Adults with primary central nervous system lymphoma (PCNSL) who are ineligible for consolidative whole-brain radiotherapy (WBRT) or autologous stem-cell transplantation (ASCT) due to advanced age, comorbidities, or impaired performance status have limited treatment options. Lenalidomide is active in relapsed PCNSL, but prospective data on its use as maintenance are limited. We conducted a multicenter phase II trial of lenalidomide maintenance in adults with PCNSL who achieved at least a partial response after 2–6 cycles of methotrexate- and rituximab-based chemoimmunotherapy and were not candidates for WBRT or ASCT. Lenalidomide 15 mg was given orally on days 1–21 of 28-day cycles for up to 12 cycles or until progression or toxicity. The primary endpoint was 2-year progression-free survival (PFS) from maintenance initiation. Thirty-one patients were enrolled (median age 72 years); 30 received lenalidomide with a median of 11 cycles, and 50% completed all 12. At a median follow-up of 20.7 months, the 2-year PFS was 58.8% (95% CI, 43.4–79.8%), exceeding the pre-specified alternative threshold of 55%, although the formal one-sample log-rank test did not reach statistical significance (p = 0.084). The 2-year overall survival was 83.9%. Grade 3–4 neutropenia occurred in 53.3%, whereas most non-hematologic adverse events were grade 1–2. Treatment was discontinued for toxicity in 13%; one grade 5 pneumonia occurred, and no thromboembolic events were observed. These findings suggest that lenalidomide maintenance is feasible and potentially beneficial in consolidation-ineligible PCNSL patients, though the hypothesis-generating nature of this single-arm study warrants confirmation in randomized comparative trials.

Bosmolisib is a novel triple inhibitor of PI3K-δ/γ and DNA-PK for malignancy treatment. This was a first-in-human, phase 1, open-label, dose-escalation, and dose-expansion trial with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL). Patients received bosmolisib orally once daily in 28-day cycles across four dose levels (50–325 mg) until disease progression or unacceptable toxicity. The study utilized a 3 + 3 dose-escalation design to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D), followed by expansion at RP2D. Primary endpoints were safety and MTD/RP2D determination; secondary endpoints included efficacy, pharmacokinetics, and pharmacodynamics. A total of 26 patients were enrolled in dose-escalation (N = 12) and dose-expansion (N = 14). Median age was 65 years with a median of 3 prior therapies. Bosmolisib demonstrated acceptable tolerability; dose-limiting toxicities were observed at 325 mg (alanine transaminase [ALT] increased and erythema multiforme), establishing MTD/RP2D at 200 mg. Most adverse events (AEs) were Grade 1–2, with the most common Grade ≥3 AEs (ALT 23.1%, aspartate transaminase 15.4%). Of 23 evaluable patients, the overall response rate (ORR) was 26.1%, and in PTCL patients, ORR was 31.6% with one patient achieving a durable complete response. Pharmacodynamics profiling showed statistically significant decrease in regulatory T-cells. These findings support evaluation of bosmolisib in a phase 2 trial (ClinicalTrials.gov number, NCT04018248).

Introduction:While anti-CD20 antibodies like obinutuzumab (OBI) have improved clinical outcomes, B-cell malignancies remain a significant therapeutic challenge. OBI induces direct cell death (DCD) and augments antibody-dependent cellular cytotoxicity (ADCC), but the molecular mechanisms involved in DCD remain unclear. This study aims to bridge this knowledge gap and develop enhanced treatment modalities. Methods:We employed an antibody-APEX2 proximity labeling platform to identify novel regulators of OBI-induced DCD. Mechanistic studies were conducted to evaluate lysosomal membrane permeabilization (LMP). Furthermore, we developed a new class of bioengineered antibody-lectin fusion proteins, termed "concabodies," and evaluated their efficacy through in vitro assays and ex vivo experiments using peripheral blood mononuclear cells (PBMCs) from patients with chronic lymphocytic leukemia (CLL). Results:Myelin protein zero-like 1 (MPZL1) was identified as a novel regulator of OBI-induced DCD, modulating LMP as a key characteristic. We found that concanavalin A (Con A) also triggers LMP and DCD via MPZL1-mediated internalization. The developed concabodies exhibited significantly enhanced DCD and ADCC while concurrently reducing the non-specific toxicity of free Con A. Notably, this enhanced cytotoxicity was maintained even in cells expressing a dominant-negative MPZL1Y241F mutant, and the concabodies efficiently depleted malignant B cells in CLL patient samples. Discussion:Taken together, this work establishes MPZL1 as a crucial molecular target for antibody-induced DCD and presents concabodies as a mechanistically rational and clinically relevant approach to improve the efficacy of anti-CD20 immunotherapy in B-cell malignancies.

Anbalcabtagene autoleucel (Anbal-cel) is a CD19-directed CAR T-cell therapy incorporating dual PD-1 and TIGIT knockdown to enhance antitumor function and durability. We report the results of a Phase 1/2 study in patients with relapsed or refractory large B-cell lymphoma (LBCL). In Phase 2, 79 patients received Anbal-cel, and efficacy was evaluated in 73 patients. The complete response (CR) and partial response (PR) rates were 67.1% and 8.2%, respectively. Median progression-free survival (PFS) was 6.04 months (95% CI, 4.34-16.46), and the 6-, 12-, and 18-month PFS rates were 50.9%, 41.1%, and 35.2%, respectively. Median overall survival (OS) was not reached, with 12- and 18-month OS rates of 66.6% and 57.3%. CAR T-cell expansion was significantly greater in responders than in non-responders (median Cmax: 20,403 vs. 8,580 copies/μg). Patients were categorized into long-term response (LR) group or non-LR group based on sustained CR at 6 months. Reduced PD-1 and TIGIT expression on CAR-positive T cells was observed in LR group. Most patients (97.5%) experienced grade ≥3 adverse events, most commonly neutropenia (93.7%), followed by thrombocytopenia (41.8%) and anemia (30.4%). Cytokine release syndrome and neurologic events occurred in 57.0% and 13.9% of patients, respectively. Grade 3 CRS occurred in 8.9% of patients, with no grade 4 events reported, and grade ≥3 neurologic events occurred in 3.8%. Serious infections occurred in 25.3% of patients, and grade 5 infection was reported in 3 patients. This trial was registered at Clinicaltrials.gov (NCT04836507).

Chronic lymphocytic leukemia (CLL) is uncommon in Asia, and longitudinal genomic data from Asian cohorts are limited. We conducted serial whole-exome sequencing (WES) in a multicenter Korean cohort of newly diagnosed, elderly CLL treated with chlorambucil-obinutuzumab to evaluate mutational heterogeneity and clonal hematopoiesis of indeterminate potential (CHIP) during treatment and follow-up. Tumor-only variants were filtered, restricted to nonsynonymous or loss-of-function coding/splice-site mutations, and summarized as a binary patient-by-gene matrix for principal component analysis (PCA), trajectory analysis, and k-means clustering. CHIP was defined as ≥1 qualifying mutation in a prespecified CHIP gene set. Baseline PCA was more compact in patients with complete response at end of treatment, whereas partial response or progressive disease cases were more dispersed. PCA trajectories were compact and directionally consistent in complete responders, more dispersed in partial responders, and highly heterogeneous without a dominant direction in progressive disease. Clustering identified dispersed and compact clusters, and CHIP-associated mutations were enriched in the dispersed cluster (55.6% vs. 8.3%, Fisher's exact p = 0.0086). In paired samples collected 3-5 months after end of treatment, CHIP status changed in some patients. Serial WES may provide complementary information to treatment response, although these observations require confirmation in larger cohorts.

Inotuzumab ozogamicin (InO), a CD22-targeted antibody-drug conjugate, delivers the cytotoxic agent, calicheamicin, to B-cell precursor of relapsed or refractory B-cell precursor acute lymphoblastic leukemia (R/R B-ALL) cells. It has demonstrated efficacy in phase 3 trials, leading to approval in multiple countries, including the U.S., Japan, and South Korea. In our post-marketing surveillance (PMS) study, we evaluated the safety and effectiveness of InO in adults with R/R B-ALL based on approximately 5 years of PMS data. A prospective, observational, multicenter PMS study was conducted in Korea to evaluate the real-world safety and effectiveness of InO in adult patients with R/R B-ALL (NCT04307134). A total of 107 patients were included in the safety analysis, with a median treatment duration of 43.0 days and a median of 2.0 InO cycles. Common adverse events (AEs) were hematologic (58.9

CD44 is a cell-surface glycoprotein frequently overexpressed in cancers and associated with poor prognosis. We evaluated the prognostic significance of CD44 overexpression in multiple myeloma (MM) and investigated the therapeutic efficacy of combining natural killer (NK) cell therapy with all-trans retinoic acid (ATRA) and bortezomib (Bor) against CD44-overexpressing MM. Clinical data from the CoMMpass database were analyzed to assess survival outcomes relative to CD44 expression. NK cells were expanded from healthy donors using K562-OX40L-mbIL-18/21 feeder cells supplemented with interleukin (IL)-2 and IL-15. Functional assays were performed using CD44-high myeloma cell lines treated with ATRA and Bor, individually or in combination with NK cells. Therapeutic efficacy was evaluated based on tumor growth, systemic dissemination, and survival in an intravenous U266–green fluorescent protein–firefly luciferase xenograft NOD/SCID IL-2Rγnull mouse model. Clinical data showed CD44 overexpression correlated with inferior overall survival (P < 0.0001) in all three stages I, II, and III of the revised International Stage System. In vitro, ATRA and Bor co-treatment downregulated β-catenin and CD44 expression, inhibited proliferation, migration, and invasion, and enhanced NK cell-mediated cytotoxicity via upregulation of MICA/B, Fas, TRAIL-R2, and intercellular adhesion molecule-1. In vivo, combination therapy with NK cells, ATRA, and Bor significantly suppressed CD44 expression, reduced extramedullary spread, and prolonged survival without notable toxicity. These preclinical findings support CD44 overexpression as a marker associated with inferior survival in MM and provide a rationale for pharmacologic tumor priming with ATRA and bortezomib to enhance NK cell-mediated cytotoxicity. However, the therapeutic strategy requires further validation in heterogeneous patient-derived models and prospective clinical studies before clinical efficacy can be inferred.

Background: Pneumocystisjiroveci pneumonia (PJP) is a common but serious opportunistic infection after allogeneic hematopoietic cell transplantation (HCT). The preferred regimen for PJP prophylaxis is trimethoprim-sulfamethoxazole (TMP-SMX), but TMP-SMX can delay engraftment and has some toxicities. This study retrospectively analyzed the efficacy and safety of aerosolized pentamidine (AP) as an alternative to TMP-SMX for PJP prophylaxis after allogeneic HCT. Methods: One hundred and fifty-five patients received AP and 86 patients received TMP-SMX. Pentamidine isethionate 300 mg was nebulized every 4 weeks and double-strength TMP-SMX was administrated once-daily and 2 days per week. Results: Incidences of suspicious PJP and confirmed PJP were not statistically different between two groups (suspicious PJP, 4.5% vs. 3.5%, P = 1.000; confirmed PJP, 0.6% vs. 0.0%, P = 1.000). There were fewer adverse reaction in AP group than TMP-SMX group (10.3% vs. 26.7%, P < 0.001). Only 1 patient (0.6%) discontinued prophylaxis due to adverse reaction in AP group, while 17 patients (19.8%) in TMP-SMX group discontinued prophylaxis due to adverse reaction (P < 0.001). There was more incidence of graft failure in TMP-SMX group and the incidence of prolonged thrombocytopenia was significantly higher in TMP-SMX group. There was no deterioration of lung function in patients received AP prophylaxis. Conclusion: In conclusion, AP is well tolerated without severe adverse events and effective in preventing PJP after allogeneic HCT.

Background: Polycythemia vera (PV) is a myeloproliferative neoplasm driven by JAK2 V617F mutations. Ropeginterferon alfa-2b effectively reduces both hematologic parameters and JAK2 allele burden, but molecular monitoring is not always readily available. Objectives: To evaluate whether a ⩾50% reduction in the neutrophil-to-lymphocyte ratio (NLR) can serve as a surrogate marker of hematologic and molecular response during ropeginterferon therapy. Design: Secondary analysis of a multicenter, phase II, open-label trial in South Korea. Methods: Ninety-five patients with PV received ropeginterferon alfa-2b biweekly for 48 weeks. NLR and JAK2 allele burden were serially measured, and generalized estimating equations and logistic regression were used to assess associations. Results: NLR half reduction significantly predicted hematologic response (week 24 OR 6.42, p = 0.001) and molecular response consistently across all time points (week 24 OR 27.94, p < 0.001). Conclusion: NLR half reduction is a simple, cost-effective biomarker that may reflect molecular response and treatment efficacy in PV.

Diffuse large B cell lymphoma (DLBCL) displays genetic and clinical heterogeneity that limits the predictive value of cell-of-origin and LymphGen. We evaluated whether diagnostic targeted next generation sequencing (NGS) could predict outcomes and delineate high-risk subsets in routine practice. We retrospectively analyzed tumors from 106 patients. Variants with allele frequency(VAF) ≥ 10

Relapsed/refractory extra-nodal natural killer/T-cell lymphoma (R/R ENKTL) has limited treatment options. Danburstotug, an antibody targeting programmed death-ligand 1 (PD-L1), was evaluated in adults with R/R ENKTL in a phase 2, open-label study (NCT04414163). Danburstotug 20 mg/kg was administered intravenously every 2 weeks up to 52 cycles, disease progression or unacceptable toxicity. In the full analysis set (n = 19), objective response rate (ORR; primary end-point) was 78.9% (95% confidence interval 54.4-94.0); complete response (CR) rate was 63.2% (38.4-83.7); 76.9% of participants maintained responses; and 90.9% of participants maintained CR for 2 years. In the intention-to-treat population (n = 23), median progression-free survival (PFS) was 29.4 months (12.0-46.9; 2-year PFS rate 62.1%); and median overall survival was 40.2 months (25.1-55.4; 2-year overall survival rate 77.9%). Treatment-emergent adverse events occurred in 91.3% of 23 participants (73/83 events were grade 1/2); grade 3 serious treatment-related adverse events comprised liver injury and uveitis (one participant each). High PD-L1 membrane specificity (MS) was associated with greater ORR, CR rate and PFS versus low PD-L1 MS. In tumour immune microenvironment assessments, clinical benefit was observed across immune tolerance and immune evasion subtypes, despite lower PD-L1 expression in immune evasion-B. Danburstotug demonstrated robust, durable efficacy and manageable safety. PD-L1 MS showed potential as a predictive biomarker.

Abstract Background In recent decades, there has been an escalation in the prevalence of obese patients with Inflammatory Bowel Disease (IBD).1-3 In addition, the correlation between Body Mass Index (BMI) at the time of diagnosis and the prognostic implication shows controversial results. Our study aims to assess the changes in BMI among Korean patients with IBD over a 14-year period and to explore how BMI at diagnosis impacts prognosis. Methods We gathered data from patients diagnosed with IBD at Asan Medical Center, Korea, between 2008 and 2021 and analysed weight, height, and laboratory data. We calculated the median BMI and mean value of laboratory data for each year, using these results as representative values for the respective years. Also, patients assessed for BMI at the time of diagnosis were further analysed for intestinal resection-free and medication-free survival using the prospectively managed registry data. Results From January 2008 to December 2021, 11,216 patients with IBD, comprising 5,502 with Crohn's disease (CD) and 5,714 with ulcerative colitis (UC), accounted for 277,179 visits. The median BMI of included patients significantly increased over the study period, from 21.2 kg/m2 in 2008 to 23.0 kg/m2 in 2021 (p-value for trend <0.001) This trend was more apparent in CD than UC, and male than female (Figure 1a, 1c) Over the years, the gap in the prevalence of obese (BMI ≥25 kg/m2) individuals between those with IBD and the general population has narrowed. (Figure 1b, 1d) Serum glucose and lipid profiles showed an upward trend during the study period. The odds of intestinal resection and the use of biologics or small molecules were comparable or even lower in CD patients who were obese at diagnosis compared to patients with a normal BMI. Obese patients with UC demonstrated a similar cumulative probability of using thiopurines and biologics or small molecules. Obesity was inversely associated with the risk of thiopurine use in CD patients (adjusted hazard ratio: 0.61, 95% confidence interval: 0.48–0.78, p<0.001, Table 1) Conclusion During a 14-year period, Korean IBD patients showed increasing trends in the prevalence of obese individuals and metabolic syndrome-associated laboratory results. CD patients with high BMI at diagnosis exhibited a similar or lower likelihood of undergoing intestinal resection and medication use compared to those with a normal BMI. It is important to acknowledge the prevalence of obesity among patients with IBD and to give increased attention to the consequences associated with metabolic syndrome, as well as the clinical outcomes related to IBD. References 1.Nic Suibhne T, Raftery TC, McMahon O, et al. High prevalence of overweight and obesity in adults with Crohn's disease: associations with disease and lifestyle factors. J Crohns Colitis. 2013;7:e241-8 2.Singh S, Dulai PS, Zarrinpar A, et al. Obesity in IBD: epidemiology, pathogenesis, disease course and treatment outcomes. Nat Rev Gastroenterol Hepatol. 2017;14:110-21 3.Seminerio JL, Koutroubakis IE, Ramos-Rivers C, et al. Impact of Obesity on the Management and Clinical Course of Patients with Inflammatory Bowel Disease. Inflamm Bowel Dis. 2015;21:2857-63.

Abstract Background/Aims Allogeneic stem cell transplantation (allo-SCT) is a curative option in adult patients with acute lymphoblastic leukemia (ALL) even in the era of immunotherapy. A successful transplant requires a suitable stem cell donor, and patients must overcome transplant-related mortality, including infections and graft-versus-host disease (GVHD). In this study, we investigated long-term survivals of the adult ALL patients who received allo-SCT. Factors affecting prognosis were also analyzed. Methods We retrospectively analyzed the adult patients with ALL who received allo-SCT between 2009 to 2022 years using the Korean Society of Blood and Marrow Transplantation registry. Event-free survival (EFS) was determined from the date of transplantation to the date of disease progression or death from any cause. Overall survival (OS) was determined from the date of allo-SCT to the date of death or last follow-up. Results A total of 756 ALL patients were enrolled in this study: 369 patients with Philadelphia chromosome (Ph) negative ALL, 267 patients with Ph-positive ALL, and 129 patients with T-ALL. At the time of transplantation, the median ages for Ph-negative ALL, Ph-positive ALL, and T-ALL were 41.2, 45.2, and 34.8 years, respectively. The 2-year EFS for Ph-negative ALL, Ph-positive ALL, and T-ALL were 49.2%, 57.2%, and 43.9%, respectively, and the 2-year OS were 53.5%, 63.1%, and 47.3%, respectively. In the Kaplan-Meier survival curve, long-term outcomes of the patients with complete remission (CR) 1 were significantly superior compared to the CR2. Significantly better outcomes for both EFS and OS were identified in patients with Human Leukocyte Antigens (HLA) full matched donors than those with haploidentical donors. Total body irradiation (TBI) was a favorable factor in patients with T-ALL. The intensity of conditioning regimen did not affect prognosis. The post-transplant cyclophosphamide strategy tended to be superior in terms of GVHD and early mortality in the haploidentical donor transplant group. Of the patients enrolled in this study, 64 underwent secondary transplantation, in which 38 patients were Ph-negative ALL, 15 were Ph-positive ALL, and 11 were T-ALL. The median EFS and OS for all patients who underwent secondary allo-SCT were 7.6 and 7.9 months, respectively. There was no significant survival difference in secondary transplant outcomes according to disease subtype. However, transplant outcomes in patients who achieved CR showed significantly superior EFS and OS compared to the group of patients transplanted with active disease status. Using TBI was identified as a favorable prognostic factor while, haploidentical donor was an adverse factor in secondary transplantation. Conclusion Allo-SCT could improve survival outcomes in patients who achieved CR1. Using HLA full-matched donor showed better outcomes in both patients with first- and secondary transplantation. In the secondary allo-SCT, TBI was a favorable prognostic factor.

Purpose:Primary breast diffuse large B-cell lymphoma (DLBCL) is a rare entity with a distinct relapse pattern involving the central nervous system (CNS). However, data regarding predictors of CNS relapse in this population remain limited. Materials and Methods:CNS relapse was retrospectively analyzed in two multicenter cohorts comprising 53 patients with newly diagnosed primary breast DLBCL, including a prospective trial and real-world cohort, all treated with rituximab-based immunochemotherapy. The impact of baseline clinical parameters, cell-of-origin, and MYC/BCL2 dual expression (DE) status on CNS relapse was assessed using a multivariate Cox regression model, separately conducted for the overall study set (n=53) and the immunohistochemical study set (n=36). Results:By the CNS-International Prognostic Index (CNS-IPI), most patients were classified as low or intermediate risk; no patients were classified as high risk. With a median follow-up of 58.8 months, the 4-year risk of CNS relapse was 15.6% in the overall study set and 14.2% in the immunohistochemical set. MYC/BCL2 DE was identified in 14 patients (38.9%) and was significantly associated with increased risk of CNS relapse (4-year risk, 30.7% vs. 0%, p=0.001). Patients with non-germinal center B-cell-like subtype had a numerically higher risk of CNS relapse. However, in multivariate analysis, only MYC/BCL2 DE status was associated with CNS relapse. Synchronous bilateral involvement was also an independent predictor of CNS relapse in both study sets. CNS-IPI was not discriminatory for CNS relapse. Conclusion:MYC/BCL2 DE and synchronous bilateral breast involvement may help identify patients at higher risk for CNS relapse. Further studies are warranted.

Purpose of the Report The usefulness of brain 18 F-FDG PET/CT in primary central nervous system lymphoma (PCNSL) remains underexplored. This study investigated whether early metabolic responses in interim brain FDG PET/CT serve as a prognostic indicator of PCNSL treatment outcomes. Patients and Methods This prospective study included 53 patients with PCNSL who underwent a high-dose methotrexate–based treatment. Brain FDG PET was performed at diagnosis (baseline PET) and after induction chemotherapy (interim PET), assessing interim PET parameters such as the highest maximum standardized uptake value (hSUV max ), sum of SUV max (sumSUV max ), highest tumor-to-normal ratio (hTNR max ), sum of TNR max (sumTNR max ), highest metabolic tumor volume (MTV) (hMTV), and sum of MTV (sumMTV) across all PET-positive lesions. Results High interim hTNR max (hazards ratio: 9.76, 95% confidence interval: 1.90–50.11, P = 0.01) was an independently significant predictor of poor progression-free survival in multivariate analysis. Patients with low interim hTNR max (≤1.0) had a significantly longer median progression-free survival than those with high interim hTNR max (>1.0) (25.0 vs 3.6 months, P < 0.001). Incorporating interim MRI-based clinical response assessments and hTNR max allowed the classification of partial response subgroups with markedly different prognoses ( P < 0.001). High interim hTNR max (hazards ratio: 2.76, 95% confidence interval: 1.39–5.48, P = 0.004) was an independently significant predictor of poor overall survival in multivariate analysis. Conclusions The hTNR max measurement from interim brain FDG PET scans emerges as an important prognostic marker in PCNSL. These findings underscore the potential of interim FDG PET evaluations to refine response assessments and inform tailored therapeutic strategies.

Purpose:Relapsed or refractory (R/R) primary central nervous system lymphoma (PCNSL) is an aggressive malignancy for which salvage chemotherapy has limited efficacy. We conducted an investigator-initiated, single-arm, multicenter phase II trial to evaluate the efficacy and safety of a chemotherapy-free salvage regimen comprising rituximab, lenalidomide, and poseltinib (R2P) in patients with R/R PCNSL. Materials and Methods:The R2P regimen consisted of two phases: six cycles of induction with rituximab, lenalidomide, and poseltinib, followed by three cycles of consolidation with lenalidomide and poseltinib. The primary endpoints were complete response rate (CRR) and overall response rate (ORR). Secondary endpoints were toxicity, progression-free survival (PFS) and overall survival (OS). Results:A total of 10 patients were enrolled (one withdrew before cycle 1; nine were evaluable for efficacy). The median age was 70 years (range, 53-75), and all had received methotrexate-based first-line chemotherapy. The ORR was 55.6%, and the CRR was 33.3%. The median PFS was 5.6 months, and the median OS was not reached. Next-generation sequencing was performed in four patients (three responders and one non-responder). CD79B missense mutations were identified in all three responders. A total of 11 adverse events (AEs) were observed in six patients. The most common AE was neutropenia (30.0%). The only grade ≥3 AE was a single case of grade 3 neutropenia. No dose modifications were required due to toxicity. Conclusion:Poseltinib in combination with lenalidomide and rituximab showed activity in patients with R/R PCNSL, warranting further investigation in larger studies.

Abstract Background: Polycythemia vera (PV), the most common myeloproliferative neoplasm, is characterized by clonal proliferation of cells from the erythroid, myeloid, and megakaryocytic cells. Ropeginterferon alfa-2b, a long-acting mono-pegylated interferon, has shown promise in improving tolerability and reducing dosing frequency. In the PROUD/CONTINUATION-PV study, achieved sustained complete hematologic response (CHR) and molecular response (MR) with favorable tolerability. However, data on long-term response maintenance and predictive factors are limited. Aims: This study aimed to evaluate the durability of CHR and MR and identify factors associated with sustained responses in PV patients treated with ropeginterferon alfa-2b. Methods: In this investigator-initiated, single-arm, open-label phase 2 study conducted at 16 institutions in Korea, PV patients who required cytoreductive therapy were treated with ropeginterferon alfa-2b using a rapid dose-escalation regimen (250→350→500 mcg every 2 weeks for 48 weeks). After initial CHR achievement, dosing intervals were adjusted based on CHR stability. CHR and MR were assessed at regular 12-week intervals through week 108. Maintenance was defined as continuous achievement of CHR or MR from initial response, and loss as any subsequent failure. Kaplan–Meier methods estimated maintenance rates. Univariate and multivariate Cox proportional hazards models identified predictors of response loss. Results: As of January 3, 2025, 95 patients were enrolled; 77 completed 2-year treatment. The CHR rates were 25 of 94 (26.6%) at 12 weeks, 40 of 87 (46.0%) at 24 weeks, 47 of 84 (56.0%) at 36 weeks, 51 of 81 (63.0%) at 48 weeks, 56 of 77 (72.7%) at 60 weeks, 55 of 77 (71.4%) at 72 weeks, 58 of 77 (75.3%) at 84 weeks, 57 of 77 (74.0%) at 96 weeks, and 63 of 77 (81.8%) at 108 weeks, respectively. Corresponding MR rates were 28 of 88 (31.8%), 29 of 81 (35.8%), 38 of 77 (49.4%), 42 of 74 (56.8%), 52 of 74 (70.3%), 51 of 74 (68.9%), 54 of 74 (73.0%), 56 of 74 (75.7%), 59 of 74 (79.7%). Among 73 patients who achieved CHR at least once, 54 (68.4%) maintained it; among 63 patients who achieved MR at least once with baseline JAK2 V617F allele burden ≥10%, 54 (85.7%) maintained it. In the univariate Cox analysis, longer time to first CHR predicted higher risk of CHR loss (HR 1.01, 95% CI 1.01–1.21, p=0.03), while female showed a lower likelihood of CHR loss compared to male (HR=0.16, 95% CI 0.05-0.57, p=0.004). Additionally, patients with higher baseline alkaline phosphatase (ALP) levels were more prone to sustained CHR than those with lower ALP levels (HR=0.98, 95% CI 0.96-1.00, p=0.04). However, time to first MR did not predict MR loss (HR 1.00, 95% CI 0.88–1.14, p=1.00).Conclusion: This study demonstrates that a rapid dose-escalation strategy of ropeginterferon alfa-2b achieved high rates of both CHR and MR with durable maintenance in patients with PV who required cytoreductive therapy. Notably, earlier achievement of CHR was significantly associated with sustained long-term CHR maintenance, highlighting the importance of prompt therapeutic response from the perspective of the timely treatment optimization. These results underscore the need for treatment strategies that prioritize earlier CHR achievement to ensure durable long-term remission.

Diffuse large B cell lymphoma (DLBCL) exhibits profound genetic heterogeneity that drives disparate clinical outcomes despite standard immunochemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). Although emerging treatments such as bispecific T-cell engagers and chimeric antigen receptor (CAR) T-cell therapy provide additional options, a substantial proportion of patients still experience relapse or refractory disease. Molecular classifiers including cell-of-origin and the LymphGen algorithm have improved prognostic stratification, yet some patients remain unclassified or lack clear guidance. Moreover, the clinical utility of diagnostic targeted gene sequencing at presentation remains controversial. We therefore hypothesized that applying a targeted lymphoma panel together with machine-learning feature selection and unsupervised clustering would uncover novel high-risk subgroups and refine prognostic stratification beyond existing frameworks. We retrospectively sequenced formalin-fixed paraffin-embedded tumors from newly diagnosed DLBCL patients (median age 69.0 years [IQR 59.0–75.5], 56 percent male) using a deep hybrid-capture assay targeting known lymphoma drivers, chromatin modifiers and epigenetic regulators. Sequence reads were aligned to GRCh37 with BWA, variants were called by GATK and non-synonymous mutations with variant allele frequency ≥10% were annotated via the Ensembl Variant Effect Predictor. A Random Forest regression model with 1 000 trees and ten-fold cross-validation selected the top 30 genes prognostic for progression-free survival (PFS) and overall survival (OS). Principal component analysis on these features followed by k-means clustering (k = 2) defined two molecular clusters. Survival endpoints were assessed by Kaplan–Meier analysis with log-rank testing (two-sided p < 0.05). Cluster 2 was distinguished by a high prevalence of adverse alterations in ATM, TP53, CREBBP, TNFAIP3, CARD11 and TNFRSF14, and by unexpected enrichment of KMT2C and TET2, genes more commonly implicated in other malignancies and not previously highlighted in DLBCL. Feature importance measures revealed that established drivers such as B2M, PTEN, NCOR1, TP53 and CREBBP ranked among the top predictors for OS, while novel candidate genes including PCDH20, NFATC1, UBXN11, SMARCA1 and PDGFRB also emerged. For PFS, canonical genes TP53, ATM, TET2 and KMT2C were prioritized alongside less characterized loci such as KLHL6, CIITA and SMARCA1. Clinically, cluster 2 patients had significantly higher Ann Arbor stage and International Prognostic Index scores than cluster 1, and tended toward elevated lactate dehydrogenase levels. Well-known prognostic clinical factors thus correlate closely with our gene-based stratification. Kaplan–Meier curves showed significantly inferior PFS in cluster 2 compared with cluster 1 (median PFS not reached versus 24 months, p = 0.02), while OS differences did not reach statistical significance (p = 0.11). Within the MCD LymphGen subtype, normally associated with favorable outcomes, patients in cluster 2 experienced both significantly worse PFS and OS (p < 0.05), underscoring substantial heterogeneity within established subtypes. The prognostic value of our clustering remained significant after adjustment for stage, IPI and lactate dehydrogenase, demonstrating concordance with known clinical risk factors. These results establish that targeted gene sequencing, when combined with machine-learning-driven feature selection and unsupervised clustering, can identify a novel high-risk DLBCL subgroup not captured by current classification systems. The originality of this study lies in the demonstration that machine learning can uncover both canonical and non-canonical genetic drivers and that the resulting cluster retains prognostic factor even within existing LymphGen subtypes. Moreover, our high-risk clustering provides a genetic framework that explains previously recognized clinical prognostic factors. This approach highlights previously unrecognized genes of biological and therapeutic relevance, supports early identification of relapse-prone patients and may inform personalized, risk-adapted therapy. Prospective multicenter validation and functional studies of the high-risk cluster are warranted to advance precision medicine in DLBCL.