The 29th Annual Meeting of the European Hematology Association (EHA) was grandly held in Madrid, Spain, from June 13 to 16, 2024. As the largest international conference in the field of hematology in Europe, it attracts experts and scholars from all over the world each year to share and discuss innovative ideas and the latest scientific and clinical research results in hematology. At this year's EHA conference, two studies by Professor Li Wang's team from Ruijin Hospital, Shanghai JiaoTong University School of Medicine (abstracts P1716 and 2074), explored minimal residual disease (MRD) monitoring in diffuse large B-cell lymphoma (DLBCL) and the application of the new BTK inhibitor orelabrutinib in the treatment of indolent non-Hodgkin lymphoma (iNHL). Oncology Frontier - Hematology Frontier specially translated and organized the content of these two studies for readers' reference.

TUMOR-INFORMED CIRCULATING TUMOR DNA ANALYSIS FOR MINIMAL RESIDUAL DISEASE (MRD) MONITORING OF DIFFUSE LARGE B-CELL LYMPHOMA (Abstract P1716)

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma (NHL), accounting for 35% to 50% of newly diagnosed NHL cases each year. Despite the treatment response to standard immunochemotherapy (R-CHOP), 30% to 40% of DLBCL patients experience disease progression, leading to a high risk of mortality. Therefore, there is an urgent need for an accurate and convenient method to evaluate the effectiveness of early treatment. Using customized circulating tumor DNA (ctDNA)-based next-generation sequencing (NGS) to monitor MRD during immunochemotherapy can promote personalized treatment for DLBCL patients.

Objective: This study aimed to establish a practical technique and application strategy to dynamically assess ctDNA through tumor-informed analysis of cell-free DNA (cfDNA) in plasma before and after treatment, combined with a fixed panel, to predict prognosis and evaluate treatment response in DLBCL patients.

Methods: A total of 214 plasma samples from 107 enrolled patients were analyzed, with IPI scores of 0-1 (46%), 2-3 (41%), and 4-5 (14%). Plasma samples were collected at baseline (n=107) and on the first day of the second treatment cycle (C2D1, n=107, i.e., before the second cycle of treatment). A new tumor-informed detection technique was used in conjunction with a fixed panel covering 152 highly pathogenic genes in DLBCL patients for deep sequencing of tumor tissue samples, plasma cfDNA, and genomic DNA. Internal bioinformatics software was used to detect somatic mutations in cfDNA, with a variant allele frequency (VAF) cut-off value of 0.1%. Paired WBC samples were used to filter germline and clonal hematopoiesis mutations and identify tumor tissue noise. Bayesian Gaussian mixture models were employed to detect and quantify ctDNA, defining ctDNA positivity as a likelihood ratio test P-value <0.001. Mid-treatment PET-CT imaging was performed after three cycles of R-CHOP immunochemotherapy to evaluate treatment response.

Results: The median ctDNA quantity before treatment was 241 haploid genome equivalents (hGE/mL) per milliliter of plasma, with median levels of 42, 320, and 1040 hGE/mL for patients with IPI scores of 0-1, 2-3, and 4-5, respectively. Among the 67 patients who achieved complete remission (CR) at mid-treatment PET-CT assessment, 9% (6/67) were ctDNA-positive at C2D1, significantly lower than the 24% (8/34) in partial remission (PR) and 100% (4/4) in stable/progressive disease (SD/PD). For all patients with ctDNA positivity at C2D1, the median ctDNA levels were 15.8 hGE/mL in CR patients, 17.1 hGE/mL in PR patients, and 26.6 hGE/mL in SD/PD patients. Considering the changes in ctDNA levels in sequential sampling, the log10-transformed fold change in ctDNA reduction was 4.4 in CR patients, 4.3 in PR patients, and 2.0 in SD/PD patients, indicating potential guidance for treatment selection.

Conclusion: Tumor-informed ctDNA analysis provides an advantageous method for mid-treatment efficacy evaluation and prognosis prediction in DLBCL patients. Dynamic ctDNA quantification monitoring can also offer valuable information for guiding early strategic treatment choices.

ORELABRUTINIB IN PATIENTS WITH INDOLENT NON-HODGKIN LYMPHOMA (INHL) INTOLERANT TO PRIOR BRUTON TYROSINE KINASE INHIBITORS (BTKI): PRELIMINARY RESULTS FROM A PHASE 2 STUDY (Abstract P2074)

Background: The emergence of BTK inhibitors (BTKi) has revolutionized the treatment of various iNHLs, with current clinical strategies involving continuous, long-term BTKi application. Although BTKis are generally well-tolerated, they have unique safety issues, and treatment intolerance is a common reason for clinical discontinuation. Drug interruption can lead to early disease progression (PD) and shorter survival, and some patients who respond to BTKi discontinue treatment due to intolerance, representing an unmet clinical need. Orelabrutinib is an effective second-generation, irreversible BTKi with better BTK selectivity and tolerability.

Objective: This ongoing phase II study aims to evaluate the safety and efficacy of orelabrutinib in iNHL patients intolerant to prior BTKi treatments.

Methods: Patients aged ≥18 years with histologically confirmed chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), Waldenström macroglobulinemia (WM), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), or follicular lymphoma (FL), and intolerant to prior BTKi treatment were included. All enrolled patients received oral orelabrutinib (150 mg/day) until PD or unacceptable toxicity. The primary endpoint was safety, and secondary endpoints included hematological responses (improvements in hemoglobin [HB], platelet [PLT] counts, or lymphocyte responses [HB/PLT/lymphocyte count recovery or ≥50% increase from baseline]), imaging responses, and survival data.

Results: As of February 26, 2024, 47 patients (40 males; 33 CLL/SLL, 6 WM, 3 MCL, 4 MZL, 1 FL) received orelabrutinib treatment, with a median age of 68 years. 87% had an ECOG PS score of ≥1, and the median number of prior treatment lines was 2. Twenty patients (43%) were intolerant to ibrutinib, and 27 (57%) to zanubrutinib. Among the 47 patients, 110 adverse events (AEs) were reported, leading to BTKi discontinuation, mainly including anemia (43%), decreased platelet count (38%), and hypertension (32%); 15 patients (32%) experienced ≥3 grade AEs. After switching from previous BTKi to orelabrutinib, 46% (51/110) of AEs were resolved, and 18% (20/110) were reduced. Resolved or reduced AEs included hypertension (12/15, 80%), cardiac events (9/11, 82%), renal insufficiency (6/14, 43%), liver dysfunction (5/5, 100%), infection (2/2, 100%), and subcutaneous bleeding (1/1, 100%). AE profiles were similar for patients intolerant to ibrutinib or zanubrutinib. After orelabrutinib treatment, 32% (15/47) of patients experienced AEs, with 3% (2/47) being ≥3 grade, mostly hematologic toxicity (leukopenia, hypoalbuminemia, neutropenia, anemia [all at 6%]). Four patients (9%) experienced particularly noteworthy AEs (AESIs): 1 pulmonary infection, 1 elevated bilirubin, and 2 hyperuricemia. No treatment-related serious AEs or deaths occurred. Efficacy-wise, with a median follow-up of 3 months, the hematologic response rate (HRR) was 58% among 38 evaluable patients, with 5 of 13 responding patients meeting ≥2 criteria. No patients experienced PD at the data cutoff. Survival data are currently immature.

Conclusion: Orelabrutinib improved the AE profile for patients intolerant to previous BTKi treatments, particularly reducing off-target toxicity (cardiac/infectious AEs). Preliminary results suggest orelabrutinib has good efficacy and safety in iNHL patients intolerant to prior BTKi treatments.