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Liquid biopsy is now considered a valuable diagnostic tool for advanced metastatic non-small cell lung cancer (NSCLC). In NSCLC, circulating tumor DNA (ctDNA) analysis has been shown to increase the chances of identifying the presence of targetable mutations and has been adopted by many clinicians owing to its low risk. Serial monitoring of ctDNA may also help assess the treatment response or for monitoring relapse. As the presence of detectable plasma ctDNA post-surgery likely indicates residual tumor burden, studies have been performed to quantify plasma ctDNA to assess minimal residual disease (MRD) in early-stage resected NSCLC. Most data on utilizing liquid biopsy for monitoring MRD in early-stage NSCLC are from small-scale studies using ctDNA. Here, we review the recent research on liquid biopsy in NSCLC, not limited to ctDNA, and focus on novel methods such as micro RNAs (miRNA) and long non-coding (lncRNA).

Background The survival rate for patients with relapsed and refractory acute myeloid leukaemia (R/R-AML) remains poor, and treatment is challenging. Chimeric antigen receptor T cells (CAR-T cells) have been widely used for haematologic malignancies. Current CAR-T therapies for acute myeloid leukaemia mostly target myeloid-lineage antigens, such as CD123 and CD33, which may be associated with potential haematopoietic toxicity. As a lineage-specific receptor, CD7 is expressed in acute myeloid leukaemia cells and T cells but is not expressed in myeloid cells. Therefore, the use of CD7 CAR-T cells for R/R-AML needs to be further explored. Methods In this report, immunohistochemistry and flow cytometry were used to analyse CD7 expression in clinical samples from R/R-AML patients and healthy donors (HDs). We designed naturally selected CD7 CAR-T cells to analyse various functions and in vitro antileukaemic efficacy based on flow cytometry, and xenograft models were used to validate in vivo tumour dynamics. Results We calculated the percentage of cells with CD7 expression in R/R-AML patients with minimal residual disease (MRD) (5/16, 31.25%) from our institution and assessed CD7 expression in myeloid and lymphoid lineage cells of R/R-AML patients, concluding that CD7 is expressed in T cells but not in myeloid cells. Subsequently, we designed and constructed naturally selected CD7 CAR-T cells (CD7 CAR). We did not perform CD7 antigen knockdown on CD7 CAR-T cells because CD7 molecule expression is naturally eliminated at Day 12 post transduction. We then evaluated the ability to target and kill CD7 + acute myeloid leukaemia cells in vitro and in vivo. Naturally selected CD7 CAR-T cells efficiently killed CD7 + acute myeloid leukaemia cells and CD7 + primary blasts of R/R-AML patients in vitro and significantly inhibited leukaemia cell growth in a xenograft mouse model. Conclusion Naturally selected CD7 CAR-T cells represent an effective treatment strategy for relapsed and refractory acute myeloid leukaemia patients in preclinical studies.

Background Moxetumomab pasudotox is a recombinant CD22-targeting immunotoxin. Here, we present the long-term follow-up analysis of the pivotal, multicenter, open-label trial (NCT01829711) of moxetumomab pasudotox in patients with relapsed/refractory (R/R) hairy cell leukemia (HCL). Methods Eligible patients had received ≥ 2 prior systemic therapies, including ≥ 2 purine nucleoside analogs (PNAs), or ≥ 1 PNA followed by rituximab or a BRAF inhibitor. Patients received 40 µg/kg moxetumomab pasudotox intravenously on Days 1, 3, and 5 of each 28-day cycle for up to six cycles. Disease response and minimal residual disease (MRD) status were determined by blinded independent central review. The primary endpoint was durable complete response (CR), defined as achieving CR with hematologic remission (HR, blood counts for CR) lasting > 180 days. Results Eighty adult patients were treated with moxetumomab pasudotox and 63% completed six cycles. Patients had received a median of three lines of prior systemic therapy; 49% were PNA-refractory, and 38% were unfit for PNA retreatment. At a median follow-up of 24.6 months, the durable CR rate (CR with HR > 180 days) was 36% (29 patients; 95% confidence interval: 26–48%); CR with HR ≥ 360 days was 33%, and overall CR was 41%. Twenty-seven complete responders (82%) were MRD-negative (34% of all patients). CR lasting ≥ 60 months was 61%, and the median progression-free survival without the loss of HR was 71.7 months. Hemolytic uremic and capillary leak syndromes were each reported in ≤ 10% of patients, and ≤ 5% had grade 3–4 events; these events were generally reversible. No treatment-related deaths were reported. Conclusions Moxetumomab pasudotox resulted in a high rate of durable responses and MRD negativity in heavily pre-treated patients with HCL, with a manageable safety profile. Thus, it represents a new and viable treatment option for patients with R/R HCL, who currently lack adequate therapy. Trial registration ClinicalTrials.gov identifier: NCT01829711; first submitted: April 9, 2013. https://clinicaltrials.gov/ct2/show/NCT01829711

Background Consolidative allogeneic hematopoietic stem cell transplantation is a controversial option for patients with relapsed/refractory acute lymphoblastic leukemia after chimeric antigen receptor T cell (CAR-T) therapy. We performed a multicenter retrospective study to assess whether patients can benefit from haploidentical hematopoietic stem cell transplantation after CAR-T therapy. Methods A total of 122 patients after CAR-T therapy were enrolled, including 67 patients without subsequent transplantation (non-transplant group) and 55 patients with subsequent haploidentical hematopoietic stem cell transplantation (transplant group). Long-term outcome was assessed, as was its association with baseline patient characteristics. Results Compared with the non-transplant group, transplantation recipients had a higher 2-year overall survival (OS; 77.0% versus 36.4%; P < 0.001) and leukemia-free survival (LFS; 65.6% versus 32.8%; P < 0.001). Multivariate analysis showed that minimal residual disease (MRD) positivity at transplantation is an independent factor associated with poor LFS ( P = 0.005), OS ( P = 0.035), and high cumulative incidence rate of relapse ( P = 0.045). Pre-transplant MRD-negative recipients (MRD− group) had a lower cumulative incidence of relapse (17.3%) than those in the non-transplant group (67.2%; P < 0.001) and pre-transplant MRD-positive recipients (MRD+ group) (65.8%; P = 0.006). The cumulative incidence of relapse in MRD+ and non-transplant groups did not differ significantly ( P = 0.139). The 2-year LFS in the non-transplant, MRD+, and MRD− groups was 32.8%, 27.6%, and 76.1%, respectively. The MRD− group had a higher LFS than the non-transplantation group ( P < 0.001) and MRD+ group ( P = 0.007), whereas the LFS in the MRD+ and non-transplant groups did not differ significantly ( P = 0.305). The 2-year OS of the MRD− group was higher than that of the non-transplant group (83.3% versus 36.4%; P < 0.001) but did not differ from that of the MRD+ group (83.3% versus 62.7%; P = 0.069). The OS in the non-transplant and MRD+ groups did not differ significantly ( P = 0.231). Conclusion Haploidentical hematopoietic stem cell transplantation with pre-transplant MRD negativity after CAR-T therapy could greatly improve LFS and OS in patients with relapsed/refractory acute lymphoblastic leukemia. Trial registration The study was registered in the Chinese clinical trial registry ( ChiCTR1900023957 ).

Lymphoma is a highly heterogeneous lymphohematopoietic tumor. As our understanding of the biological and pathological characteristics of lymphoma improves, we are identifying an increasing number of lymphoma subtypes. Genotyping has enhanced our ability to diagnose, treat, and monitor the prognosis of lymphoma. Despite significant improvements in treatment effectiveness, traditional methods for assessing disease response and monitoring prognosis are imperfect, and there is no significant improvement in overall remission rates for lymphoma patients. Minimal Residual Disease (MRD) is often indicative of refractory disease or early relapse. For lymphoma patients, personalized MRD monitoring techniques offer an efficient means to estimate disease remission levels, predict early relapse risk, and assess the effectiveness of new drug regimens. In this review, we delve into the MRD procedures in lymphoma, including sample selection and requirements, detection methods and their limitations and advantages, result interpretation. Besides, we also introduce the clinical applications of MRD detection in lymphoma.

Background The feasibility of DNA methylation-based assays in detecting minimal residual disease (MRD) and postoperative monitoring remains unestablished. We aim to investigate the dynamic characteristics of cancer-related methylation signals and the feasibility of methylation-based MRD detection in surgical lung cancer patients. Methods Matched tumor, tumor-adjacent tissues, and longitudinal blood samples from a cohort (MEDAL) were analyzed by ultra-deep targeted sequencing and bisulfite sequencing. A tumor-informed methylation-based MRD (timMRD) was employed to evaluate the methylation status of each blood sample. Survival analysis was performed in the MEDAL cohort ( n  = 195) and validated in an independent cohort (DYNAMIC, n  = 36). Results Tumor-informed methylation status enabled an accurate recurrence risk assessment better than the tumor-naïve methylation approach. Baseline timMRD-scores were positively correlated with tumor burden, invasiveness, and the existence and abundance of somatic mutations. Patients with higher timMRD-scores at postoperative time-points demonstrated significantly shorter disease-free survival in the MEDAL cohort (HR: 3.08, 95% CI: 1.48–6.42; P  = 0.002) and the independent DYNAMIC cohort (HR: 2.80, 95% CI: 0.96–8.20; P  = 0.041). Multivariable regression analysis identified postoperative timMRD-score as an independent prognostic factor for lung cancer. Compared to tumor-informed somatic mutation status, timMRD-scores yielded better performance in identifying the relapsed patients during postoperative follow-up, including subgroups with lower tumor burden like stage I, and was more accurate among relapsed patients with baseline ctDNA-negative status. Comparing to the average lead time of ctDNA mutation, timMRD-score yielded a negative predictive value of 97.2% at 120 days prior to relapse. Conclusions The dynamic methylation-based analysis of peripheral blood provides a promising strategy for postoperative cancer surveillance. Trial registration This study (MEDAL, ME thylation based D ynamic A nalysis for L ung cancer) was registered on ClinicalTrials.gov on 08/05/2018 (NCT03634826). https://clinicaltrials.gov/ct2/show/NCT03634826 .

B-cell lymphoma, the most common subtype of non-Hodgkin lymphoma, presents major therapeutic challenges due to molecular heterogeneity and high relapse rates. While autologous hematopoietic stem cell transplantation (ASCT) has been a cornerstone for relapsed/refractory (R/R) B-cell lymphoma, its efficacy is often compromised by minimal residual disease (MRD) persistence and an immunosuppressive tumor microenvironment. Chimeric antigen receptor (CAR)-T cell therapy has transformed treatment paradigms but faces limited long-term durability due to antigen escape and T-cell exhaustion. The integration of ASCT with CAR-T therapy may offer a complementary approach to address these limitations, leveraging ASCT-induced immune reconstitution to enhance CAR-T-cell persistence and reprogram the tumor milieu. Emerging clinical evidence supports this approach, indicating improved disease control and progression-free survival. Although preliminary clinical outcomes are encouraging, unresolved challenges persist, particularly in terms of cumulative toxicity, optimal therapeutic sequencing, CAR-T-cell longevity, and financial feasibility associated with these advanced therapies. This review provides a comprehensive overview of mechanistic synergies between ASCT and CAR-T therapy, critically evaluates emerging clinical evidence on treatment sequencing, and explores innovative strategies to increase safety, efficacy, and accessibility. Graphical Abstract

The current standard treatment for patients with early-stage colon cancer consists of surgical resection, followed by adjuvant therapy in a select group of patients deemed at risk of cancer recurrence. The decision to administer adjuvant therapy, intended to eradicate the clinically inapparent minimal residual disease (MRD) to achieve a cure, is guided by clinicopathologic characteristics of the tumor. However, the risk stratification based on clinicopathologic characteristics is imprecise and results in under or overtreatment in a substantial number of patients. Emerging research indicates that the circulating tumor DNA (ctDNA), a fraction of cell-free DNA (cfDNA) in the bloodstream that originates from the neoplastic cells and carry tumor-specific genomic alterations, is a promising surrogate marker of MRD. Several recent studies suggest that ctDNA-guided risk stratification for adjuvant therapy outperforms existing clinicopathologic prognostic indicators. Preliminary data also indicate that, aside from being a prognostic indicator, ctDNA can inform on the efficacy of adjuvant therapy, which is the underlying scientific rationale for several ongoing clinical trials evaluating ctDNA-guided therapy escalation or de-escalation. Furthermore, serial monitoring of ctDNA after completion of definitive therapy can potentially detect cancer recurrence much earlier than conventional surveillance methods that may provide a critical window of opportunity for additional curative-intent therapeutic interventions. This article presents a critical overview of published studies that evaluated the clinical utility of ctDNA in the management of patients with early-stage colon cancer, and discusses the potential of ctDNA to transform the adjuvant therapy strategies.

Background The predictive importance of IKZF1 del in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) has shown variability across different studies. Thus, the optimal treatment approach for children with IKZF1 del BCP-ALL remains contentious, with the ongoing debate surrounding the use of IKZF1 del -based high-risk stratification versus a minimal residual disease (MRD)-guided protocol. Methods IKZF1 status was reliably determined in 804 patients using multiplex ligation-dependent probe amplification (MLPA) data obtained from four hospitals in Fujian, a province of China. In the Chinese Children Leukemia Group (CCLG)-ALL 2008 cohort, IKZF1 status was included in the risk assignment, with all IKZF1 del patients receiving a high-risk regimen. Conversely, in the Chinese Children’s Cancer Group (CCCG)-ALL 2015 cohort, IKZF1 del was not incorporated into the risk assignment, and patients were treated based on an MRD-guided risk stratification protocol. Results IKZF1 del was found in 86 patients (86/804, 10.7%) overall and in 30 (30/46, 65.2%) BCR::ABL1 -positive patients. Overall, IKZF1 del was a poor prognostic predictor for patients, though the significance diminished upon age adjustment, white blood cell (WBC) count at diagnosis, treatment group, and MRD status. In the CCLG-ALL 2008 cohort, IKZF1 del conferred a notably lower 5-year overall survival (OS) and event-free survival (EFS) and a significantly higher 5-year cumulative incidence of relapse (CIR) than IKZF1 wt . In the CCLG-ALL 2015 cohort, IKZF1 del conferred a lower 5-year OS and EFS and a higher 5-year CIR than IKZF1 wt , but the differences were insignificant. The IKZF1 del patients treated with higher intensity chemotherapy (CCLG-ALL 2008 high-risk regimen) had a markedly lower 5-year OS and EFS compared with those treated with the MRD-guided protocol (CCCG-ALL 2015 protocol). Furthermore, patients treated with the CCLG-ALL 2008 high-risk regimen experienced a higher frequency of serious adverse events (SAEs), especially infection-related SAEs, compared with those treated with the CCCG-ALL 2015 MRD-guided protocol. Conclusions The prognostic effect of IKZF1 del may vary in different protocols. Compared with higher intensity chemotherapy, the MRD-guided protocol may be a more effective approach to treating BCP-ALL with IKZF1 del in children.

Introduction: Despite the approval of novel agents that have significantly improved long-term survival rates for multiple myeloma (MM) patients undergoing autologous stem cell transplant (ASCT), most patients eventually relapse. The failure to achieve or maintain bone marrow (BM) minimal residual disease (MRD) negativity is a recognised adverse prognostic factor for progression-free survival (PFS) and overall survival (OS). Contamination of stem cell apheresis by clonal plasma cells may also affect prognosis, though data remain limited. Methods: We conducted a prospective, single-centre observational study including 100 newly diagnosed MM patients eligible for ASCT and treated with bortezomib-based triplet induction. MRD was assessed both on BM and apheresis samples using multiparameter flow cytometry (MFC-MRD) with a sensitivity of 10−5. Results: Clonal plasma cells were detected in 22 apheresis samples (aMRD+), all of which were associated with BM MRD positivity. Patients with aMRD+ had inferior pre-ASCT responses (≥VGPR: 10% vs. 63%, p = 0.005) and worse post-ASCT BM MRD negativity rates (4% vs. 49%, p = 0.048). After a median follow-up of 52.4 months, aMRD+ was associated with shorter progression-free survival (median 38.5 vs. not reached, p = 0.007) and overall survival (median 60 months vs. not reached, p = 0.003). Conclusions: Contamination of the apheresis product is associated with persistent BM disease and poorer outcomes. Combined MRD assessment in both bone marrow and apheresis may improve risk stratification in MM patients undergoing ASCT.