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PD-1 blockade via pembrolizumab monotherapy has shown antitumour activity and toxicity in patients with relapsed or refractory classical Hodgkin lymphoma. Here, we present interim analyses from the KEYNOTE-204 study evaluating pembrolizumab versus brentuximab vedotin for relapsed or refractory classical Hodgkin lymphoma. In this randomised, open-label, phase 3 study, patients aged 18 years or older with relapsed or refractory classical Hodgkin lymphoma with measurable disease and an Eastern Cooperative Oncology Group performance status of 0 or 1 who were ineligible for or had relapsed after autologous haematopoietic stem-cell transplantation (HSCT) were enrolled at 78 hospitals and cancer centres in 20 countries and territories. Patients were randomly assigned (1:1) with an interactive voice response system to pembrolizumab 200 mg intravenously every 3 weeks or brentuximab vedotin 1·8 mg/kg intravenously every 3 weeks. Randomisation was stratified by previous autologous HSCT and status after front-line therapy. Results from the second interim analysis are presented here, with a database cutoff of Jan 16, 2020. The dual primary endpoints assessed in the intention-to-treat population were progression-free survival as assessed by blinded independent central review, and overall survival (not analysed at this interim analysis). Safety was assessed in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, NCT02684292. Recruitment for this trial is closed. Between July 8, 2016, and July 13, 2018, 151 patients were randomly assigned to pembrolizumab and 153 to brentuximab vedotin. After a median time from randomisation to data cutoff of 25·7 months (IQR 23·4–33·0), median progression-free survival was 13·2 months (95% CI 10·9–19·4) for pembrolizumab versus 8·3 months (5·7–8·8) for brentuximab vedotin (hazard ratio 0·65 [95% CI 0·48–0·88]; p=0·0027). The most common grade 3–5 treatment-related adverse events were pneumonitis (six [4%] of 148 patients in the pembrolizumab group vs one [1%] of 152 patients in the brentuximab vedotin group), neutropenia (three [2%] vs 11 [7%]), decreased neutrophil count (one [1%] vs seven [5%]), and peripheral neuropathy (one [1%] vs five [3%]). Serious treatment-related adverse events occurred in 24 (16%) of 148 patients receiving pembrolizumab and 16 (11%) of 152 patients receiving brentuximab vedotin. One treatment-related death due to pneumonia occurred in the pembrolizumab group. Pembrolizumab showed statistically significant and clinically meaningful improvement in progression-free survival compared with brentuximab vedotin, with safety consistent with previous reports. These data support pembrolizumab as the preferred treatment option for patients with relapsed or refractory classical Hodgkin lymphoma who have relapsed post-autologous HSCT or are ineligible for autologous HSCT. Merck Sharp & Dohme Corp (a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA). For the Portuguese translation of the Article see Supplementary Materials section.

Early detection of relapsed lymphoma improves response and survival. Current tools lack power for detection of early relapse, while being cumbersome and expensive. We searched for sensitive biomarkers that precede clinical relapse, and serve for further studies on therapy response and relapse. We recruited 20 healthy adults, 14 diffuse large B-cell lymphoma (DLBCL) patients and 11 Hodgkin lymphoma (HL) patients at diagnosis. Using small-RNA sequencing we identified in DLBCL patients increased plasma levels of miR-124 and miR-532-5p, and decreased levels of miR-425, miR-141, miR-145, miR-197, miR-345, miR-424, miR-128 and miR-122. In the HL group, we identified miR-25, miR-30a/d, miR-26b, miR-182, miR-186, miR-140* and miR-125a to be up-regulated, while miR-23a, miR-122, miR-93 and miR-144 were down-regulated. Pathway analysis of potential mRNAs targets of these miRNA revealed in the DLBCL group potential up-regulation of STAT3, IL8, p13k/AKT and TGF-B signaling, and potential down-regulation of the PTEN and p53 pathways; while in the HL group we have found the cAMP-mediated pathway and p53 pathway to be potentially down-regulated. Survival analyses revealed that plasma levels of miR-20a/b, miR-93 and miR-106a/b were associated with higher mortality. In conclusion, we identified sets of dysregulated circulating miRNA that might serve as reliable biomarkers for relapsed lymphoma.

Purpose Primary mediastinal B‐cell lymphoma (PMBCL) is a rare subtype of diffuse large B‐cell lymphoma (DLBCL). Despite its aggressive course, PMBCL is considered curable. While in recent years dose‐adjusted (DA) EPOCH‐R (rituximab, etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin) has become widely endorsed as first‐line therapy for newly‐diagnosed PMBCL, the optimal treatment for this disease and the role of radiotherapy (RT) remains unclear. DA‐EPOCH‐R provides good clinical outcomes, albeit is associated with short‐ and long‐term toxicity. To address this issue, the current retrospective bi‐icenter analysis compared efficacy and toxicity of DA‐EPOCH‐R and a less toxic R‐CHOP/R‐ICE regimen used for the treatment of newly‐diagnosed PMBCL. Patients and Methods The study included all patients with a histologically confirmed PMBCL diagnosis treated with DA‐EPOCH‐R or R‐CHOP/R‐ICE between 01/2013‐12/2020 at two tertiary medical centers. Patient demographic and clinical data were derived from institutional electronic medical records. The analysis included 56 patients: 31 received DA‐EPOCH‐R and 25 – R‐CHOP/R‐ICE. Results At a median follow‐up of 1.9 years (IQR 3.1 years), similar progression‐free survival (2.1 versus 2.4 years; p = 0.7667), overall survival (2.5 versus 2.7 years; p = 0.8047) and complete response (80%) were observed in both groups. However, DA‐EPOCH‐R was associated with significantly longer hospitalization required for its administration (p < 0.001) and a trend for higher frequency of infections, stomatitis, thrombotic complications and febrile neutropenia‐related hospitalizations. Conclusion DA‐EPOCH‐R and R‐CHOP/R‐ICE provide similarly encouraging outcomes in newly‐diagnosed PMBCL patients. R‐CHOP/R‐ICE is associated with lower toxicity and significantly reduced hospitalization. Our findings suggest that this regimen may be considered as an alternative to DA‐EPOCH‐R in this patient population. Primary mediastinal B‐cell lymphoma (PMBCL) is a rare subtype of diffuse large B‐cell lymphoma that is considered curable despite its aggressive course. DA‐EPOCH‐R, widely employed as a first‐line therapy for newly diagnosed PMBCL, offers good clinical results, but its utility is hampered by high rates of short‐ and long‐term toxicity. Our findings suggest that the use of R‐CHOP/R‐ICE could be consider as an alternative to DA‐EPOCH‐R in PMBCL patients, since the former regimen, while providing similarly encouraging outcomes, is associated with lower toxicity and significantly reduced hospitalization.

Background Severe epistaxis is often difficult to control in patients with hereditary hemorrhagic telangiectasia (HHT). Propranolol has been shown to have antiangiogenic properties in vitro and in vivo and is commonly used to treat hemangiomas. We present our experience with topical nasal propranolol for the treatment of moderate to severe epistaxis in patients with HHT. Methods Retrospective case series. Six patients with HHT were treated with 0.5 cm 3 of 1.5% propranolol gel, applied to each nostril twice daily for at least 12 weeks. Outcome measures were epistaxis severity score (ESS), hemoglobin level, and number of blood transfusions prior to and while on treatment. Local and systemic side effects were recorded. Results The mean duration of treatment was 30 ± 5.6 weeks. A significant improvement in the ESS was found in all patients, with a mean decrease from 6.4 ± 2.1 at treatment onset to 3.5 ± 1.7 at 12 weeks ( p  = 0.028). Hemoglobin level increased significantly from 8.4 ± 3.1 to 11.0 ± 1.8 g/dL at 12 weeks ( p  = 0.043). The mean number of blood transfusions decreased from 4.5 ± 4.9 before treatment to 2.5 ± 2.9 at 12 weeks and 0.3 ± 0.8 at 24 weeks, but the difference did not reach statistical significance ( p  = 0.109 for both). No significant side effects of treatment were recorded. Conclusions These preliminary results suggest that topical propranolol may be effective for the treatment of epistaxis in patients with HHT. A prospective controlled trial is required to confirm our findings.

Polatuzumab (Pola)-based regimens and chimeric antigen receptor T (CAR T) cells provide superior outcome compared to conventional chemoimmunotherapy in patients with relapsed/refractory diffuse large B cell lymphoma (R/R DLBCL). Choosing between these strategies remains controversial. The efficacy of CAR T versus Pola-rituximab(R) /Pola-bendamustine(B)-R in R/R DLBCL patients after failing ≥2 lines of treatment was compared in a retrospective, ‘real-world’ study. Propensity score matching, for age, lymphoma category (de-novo/transformed), number of prior lines, Eastern Cooperative Oncology Group performance status and lactate dehydrogenase level, was applied to control for differences in patients’ characteristics. Response rate, progression-free survival (PFS) and overall survival (OS) were analyzed. A total of 82 patients, treated with CAR T (n=41) or Pola-based regimens (n=41), were included. No treatment-related deaths occurred with CAR T vs. 3 (7.3%) with Pola. The overall and complete response rates were 83% and 58% with CAR T vs. 66% and 44% with Pola-based-regimens (p=0.077 and p=0.18, respectively). At a median follow-up of 9 months (range 1–19.2) and 16 months (range 0.7–25.3) for the CAR T and Pola arm respectively, the median PFS has not been reached for CAR T vs. 5.6 months for Pola (95% CI 3.6–7.6, p=0.014). Median OS has not been reached for CAR T vs. 10.8 months (95% CI 2.2–19.4) for Pola (p=0.026). To conclude, in a real-world setting, treatment with CAR T achieved superior PFS and OS compared to Pola-based regimens in patients with R/R DLBCL.

Epistaxis is a common debilitating manifestation in hereditary hemorrhagic telangiectasia (HHT), due to mucocutaneous telangiectases. The epistaxis can be difficult to control despite available treatments. Dysregulated angiogenesis has been shown to be associated with telangiectases formation. Topical propranolol has demonstrated antiangiogenic properties. We performed a two-phase study, i.e., a double-blind placebo-controlled phase, followed by an open-label phase. The aim of the study was assessment of safety and efficacy of nasal propranolol gel in HHT-related epistaxis. Twenty participants with moderate-severe HHT-related epistaxis were randomized to eight weeks of propranolol gel 1.5%, or placebo 0.5 cc, applied to each nostril twice daily; and continued propranolol for eight weeks in an open-label study. For the propranolol group, the epistaxis severity score (ESS) improved significantly (−2.03 ± 1.7 as compared with −0.35 ± 0.68 for the placebo group, p = 0.009); hemoglobin levels improved significantly (10.5 ± 2.6 to 11.4 ± 2.02 g/dL, p = 0.009); and intravenous iron and blood transfusion requirement decreased. The change in nasal endoscopy findings was not significant. During the open-label period, the ESS score improved significantly in the former placebo group (−1.99 ± 1.41, p = 0.005). The most common adverse event was nasal mucosa burning sensation. No cardiovascular events were reported. Our results suggest that topical propranolol gel is safe and effective in HHT-related epistaxis.

In the primary analysis report of the GAIA/CLL13 trial, we found that venetoclax–obinutuzumab and venetoclax–obinutuzumab–ibrutinib improved undetectable measurable residual disease (MRD) rates and progression-free survival compared with chemoimmunotherapy in patients with previously untreated chronic lymphocytic leukaemia. However, to our knowledge, no data on direct comparisons of different venetoclax-based combinations are available. GAIA/CLL13 is an open-label, randomised, phase 3 study conducted at 159 sites in ten countries in Europe and the Middle East. Eligible patients were aged 18 years or older, with a life expectancy of at least 6 months, an Eastern Cooperative Oncology group performance status of 0–2, a cumulative illness rating scale score of 6 or lower or a single score of 4 or lower, and no TP53 aberrations. Patients were randomly assigned (1:1:1:1), with a computer-generated list stratified by age, Binet stage, and regional study group, to either chemoimmunotherapy, venetoclax–rituximab, venetoclax–obinutuzumab, or venetoclax–obinutuzumab–ibrutinib. All treatments were administered in 28-day cycles. Patients in the chemoimmunotherapy group received six cycles of treatment, with patients older than 65 years receiving intravenous bendamustine (90 mg/m2, days 1–2), whereas patients aged 65 years or younger received intravenous fludarabine (25 mg/m2, days 1–3) and intravenous cyclophosphamide (250 mg/m2, days 1–3). Intravenous rituximab (375 mg/m2, day 1 of cycle 1; 500 mg/m2, day 1 of cycles 2–6) was added to chemotherapy. In the experimental groups, patients received daily venetoclax (400 mg orally) for ten cycles after a 5-week ramp-up phase starting on day 22 of cycle 1. In the venetoclax–rituximab group, intravenous rituximab (375 mg/m2, day 1 of cycle 1; 500 mg/m2, day 1 of cycles 2–6) was added. In the obinutuzumab-containing groups, obinutuzumab was added (cycle 1: 100 mg on day 1, 900 mg on day 2, and 1000 mg on days 8 and 15; cycles 2–6: 1000 mg on day 1). In the venetoclax–obinutuzumab–ibrutinib group, daily ibrutinib (420 mg orally, from day 1 of cycle 1) was added until undetectable MRD was reached in two consecutive measurements (3 months apart) or until cycle 36. The planned treatment duration was six cycles in the chemoimmunotherapy group, 12 cycles in the venetoclax–rituximab and the venetoclax–obinutuzumab group and between 12 and 36 cycles in the venetoclax–obinutuzumab–ibrutinib group. Coprimary endpoints were the undetectable MRD rate in peripheral blood at month 15 for the comparison of venetoclax-obinutuzumab versus standard chemoimmunotherapy and investigator-assessed progression-free survival for the comparison of venetoclax-obinutuzumab-ibrutinib versus standard chemoimmunotherapy, both analysed in the intention-to-treat population (ie, all patients randomly assigned to treatment) with a split α of 0·025 for each coprimary endpoint. Both coprimary endpoints have been reported elsewhere. Here we report a post-hoc exploratory analysis of updated progression-free survival results after a 4-year follow-up of our study population. Safety analyses included all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT02950051, recruitment is complete, and all patients are off study treatment. Between Dec 13, 2016, and Oct 13, 2019, 1080 patients were screened and 926 were randomly assigned to treatment (chemoimmunotherapy group n=229; venetoclax–rituximab group n=237; venetoclax–obinutuzumab group n=229; and venetoclax–obinutuzumab–ibrutinib group n=231); mean age 60·8 years (SD 10·2), 259 (28%) of 926 patients were female, and 667 (72%) were male (data on race and ethnicity are not reported). At data cutoff for this exploratory follow-up analysis (Jan 31, 2023; median follow-up 50·7 months [IQR 44·6–57·9]), patients in the venetoclax–obinutuzumab group had significantly longer progression-free survival than those in the chemoimmunotherapy group (hazard ratio [HR] 0·47 [97·5% CI 0·32–0·69], p<0·0001) and the venetoclax–rituximab group (0·57 [0·38–0·84], p=0·0011). The venetoclax–obinutuzumab–ibrutinib group also had a significantly longer progression-free survival than the chemoimmunotherapy group (0·30 [0·19–0·47]; p<0·0001) and the venetoclax–rituximab group (0·38 [0·24–0·59]; p<0·0001). There was no difference in progression-free survival between the venetoclax–obinutuzumab–ibrutinib and venetoclax–obinutuzumab groups (0·63 [0·39–1·02]; p=0·031), and the proportional hazards assumption was not met for the comparison between the venetoclax–rituximab group versus the chemoimmunotherapy group (log-rank p=0·10). The estimated 4-year progression-free survival rate was 85·5% (97·5% CI 79·9–91·1; 37 [16%] events) in the venetoclax–obinutuzumab–ibrutinib group, 81·8% (75·8–87·8; 55 [24%] events) in the venetoclax–obinutuzumab group, 70·1% (63·0–77·3; 84 [35%] events) in the venetoclax–rituximab group, and 62·0% (54·4–69·7; 90 [39%] events) in the chemoimmunotherapy group. The most common grade 3 or worse treatment-related adverse event was neutropenia (114 [53%] of 216 patients in the chemoimmunotherapy group, 109 [46%] of 237 in the venetoclax–rituximab group, 127 [56%] of 228 in the venetoclax–obinutuzumab group, and 112 [48%] of 231 in the venetoclax–obinutuzumab–ibrutinib group). Deaths determined to be associated with study treatment by the investigator occurred in three (1%) patients in the chemoimmunotherapy group (n=1 due to each of sepsis, metastatic squamous cell carcinoma, and Richter's syndrome), none in the venetoclax–rituximab and venetoclax–obinutuzumab groups, and four (2%) in the venetoclax–obinutuzumab–ibrutinib group (n=1 due to each of acute myeloid leukaemia, fungal encephalitis, small-cell lung cancer, and toxic leukoencephalopathy). With more than 4 years of follow-up, venetoclax–obinutuzumab and venetoclax–obinutuzumab–ibrutinib significantly extended progression-free survival compared with both chemoimmunotherapy and venetoclax–rituximab in previously untreated, fit patients with chronic lymphocytic leukaemia, thereby supporting their use and further evaluation in this patient group, while still considering the higher toxicities observed with the triple combination. AbbVie, Janssen, and F Hoffmann-La Roche.

Glofitamab, a CD20-directed CD3 T-cell engager, was recently FDA-approved after demonstrating a 52% overall response rate (ORR) and a 39% complete response (CR) rate in heavily pretreated diffuse large B-cell lymphoma (DLBCL) patients. However, real-world data on its efficacy and safety remain limited. This study evaluated glofitamab’s performance in clinical practice. We conducted a retrospective multicenter study of adults with relapsed/refractory (R/R) DLBCL treated via a national compassionate use program. Patients received at least one dose of glofitamab after failing ≥ 2 prior therapies. Recruitment spanned September 2020–January 2023. Outcomes included ORR, CR (per Lugano criteria), progression-free survival (PFS), and overall survival (OS). Adverse events were classified per ASTCT 2019 criteria, and risk factors for PFS and OS were assessed via logistic regression. Thirty-five patients from six Israeli centers were included (median age: 67 years; 66% male). The median number of prior therapies was 5, with 43% being primary refractory and 91% post-CAR-T therapy. ORR was 34%, with 14% achieving CR. Median PFS and OS were 2 and 4 months, respectively. Treatment was prematurely discontinued in 86%, mainly due to disease progression (46%) and to infections in responding patients (17%). Male sex was a significant risk factor for poor PFS and OS. In this real-world cohort, glofitamab’s efficacy was lower than in clinical trials, likely due to a more heavily pretreated population. However, its manageable toxicity supports its potential role in r/r DLBCL treatment.

Despite improved initial therapies, a subgroup of patients with aggressive non-Hodgkin (A-NHL) and Hodgkin lymphomas (HL) will relapse after first remission. The optimal follow-up strategy for the detection of relapse has not been clarified and periodic imaging is not recommended in most written guidelines. We identified 125 patients with HL and A-NHL diagnosed between January 1993 and September 2008 who relapsed at least 1 month after the end of initial therapy. We assessed whether relapse was detected based on clinical signs or periodic computed tomography (CT), [¹⁸F] fluorodeoxyglucose positron emission tomography (PET), or combined PET/CT and whether the mode of detection influenced the pattern and outcome of relapsed disease. Overall, most relapses (62%) were diagnosed clinically especially in A-NHL and in patients with extranodal involvement at diagnosis (p < 0.05); however, relapses of HL occurring after 2001 when PET/CT became available were more commonly detected by routine imaging (p < 0.05). Imaging-detected relapse was not associated with improved survival. While clinical exam remains the most common mode of detecting relapse, our results suggest a potential role for routine PET/CT surveillance in HL patients; however, survival does not appear to be affected by mode of detection.

The GALLIUM study showed a progression-free survival advantage of 7% in favor of obinutuzumab vs. rituximab-based immunochemotherapies as first-line therapy in follicular lymphoma (FL) patients. Yet, the toxicity appears to be increased with obinutuzumab-based therapy. This is a multicenter retrospective-cohort study including adult FL patients comparing the toxicity of first-line rituximab vs. obinutuzumab-based chemo-immunotherapies (R and O groups, respectively). We compared the best standard-of-care therapy used per time period, before and after obinutuzumab approval. The primary outcome was any infection during induction and 6 months post-induction. Secondary outcomes included rates of febrile neutropenia, severe and fatal infections, other adverse events, and all-cause mortality. Outcomes were compared between groups. A total of 156 patients were included in the analysis, 78 patients per group. Most patients received bendamustine (59%) or CHOP (31.4%) as adjacent chemotherapy. Half of the patients received growth-factor prophylaxis. Overall, 69 patients (44.2%) experienced infections, and a total of 106 infectious episodes were recorded. Patients in the R and O groups had similar rates of any infection (44.8% and 43.5%, p = 1), severe infections (43.3% vs. 47.8%, p = 0.844), febrile neutropenia (15% vs. 19.6%, p = 0.606), and treatment discontinuation, as well as similar types of infections. No covariate was associated with infection in multivariable analysis. No statistically significant difference was evident in adverse events of grades 3–5 (76.9% vs. 82%, p = 0.427). To conclude, in this largest real-life study of first-line treated FL patients comparing R- to O-based therapy, we did not observe any difference in toxicity during the induction and 6 months post-induction period.