Minimal Residual Disease In Patients Research Articles

Role of biomarkers in the diagnosis and management of HCC.

For many cancers, biomarkers have served as an important tool across the cancer care continuum from risk stratification and early detection to diagnosis and treatment. Alpha fetoprotein (AFP) remains one of the few validated biomarkers for patients with hepatocellular carcinoma (HCC). Although AFP has shown potential for each of these steps, its performance when used alone has often been suboptimal. There continues to be discordant recommendations about AFP's value when combined with ultrasound for surveillance as well as its role in diagnostic algorithms. Conversely, high AFP levels are associated with aggressive tumor biology and survival, so it remains a key factor for selection of liver transplant candidates. There have been immense efforts to identify and validate additional biomarkers for each of these steps in the HCC care continuum. Indeed, biomarker panels have shown promising data for HCC risk stratification and surveillance among patients with cirrhosis, as well as prognostication and detection of minimal residual disease in patients undergoing HCC treatment. Several large prospective studies to evaluate the role of these emerging biomarkers in clinical practice are currently ongoing.

CtDNA as an Adjunct to Posttreatment PET for Head and Neck Cancer Recurrence Risk Assessment.

Circulating tumor DNA (ctDNA) detection is an emerging technique that identifies minimal residual disease in patients with solid tumors. ctDNA can act as an adjunct method to help overcome the limitations of positron emission tomography (PET) and select patients who are at high risk for recurrence. Retrospective Single Institutional Study. University Hospital Setting. Twenty-nine patients who underwent definitive treatment for squamous cell carcinoma of the head and neck (HNSCC) from 8/2021 to 01/2023 had ctDNA levels analyzed at 1 to 3, 6, 9, and 12 months after definitive treatment. A personalized, tumor-informed, multiplex polymerase chain reaction (PCR) next-generation sequencing (NGS) assay was used to detect the ctDNA levels. The primary outcome was recurrence-free probability (RFP), and the secondary outcomes were overall survival (OS), sensitivity, specificity, and the test's negative (NPV) and positive predictive values (PPV). The median age of patients was 65 years (interquartile range: 56-69), with majority being males (n = 22, 76%). The primary sites were larynx (n = 12), oropharynx (n = 10), and oral cavity (n = 6). Posttreatment ctDNA was detected in 7 patients, all of whom had disease recurrence. ctDNA detection after definitive treatment was associated with a higher risk of disease recurrence (hazard ratio: 9.94, 95% confidence interval: 1.56-63.3, P = .015). ctDNA identified recurrence with 100% specificity and 78% sensitivity. The NPV and PPV were 91% and 100%. PET had 78% sensitivity but only 68% specificity with 86% NPV, and 54% PPV. Based on our data, ctDNA can be an excellent adjunct test for posttreatment PET and can help guide physicians in cases where PET results are inconclusive and difficult to interpret.

Monitoring Minimal Residual Disease in Patients with Multiple Myeloma by Targeted Tracking Serum M-Protein Using Mass Spectrometry (EasyM).

We investigated both the clinical utilities and the prognostic impacts of the clonotypic peptide mass spectrometry (MS)-EasyM, a blood-based minimal residual disease (MRD) monitoring protocol in multiple myeloma. A total of 447 sequential serum samples from 56 patients with multiple myeloma were analyzed using EasyM. Patient-specific M-protein peptides were sequenced from diagnostic samples; sequential samples were quantified by EasyM to monitor the M-protein. The performance of EasyM was compared with serum immunofixation electrophoresis (IFE), bone marrow multiparameter flow cytometry (MFC), and next-generation flow cytometry (NGF) detection. The optimal balance of EasyM sensitivity/specificity versus NGF (10-5 sensitivity) was determined and the prognostic impact of MS-MRD status was investigated. Of the 447 serum samples detected and measured by EasyM, 397, 126, and 92 had time-matching results for comparison with serum IFE, MFC-MRD, and NGF-MRD, respectively. Using a dotp >0.9 as the MS-MRD positive, sensitivity was 99.6% versus IFE and 100.0% versus MFC and NGF. Using an MS negative cutoff informed by ROC analysis (<1.86% of that at diagnosis), EasyM sensitivity remained high versus IFE (88.3%), MFC (85.1%), and NGF (93.2%), whereas specificity increased to 90.4%, 55.8%, and 93.2%, respectively. In the multivariate analysis, older diagnostic age was an independent predictor for progression-free survival [PFS; high risk (HR), 3.15; 1.26-7.86], the best MS-MRD status (MS-MRD negative) was independent predictor for both PFS (HR, 0.25; 0.12-0.52) and overall survival (HR, 0.16; 0.06-0.40). EasyM is a highly sensitive and minimal invasive method of MRD monitoring in multiple myeloma; MS-MRD had significant predictive ability for survival outcomes.

Impact of pretransplant minimal residual disease in patients with multiple myeloma and a very good partial response or better receiving autologous hematopoietic stem cell transplantation.

The prognostic significance of minimal residual disease (MRD) status before autologous hematopoietic stem cell transplantation (autoHCT) in patients with multiple myeloma (MM) has not been clearly elucidated. Retrospective single-center study of adult MM patients who achieved ≥very good partial response (VGPR) after induction therapy from 2015 to 2021 received upfront autoHCT and had available pretransplant MRD status by next-generation flow cytometry. The cohort was divided into pretransplant MRD-negative (MRDneg) and MRD-positive (MRDpos) groups. A total of 733 patients were included in our analysis; 425 were MRDneg and 308 MRDpos at autoHCT. In the MRDpos group, more patients had high-risk cytogenetic abnormalities (48% vs. 38%, respectively; p=.025), whereas fewer patients achieved ≥CR before autoHCT (14% vs. 40%; p<.001). At day 100 after autoHCT, 37% of the MRDpos versus 71% of the MRDneg achieved ≥CR, and at best posttransplant response 65% versus 88% achieved ≥CR, respectively. After a median follow-up of 27.6months (range, 0.7-82.3), the median PFS was significantly shorter for patients in the MRDpos group compared to the MRDneg group: 48.2months (95% confidence interval [CI], 0.3-80.5) versus 80.1months (95% CI, 0.5-80.1), respectively (p<.001). There was no significant difference in overall survival between the two groups (p=.41). Pretransplant MRDpos status was predictive of shorter PFS in multivariate analysis (hazard ratio, 1.80; 95% CI, 1.31-2.46; p<.001). The impact of pretransplant MRD status was retained in most of the examined subgroups. In patients achieving ≥VGPR to induction, pretransplant MRDpos status was associated with a lower CR rate after autoHCT and a shorter PFS.

Monitoring Minimal Residual Disease in Patients with Multiple Myeloma By Tracking Serum M-Protein Using Mass Spectrometry

Objective： We performed this retrospective real-world study to evaluate the clinical utility of blood-based mass spectrometry for longitudinal M-protein monitoring during the disease course of patients of multiple myeloma（MM）. Methods：We initially analyzed serial serum samples of 56 patients with MM by clonal peptide MS Method named EasyM MS, then we compared the MS results with those determined using serum immunofixation electrophoresis (IFE),multiparameter flow cytometry (MFC), next-generation flow cytometry (NGF), to establish the concordance between different disease-monitoring protocols. A sensitivity for MFC MRD negativity of at least 1×10 -4 anda sensitivity for NGF MRD negativity of at least 1×10 -5.Additionally, we determined the optimal cutoff value of EasyM MS negativity to satisfy both the sensitivity and specificity between MS and NGF, and explored the prognostic impact of MS-MRD status. Results：The median diagnostic age of 56 NDMM patients was 56 years old, including 34 males (60.7%). There were 38 patients with IgG type MP and 18 patients with IgA type MP. 47 patients (83.9%) chose to receive proteasome inhibitor - based induction therapy, and a total of 44 patients (78.6%) received first-line ASCT treatment.Among 56 MM patients，38 patients with IgG type MP can further identify IgG subclasses through mass spectrometry. Additionally, 56 patients with MM have successfully used MS to identify their unique clonal peptides of MP. 56 patients provided a total of 447 samples of serum and all sequential serum samples were successfully measured by using the MS method. The initial comparison of the performance of blood-based MS-MRD with that of the conventional M-protein diagnostic method IFE used . Among the 397 comparable results collected at similar timepoints, 70.8% (281/397) of the samples were both M-MRD- and IFE-positive, 3.3% (13/397) were both MS-MRD- and IFE-negative, 25.7% (102/397) were MS-MRD-positive and IFE-negative.Flow cytometry MRD was performed on 218 bone marrow aspirates in this cohort, including 126 analyzed with MFC and 92 analyzed with NGF. MS-MRD detection was also performed on comparable serum acquired at the same time points. The sensitivity of MS-MRD was 100.0% in comparison with both MFC and NGF, with specificity of 1.9% and 22.2%, respectively. Considering the overly high sensitivity of EasyM at a cutoff of dotp &amp;gt;0.9, we used the sensitivity of NGF as the standard for detection (i.e., a detection sensitivity ≤10 -5) and set the EasyM MS negative cutoff value using ROC analysis, determined to be &amp;lt;1.86% of that at first diagnosis. Using these assumptions, we again performed the aforementioned analyses comparing the sensitivity and specificity between EasyM and IFE, MFC, and NGF. Under this scenario, the sensitivity of EasyM remained high in comparison with IFE (88.3%), MFC (85.1%), and NGF (93.2%), but the specificity was also greatly increased to 90.4%, 55.8%, and 93.2%, respectively. We then divided patients into MS-positive and MS-negative groups according to whether they achieved MS-MRD negativity, and median PFS and OS were calculated for each group. The median PFS of the MS-positive and MS-negative groups was 20.6 (95% CI: 16.6, 24.6) and 61.8 (39.7, 83.9) months, respectively . The median OS was 55.7 (95% CI:31.8, 79.5) months for the MS-positive group and not reached (NR) for the MS-negative group ,Both mPFS and mOS were significantly longer among the MS-negative group compared with the MS-positive group (both p &amp;lt; 0.001). Conclusion：EasyM exhibits high sensitivity and minimally invasive technological advantages, and also has important significance in efficacy evaluation and prognosis evaluation. In the future, EasyM MS detection can be used as a minimally invasive MRD monitoring method based on peripheral blood in clinical practice.

Impact of Pre-Transplant Minimal Residual Disease in Patients with Multiple Myeloma with ≥ Very Good Partial Response Receiving Autologous Hematopoietic Stem Cell Transplantation

Background: Minimal residual disease (MRD) has emerged as one of the most important prognostic markers in patients with multiple myeloma (MM). However, the prognostic significance of MRD status prior to autologous hematopoietic stem cell transplantation (autoHCT) has not been clearly elucidated. Methods: In this retrospective single-center study we included adult MM patients who achieved ≥VGPR after induction therapy between 2015-2021, received an upfront autoHCT and had available data for pre-transplant MRD status by next-generation flow cytometry (NGF). The sensitivity of our assay is 1/10 -5 cells (0.001%) based on acquisition and analysis of at least 2 million events. We divided the cohort into pre-transplant MRD negative (MRDneg) and MRD positive (MRDpos) groups. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Results: A total of 734 patients were included in our analysis, 425 were MRDneg and 309 were MRDpos at autoHCT. Median age of the entire cohort was 60 (range 25-82) years and 436 (59%) were male. In the MRDpos group, more patients had high-risk cytogenetic abnormalities (48% vs. 38%, respectively; p=0.025), while fewer patients had achieved &amp;gt;CR prior to autoHCT (14% vs. 40%; p&amp;lt;0.001) (Table 1). At day 100 after autoHCT, 37% of the MRDpos achieved &amp;gt;CR vs. 71% of the MRDneg group, and at best post-transplant response 65% vs. 88% achieved &amp;gt;CR, respectively. At day 100, 16% of the patients in the MRDpos group achieved MRD negative ≥VGPR vs. 27% in the MRDneg group, and at best post-transplant response 33% vs. 37% achieved MRD negative ≥VGPR, respectively. After a median follow up of 27.6 months (0.7-82.3), the median PFS of the entire cohort was 63.4 months (95% CI 0.3-8.5), and median OS was 80.0 months (95% CI 0.3-82.3). Median PFS was significantly shorter for patients in the MRDpos group compared to MRDneg: 48.2 months (95% CI 0.3-80.5) vs. 80.1 months (95% CI 0.5-80.1), respectively; p&amp;lt;0.001 (Figure 1). There was no significant difference in OS between the two groups (p=0.41). Pre-transplant MRDpos status (HR 1.80, 95% CI 1.31-2.46; p&amp;lt;0.001) and high-risk cytogenetics (HR 1.86, 95% CI 1.32-2.61; p&amp;lt;0.001) were predictive of shorter PFS in MVA. Use of post-transplant maintenance was predictive of longer PFS (HR 0.49, 95% CI 0.34-0.69; p&amp;lt;0.001) and OS (HR 0.19, 95% CI 0.11-0.32; p&amp;lt;0.001) in MVA. In a subset analysis, pre-transplant MRD status remained highly predictive of PFS in patients with high-risk cytogenetics (HR 1.48; 95% CI 1.03-2.11; p=0.033) as well as non-high-risk cytogenetics (HR 1.75; 95% CI 1.13-2.70; p=0.012) and in patients with a response of VGPR prior to transplant (HR 1.79; 95% CI 1.33-2.42; p&amp;lt;0.001). Similarly, in patients with R-ISS stage I and II MM, pre-transplant MRD status was highly predictive of PFS [(HR 2.28; 95% CI 1.21-4.29; p=0.011) and (HR 1.73; 95% CI 1.17-2.56; p=0.006), respectively]. However, for patients with R-ISS III disease (HR 2.00; p=0.079), for patients with a response of ≥CR prior to transplant (HR=0.85; p=0.67) and for patients ≥65 years (HR=1.46; p=0.062) the pre-transplant MRD status was not significantly predictive of PFS. Conclusions: In patients achieving &amp;gt;VGPR to induction, pre-transplant MRDpos status was associated with a lower CR rate after autoHCT and a shorter PFS.

POSTER: AML-053 Assessment of Minimal Residual Disease in Patients With Adult Acute Myeloid Leukemia: Single Egyptian Center Experience

POSTER: AML-053 Assessment of Minimal Residual Disease in Patients With Adult Acute Myeloid Leukemia: Single Egyptian Center Experience

AML-053 Assessment of Minimal Residual Disease in Patients With Adult Acute Myeloid Leukemia: Single Egyptian Center Experience

AML-053 Assessment of Minimal Residual Disease in Patients With Adult Acute Myeloid Leukemia: Single Egyptian Center Experience

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

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

RF2 Feasibility and preliminary results of the first clinical trial targeting minimal residual disease in patients with homologous recombination proficient (HRP) ovarian cancer

RF2 Feasibility and preliminary results of the first clinical trial targeting minimal residual disease in patients with homologous recombination proficient (HRP) ovarian cancer

The use of minimal residual disease in patients with high-risk breast cancer.

e12521 Background: Breast cancer is the most frequently diagnosed cancer worldwide and the second leading cause of cancer death in women in the United States. Despite being disease-free after primary treatment, studies have shown that up to 30% of patients present with disease recurrence. Circulating tumor DNA (ctDNA) in blood is a minimally invasive technique to characterize individual cancer biology and monitor disease. Previous studies have demonstrated that ctDNA can be a sensitive and specific approach to breast cancer follow up and surveillance of disease recurrence for all subtypes. Methods: We evaluated 38 high risk breast cancer patients utilizing a personalized and tumor-informed ctDNA assay at 3-6 month intervals. We defined high risk as: any stage III disease, triple negative breast cancer (TNBC) or HR-/HER2+ breast cancer who received neoadjuvant chemotherapy treatment (NACT), pregnancy associated breast cancer, metastatic breast cancer without any evidence of disease, history of bilateral breast cancer, high risk genetics (i.e. BRCA1 or BRCA2 mutations), young age at diagnosis (&lt;40 years old) and/or breast cancer recurrence of any subtype. Results: Patient ages ranged from 34 to 83 (average: 53.3 years old) and included a diverse race/ethnicity population: White (n=12, 31%), Japanese (n=9, 23.7%), Native Hawaiian (n=6, 15.8%), Chinese (n=4, 10.5%), Filipino (n=4, 10.5%), Black (n=1, 2.6%), Hispanic (n=1, 2.6%), and Korean (n=1, 2.6%). Of the 38 cases, there was one ctDNA positive finding seen in a high risk case (young age at diagnosis and BRCA2 mutation) of clinical stage IIA HR+/HER2- breast cancer. After NACT, bilateral mastectomies, and radiation, patient remained on tamoxifen (declined ovarian function suppression) and was initially ctDNA negative until a second test identified detectable ctDNA. Restaging scans however did not show any evidence of disease. A third ctDNA test three months later, continued to be positive without any evidence of disease. All other cases showed negative ctDNA testing with an average of 1.55 ctDNA tests done per patient over two years. However, one case of clinical stage IIB TNBC had contralateral recurrence despite negative testing. After receiving NACT, bilateral mastectomies, post-operative paclitaxel and radiation, two ctDNA tests done three months apart were negative. Conclusions: There is potential use for this ctDNA platform in high risk breast cancer patients but larger studies need to be done. [Table: see text]

Utility of circulating tumor DNA as a tool to detect minimal residual disease in patients with metastatic cancer and durable response following treatment with immune checkpoint inhibitors.

e21563 Background: Circulating tumor DNA (ctDNA) is tumor-derived fragment of DNA circulating in plasma. ctDNA has been used to detect minimal residual disease (MRD) in early-stage cancers after curative intent therapy. However, ctDNA based MRD concept is not investigated in metastatic disease. There is a lack of clarity around optimal timing to stop immune checkpoint inhibitors (ICI) in melanoma and lung cancer patients who have achieved durable response (DR) and MRD may have a role here to select right patients to stop therapy at an optimal time. Methods: This is prospective study on metastatic lung cancer and melanoma patients with DR treated with ICI. DR is identified as objective response (CR/PR) by modified WHO criteria lasting ≥6 months continuously. We utilized Signatera assay by Natera. Signatera uses tissue from original biopsy of the patients and develop multiplex PCR based personalized assay to detect MRD. The level of ctDNA is reported in mean tumor molecules per mL. We obtained ctDNA assay at baseline, month 3 and month 6 at their routine follow up visits. If applicable, ctDNA assay was done at the time of progression, and 3 months after resuming treatment. Results: We identified 29 melanoma and 17 Lung cancer (both small cell and non-small cell) patients with metastases and DR. Median age was 69 years in both cohorts. Median duration of ICI was 14 months in melanoma and 24 months in lung cancer cohort. ctDNA assay was obtained in 26 melanoma and 13 lung cancer patients. One small cell lung cancer patient had detectable ctDNA at baseline, although radiographically, the patient had DR. The rest of the patients in both cohorts had undetectable ctDNA. 2 melanoma patients developed detectable ctDNA on subsequent assays and their therapies were changed. One small cell lung cancer patient has persistently detectable ctDNA on subsequent assays but remained in DR. A total of 10 patients in both cohorts decided to stop their therapy following several -ve ctDNA assay. Conclusions: The role of ctDNA needs to be investigated in advanced/metastatic settings as MRD may have a role to identify patients who may benefit from treatment break. MRD surveillance may also support radiographic assessment. [Table: see text]

Abstract CT046: A randomized, phase 2 study of pembrolizumab plus chemotherapy with or without anti—immunoglobulin-like transcript 4 monoclonal antibody MK-4830 as neoadjuvant treatment for high-grade serous ovarian cancer

Abstract Background: Combination therapy with the anti-PD-1 monoclonal antibody (mAb) pembrolizumab and chemotherapy in advanced solid tumors has shown efficacy in the (neo)adjuvant and first-line setting, including high-grade serous ovarian cancer (HGSOC). The immunoglobulin-like transcript 4 (ILT4) receptor expressed on myeloid cells is involved in immune tolerance and suppression within the tumor microenvironment, and its blockade may improve treatment outcomes with combination therapies. Pembrolizumab plus chemotherapy with or without MK-4830 (a novel humanized anti-ILT4 mAb) will be investigated as neoadjuvant therapy for HGSOC in a randomized, open-label, phase 2 study (NCT05446870). Specifically, this trial is designed to evaluate the utility of circulating tumor DNA (ctDNA) as a biomarker of response and minimal residual disease in patients with treatment-naive HGSOC. Methods: Key eligibility criteria include adult patients with treatment-naive International Federation of Gynecology and Obstetrics Stage IIIA-C/IV HGSOC, primary peritoneal cancer, or fallopian tube cancer who are candidates for neoadjuvant and adjuvant chemotherapy and interval debulking surgery (IDS), and have an ECOG performance status of 0 or 1. Approximately 160 patients will be randomly assigned (1:1) to receive 3 cycles each of neoadjuvant and adjuvant therapy with patients in arm 1 receiving chemotherapy (carboplatin AUC 5 or 6 plus paclitaxel 175 mg/m2 or docetaxel 75 mg/m2) + pembrolizumab 200 mg and patients in arm 2 receiving chemotherapy + pembrolizumab + MK-4830 800 mg. Bevacizumab (or biosimilar) may be added to either arm in the adjuvant setting. All treatments will be given on day 1 of each 3-week cycle. For patients who undergo IDS, the last dose of neoadjuvant therapy will be administered 3-6 weeks before IDS, and adjuvant therapy will commence &amp;lt;7 weeks after IDS. Adjuvant therapy will be administered for up to 3 cycles or until disease progression, unacceptable toxicity, or withdrawal. Upon completion of adjuvant therapy, patients may undertake maintenance therapy per investigator discretion and local guidelines. Tumor imaging will be performed at baseline, ≥21 days after neoadjuvant therapy or prior to IDS, after IDS or prior to the start of adjuvant therapy, and at the end of treatment. The primary objective is to evaluate the change from baseline in ctDNA, defined as the continuous mean mutant/tumor molecules/mL as measured in a blood sample, at cycle 3. Secondary objectives are to evaluate the association between change from baseline in ctDNA at cycle 3 and surgical outcomes (including pathologic complete response and chemotherapy response score), and safety and tolerability. Enrollment is ongoing. Citation Format: Jung-Yun Lee, Maria Bell, Mariusz Bidzinski, Lubomir Bodnar, Jack Junjie Chan, Marta Gill-Martin, Carolina Ibanez, Domenica Lorusso, Chien-Hsing Lu, Ora Rosengarten, Steven M. Townson, Julie Kobie, Yiwei Zhang, Scott Pruitt, Ronnie Shapira-Frommer. A randomized, phase 2 study of pembrolizumab plus chemotherapy with or without anti—immunoglobulin-like transcript 4 monoclonal antibody MK-4830 as neoadjuvant treatment for high-grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT046.

Abstract 2305: Ultra-sensitive detection of circulating tumor DNA by whole-genome sequencing of blood samples from locally advanced rectal cancer patients receiving neoadjuvant therapy and enrolled in watch-and-wait strategies for organ preservation

Abstract Background. We hypothesized that circulating tumor DNA (ctDNA) can be used as a prognostic biomarker, improve the assessment of response and enhance detection of minimal residual disease in patients with locally advanced rectal cancer (LARC) treated with neoadjuvant therapy (NAT). Methods. We analyzed data from 31 LARC patients treated at Memorial Sloan Kettering as part of the Organ Preservation in Rectal Adenocarcinoma (OPRA) phase II clinical trial. Patients had stage II or III rectal adenocarcinoma and received NAT including chemoradiation and chemotherapy. Patients without a clinical complete response (cCR) underwent surgical resection, while patients with a cCR were enrolled in a watch-and-wait protocol for organ preservation. Complete response (CR) after NAT was defined as either pathological complete response or a cCR sustained for ≥2 years. Disease-free survival (DFS) was measured from the start of NAT. Median follow-up was 5.41 years [range 2.96-8.38]. ctDNA analyses were performed using the C2i Genomics platform. A patient-specific molecular profile was created by performing whole-genome sequencing (WGS) of their tumor and matched normal DNA (40x coverage). WGS (20x coverage) was performed on plasma samples collected at baseline (before NAT), interval evaluation (halfway through NAT), re-staging evaluation (8 weeks after NAT) and follow-up (3-6 months after NAT). Results. Tumor was detected in plasma samples from 24/25 patients at baseline (96% sensitivity). The tumor fraction (TF) levels detected at baseline separated responders from non-responders (median TF 6.2e-4 vs 1.4e-3; p=0.055). Tumor detection at interval was associated with a lower rate of CR (25% vs. 75%, p=0.0095) and shorter time to recurrence (58.3% vs. 94.1% 3-year DFS, p=0.02). Tumor detection at follow-up was associated with a higher rate of recurrence (p=0.037) and tumor was detected at follow-up for all 5/5 patients who developed recurrence. Overall TF dynamics showed clearance of ctDNA down to the non-detection level throughout treatment in patients with a CR, while non-responders exhibited non-decreasing and often increasing estimates of ctDNA burden. Analysis of tissue WGS data identified multiple patients with colibactin associated mutational signatures, which provides additional insights into their cancer etiology. Conclusions. The WGS-based approach for ctDNA analysis exhibited very high sensitivity for detection at baseline. TF across multiple time points separated responders from non-responders, suggesting potential value as a prognostic marker. Detection of ctDNA at follow-up for all patients who recurred is indicative of potential clinical utility for treatment de-escalation in the context of organ preservation strategies. Citation Format: Francisco Sanchez-Vega, Chin-Tung Chen, Danielle Afterman, Dana Omer, Madison Darmofal, Ino de Bruijn, Walid K. Chatila, Matthew Drescher, Grittney Tam, Tomer Lauterman, Maja Kuzman, Santiago Gonzalez, Dunja Glavas, James Samdbeck, Dillon Maloney, Jurica Levatic, Sunil Deochand, Michael Yahalom, Ryan Ptashkin, Iman Tavassoly, Zohar Donenhirsh, Eric White, Ravi Kandasamy, Ury Alon, Michael F. Berger, Brian Loomis, Paz Polak, Boris Oklander, Asaf Zviran, Julio Garcia-Aguilar. Ultra-sensitive detection of circulating tumor DNA by whole-genome sequencing of blood samples from locally advanced rectal cancer patients receiving neoadjuvant therapy and enrolled in watch-and-wait strategies for organ preservation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2305.

Lumbar MR-based radiomics nomogram for detecting minimal residual disease in patients with multiple myeloma.

Minimal residual disease (MRD) is a standard for assessing treatment response in multiple myeloma (MM). MRD negativity is considered to be the most powerful predictor of long-term good outcomes. This study aimed to develop and validate a radiomics nomogram based on magnetic resonance imaging (MRI) of the lumbarspine to detect MRD after MM treatment. A total of 130 MM patients (55 MRD negative and 75 MRD positive) who had undergone MRD testing through next-generation flow cytometry were divided into a training set (n = 90) and a test set (n = 40). Radiomics features were extracted from lumbar spinal MRI (T1-weighted images and fat-suppressed T2-weighted images) by means of the minimum redundancy maximum relevance method and the least absolute shrinkage and selection operator algorithm. A radiomics signature model was constructed. A clinical model was established using demographic features. A radiomics nomogram incorporating the radiomics signature and independent clinical factor was developed using multivariate logistic regression analysis. Sixteen features were used to establish the radiomics signature. The radiomics nomogram included the radiomics signature and the independent clinical factor (free light chain ratio) and showed good performance in detecting the MRD status (area under the curve: 0.980 in the training set and 0.903 in the test set). The lumbar MRI-based radiomics nomogram showed good performance in detecting MRD status in MM patients after treatment, and it is helpful for clinical decision-making. • The presence or absence of minimal residual disease status has a strong predictive significance for the prognosis of patients with multiple myeloma. • A radiomics nomogram based on lumbar MRI is a potential and reliable tool for evaluating minimal residual disease status in MM.

The role of blinatumomab in the treatment of B-cell relapses of acute lymphoblastic leukemia in children: own experience

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Despite remarkable improvements in the treatment of pediatric acute lymphoblastic leukemia over last years, relapse still carries a poor prognosis with considerable morbidity and mortality. New immunotherapeutic approaches will change the way we treated our patients and the results we had. Blinatumomab is a bispecific T-cell-engaging antibody indicated for the treatment of relapsed/refractory B-cell lymphoblastic leukemia. The use of Blinatumomab in relapsed B-cell ALL has shown promising effects, especially as a bridging tool to hematopoietic stem cell transplantation. The therapy results for patients in the high risk group remain far from optimal due to refractoriness to chemotherapy, death from infectious complications, as well as acute chemotherapy toxicity. This article demonstrates the results of our experience of using Blinatumomab in children with the high-risk group relapsed B-cell ALL treated according to the ALL-REZ 2016 protocol. The study was approved by the Independent Ethics Committee and the Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. The efficacy and toxicity of innovational blocks with the use of fludarabine and clofarabine with subsequent Blinatumomab infusion are shown. And we present the efficacy of autologous CD3+ lymphocytes infusion once a week during the continuous blinatumomab therapy. Also we demonstrate the results of using Blinatumomab for the treatment of patients with refractory to the first line therapy relapsed B-lymphoblastic leukemia and patients with a second relapse of B-cell ALL. The first line therapy in these patients was carried out according to the ALL-REZ 2014 protocol. Our results show an improved reduction in minimal residual disease in patients with refractory relapsed B-cell ALL as well as an increased event free survival in children with the high-risk group relapsed B-cell ALL.

Anti CD19 CAR-T Cell Therapy Can Clear Minimal Residual Disease in Bone Marrow of Patients with Relapsed or Refractory B Cell Non-Hodgkin's Lymphomas

Background: Anti CD19 Chimeric Antigen Receptor T (CAR-T) cell therapy is an effective treatment option for patients with relapsed/refractory B-cell lymphomas. There is limited data on the impact of CAR-T cell therapy on measurable residual disease (MRD) in the bone marrow of these patients. We hereby report CAR-T cell therapy's efficacy to treat bone marrow MRD in patient with relapsed/refractory B-cell lymphomas. Methods: In this retrospective review, patients receiving CAR-T cell therapy for relapsed/refractory B-cell lymphomas who had bone marrow MRD evaluation pre-and post-CAR-T infusion at the University of Arizona Cancer Center (UACC) were analyzed. MRD testing was performed via ClonoSEQ (Adaptive Biotechnologies) on bone marrow aspirates prior to CAR-T cell infusion. Patients with MRD+ (10^6) disease had serial MRD evaluations at day+30, +90, +180, +365 post CAR-T cell infusion. Results: Thirty-three patients with B-cell lymphomas received CAR-T cell therapy at UACC from January 2019 to July 2022. Bone marrow MRD pre-and post-CART was evaluated in ten patients. Baseline characteristics of these patients are outlined in Table 1. Seven (70%) were female, five (50%) had diffuse large B cell lymphoma (DLBCL), two (20%) patients had Richter's syndrome, two patients had transformed DLBCL from follicular lymphoma (FL), one patient had FL grade 3A. Nine (90%) patients were treated with Tisagenlecleucel and one (10%) patient received Axicabtagene ciloleucel CAR-T product. Of the ten patients who had MRD testing done pre-and post-CAR-T, seven (70%) had MRD positive disease prior to treatment. Five of the seven patients converted to MRD negative 10^6 post-CAR-T cell infusion. One patient tested MRD positive below the level of detection on day +30 bone marrow aspirate. One patient is still MRD positive 6 months post-CAR-T infusion but the depth of response continues to improve from MRD positive at 10^4 to MRD negative at 10^5, 6 months post-CAR-T infusion. All MRD positive patients achieved complete metabolic response (CMR) based on the positron emission tomography scans. Conclusion: CAR-T cell therapy has the potential to treat minimal residual disease in patients with B-cell lymphoma. Depth of bone marrow response continues to improve over time. All patients continue to be in CMR. Long term follow-up will help determine if persistent MRD can be used as prognostic marker in B cell lymphomas post CAR-T cell therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

TIM3 Is Upregulated in Cell Lysates of Patients with Acute Myeloid Leukemia

Background T-cell immunoglobulin and mucin domain-containing molecule3 (TIM3) is known to be a member of a multiple checkpoint receptors. It is expressed on dysfunctional or 'exhausted' T cells during cancer or chronic viral infection. However, its role in some specific cancers such as acute myeloid leukemia (AML) and its relationship to prognostic factors is still unclear. Aims This study aimed to compare the concentrations of TIM3 at the diagnosis and remission stages in acute myeloid leukemia. Methods Paired bone marrow and peripheral blood samples of patients with AML were collected at diagnosis and remission after treatment with standard doses of intensive chemotherapy using daunorubicin and cytarabine. Upon collection, cell lysates were obtained from both samples. The concentrations of TIM3 were then estimated using ELISA. Results Forty samples for 15 patients with AML and seven healthy controls were included in this study, with 13 men (87%) and two women (13%) with a mean age of 38.2 ± 16.3 years. The healthy controls included four men and three women. For patients, the median hemoglobin and platelet counts at diagnosis were 8.3 g/dL (Range 5 - 14) and 56 *109/L (Range 26 - 198), respectively. The median white blood cells count, peripheral blood blasts percentage, and bone marrow blasts percentage were 26.6 *109/L (Range 1.2 - 213), 49% (Range 3 - 72), and 72% (Range 31 - 91), respectively. In peripheral blood, TIM3 concentration was significantly higher in patients with AML compared to healthy controls (p = 0.01), with a median concentration of 9.26 pg/ml (Range 0.45- 72.2) in patients and 5.1 pg/ml (Range 4.5-6.6) in healthy controls (Figure 1). In patients, TIM3 concentration of peripheral blood cell lysates was higher at diagnosis compared to remission, with a median concentration of 9.25 pg/ml (Range 0.45 - 72.2) and 5.57 pg/ml (Range 1.86 - 27.2), respectively (p =0.03). In bone marrow cell lysates at diagnosis, TIM3 concentration was higher compared with healthy controls (p = 0.04) with a median concentration of 10.89 pg/ml (Range 8.14 - 39.85) and 5.1 pg/ml (Range 4.5-6.6), respectively. In patients, TIM3 concentration of bone marrow cell lysates was not statistically different at diagnosis than at remission, with a median concentration of 10.8 pg/ml (Range 8.14 - 39.85)and 5.1 pg/ml (Range 4.85 -15.61), respectively (p = 0.1) (Figure 2). Conclusion In conclusion, TIM3 is upregulated in cell lysates of patients with AML. Therefore, the reduction of TIM3 in peripheral blood or bone marrow may be used as a minimal residual disease in patients with high TIM3 concentration at diagnosis. These findings should be validated in a larger prospective study. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Circulating Tumor DNA as a Marker of Minimal Residual Disease After Radical Resection of Colorectal Liver Metastases.

Prognostic tools to estimate the risk of relapse for patients with liver-limited metastatic colorectal cancer (LL-mCRC) undergoing resection with curative intent are needed. Circulating tumor DNA (ctDNA) as a surrogate of postsurgical minimal residual disease is a promising marker in localized CRC. We explored the role of postoperative ctDNA as a marker of minimal residual disease in patients with radically resected LL-mCRC. Seventy-six patients with LL-mCRC were retrospectively included. DNA from tumor tissue was sequenced, and one somatic mutation was then assessed by digital droplet polymerase chain reaction in plasma samples collected after surgery to identify the persistence of ctDNA. Relapse-free survival and postresection overall survival were compared between patients with positive vs negative postoperative ctDNA. ctDNA was found in 39 (51%) of 76 patients with LL-mCRC. At a median follow-up of 77 months, 33 of 39 ctDNA-positive patients and 20 of 37 ctDNA-negative patients experienced disease relapse (P = .008). ctDNA-positive patients reported significantly shorter RFS than ctDNA-negative ones (median RFS 12.7 v 27.4 months hazard ratio, 2.09, P = .008). In the multivariable model including other prognostic covariates, this association was still significant (P = .046) and a trend toward shorter overall survival among ctDNA-positive patients was reported (hazard ratio, 1.65, P = .183). The detection of postsurgical ctDNA is an independent negative prognostic marker and identifies patients at high risk of relapse after liver metastases resection.

Effect of autologous hematopoietic stem cell transplantation on minimal residual disease in patients with multiple myeloma

Objective: To evaluate the effect of autologous hematopoietic stem cell transplantation (ASCT) on minimal residual disease (MRD) in patients with multiple myeloma (MM). Method: From August 2018 to August 2021, 92 patients newly diagnosed with MM who had received either the bortezomib combined with cyclophosphamide and dexamethasone (VCD) or the bortezomib, lenalidomide and dexamethasone (VRD) induction regimens followed by sequential ASCT were assessed for overall survival (OS) and the MRD negative rate. The differences in efficacy at 100 days after transplantation were assessed according to factors, including age, risk stratification, target organ damage, and pre-transplant regimen, etc. Results: Among the 92 patients, there were 45 males and 47 females, with a median age of 57.3 (35-67) years. Fifty-seven patients received the VCD regimen, and 35 received VRD as induction regimen. Forty-three patients received busulphan combined with cyclophosphamide and etoposide (BCV), and 49 patients received high-dose melphan (HDM) regimen as pre-transplantation treatment. After transplantation, the total complete remission (CR) rate of 92 patients increased from 23.9% (22/92) to 58.7% (54/92), and the MRD negative rate increased from 4.4% (4/92) to 33.7% (31/92), and the differences were statistically significant (all P<0.05). After transplantation, the MRD negative rates of patients with PR, VGPR and ≥CR before transplantation were 17.6% (6/34), 33.3% (12/36) and 59.1% (13/22), respectively (P=0.006). The CR rates of patients with or without plasmacytoma at initial diagnosis were 36.4% (4/11) and 65.4% (53/81), respectively (P=0.029), and the MRD negative rates were 18.2% (2/11) and 39.5% (32/81), respectively (P=0.037), and the differences were statistically significant. The MRD negative rates in high-risk patients and standard-risk group were 30.5% (12/28) and 42.9% (18/59), respectively (P=0.258). For patients who achieved efficacy above VGPR before transplantation, the MRD negative rates after transplantation in VCD-induced group and VRD group were 29% (9/31) and 59.3% (16/27), respectively (P=0.033), and in BCV group and HDM group were 24% (6/25) and 57.6% (19/33), respectively (P=0.016), the differences between the groups were both statistically significant. Conclusion: ASCT can overcome the adverse factors such as high-risk cytogenetic abnormalities, and significantly improve the CR rate and MRD negative rate of MM patients. However, the benefit for patients with plasmacytoma at initial diagnosis is not as good as that of patients without.