Research Appraisals
Evidence-based critical appraisals of the latest medical research, systematically evaluated using Oxford CEBM methodology.
Showing 10 appraisals
Blood advances
Phase 1 study of zanubrutinib plus lenalidomide for patients with relapsed/refractory diffuse large B-cell lymphoma
Patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) typically have a poor prognosis. In preclinical studies, lenalidomide and a Bruton tyrosine kinase (BTK) inhibitor demonstrated synergistic antitumor effects. Zanubrutinib, a next-generation BTK inhibitor, has greater selectivity to minimize off-target binding. BGB-3111-110 was a phase 1 multicenter dose-escalation/-expansion study. Patients with R/R DLBCL received zanubrutinib 160 mg twice daily plus lenalidomide (15, 20, or 25 mg once daily) until progression or unacceptable toxicity. Primary end points were safety, recommended phase 2 dose (RP2D), and overall response rate (ORR; Lugano 2014 criteria). Sixty-six patients were enrolled and treated. Patients had a median of 2 previous therapies, 83% had stage III/IV disease, and ∼67% had non-geminal center B-cell-like or activated B-cell-like DLBCL. No dose-limiting toxicities occurred; the lenalidomide RP2D was 25 mg once daily when combined with zanubrutinib 160 mg twice daily. Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 74%; the most common (>20%) grade ≥3 TEAEs were decreased neutrophil count (58%) and decreased white blood cell count (29%). TEAEs led to 7 treatment discontinuations (11%) and 2 deaths (3%). At the RP2D, ORR and complete response rate were 58% and 42%, respectively; median time to response was 2.8 months. Median duration of response was 14.9 months. Median progression-free survival was 5.5 months (95% confidence interval [CI], 2.9-11.1); the 12-month event-free rate was 34% (95% CI, 21-48). Zanubrutinib plus lenalidomide demonstrated acceptable tolerability and antitumor activity in patients with R/R DLBCL. This trial was registered at www.clinicaltrials.gov as NCT04436107.
9 June 2026
Read appraisal →Clinical chemistry and laboratory medicine
T-cell receptor beta constant 1 flow cytometry for diagnosing clonality in mature T-cell neoplasms: a systematic review and meta-analysis of diagnostic accuracy
INTRODUCTION: Accurate assessment of T-cell clonality is key for diagnosing mature T-cell neoplasms. TRBC1-based flow cytometry provides a rapid, robust, and cost-efficient approach. This systematic review and meta-analysis assessed the diagnostic accuracy of TRBC1 flow cytometry (TRBC1-FC) for detecting T-cell clonality in mature T-cell neoplasms. CONTENT: We systematically searched Scopus, PubMed (MEDLINE), and Google Scholar for articles on TRBC1-FC diagnostic accuracy published up to July 1, 2025. Pooled sensitivity and specificity were estimated, between-study heterogeneity was evaluated and small-study effects were examined. SUMMARY: This meta-analysis included 10 studies. The pooled sensitivity was 97.6 % (95 % CI, 95.1-99.4 %) and specificity 90.7 % (95 % CI, 76.0-99.3 %). The pooled LR+ was 10.9 (95 % CI, 4.1-28.9), LR-was 0.053 (95 % CI, 0.025-0.12), and DOR 339 (95 % CI, 64-1,788). The HSROC curve demonstrated an AUC of 0.974 (partial AUC=0.970), confirming excellent global discriminatory capacity. Between-study heterogeneity was substantial (I2=83.3 %), mainly affecting specificity and DOR, while sensitivity remained highly consistent. No evidence of a threshold effect was found. Deeks' test showed significant small-study effects (p<0.001), and sensitivity analyses identified one influential study whose exclusion markedly reduced heterogeneity. These results confirm the high diagnostic performance and robustness of TRBC1-FC for T-cell clonality assessment. OUTLOOK: TRBC1-FC demonstrates high sensitivity and low LR-, supporting its role as a rule-out test. Variability in specificity, LR+ and DOR, mainly due to small-study effects, advises caution for rule-in use. Standardized protocols and cost-effectiveness analyses are needed before broad clinical adoption.
26 May 2026
Read appraisal →Journal for immunotherapy of cancer
Clinical outcomes and spatial transcriptomic profiles of CD19/20 CAR-T therapy in relapsed or refractory B-cell non-Hodgkin's lymphoma
BACKGROUND: Relapsed or refractory (R/R) B-cell non-Hodgkin's lymphoma (B-NHL) remains a major therapeutic challenge despite CD19-directed chimeric antigen receptor (CAR) T-cell therapies, with treatment failure often driven by antigen escape and limited CAR-T persistence. Dual targeting of CD19 and CD20 may mitigate antigen loss. We conducted an expanded phase I/II study of bispecific CD19/20 CAR-T cells and incorporated spatially resolved single-cell transcriptomics to evaluate tumor-intrinsic and microenvironmental factors of clinical response. METHODS: Patients with R/R B-NHL received CD19/20 CAR-T cells following lymphodepletion. Efficacy, safety, CAR-T expansion/persistence, and B-cell reconstitution were assessed. Pretreatment tumor biopsies from five patients with divergent outcomes underwent spatial single-cell transcriptomic profiling. RESULTS: 32 patients were treated, including 24 with diffuse large B-cell lymphoma. Among 31 evaluable patients, the best overall response rate was 74%, including 58% achieving complete remission. Median progression-free and overall survival were 6.8 and 22.1 months, respectively. Response rates were higher in patients with normal lactate dehydrogenase. CAR-T expansion peaked on days 7-17, and persistence exceeded 500 days in long-term responders. Cytokine release syndrome occurred in 53% (12% grade ≥3) and immune effector cell-associated neurotoxicity syndrome in 9% (all grade 3), with no lasting deficits. Spatial profiling identified two dominant tumor architectures: (1) a B-cell-dominant phenotype, in which durable remission was associated with heightened apoptotic competence in malignant B cells, and (2) a fibroblast-enriched and monocyte/macrophage-enriched phenotype, in which response correlated with a chemokine-rich, T-cell-permissive microenvironment. CONCLUSIONS: Bispecific CD19/20 CAR-T therapy produced durable clinical activity with manageable toxicity. Spatial single-cell analysis reveals distinct tumor-intrinsic and microenvironmental features associated with CAR-T responsiveness, providing a spatially informed framework for understanding heterogeneous therapeutic outcomes. TRIAL REGISTRATION NUMBER: NCT04723914.
18 May 2026
Read appraisal →Lancet (London, England)
Addition of autologous stem-cell transplantation to an ibrutinib-containing first-line treatment in patients aged 18-65 years with mantle cell lymphoma (TRIANGLE): 4·5-year follow-up of a three-arm, randomised, open-label, phase 3 superiority trial of the European MCL Network
BACKGROUND: Adding ibrutinib to standard, first-line immunochemotherapy improves failure-free survival in adult patients aged 18-65 years with mantle cell lymphoma, according to the first results from the TRIANGLE trial. With prolonged follow-up, we investigated whether the addition of autologous stem-cell transplantation (ASCT) to an ibrutinib-containing regimen improves failure-free survival, and evaluated effects on overall survival. METHODS: We conducted a three-arm, randomised, open-label, phase 3 superiority trial (TRIANGLE) in 165 secondary or tertiary clinical centres, with experience in mantle cell lymphoma treatment and the capability to perform ASCT or an association with such a centre, in 13 European countries and Israel. Patients aged 18-65 years with untreated, stage II-IV mantle cell lymphoma and suitable for ASCT were randomly assigned (1:1:1) to control group A or experimental groups A + I or I. Randomisation was done using computer-generated random numbers and stratified by study groups and Mantle Cell Lymphoma International Prognostic Index risk groups. Treatment in group A consisted of six alternating, 21-day cycles of R-CHOP (intravenous rituximab 375 mg/m2 on day 0 or 1, cyclophosphamide 750 mg/m2 on day 1, doxorubicin 50 mg/m2 on day 1, vincristine 1·4 mg/m2 on day 1 [up to a maximum of 2 mg], and oral prednisone 100 mg on days 1-5) and R-DHAP or R-DHAOx (intravenous rituximab 375 mg/m2 on day 0 or 1, intravenous or oral dexamethasone 40 mg on days 1-4, high-dose intravenous cytarabine 2 × 2 g/m2 for 3 h every 12 h on day 2, plus either intravenous cisplatin 100 mg/m2 over 24 h on day 1 [R-DHAP] or intravenous oxaliplatin 130 mg/m2 on day 1 [R-DHAOx]), followed by ASCT. In group A + I, oral ibrutinib (560 mg daily) was added on days 1-19 of R-CHOP cycles and as 2-year maintenance after ASCT. In group I, ibrutinib was given the same way, but ASCT was omitted. Rituximab maintenance was allowed in all treatment groups according to national guidelines. Three pairwise, one-sided, log-rank tests for the primary outcome (failure-free survival) were statistically monitored. The primary analysis was by intention to treat and included all randomly assigned patients, ignoring protocol deviations. Safety was assessed in randomly assigned patients who started any trial treatment component of the respective treatment phase. The trial is registered with ClinicalTrials.gov (NCT02858258) and is complete. FINDINGS: Between July 29, 2016, and Dec 28, 2020, 870 patients (662 [76%] were male, 208 [24%] were female) were randomly assigned to group A (n=288), group A + I (n=292), or group I (n=290). After median follow-up of 54·9 months (95% CI 54·4-56·0), group A + I did not show superiority over group I, with 4-year failure-free survival of 82% (95% CI 78-87) versus 81% (76-86; hazard ratio [HR] 0·86 [one-sided 98·33% CI 0·00-1·27]; one-sided p=0·21). Group A + I remained superior to group A (82% [78-87] vs 70% [65-76]; HR 0·63 [one-sided 98·33% CI 0·00-0·89]; one-sided p=0·0026) and, as before, group A did not show superiority over group I (70% [65-76] vs 81% [76-86]; HR 1·45 [one-sided 98·33% CI 0·00-2·02]; one-sided p=0·99). 4-year overall survival was 88% (95% CI 84-92) in group A + I versus 81% (76-85) in group A (HR 0·59 [95% CI 0·38-0·92], p=0·0036) and 90% (87-94) in group I versus 81% (76-85) in group A (0·57 [0·36-0·90], p=0·0019). During maintenance or follow-up, the most common grade 3-5 adverse events were haematological disorders, reported in 127 (54%) of 234 patients in group A + I versus 74 (28%) of 269 in group I and 56 (23%) of 240 patients in group A, and infections, reported in 80 (34%) of 234 patients in group A + I versus 71 (26%) of 269 in group I and 37 (15%) of 240 patients in group A. Infections and infestations were the most common fatal adverse events during maintenance or follow-up, occurring in four (2%) of 234 patients in group A + I and five (2%) of 269 patients in group I. INTERPRETATION: After a prolonged follow-up of 55 months, both ibrutinib-containing groups showed relevant improvements not only in failure-free survival-a modified form of progression-free survival-but also in overall survival. In contrast, the addition of ASCT to an ibrutinib-containing regimen had no supplementary benefit but increased toxicity. Induction treatment with ibrutinib and R-CHOP plus R-DHAP (or R-DHAOx), followed by 2 years of maintenance treatment with ibrutinib, should be considered as a new standard of care for younger patients with mantle cell lymphoma. FUNDING: Janssen.
18 May 2026
Read appraisal →Blood
Evolution of tumor subclones and T-cell dynamics underlie variable ibrutinib responses in Waldenström macroglobulinemia
To elucidate the molecular basis underlying differential responses and resistance to ibrutinib in Waldenström macroglobulinemia (WM), we conducted a prospective phase 2 trial of ibrutinib monotherapy in treatment-naïve patients. A total of 74 sequential bone marrow (BM) aspirates from 17 patients, collected from baseline through 48 treatment cycles, were profiled using single-cell multiomics. BM cells were segregated primarily into B-cell/plasma cell and T-cell compartments. Longitudinal clonal tracking of malignant B cells/plasma cells identified 3 distinct evolutionary patterns: evolution (early clone contraction with late clone expansion and increasing genomic complexity), devolution (early clone expansion with late clone contraction and genomic simplification), and no evolution (stable clonal architecture). The evolution pattern was strongly associated with disease progression, whereas devolution correlated with durable clinical response. Transcriptomic profiling of resistant clones enabled development and validation of the Waldenström ibrutinib prediction (WIP) score, which predicted treatment response at baseline. Within the WIP signature, LYN emerged as a key regulator; LYN knockdown or inhibition significantly increased WM cell sensitivity to ibrutinib, suggesting a rational combination strategy. In parallel, GZMB+ CD8+ effector-memory T cells expanded after treatment in patients with progressive disease and coexisted with tumor evolution. These cells exhibited persistently impaired cytotoxic programs (eg, GNLY), a dedifferentiated memory-like state, elevated PDCD1 expression, and reduced T-cell receptor diversity. Together, this study provides, to our knowledge, the first single-cell framework of tumor clonal evolution and T-cell dysfunction under ibrutinib in WM, introduces the WIP score as a predictive biomarker for treatment response, and identifies actionable tumor-intrinsic and immune mechanisms driving resistance. This trial was registered at www.ClinicalTrials.gov as NCT02604511.
16 May 2026
Read appraisal →Signal transduction and targeted therapy
Abexinostat, a histone deacetylases inhibitor, for patients with relapsed or refractory follicular lymphoma: a multi-center, single-arm phase 2 study
This phase 2, single-arm, multi-center study (NCT03934567) evaluates the efficacy and safety of abexinostat, a histone deacetylase inhibitor, in patients with relapsed or refractory (r/r) follicular lymphoma (FL). Eligible participants had previously received a minimum of two systemic treatment lines, such as cytotoxic agents and/or anti-CD20 monoclonal antibodies. Participants received abexinostat 80 mg oral twice daily on a schedule of seven days on and seven days off, within 28-day cycles, continuing until unacceptable toxicity or disease progression occurred. The primary endpoint was objective response rate (ORR), evaluated by an independent review committee (IRC). Secondary endpoints comprised duration of response (DoR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Between May 2, 2019, and November 19, 2023, 90 patients were enrolled. As of October 08, 2024, with a median follow-up of 30.55 months (95% confidence interval [CI] 23.72-33.64), 17.8% (16/90) of patients were still on study treatment. The ORR was 69.5% (57/82, 95% CI 58.4-79.2), with a complete response rate of 14.6% (12/82). The DCR was 91.5% (75/82, 95% CI 83.2-96.5). Tumor size reduced in 89% (73/82) of patients. The median DoR was 13.96 months (95% CI 9.20-not reached [NR]) and the median PFS was 13.80 months (95% CI 9.69-30.26). The median OS was 47.18 months (95% CI 45.70-NR). The most common treatment-emergent adverse events were thrombocytopenia (77/90, 85.6%), neutropenia (53/90, 58.9%), and leukopenia (47/90, 52.2%). The results of this study demonstrated that abexinostat had promising efficacy and manageable safety profile, supporting abexinostat as a new treatment option for the third-line or later-line treatment of r/r FL.
2 May 2026
Read appraisal →Blood advances
Zamtocabtagene autoleucel in relapsed/refractory B-NHL: 5-year follow-up of a CD20/19 tandem CAR T-cell phase 1 trial
Emerging long-term data indicate relapse rates of >50% after CD19-redirected chimeric antigen receptor (CAR) T-cell therapy in relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL). To reduce selective pressure on the CD19 antigen, we conducted a first-in-human phase 1 clinical trial of zamtocabtagene autoleucel (zamto-cel), a noncryopreserved tandem CD20-CD19-directed CAR T-cell therapy. Two predefined dose levels (dose level 1 [DL1], 1 × 106 and DL2, 2.5 × 106 CAR+ T cells per kg bodyweight) were applied. The primary end point (EP) was the maximum tolerated dose (MTD). Secondary EPs included adverse events, best overall response (BOR), and biomarker assessments. A total of 12 patients, 6 patients per DL, were treated. No dose-limiting toxicity and no cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome of grade ≥3 were observed. Thus, MTD was not reached. The BOR by investigator assessment was 75%, with 5 of 12 patients (42%) achieving complete remission (CR) until month 12 with no relapse in clinical evaluation up to 5 years after infusion. CR was associated with a higher mean maximum observed concentration of zamto-cel and detection of zamto-cel beyond month 6. Additional product characterization revealed increased expression of CD27 and CD127 along with increased expansion of CAR+ central memory T cells in patients with CR, facilitating persistence and improved outcomes in R/R B-NHL treated with zamto-cel. Based on the promising risk-to-benefit ratio, evaluation of zamto-cel at DL2 is ongoing in pivotal phase 2 clinical trials for patients with R/R aggressive B-NHL. This trial was registered at www.ClinicalTrials.gov as NCT03870945.
15 Apr 2026
Read appraisal →Blood advances
Treatment and survival outcomes for patients with follicular lymphoma and POD24: a systematic review and meta-analysis
Follicular lymphoma with progression of disease within 24 months (POD24) is associated with poor prognosis and represents clinical challenges. Therefore, we performed a systematic review and pooled analysis of patients with POD24. Twenty-one trials involving 1242 participants were included, assessing the overall response rate (ORR), complete response (CR), duration of response, and progression-free survival. In some trials, we compared pooled response rates between POD24 and non-POD24 populations with the same treatment regimen. Four trials evaluated chimeric antigen receptor (CAR) T-cell therapy in patients with POD24. Pooled analysis showed an ORR of 91.2% (95% confidence interval [CI], 83.7-98.7) with significant heterogeneity (P = .0414; I2 = 68.61%) and a CR of 75.7% (95% CI, 55.1-96.4) with significant heterogeneity (P< .0001; I2 = 93.99%). The specific response rates for different bispecific antibodies in POD24 were pooled analysis, the ORR was 81.6% (95% CI, 75.9-87.3) with no heterogeneity (P = .6958; I2 = 0%), and the CR was 65.7% (95% CI, 57.1-74.3) with moderate heterogeneity (P = .2148; I2 = 34.99%). For anti-CD19 antibody-drug conjugates (ADCs)/monoclonal antibodies (mAbs), the ORR and CR rate for loncastuximab plus rituximab and tafasitamab plus R2 (lenalidomide + rituximab) were 100% and 79.3%, and 87.5% and 43.2%, respectively. Phosphatidylinositol 3-kinase inhibitors and anti-CD20 mAb-containing regimens were also analyzed in pooled analyses. Our results demonstrated that anti-CD19 CAR T-cell therapy achieved the highest CR rate. Additionally, bispecific antibodies, anti-CD19 ADCs/mAbs, and the combination of lenalidomide with obinutuzumab or rituximab also exhibited excellent efficacy. Notably, lenalidomide plus obinutuzumab showed superior efficacy compared with R2.
15 Apr 2026
Read appraisal →Journal for immunotherapy of cancer
Anti-TIM-3 antibody TQB2618 in combination with penpulimab in relapsed or refractory classic Hodgkin lymphoma previously treated with PD-1/PD-L1 therapy: a multicenter, open-label, single-arm, phase Ib clinical trial
BACKGROUND: Immune checkpoint inhibitors achieve high response rates in relapsed or refractory (r/r) classical Hodgkin lymphoma (cHL), but few treatment options are available for patients who experience failure after PD-1/PD-L1 blockade. T cell immunoglobulin and mucin-domain containing-3, a key mediator of immune escape from PD-1/PD-L1 inhibition, is targeted by TQB2618, a humanized IgG4 monoclonal antibody. This phase Ib study aimed to evaluate the safety and efficacy of TQB2618 in combination with the anti-PD-1 antibody penpulimab in patients with r/r cHL. METHODS: This multicenter phase 1b study was conducted from June 2022 to September 2024 at 12 sites in China (NCT05400876). The study included a dose-escalation phase in which patients with r/r lymphoma received TQB2618 (600 or 1200 mg, every 3 weeks, Q3W) plus penpulimab (200 mg, Q3W) to evaluate dose-limiting toxicities and determine the recommended phase II dose (RP2D). The subsequent dose-expansion phase enrolled patients with r/r cHL previously treated with PD-1/PD-L1 inhibitors to assess the objective response rate (ORR). RESULTS: 10 patients with r/r lymphoma were enrolled in the dose-escalation phase, and TQB2618 (600 mg, Q3W) plus penpulimab (200 mg, Q3W) was selected as the RP2D. In the dose-expansion phase, 18 additional patients with r/r cHL previously treated with PD-1/PD-L1 inhibitors were enrolled. Among the total 21 r/r cHL patients, the median age was 32 years (range, 22-65), and 12 (57%) were male. The ORR was 52%, including 1 complete response and 10 partial responses. Treatment-related adverse events (TRAEs) occurred in 18 patients (86%), with grade ≥3 TRAEs in 5 (24%). The most common TRAEs (≥20%) were platelet count decreased (24%), anemia (24%), and aspartate aminotransferase increased (24%). As of the data cut-off in December 2024, the median follow-up was 14.1 months, the median duration of response and the median overall survival had not yet been reached. CONCLUSIONS: TQB2618 in combination with penpulimab was well tolerated and demonstrated promising efficacy in patients with cHL who had failed prior anti-PD-1/PD-L1 therapy, supporting its potential as a therapeutic option for this difficult-to-treat population. TRIAL REGISTRATION NUMBER: NCT05400876.
12 Apr 2026
Read appraisal →Blood
Brentuximab vedotin and nivolumab in combination with chemotherapy for nonbulky, early-stage classical Hodgkin lymphoma
Most patients with early-stage classical Hodgkin lymphoma (cHL) are treated with doxorubicin, bleomycin, vinblastine, and dacarbazine with or without radiation therapy, although studies are now evaluating the incorporation of novel agents paired with abbreviated chemotherapy. We present the efficacy and safety of AN+AD (brentuximab vedotin [BV] and nivolumab in combination with doxorubicin and dacarbazine) in patients with early-stage cHL. In this phase 2 study, patients with nonbulky (<10 cm) Ann Arbor stage I or II cHL received 4 cycles of AN+AD. The primary end point was complete response (CR) rate at end of treatment (EOT) by investigator. At the time of this analysis, 154 patients received ≥1 dose of AN+AD. The objective response rate at EOT was 96% (95% confidence interval [CI], 91.7-98.6), and the CR rate was 92% (95% CI, 86.0-95.4). In the favorable (n = 56) and unfavorable (n = 97) subgroups, CR rates were 95% (95% CI, 85.1-98.9) and 91% (95% CI, 83.1-95.7), respectively. The proportion of patients with duration of CR of at least 2 years was 96% (95% CI, 90.9-98.4). At a median follow-up of 27.9 months, the estimated 2-year progression-free survival rate was 97% (95% CI, 92.0-98.8). Any-grade and grade ≥3 treatment-emergent adverse events occurred in 99% and 44% of patients, respectively; no events of febrile neutropenia were reported. Any-grade treatment-emergent immune-mediated adverse events occurred in 22% of patients. One disease-related death was reported after the safety reporting period. Results from this study support the use of BV and nivolumab in combination with limited chemotherapy for patients with nonbulky, early-stage cHL. This trial was registered at www.clinicaltrials.gov as NCT03646123.
10 Apr 2026
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