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The MInT study was the first to show improved 3-year outcomes with the addition of rituximab to a CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-like regimen in young patients with good-prognosis diffuse large-B-cell lymphoma. Extended follow-up was needed to establish long-term effects. In the randomised open-label MInT study, patients from 18 countries (aged 18–60 years with none or one risk factor according to the age-adjusted International Prognostic Index [IPI], stage II–IV disease or stage I disease with bulk) were randomly assigned to receive six cycles of a CHOP-like chemotherapy with or without rituximab. Bulky and extranodal sites received additional radiotherapy. Randomisation was done centrally with a computer-based tool and was stratified by centre, bulky disease, age-adjusted IPI, and chemotherapy regimen by use of a modified minimisation algorithm that incorporated a stochastic component. Patients and investigators were not masked to treatment allocation. The primary endpoint was event-free survival. Analyses were by intention to treat. This observational study is a follow-up of the MInT trial, which was stopped in 2003, and is registered at ClinicalTrials.gov, number NCT00400907. The intention-to-treat population included 410 patients assigned to chemotherapy alone and 413 assigned to chemotherapy plus rituximab. After a median follow-up of 72 months (range 0·03–119), 6-year event-free survival was 55·8% (95% CI 50·4–60·9; 166 events) for patients assigned to chemotherapy alone and 74·3% (69·3–78·6; 98 events) for those assigned to chemotherapy plus rituximab (difference between groups 18·5%, 11·5–25·4, log-rank p<0·0001). Multivariable analyses showed that event-free survival was affected by treatment group, presence of bulky disease, and age-adjusted IPI and that overall survival was affected by treatment group and presence of bulky disease only. After chemotherapy and rituximab, a favourable subgroup (IPI=0, no bulk) could be defined from a less favourable subgroup (IPI=1 or bulk, or both; event-free survival 84·3% [95% CI 74·2–90·7] vs 71·0% [65·1–76·1], log-rank p=0·005). 18 (4·4%, 95% CI 2·6–6·9) second malignancies occurred in the chemotherapy-alone group and 16 (3·9%, 2·2–6·2) in the chemotherapy and rituximab group (Fisher's exact p=0·730). Rituximab added to six cycles of CHOP-like chemotherapy improved long-term outcomes for young patients with good-prognosis diffuse large-B-cell lymphoma. The definition of two prognostic subgroups allows a more refined therapeutic approach to these patients than does assessment by IPI alone. Hoffmann–La Roche.

Immune checkpoint inhibitors (ICIs) show efficacy in the treatment of non-Hodgkin lymphomas (NHL). However, these agents are associated with a unique group of side effects called immune-related adverse events (irAEs). We conducted an observational retrospective/prospective study on patients with relapsed/refractory NHL treated with ICI to determine the incidence of irAEs assessing the type, severity, and timing of onset, outcome and relationship with study drugs of these events. Thirty-two patients underwent ICI as single agent (N = 20) or in combination (N = 12). Ten patients (31.3%) developed at least one irAE for a total of 17 irAEs. Median time to presentation of irAEs was 69 days (range 0–407) with a median resolution time of 16 days (range 0–98). Progression free survival at 24 months for patients who developed an irAE was 40% and 31.8% for who did not. Overall survival for the two groups did not differ (at 24 months 40.0% and 62.5% for patients without and with irAE, respectively), but the median for who developed an irAE was not reached. The incidence of irAEs was associated with better long-term survival in NHL treated with ICIs but patients’ disease conditions need to be carefully evaluated to decide the optimal management.

IntroductionBiopsy of affected tissue is required for lymphoma diagnosis and to plan treatment. Open incisional biopsy is traditionally the method of choice. Nevertheless, it requires hospitalization, availability of an operating room, and sometimes general anesthesia, and it is associated with several drawbacks. Fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) can be potentially used to drive biopsy to the most metabolically active area within a lymph node or extranodal masses.MethodsA study of diagnostic accuracy was conducted to assess the performance of a PET-driven needle biopsy in patients with suspect active lymphoma.ResultsOverall, 99 procedures have been performed: three (3.0%) were interrupted because of pain but were successfully repeated in two cases. Median SUVmax of target lesions was 10.7. In 84/96 cases, the tissue was considered adequate to formulate a diagnosis (diagnostic yield of 87.5%) and to guide the following clinical decision. The target specimen was a lymph node in 60 cases and an extranodal site in 36. No serious adverse events occurred. The sensitivity of this procedure was 96%, with a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 75%.ConclusionPatients can benefit from a minimally invasive procedure which allows a timely and accurate diagnosis of lymphoma at onset or relapse.

Background/Objectives: Diffuse large B-cell lymphoma (DLBCL) exhibits substantial clinical heterogeneity and poor prognosis in relapsed/refractory (R/R) settings. PRO-MIND is a prospective, multicenter real-world study evaluating tafasitamab–lenalidomide followed by tafasitamab monotherapy in patients with transplant-ineligible R/R DLBCL in Italy. This ad hoc, cross-sectional, baseline analysis aimed to characterize health-related quality of life (HRQoL) and symptom burden before tafasitamab–lenalidomide initiation in the PRO-MIND cohort. Methods: Thirty-eight patients across 30 centers completed the EORTC QLQ-C30 and QLQ-NHL-HG29 questionnaires at pretreatment baseline, prior to starting tafasitamab–lenalidomide. EORTC QLQ-C30 scores (0–100) were compared with age-specific normative values for the Italian general population using Welch’s t-test. Differences of ≥5 points were considered clinically meaningful and ≥10 points clearly clinically important. Effect sizes (Cohen’s d) were calculated to complement p-values for between-group comparisons. Results: Compared with normative data, the PRO-MIND cohort had significantly lower EORTC QLQ-C30 functioning scores for physical (Δ 12.7, p = 0.0135), role (Δ 16.1, p = 0.0168), social (Δ 15.2, p = 0.0019), and cognitive (Δ 8.5, p = 0.0460) functioning. Symptom scales revealed worse fatigue (Δ 14.8, p = 0.0097), insomnia (Δ 13.9, p = 0.0291), appetite loss (Δ 9.4, p = 0.0435), and pain (Δ 8.7, p = 0.0430) in the PRO-MIND cohort versus normative data, with effect sizes in the small-to-moderate range. EORTC QLQ-NHL-HG29 scores indicated a high prevalence of concerns about future health (84.2%), disease recurrence (81.6%), and dependency (78.9%), as well as physical symptoms, including lack of energy (71.1%), sleep difficulties (63.2%), and pain or discomfort (60.5%). Conclusions: This cross-sectional, baseline-only analysis of the PRO-MIND real-world cohort showed that patients with transplant-ineligible R/R DLBCL scheduled to receive tafasitamab–lenalidomide already had pronounced impairments in physical, role, social, and cognitive functioning, along with substantial fatigue, insomnia, pain, appetite loss, and psychological concerns. These baseline benchmarks underscore the importance of systematic HRQoL assessment and targeted supportive interventions focusing on these domains before and during treatment. Future longitudinal PRO-MIND analyses will complement these findings by describing how HRQoL evolves after tafasitamab–lenalidomide initiation.

Peripheral T cell lymphomas (PTCLs) are a heterogeneous group of orphan neoplasms. Despite the introduction of anthracycline-based chemotherapy protocols, with or without autologous haematopoietic transplantation and a plethora of new agents, the progression-free survival of patients with PTCLs needs to be improved. The rarity of these neoplasms, the limited knowledge of their driving defects and the lack of experimental models have impaired clinical successes. This scenario is now rapidly changing with the discovery of a spectrum of genomic defects that hijack essential signalling pathways and foster T cell transformation. This knowledge has led to new genomic-based stratifications, which are being used to establish objective diagnostic criteria, more effective risk assessment and target-based interventions. The integration of genomic and functional data has provided the basis for targeted therapies and immunological approaches that underlie individual tumour vulnerabilities. Fortunately, novel therapeutic strategies can now be rapidly tested in preclinical models and effectively translated to the clinic by means of well-designed clinical trials. We believe that by combining new targeted agents with immune regulators and chimeric antigen receptor-expressing natural killer and T cells, the overall survival of patients with PTCLs will dramatically increase.Peripheral T cell lymphomas (PTCLs) are a heterogeneous group of rare neoplasms. This Review outlines our current understanding of the genomic defects and host environment characteristics that promote PTCL development with the aim of improving molecular stratification and targeted therapy for PTCLs.

The definition and role of bulky disease in young patients (ie, aged 18–60 years) with good-prognosis diffuse large-B-cell lymphoma (DLBCL), who have been treated with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone)-like chemotherapy with or without rituximab, remain controversial. We aimed to assess the effect of maximum tumour diameter (MTD) in these patients. Patients from the MInT (Mabthera International Trial Group) study were eligible. We analysed event-free (EFS) and overall survival (OS) after CHOP-like chemotherapy with or without rituximab, according to MTD, by Martingale residual analyses and Cox regression models. Radiotherapy was given to sites of primary bulky disease according to national standards, and to primary extranodal disease at physician discretion. The primary endpoint was EFS and the secondary endpoint was OS. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT 00064116. Of the 824 patients enrolled in the MInT study, the informed-consent form of one patient was missing, leaving 823 patients evaluable for intention-to-treat analysis. Data on MTD of involved sites were available for 802 patients. Martingale residual analysis showed an adverse prognostic effect of MTD on EFS and OS, which increased linearly. In a multivariable analysis with MTD as a linear regression variable, the effect of MTD was significant after CHOP-like treatment alone for EFS (hazard ratio 1·090 [95% CI 1·051–1·130], p<0·0001) and OS (1·119 [1·057–1·184], p=0·0001), and after CHOP-like treatment and rituximab for OS (1·089 [1·003–1·183], p=0·043), but not for EFS (1·044 [0·991–1·099], p=0·103). For CHOP-like treatment alone, 3-year EFS ranged from 78·2% (MTD <5·0 cm, 95% CI 68·3–85·4) to 41·3% (MTD ≥10·0 cm, 31·8–50·4). For CHOP-like treatment and rituximab, 3-year EFS ranged from 83·2% (MTD <5·0 cm, 72·8–89·9) to 72·7% (MTD ≥10·0 cm, 63·8–79·7). With CHOP-like treatment alone, 3-year OS decreased from 92·9% (MTD <5·0 cm, 84·9–96·8) to 73·5% (MTD ≥10·0 cm, 63·9–81·0); for CHOP-like treatment and rituximab, 3-year OS decreased from 98·0% (MTD <5·0 cm, 92·2–99·5) to 85·2% (MTD ≥10·0 cm, 77·0–90·6). For CHOP-like treatment, any cut-off point between 5·0 cm and 10·0 cm separated two populations with a significant EFS difference (p<0·0001 for all log-rank tests) and OS difference (p≤0·003 for all log-rank tests). For CHOP-like treatment and rituximab, only a cut-off point of 10·0 cm separated two populations with a significant EFS difference (log-rank p=0·047), but any cut-off point of 6·0 cm or more separated two populations with a significant OS difference (log-rank p values 0·0009–0·037). Rituximab decreased, but did not eliminate the adverse prognostic effect of MTD in young patients with good-prognosis DLBCL. Due to the linear prognostic effect of MTD on outcome, arbitrary cut-off points for bulky disease can be set between 5·0 cm and 10·0 cm, depending on clinical considerations. Based on this study, a cut-off point of 10·0 cm might be a suitable margin in the rituximab era to delineate those patients with bulky disease. Roche, Basel, Switzerland (M39045).

Copanlisib dose selection was established under the maximum tolerated dose paradigm, and no dedicated dose‐finding studies have investigated copanlisib dose selection when used in combination with rituximab. In CHRONOS‐3, copanlisib plus rituximab demonstrated significantly improved progression‐free survival versus placebo plus rituximab in patients with relapsed indolent non‐Hodgkin lymphoma (iNHL). We conducted a comprehensive investigation of copanlisib population pharmacokinetics (PopPK) from a pooled analysis of 712 patients across nine copanlisib phase I–III studies and exposure–response (ER) relationships for efficacy and safety from the 1‐year follow‐up of CHRONOS‐3. PopPK analyses examined the impact of demographic, laboratory, and comedication covariates on copanlisib between‐patient PK variability. Individual static and time‐varying exposure estimates were derived to investigate exposure–efficacy and exposure–safety relationships. Multivariate Cox proportional hazards and logistic regression analyses examined ER relationships with consideration of predefined potentially prognostic demographic‐, laboratory‐, and/or disease‐related baseline covariates. Copanlisib PK were best described by a three‐compartment model with first‐order elimination. Individual identified covariates had modest effects on copanlisib PK and were generally in line with known copanlisib disposition properties. In CHRONOS‐3, ER analyses showed a significant relationship between time‐varying exposure estimates and progression‐free survival, and no significant exposure–safety relationships. Thus, lower copanlisib doses may result in reduced efficacy but not necessarily improved safety or tolerability. These outcomes substantiate the current intermittent dosing regimen of copanlisib 60 mg on days 1, 8, and 15 of a 28‐day cycle and support the observed clinical results of copanlisib in combination with rituximab in the iNHL population.

Patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who do not respond to or who have progressive disease after salvage therapies have a poor prognosis. Loncastuximab tesirine is a CD19-directed antibody–drug conjugate with encouraging phase 1 single-agent antitumour activity and acceptable safety in non-Hodgkin lymphoma. We aimed to evaluate the antitumour activity and safety of loncastuximab tesirine in patients with relapsed or refractory DLBCL. We did a multicentre (28 hospital sites in the USA, UK, Italy, and Switzerland), open-label, single-arm, phase 2 trial (LOTIS-2) in patients aged 18 years or older with relapsed or refractory DLBCL after two or more multiagent systemic treatments, who had measurable disease and Eastern Cooperative Oncology Group performance status 0–2. Eligible patients received loncastuximab tesirine intravenously on day 1 of each 21-day cycle, at 150 μg/kg for two cycles, then 75 μg/kg thereafter, for up to 1 year or until disease relapse or progression, unacceptable toxicity, death, major protocol deviation, pregnancy, or patient, investigator, or sponsor decision. The primary endpoint was overall response rate assessed by central review. Primary antitumour activity and safety analyses were done in the as-treated population (patients who received at least one dose of loncastuximab tesirine), when all responding patients had at least 6 months of follow-up after initial documented response. Enrolment is complete. This trial is registered with ClinicalTrials.gov, NCT03589469. Between Aug 1, 2018, and Sept 24, 2019, 184 patients were assessed for eligibility and 145 (79%) were enrolled and received at least one dose of loncastuximab tesirine, including patients with high-risk characteristics for poor prognosis, such as double-hit, triple-hit, transformed, or primary refractory DLBCL. 70 of 145 patients had complete or partial response (overall response rate 48·3% [95% CI 39·9–56·7]); 35 had complete response and 35 had partial response. The most common grade 3 or higher treatment-emergent adverse events were neutropenia (37 [26%] of 145 patients), thrombocytopenia (26 [18%]), and increased gamma-glutamyltransferase (24 [17%]). Serious adverse events were reported in 57 (39%) of 145 patients. Treatment-emergent adverse events with a fatal outcome occurred in eight (6%) of 145 patients; none were considered related to loncastuximab tesirine. Loncastuximab tesirine has substantial single-agent antitumour activity and produces durable responses with an acceptable safety profile, potentially offering a new therapeutic option for heavily pretreated patients with relapsed or refractory DLBCL. ADC Therapeutics.

Bruton tyrosine kinase is a clinically validated target in mantle cell lymphoma. Acalabrutinib (ACP-196) is a highly selective, potent Bruton tyrosine kinase inhibitor developed to minimise off-target activity. In this open-label, phase 2 study, oral acalabrutinib (100 mg twice per day) was given to patients with relapsed or refractory mantle cell lymphoma, until disease progression or unacceptable toxicity. The primary endpoint was overall response assessed according to the Lugano classification, and safety analyses were done in all participants. This trial is registered with ClinicalTrials.gov, number NCT02213926. From March 12, 2015, to Jan 5, 2016, 124 patients with relapsed or refractory mantle cell lymphoma were enrolled and all patients received treatment; median age 68 years. Patients received a median of two (IQR 1–2) previous therapies. At a median follow-up of 15·2 months, 100 (81%) patients achieved an overall response and 49 (40%) patients achieved a complete response. The Kaplan-Meier estimated medians for duration of response, progression-free survival, and overall survival were not reached; the 12-month rates were 72% (95% CI 62–80), 67% (58–75), and 87% (79–92%), respectively. The most common adverse events were primarily grade 1 or 2 and were headache (47 [38%]), diarrhoea (38 [31%]), fatigue (34 [27%]), and myalgia (26 [21%]). The most common grade 3 or worse adverse events were neutropenia (13 [10%]), anaemia (11 [9%]), and pneumonia (six [5%]). There were no cases of atrial fibrillation and one case of grade 3 or worse haemorrhage. The median duration of treatment was 13·8 months. Treatment was discontinued in 54 (44%) patients, primarily due to progressive disease (39 [31%]) and adverse events (seven [6%]). Acalabrutinib treatment provided a high rate of durable responses and a favourable safety profile in patients with relapsed or refractory mantle cell lymphoma. These findings suggest an important role for acalabrutinib in the treatment of this disease population. Acerta Pharma, a member of the AstraZeneca Group.

Malignant cells of classical Hodgkin's lymphoma are characterised by genetic alterations at the 9p24.1 locus, leading to overexpression of PD-1 ligands and evasion of immune surveillance. In a phase 1b study, nivolumab, a PD-1-blocking antibody, produced a high response in patients with relapsed and refractory classical Hodgkin's lymphoma, with an acceptable safety profile. We aimed to assess the clinical benefit and safety of nivolumab monotherapy in patients with classical Hodgkin's lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin. In this ongoing, single-arm phase 2 study, adult patients (aged ≥18 years) with recurrent classical Hodgkin's lymphoma who had failed to respond to autologous stem-cell transplantation and had either relapsed after or failed to respond to brentuximab vedotin, and with an Eastern Cooperative Oncology Group performance status score of 0 or 1, were enrolled from 34 hospitals and academic centres across Europe and North America. Patients were given nivolumab intravenously over 60 min at 3 mg/kg every 2 weeks until progression, death, unacceptable toxicity, or withdrawal from study. The primary endpoint was objective response following a prespecified minimum follow-up period of 6 months, assessed by an independent radiological review committee (IRRC). All patients who received at least one dose of nivolumab were included in the primary and safety analyses. This trial is registered with ClinicalTrials.gov, number NCT02181738. Among 80 treated patients recruited between Aug 26, 2014, and Feb 20, 2015, the median number of previous therapies was four (IQR 4–7). At a median follow-up of 8·9 months (IQR 7·8–9·9), 53 (66·3%, 95% CI 54·8–76·4) of 80 patients achieved an IRRC-assessed objective response. The most common drug-related adverse events (those that occurred in ≥15% of patients) included fatigue (20 [25%] patients), infusion-related reaction (16 [20%]), and rash (13 [16%]). The most common drug-related grade 3 or 4 adverse events were neutropenia (four [5%] patients) and increased lipase concentrations (four [5%]). The most common serious adverse event (any grade) was pyrexia (three [4%] patients). Three patients died during the study; none of these deaths were judged to be treatment related. Nivolumab resulted in frequent responses with an acceptable safety profile in patients with classical Hodgkin's lymphoma who progressed after autologous stem-cell transplantation and brentuximab vedotin. Therefore, nivolumab might be a new treatment option for a patient population with a high unmet need. Ongoing follow-up will help to assess the durability of response. Bristol-Myers Squibb.