in D5-PBCR (+) group. Details were showed in table. The overall composite CR rate after one course of induction was 73.2% in the ITT cohort. For patients in D5-PBCR (-) and D5-PBCR (+) groups, the CR rates were 82.8% and 60.4% , respectively (P&amp;lt;0.001). In the ITT cohort of D5-PBCR (+) group, CR rates were 51.1% and 68.3% for control and intervention arm, respectively (P=0.0046). In the Per-Protocol (PP) cohort, CR rates were 52.8% and 71.2% for IA and IA+HHT arm, respectively (P=0.0027). The overall early mortality rate was 4.9% in whole cohort, which were similar between two treatment arms. The last follow-up time was April 2023. Patients in the PP cohort who enrolled before April 2022 were included in this survival analysis (n=486), and the median duration of follow-up was 23.4 months. The median EFS was 40.6 months in the PP cohort, which showed significant difference between D5-PBCR (-) and D5-PBCR (+) groups [D5-PBCR (-): not reached, D5-PBCR (+): 16.0±1.9 months, P&amp;lt;0.001]. For patients in the D5-PBCR (+) group, no significant difference was found in 3-year EFS till the latest follow-up. While, the 3-year EFS was improved from 34.0±5.5% to 47.1±6.1% with the addition of HHT ( P=0.086). Conclusion: Current analysis indicated that addition of HHT can benefit young AML patients in the D5-PBCR (+) group. Complete follow-up combining with cytogenetic-molecular information can provide more reliable results. 1. Zhang Y, et al. Am J Hematol. 2022;97(1):43-51.

Early Peripheral Blood Minimal Residual Disease Status By NGS in Patients with Newly Diagnosed Multiple Myeloma (MM) on a Phase 2 Trial Receiving Elotuzumab, Carfilzomib, Lenalidomide, and Dexamethasone (Elo-KRd)

Background: Assaying for minimal residual disease (MRD) in the peripheral blood (PB) of patients with multiple myeloma (MM) could solve issues of patchy and extramedullary disease leading to false-negative MRD tests based on bone marrow (BM) only assessments. However, PB testing is challenging due to limited circulating myeloma cells and/or paraprotein. Further, early PB assessments for MRD by paraprotein are unreliable due to the extended half-lives of immunoglobulins. In this analysis, we investigated the concordance and prognostic significance of early MRD status after 4 cycles of treatment with Elo-KRd by next generation sequencing (NGS) in both the BM and PB and by International Myeloma Working Group (IMWG) response criteria. Methods: All patients received 12 cycles of Elo-KRd in 28-day cycles without intent for stem cell transplant: Elo per standard dosing; K 56/70 mg/m 2 (highest tolerated) days 1, 8 and 15 (20 mg/m 2 on day 1 of cycle 1) ; R 25 mg days 1-21; and dexamethasone 40 mg days 1, 8, 15, 22. An MRD-adapted design was used to determine the duration of carfilzomib as previously reported (Derman et al. JAMA Oncology 2022). MRD by NGS in BM (sensitivity threshold 10 -6,clonoSEQ, Adaptive Biotechnologies) was performed at multiple timepoints per protocol. PB mononuclear cells were evaluated for MRD using the same assay; any quantifiable signal was considered positive in PB. Conventional response was assessed per IMWG response criteria. Paired IMWG response and MRD status in the PB and BM were assessed for concordance and prognostic significance at the end of cycle 4 (C4). The Kaplan-Meier method was used to assess progression free survival (PFS) based on a landmark assessment at C4. Results: A total of 46 patients initiated treatment with Elo-KRd; patient baseline characteristics were reported previously (Derman et al. JAMA Oncology 2022). With a median follow-up of 39 months, estimated 4-year PFS was 75%. Of the 42 patients in response at C4, 39 (93%) achieved &amp;gt;VGPR, and 13 (31%) reached &amp;gt;CR. When stratified by &amp;gt;CR vs &amp;lt;CR at C4, there was no difference in PFS (HR 1.4, 95% CI 0.3-6.9, p=0.7). BM MRD status at C4 was available for 34 patients: 11 (32%) patients were BM MRD(-)and 23 (68%) were MRD(+). Matched PB MRD samples at C4 were available for 31 patients; 22 (69%) patients were PB MRD(-) using the best available threshold based on sample input (16 at 10 -6, 6 at 10 -5). Of the 9 (31%) patients with PB MRD(+), 6 (67%) had at least one high-risk cytogenetic abnormality (del17p in n=4, +1q in n=2, t(4;14) in n=1). Extramedullary disease relapse was a manifestation of progression in 4 (44%) patients. BM MRD(-) at C4 was associated with superior PFS (HR not estimable, p=0.04; Figure 1A). No patient with MRD(-) BM after C4 had disease progression. PB MRD(+) at C4 was also associated with inferior PFS (HR 21, 95% CI 2.3-184, p=0.002; Figure 1B). In comparing BM and PB MRD status, 8/9 (89%) patients with PB MRD(+) at C4 had BM MRD(+), and 14/22 (61%) patients with BM MRD(+) at C4 had PB MRD(-). 3/9 (33%) patients with PB MRD(+) at C4 were in &amp;gt;CR; 16/22 (73%) patients with PB MRD(-) at C4 were in a PR/VGPR. With progression serving as the reference standard, PB MRD(+) carried a sensitivity of 71%, a specificity of 83%, a positive predictive value of 56%, and a negative predictive value of 91%. There were 19 matched BM MRD(+)/PB MRD(+) samples across all timepoints; Pearson's correlation coefficient of detected cells per million between BM and PB MRD was r=0.93. BM MRD detected aberrant cells at higher concentrations, with a median log difference of 1.38 compared to PB MRD (range 0.07-3). Conclusions: MRD by NGS in the PB was less sensitive compared to the same assessment in the BM by 1-2 logs; however, PB MRD status following 4 cycles of induction therapy was strongly prognostic given its association with PFS. PB MRD status early in treatment may represent a leading indicator of early response and/or a marker of high-risk disease features, and validation of these findings may help to eventually guide intensification of therapy.

NIMG-29. ADVANCED MRI BIOMARKERS PREDICT EARLY RESPONSE TO TUMOR TREATING FIELDS IN GLIOBLASTOMA

Abstract BACKGROUND Tumor-treating fields (TTFields) is a novel US FDA-approved antimitotic treatment modality for patients with newly diagnosed and recurrent glioblastoma, shown to improve both OS and PFS (Stupp et al 2015). Yet, how to best monitor response to TTfields remains unclear. Conventional (anatomic) MRI is unreliable, often showing initial early radiographic progression followed by tumor regression and clinical benefit, thereby delaying confirmation of response. To address this limitation, we evaluate the utility of quantitative (physiologic) MRI biomarkers. METHODS Patients with newly diagnosed or recurrent IDH wildtype glioblastoma who underwent MRI with DSC-MRI perfusion imaging at 1-2, 3-4 and 5-6 months after TTField treatment were retrospectively identified for this study. Delta T1 (dT1) images were created from standardized (calibrated) pre- and post-contrast T1-weighted images, from which an enhancing lesion volume was objectively determined. Standardized and leakage-corrected relative cerebral blood volume (sRCBV) images were created from the DSC-MRI data. Together, dT1 and sRCBV were used to generate class maps of fractional tumor burden (FTB), which identify highly-vascular and avascular (treatment effect) regions within contrast-enhancement. Kaplan-Meier survival analysis was performed to determine if positive versus negative changes in these metrics, at each time-point relative to pre-treatment values, are predictive of survival. RESULTS 20 patients with newly diagnosed (n=17) or recurrent (n=4) IDH wildtype glioblastoma with a mean TTField compliance of 74.9% were identified. At 1-2 months no metric predicted a survival difference, consistent with the known 4-week delay in tumor stabilization following TTField therapy. At months 3-4 and 5-6 decreasing dT1-determined enhancing volumes showed a survival benefit (p=0.0081, p=0.03). Likewise, a decreasing percentage of highly-vascular tissue, determined from FTB class maps, demonstrated a survival benefit (p=0.0013). CONCLUSIONS Quantitative MRI metrics, including dT1-derived enhancing volumes and FTB/sRCBV-defined regions of high vascularity, demonstrate an ability to provide early indicators of response to TTField treatment.

CXC chemokine ligand 13 and galectin-9 plasma levels collaboratively provide prediction of disease activity and progression-free survival in chronic lymphocytic leukemia

The clinical outcome of lymphocytic leukemia (CLL) is quite heterogeneous. The purpose of this observational study was to investigate the clinical merit of measuring plasma galectin-9 and CXCL-13 concentrations as predictors of CLL activity, prognosis, and early indicators of therapeutic response. These biomarkers were compared with other prognostic indicators, progression-free survival (PFS), time to first treatment (TTT), and overall survival (OS) over a follow-up period (4 years). First, plasma galectin-9 and CXCL-13 concentrations were analyzed in CLL patients at the time of diagnosis as well as healthy controls. Compared to controls, CLL patients had significantly higher serum levels of CXCL-13 and galectin-9. Second, we observed that CLL patients with high soluble CXCL-13 and galectin-9 levels had advanced clinical stages, poor prognosis, 17p del, short PFS, short TTT, and therapy resistance. The levels of CXCL-13, β2-microglobulin, LDH, CD38%, and high grade of Rai-stage were all strongly correlated with the galectin-9 levels. Soluble CXCL-13 and galectin-9 had very good specificity and sensitivity in detecting CLL disease progression and high-risk patients with the superiority of galectin-9 over CXCL-13. Although the two biomarkers were equal in prediction of TTT and treatment response, the soluble CXCL13 was superior in prediction of OS. High CXCL-13 and galectin-9 plasma levels upon CLL diagnosis are associated with disease activity, progression, advanced clinical stages, short periods of PFS, short TTT, and unfavorable treatment response.

Apoptotic abnormal lymphocytes as a possible early indicator of clinical response in patients with ATL.

Apoptotic abnormal lymphocytes as a possible early indicator of clinical response in patients with ATL.

First-in-human study of a novel cell death tracer [99mTc]Tc-Duramycin: safety, biodistribution and radiation dosimetry in healthy volunteers

BackgroundImaging of cell death can provide an early indication of treatment response in cancer. [99mTc]Tc-Duramycin is a small-peptide SPECT tracer that recognizes both apoptotic and necrotic cells by binding to phosphatidylethanolamine present in the cell membrane. Preclinically, this tracer has shown to have favorable pharmacokinetics and selective tumor accumulation early after the onset of anticancer therapy. In this first-in-human study, we report the safety, biodistribution and internal radiation dosimetry of [99mTc]Tc-Duramycin in healthy human volunteers.ResultsSix healthy volunteers (3 males, 3 females) were injected intravenously with [99mTc]Tc-Duramycin (dose: 6 MBq/kg; 473 ± 36 MBq). [99mTc]Tc-Duramycin was well tolerated in all subjects, with no serious adverse events reported. Following injection, a 30-min dynamic planar imaging of the abdomen was performed, and whole-body (WB) planar scans were acquired at 1, 2, 3, 6 and 23 h post-injection (PI), with SPECT acquisitions after each WB scan and one low-dose CT after the first SPECT. In vivo 99mTc activities were determined from semi-quantitative analysis of the images, and time-activity curves were generated. Residence times were calculated from the dynamic and WB planar scans. The mean effective dose was 7.61 ± 0.75 µSv/MBq, with the kidneys receiving the highest absorbed dose (planar analysis: 43.82 ± 4.07 µGy/MBq, SPECT analysis: 19.72 ± 3.42 μGy/MBq), followed by liver and spleen. The median effective dose was 3.61 mSv (range, 2.85–4.14). The tracer cleared slowly from the blood (effective half-life of 2.0 ± 0.4 h) due to high plasma protein binding with < 5% free tracer 3 h PI. Excretion was almost exclusively renal.Conclusion[99mTc]Tc-Duramycin demonstrated acceptable dosimetry (< 5 mSv) and a favorable safety profile. Due to slow blood clearance, optimal target-to-background ratios are expected 5 h PI. These data support the further assessment of [99mTc]Tc-Duramycin for clinical treatment response evaluation.Trial registration: NCT05177640, Registered April 30, 2021, https://clinicaltrials.gov/study/NCT05177640.

Early indicators of response to transdiagnostic treatment of pediatric anxiety and depression.

Pediatric anxiety and depression are prevalent, impairing, and highly comorbid. Available evidence-based treatments have an average response rate of 60%. One path to increasing response may be to identify likely non-responders midway through treatment to adjust course prior to completing an episode of care. The aims of this study, thus, were to identify predictors of post-intervention response assessing (a) mid-treatment symptom severity, (b) session-by-session treatment process factors, and (c) a model optimizing the combination of these. Data were drawn from the treatment arm (N = 95, ages 8-16) of a randomized transdiagnostic intervention trial (Msessions = 11.2). Mid-point measures of youth- and parent-reported anxiety and depression were collected, and therapists rated homework completion, youth and parent engagement, and youth therapeutic alliance at each session. Logistic regression was used to predict response on the Clinical Global Impression Improvement Scale (CGI-I ≤2) rated by independent evaluators masked to treatment condition. Mid-point symptom measures were significant predictors of treatment response, as were therapist-ratings of youth and parent engagement, therapeutic alliance, and homework completion. Therapist ratings were significant when tested as mean ratings summing across the first eight sessions of treatment (all ps < .004) and at individual session points (all ps <0.05). A combined prediction model included youth-reported anxiety, parent-reported depression, youth engagement at Session 2, and parent engagement at Session 8. This model correctly classified 76.5% of youth as non-responders and 91.3% as responders at post-treatment (Nagelkerke R2 = .59, χ2 (4, 80) = 46.54, p < .001). This study provides initial evidence that response to transdiagnostic intervention for pediatric anxiety and depression may be reliably predicted by mid-point. These data may serve as foundational evidence to develop adaptive treatment strategies to personalize intervention, correct treatment course, and optimize outcomes for youth with anxiety and depression.

Real-world Outcomes and Predictive Biomarkers for 177Lutetium Prostate-specific Membrane Antigen Ligand Treatment in Metastatic Castration-resistant Prostate Cancer: A European Association of Urology Young Academic Urologists Prostate Cancer Working Group Multi-institutional Observational Study

BackgroundThe European Association of Urology guidelines include the lutetium-177 (177Lu) PSMA-617 prostate-specific membrane antigen (PSMA) ligand as a therapy option for metastatic castration-resistant prostate cancer (mCRPC). A major challenge in clinical practice is to pursue a personalized treatment approach based on robust predictive biomarkers. ObjectiveTo assess the performance of 177Lu PSMA in real-world practice and to elaborate clinical biomarkers for evaluating treatment responses. Design, setting, and participantsWe conducted a retrospective observational study including 233 patients with mCRPC treated with 177Lu PSMA in eight high-volume European centers. Outcome measurements and statistical analysisBaseline characteristics and clinical parameters during and after 177Lu PSMA treatment were documented. Correlations to treatment response were analyzed using χ2 and log-rank tests, with differences between groups with and without disease progression calculated using a Mann-Whitney U test. Univariate and multivariate-adjusted hazard ratios (HRs) were measured using Cox proportional hazards models. Results and limitationsA prostate-specific antigen (PSA) decrease of ≥30% was observed in 41.7%, 63.5%, and 77.8% of patients after the first, second, and third treatment cycle, respectively. Restaging performed via PSMA positron emission tomography-computed tomography revealed that 33.7% of patients had an imaging-based response, including two patients with a complete response, while 13.4% had stable disease. The median time to progression was 5 mo and the median time until the start of a consecutive antineoplastic therapy was 8.5 mo. Of importance, a PSA decrease ≥30% after the first two cycles of 177Lu PSMA (1 cycle: p = 0.0003; 2 cycles: p = 0.004), absolute PSA after the first three cycles (1 cycle: p = 0.011; 2 cycles: p = 0.0005; 3 cycles: p = 0.002), and a PSA doubling time >6 mo (p = 0.009) were significantly correlated to treatment response. Furthermore, gamma-glutamyl transferase ≤31 U/L at the start of 177Lu PSMA therapy was correlated with 1.5 times higher risk of progression for patients without but not with visceral metastases (p = 0.046). Conclusions177Lu PSMA is an effective treatment option in mCRPC in the real-world setting. A PSA decrease ≥30% after the first two cycles is an early marker of response that can be easily implemented in clinical practice. Patient summary177Lu PSMA is a radioactive agent approved for treatment of advanced prostate cancer. We reviewed its use outside of clinical trials for patients treated at eight European centers. We found that 177Lu PSMA is an effective treatment option in real-world practice. A PSA (prostate-specific antigen) decrease of ≥30% after the first two therapy cycles is an early indicator of response to treatment and can be used in personalizing treatments for patients.