Rios‐Olais, Fausto Alfredo

e19023 Background: Undetectable measurable residual disease (uMRD) is associated with prolonged progression free survival in patients with chronic lymphocytic leukemia (CLL) (Rios-Olais et al., 2024). Peripheral blood (PB) MRD testing is less invasive and allows more frequent MRD monitoring than bone marrow (BM) MRD testing. As MRD testing and MRD-guided time-limited therapies become more common, there is a need to determine the concordance between rates of uMRD in the PB and BM. Methods: We performed a systematic review and meta-analysis of studies in CLL to determine the concordance between rates of uMRD in the PB and BM. Prospective clinical trials evaluating first-line, time-limited treatment of CLL with targeted agents or anti-CD20 monoclonal antibodies (mAbs) were identified via searches of PubMed, Embase, Scopus, and Web of Science from inception until December 15 th , 2025. Studies were included if they reported rates of BM and PB uMRD at the same timepoint using the same method of MRD testing. Study arms evaluating chemotherapy, single-agent targeted therapy or single-agent anti-CD20 mAbs were excluded. Study sample size, number of patients receiving MRD testing, rates of uMRD in PB and BM, time and method of MRD testing, depth of MRD testing, and treatment arm were extracted. The agreement of uMRD rates between PB and BM was assessed using intraclass correlation coefficients (ICC). Results: 3128 studies were identified on initial search. After study selection criteria were applied, 24 timepoints across 12 prospective clinical trials were analyzed. Across all timepoints, 3121 PB and 2782 BM MRD measurements were included. All timepoints defined uMRD at a depth of under 0.01% CLL cells (10^-4). 20/24 timepoints utilized flow cytometry for MRD testing, 3 utilized allele-specific oligonucleotide PCR (ASO-PCR), and one utilized next-generation sequencing (NGS). 8 timepoints evaluated patients treated with a BTK inhibitor + venetoclax, 10 evaluated patients treated with venetoclax + an anti-CD20 mAb, and 6 evaluated patients treated with triplet therapy. The ICC between rates of uMRD in PB and BM was 0.925 (95% CI: 0.89, 0.95), indicating an excellent degree of agreement between the two methods of testing.(Koo & Li, 2016) The mean uMRD rates in PB and BM were 70.1% and 64.3%, respectively. The mean rate of uMRD in the PB was 5.87% (95% CI: -7.05, 18.80%) higher than in the BM; indicating a consistent slight bias of higher PB uMRD rates compared to BM across timepoints. Conclusions: Overall, we demonstrate that in patients with CLL treated with modern, time-limited therapy, there is high concordance in uMRD rates between PB and BM. Rates of uMRD in the PB are typically slightly higher than in BM.

Portal vein thrombosis in non-cirrhotic individuals, although uncommon, is an increasingly explored condition that affects mainly young people, consequently representing a significant disease burden. Reports primarily including western European populations have recently shed light regarding the pathophysiology, risk factors, natural history, treatment, and prognosis of this entity. Underlying predisposing conditions are documented in ~70% of cases, encompassing local risk factors, inherited and acquired thrombophilia, cancer, and systemic inflammatory conditions. Non-cirrhotic portal vein thrombosis can cause significant portal hypertension in the acute setting, but, more frequently, significant portal hypertension-related complications arise when the condition becomes chronic and portosystemic collaterals develop, increasing the risk for variceal bleeding and ascites. The diagnostic approach to screen for underlying thrombophilia remains a challenge, and recommendations in this regard, although scarce and backed by scarce evidence, have changed notably in the last years, leaning toward a universal screen in patients who develop this condition without a clear provoking factor. Recently, studies have shown that long-term anticoagulation may be appropriate even in the absence of clear provoking factors or underlying thrombophilia. Future studies should address which patients may benefit from this approach, which patients may not need it, and what the most appropriate strategies are to approach patients who do not recover portal vein patency with anticoagulation to further prevent portal hypertension-related complications.

Background Bispecific antibodies (bsAbs) have gained momentum during the last several years in the treatment of hematological malignancies. Their novel mechanism of action has resulted in improvement in outcomes of patients with hematological malignancies refractory and/or relapsing after conventional therapies. This resulted in 7 regulatory approvals of bsAbs by the US FDA to treat hematological malignancies. Excluding blinatumomab, all have gained accelerated approval through phase II trials to treat relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL); primarily diffuse large B-cell lymphoma (DLBCL and follicular lymphoma (FL), and R/R multiple myeloma (MM). Although these agents are associated with overall response rates (ORR) of greater than 50% in heavily treated patients, the real-world eligibility and response to these therapies in the United States is not known. Methods We aimed to estimate the number of US patients with NHL and MM who are eligible for and may respond to FDA approved bsAbs for R/R NHL and MM. A person was considered to be eligible for treatment with a bsAb if they had the FDA approved indication and inclusion criteria. We defined response based on the best available response rate for that indication from the FDA drug label. We used the incidence rate of NHL and MM from American Cancer Society's Cancer Facts and Figures during the years each bsAb had an approval. We made assumptions to estimate eligibility by incorporating attrition rates between lines of therapy according to what is published in the literature. For NHL, we assumed 75% of NHL diagnoses are DLBCL, while 20% are FL. For DLBCL, we assumed that 30% (10% primary refractory and 20% in relapse) of newly diagnosed DLCBL would receive a second-line therapy; of these patients, we assumed that 50% would proceed to receive a bsAb as third-line therapy. For FL, we assumed that 75% of newly diagnosed FL patients are grade 1-3A; of these, 85% will require first-line treatment, and 13% of these patients will eventually relapse to receive a bsAb as third-line therapy. For MM, we assumed that 14% of newly diagnosed MM will eventually be triple class refractory (refractory to a proteasome inhibitor, an immunomodulatory drug, and a monoclonal antibody) patients potentially eligible to receive a bsAb. The calculated number of people eligible was multiplied by the overall response rate (ORR) reported in the trial that led to the bsAb approval for each year a therapy had an approval, using the highest calculated response, to estimate the population who would potentially benefit of these therapies. Results Six bsAbs were approved in the US since 2022 to treat NLH and MM: epcoritamab and glofitamab in 2023 to treat R/R DLBCL and other mature B-cell neoplasms, mosunetuzumab in 2022 and epcoritamab in 2024 to treat R/R grade 1-3A FL, and for MM, teclistamab in 2022, and elranatamab and talquetamab in 2023. All of them were authorized via accelerated approval after a phase II trial. There were 80550 and 80620 new NHL cases in 2023 and 2024, respectively, and 12640, 12590, and 12540 new MM cases in 2022, 2023, and 2024, respectively. Of these, we estimated 21033 DLCBL patients would be potentially eligible to receive bsAbs since 2023, 2733 FL patients potentially eligible to receive bsAbs since 2023, and 5666 MM patients potentially eligible to receive bsAbs since 2022. The percentage of patients per year that were potentially eligible for bsAbs was 13% for DLCBL, 8.5% for FL, and 15% for MM. Based on best available response rates from registration trials, we estimated that 9.6% and 10.5% newly diagnosed NHL and MM patients, respectively, would potentially benefit from bsAbs. Conclusions Even though CR and ORR of bsAbs are high for highly pretreated patients, we found the percentage of newly diagnosed NHL and MM patients who would become potentially eligible and would respond to these therapies to be quite low (approximately only 1 out of 10). Even though these conclusions are driven by best-case scenario assumptions and have a risk of bias, they provide insights of the actual impact and reach of these newer therapies.

ImportanceMeasurable residual disease (MRD) refers to the presence of disease at low levels not detected by conventional pathologic analysis. The association of MRD status as a surrogate end point of clinical outcome in chronic lymphocytic leukemia (CLL) has not been established in the era of targeted agents. Assessing the association of MRD with progression-free survival (PFS) may improve its role as a surrogate marker and allow its use to accelerate drug development.ObjectiveTo assess the association between MRD and PFS in CLL using data from prospective clinical trials that studied targeted agents or obinutuzumab-based treatment.Data SourcesClinical studies on CLL were identified via searches of PubMed, Embase, Scopus, and Web of Science from inception through July 31, 2023.Study SelectionProspective, single-arm, and randomized clinical trials that assessed targeted agents or obinutuzumab-based treatment and reported PFS by MRD status were included. Studies with insufficient description of MRD information were excluded.Data Extraction and SynthesisStudy sample size, median patient age, median follow-up time, line of treatment, MRD detection method and time points, and survival outcomes were extracted.Main Outcomes and MeasuresAnalyses of survival probabilities and hazard ratios (HRs) were conducted for PFS according to MRD status. Meta-analyses were performed using a random-effects model.ResultsA total of 11 prospective clinical trials (9 randomized and 2 nonrandomized) including 2765 patients were analyzed. Achieving undetectable MRD (uMRD) at 0.01% was associated with an HR of 0.28 (95% CI, 0.20-0.39; P < .001) for PFS. Median PFS was not reached in both groups (uMRD vs MRD), but the estimated 24-month PFS was better in the uMRD group (91.9% [95% CI, 88.8%-95.2%] vs 75.3% [95% CI, 64.7%-87.6%]; P < .001). The association of uMRD with PFS was observed in subgroup analyses in the first-line treatment setting (HR, 0.24; 95% CI, 0.18-0.33), relapsed or refractory disease setting (HR, 0.34; 95% CI, 0.16-0.71), and trials using time-limited therapy (HR, 0.28; 95% CI, 0.19-0.40).Conclusions and RelevanceThe findings of this systematic review and meta-analysis suggest that assessing MRD status as an end point in clinical trials and as a surrogate of PFS may improve trial efficiency and potentially allow for accelerated drug registration.