Summary Background 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. Methods 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. Findings 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. Interpretation 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. Funding Bristol-Myers Squibb.
Summary Background Endogenous or iatrogenic antitumour immune responses can improve the course of follicular lymphoma, but might be diminished by immune checkpoints in the tumour microenvironment. ...These checkpoints might include effects of programmed cell death 1 (PD1), a co-inhibitory receptor that impairs T-cell function and is highly expressed on intratumoral T cells. We did this phase 2 trial to investigate the activity of pidilizumab, a humanised anti-PD1 monoclonal antibody, with rituximab in patients with relapsed follicular lymphoma. Methods We did this open-label, non-randomised trial at the University of Texas MD Anderson Cancer Center (Houston, TX, USA). Adult (≥18 years) patients with rituximab-sensitive follicular lymphoma relapsing after one to four previous therapies were eligible. Pidilizumab was administered at 3 mg/kg intravenously every 4 weeks for four infusions, plus eight optional infusions every 4 weeks for patients with stable disease or better. Starting 17 days after the first infusion of pidilizumab, rituximab was given at 375 mg/m2 intravenously weekly for 4 weeks. The primary endpoint was the proportion of patients who achieved an objective response (complete response plus partial response according to Revised Response Criteria for Malignant Lymphoma). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT00904722. Findings We enrolled 32 patients between Jan 13, 2010, and Jan 20, 2012. Median follow-up was 15·4 months (IQR 10·1–21·0). The combination of pidilizumab and rituximab was well tolerated, with no autoimmune or treatment-related adverse events of grade 3 or 4. The most common adverse events of grade 1 were anaemia (14 patients) and fatigue (13 patients), and the most common adverse event of grade 2 was respiratory infection (five patients). Of the 29 patients evaluable for activity, 19 (66%) achieved an objective response: complete responses were noted in 15 (52%) patients and partial responses in four (14%). Interpretation The combination of pidilizumab plus rituximab is well tolerated and active in patients with relapsed follicular lymphoma. Our results suggest that immune checkpoint blockade is worthy of further study in follicular lymphoma. Funding National Institutes of Health, Leukemia and Lymphoma Society, Cure Tech, and University of Texas MD Anderson Cancer Center.
Summary Background Roughly 70–80% of patients with advanced stage Hodgkin's lymphoma are cured with various first-line and second-line treatments, including ABVD, BEACOPP, and stem-cell ...transplantation. Brentuximab vedotin has shown significant clinical activity, with a manageable safety profile, in patients with relapsed or refractory Hodgkin's lymphoma. We aimed to assess the safety and early clinical efficacy of this drug as first-line treatment in combination with standard or modified-standard treatment in patients with previously untreated Hodgkin's lymphoma. Methods We did a phase 1, open-label, dose-escalation safety study comparing brentuximab vedotin in combination with standard (ABVD) or a modified-standard (AVD) treatment. Patients were enrolled into the groups sequentially. Main entry criteria were newly diagnosed, treatment-naive, CD30-positive patients with Hodgkin's lymphoma who had histologically confirmed stage IIA bulky disease or stage IIB–IV disease and an Eastern Cooperative Oncology Group performance status of two or less. Patients received doses of 0·6, 0·9, or 1·2 mg/kg brentuximab vedotin by intravenous infusion every 2 weeks with either ABVD (25 mg/m2 doxorubicin, 10 units/m2 bleomycin, 6 mg/m2 vinblastine, and 375 mg/m2 dacarbazine) or AVD (ABVD modified regimen without the inclusion of bleomycin) for up to six cycles. Our primary objectives were to assess the safety profile and establish the maximum tolerated dose (MTD) of brentuximab vedotin in combination with ABVD and AVD. The safety profile and MTD was assessed for the safety population. The study has completed and the final analysis is presented. This study was registered with ClinicalTrials.gov , number NCT01060904. Findings Between Jan 29, 2010, and Sept 17, 2012, 51 patients were enrolled and received at least one dose of brentuximab vedotin. The maximum tolerated dose of brentuximab vedotin when combined with ABVD or AVD was not exceeded at 1·2 mg/kg. 21 (95%) of 22 patients given brentuximab vedotin and ABVD achieved complete remission, as did 24 (96%) of 25 patients given brentuximab vedotin and AVD. Adverse events were generally grade 1 or 2; however, an unacceptable number of patients in the brentuximab vedotin and ABVD groups had pulmonary toxic effects (11 44% of 25), which exceeded the historical incidence for ABVD alone. No patients experienced pulmonary toxic effects when treated with brentuximab vedotin plus AVD. The most common grade 3 or worse events were neutropenia (20 80% of 25 patients in the brentuximab vedotin and ABVD group vs 20 77% of 26 patients in the brentuximab vedotin and AVD group), anaemia (five 20% vs three 12%), febrile neutropenia (five 20% vs two 8%), pulmonary toxic effects (six 24% vs 0), syncope (three 12% vs two 8%), dyspnoea (three 12% vs one 4%), pulmonary embolism (three 12% vs 0), fatigue (one 4% each), and leucopenia (one 4% each). Serious events occured in 41% of all patients (14 56% in the brentuximab vedotin and ABVD group and seven 27% in the brentuximab vedotin and AVD group). Serious events occurring in 10% of patients or more overall were febrile neutropenia (four 16% in the brentuximab vedotin and ABVD group vs two 8% in the brentuximab vedotin and AVD group), and, in the brentuximab vedotin and ABVD group only, pulmonary toxic effects (six 24%). Interpretation Brentuximab vedotin should not be given with bleomycin in general or specifically as first-line therapy for patients with treatment naive, advanced stage Hodgkin's lymphoma. 1·2 mg/kg brentuximab vedotin combined with AVD given every 2 weeks was generally well tolerated by patients. At present, a phase 3 trial comparing brentuximab vedotin plus AVD to ABVD alone is ongoing ( ClinicalTrials.gov , number NCT01712490 ) and will formally assess whether brentuximab vedotin plus AVD might redefine therapy in treatment-naive patients with Hodgkin's lymphoma. Funding Seattle Genetics Inc and Takeda Pharmaceuticals International Co.
Summary Background The prognosis of patients with relapsed Hodgkin's lymphoma, especially those who relapse after stem-cell transplantation, is poor, and the development of new agents for this ...patient population is an unmet medical need. We tested the safety and efficacy of mocetinostat, an oral isotype-selective histone deacetylase inhibitor, in patients with relapsed classical Hodgkin's lymphoma. Methods Patients with relapsed or refractory classical Hodgkin's lymphoma aged 18 years or older were treated with mocetinostat administered orally three times per week, in 28-day cycles. Two doses were assessed (85 mg and 110 mg). Patients were treated until disease progression or prohibitive toxicity. The primary outcome was disease control rate, defined as complete response, partial response, or stable disease (for at least six cycles), analysed by intention to treat. This trial has been completed and is registered with ClinicalTrials.gov , number NCT00358982. Findings 51 patients were enrolled. Initially, 23 patients were enrolled in the 110 mg cohort. Subsequently, because toxicity-related dose reductions were necessary in the 110 mg cohort, we treated 28 additional patients with a dose of 85 mg. On the basis of intent-to-treat analysis, the disease control rate was 35% (eight of 23 patients) in the 110 mg group and 25% (seven of 28) in the 85 mg group. 12 patients (24%) discontinued treatment because of adverse events, nine (32%) in the 85 mg cohort and three (13%) in the 110 mg cohort. The most frequent treatment-related grade 3 and 4 adverse events were neutropenia (four patients 17% in the 110 mg group, three 11% in the 85 mg group); fatigue (five patients 22% in the 110 mg group, three 11% in the 85 mg group); and pneumonia (four patients 17% in the 110 mg group, two 7% in the 85 mg group). Four patients, all in the 110 mg cohort, died during the study, of which two might have been related to treatment. Interpretation Mocetinostat, 85 mg three times per week, has promising single-agent clinical activity with manageable toxicity in patients with relapsed classical Hodgkin's lymphoma. Funding MethylGene Inc, Montreal, Canada; Celgene Corporation, Summit, NJ, USA; Tufts Medical Center, Boston, MA, USA.
Summary Background The combination of rituximab and lenalidomide has shown promise for the treatment of mantle-cell lymphoma (MCL) in preclinical studies. We aimed to identify the maximum tolerated ...dose (MTD) of lenalidomide when combined with rituximab in a phase 1 trial and to assess the efficacy and safety of this combination in a phase 2 trial in patients with relapsed or refractory MCL. Methods Patients with relapsed or refractory MCL who had received one to four previous lines of treatment were enrolled in this single-arm, open-label, phase 1/2 trial at MD Anderson Cancer Center. In phase 1, to identify the MTD of lenalidomide, four patient cohorts received escalating doses (10, 15, 20, and 25 mg) of daily oral lenalidomide on days 1–21 of each 28-day cycle. 375 mg/m2 intravenous rituximab was also administered in four weekly doses during cycle 1 only. In phase 2, patients received rituximab plus the MTD of lenalidomide, following the same cycles as for phase 1. Treatment in both phases continued until disease progression, stem-cell transplantation, or severe toxicity. The primary efficacy endpoint was overall response (complete or partial response). The secondary efficacy endpoint was survival. We used the Kaplan-Meier method to estimate response duration, progression-free survival, and overall survival. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov , number NCT00294632. Findings 52 patients were enrolled between Feb 10, 2006 and July 30, 2009, 14 in phase 1 and 44 (including six patients who received the MTD of lenalidomide in the phase 1 portion) in phase 2. The MTD was 20 mg lenalidomide. One patient who was treated with 25 mg lenalidomide developed a grade 4 non-neutropenic infection and died. In the phase 2 portion of the study, grade 3–4 haematological toxicities included neutropenia (29 patients), lymphopenia (16 patients), leucopenia (13 patients), and thrombocytopenia (ten patients). There were only two episodes of febrile neutropenia. Among 44 patients in phase 2, 25 (57%) had an overall response: 16 (36%) had a complete response and nine (20%) had a partial response. The median response duration was 18·9 months (95% CI 17·0 months to not reached NR). The median progression-free survival was 11·1 months (95% CI 8·3 to 24·9 months), and the median overall survival was 24·3 months (19·8 months to NR). Five of 14 patients who had received bortezomib treatment before enrolment achieved an overall response. Interpretation Oral lenalidomide plus rituximab is well tolerated and effective for patients with relapsed or refractory MCL. Funding Celgene.
Highlights • Cardiac biomarkers, particularly BNP, can be part of an effective screening strategy for anthracycline-related cardiotoxicity. • In this study, LVEF did not appear to be adequate for the ...detection of cardiotoxicity. • BNP may allow us to direct cardioprotective therapy. More analysis with high-sensitivity troponin is needed.
Abstract Purpose We identified lung dosimetric constraints to assist in predicting the radiation pneumonitis (RP) risk in patients with mediastinal lymphoma and then identified the clinical ...prognostic factors that were associated with the achievement of key dosimetric constraints. Methods and Materials In 190 patients who received mediastinal intensity modulated radiation therapy, we used univariate χ2 and multivariate logistic models to identify the predictors of RP and achievement of lung dose-volume histogram (DVH) constraints and build a predictive nomogram for RP. Results An increased risk of RP was strongly associated with mean lung dose (MLD) > 13.5 Gy (odds ratio OR: 8.13; 95% confidence interval CI, 3.01-21.93; P < .001) and the percent of lung volume receiving ≥5 Gy (V5) > 55% (OR: 7.01; 95% CI, 2.94-16.72; P < .001). Therefore, patients had low RP risk (8%) if both MLD ≤13.5 and V5 ≤55 constraints were achieved, moderate risk (24%) if only MLD was achieved, and the highest risk (48%) if MLD was not achieved. Deep-inspiration breath-hold (DIBH) technique during treatment strongly prognosticated achieving MLD and V5 DVH constraints (OR,3.88; 95% CI, 1.84-8.19; P < .001). Specifically, 86% of patients who were treated with DIBH versus 63% without DIBH achieved DVH constraints ( P < .001). This translated into a “number needed to treat” with DIBH of 4 patients to enable 1 additional patient to achieve both constraints. In comparison, the clinical characteristics were marginal prognosticators: DVH constraints were more likely achieved in nonbulky disease (OR: 3.01; 95% CI, 0.89-4.53; P = .09) and patients who had not previously received salvage chemotherapy (OR, 2.44; 95% CI, 0.98-6.11; P = .06). Nomogram-predicted risks of RP ranged from 4% to 60% on the basis of MLD and V5, total radiation dose, and use of salvage chemotherapy. Conclusions Achieving mean lung and V5 DVH constraints is critical to reduce RP risk in patients with lymphoma who receive mediastinal intensity modulated radiation therapy. The use of the DIBH technique is a promising risk-modifying treatment approach in patients with mediastinal lymphoma and especially in patients with a history of nonmodifiable risk factors for RP such as bulky disease and salvage chemotherapy.
Anaplastic large cell lymphoma (ALCL) is one of the most common peripheral T-cell lymphomas, and the incidence is higher in blacks than non-Hispanic whites. ALK-positive and ALK-negative ALCL are ...distinct subtypes that have different characteristics and clinical outcomes. Breast implant-associated ALCL is a rare lymphoma that has a good survival outcome, and a recent study showed that total capsulectomy is essential for treatment. Brentuximab vedotin (BV) is a standard treatment for relapsed/refractory ALCL. The response rate is high at 80-90%; however, once the disease progresses in patients on BV, survival outcome is very poor, with a median overall survival of less than two months.
Bleomycin pulmonary toxicity (BPT) is a well-known complication of treatment in patients with Hodgkin lymphoma (HL). We undertook the present study to investigate the risk of radiation pneumonitis ...(RP) in the setting of BPT and to determine the need for delay or omission of radiation therapy (RT) in these patients.
We identified 123 HL patients treated with ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine) followed by RT to the chest from January 2009 to December 2014. The medical records were reviewed for clinical, pathologic, and treatment information and toxicities. Our primary outcome was RP of any grade. Univariate and multivariate analyses were used to assess the association of BPT, baseline patient characteristics, and treatment variables with the incidence of RP.
A total of 123 patients were included, of whom 99 (80%) received consolidation intensity modulated RT after ABVD treatment. We identified 31 patients (25.2%) with BPT after frontline ABVD. Seventeen patients (13.8%) developed RP a median of 8 weeks (range 1-39) after RT completion. BPT did not correlate with the risk of developing RP (P=.36). We evaluated the RP outcomes with respect to the bleomycin to RT interval (≤6 weeks vs >6 weeks), and we found that this interval did not predict for RP risk (P=.60). Dosimetric parameters such as the volume covered by 5 Gy and the mean lung dose were analyzed. A volume covered by 5 Gy of >55% and mean lung dose >13.5 Gy increased the risk of RP by 1.14-fold (P=.002) and 4.24-fold (P=.007), respectively.
The results of our study suggest that BPT does not increase the risk of developing RP. Furthermore, RT initiation does not need to be delayed after chemotherapy, except to allow for the completion of steroid therapy or clinical recovery from BPT.
Abstract Background For patients with primary diffuse large B-cell lymphoma of the central nervous system (PCNSL), whole-brain radiation therapy (WBRT) to doses of ≥45 Gy are often given after a ...partial response (PR) to methotrexate-based induction chemotherapy. We conducted an exploratory analysis to determine whether lower-dose WBRT, given with a boost to sites of persistent disease, might be a reasonable alternative. Methods and materials We retrospectively reviewed the records of 22 patients with PCNSL who received WBRT, with or without a boost, after methotrexate-based induction chemotherapy. Outcomes were compared among patients according to response to chemotherapy using the Kaplan-Meier method. Results Median follow-up was 52 months. All patients with a complete response (CR) (n = 5) received WBRT to 23.4 Gy. One CR patient died after an in-field relapse. Patients with partial response (PR) (n = 10) received a median whole-brain dose of 23.4 Gy with (n = 8) or without (n = 2) a boost; there were 2 relapses within the central nervous system (CNS). All PR patients were alive at the time of analysis. The overall survival ( P = .127) and freedom from relapse within the CNS ( P = .967) were not different for patients with CR versus PR. Baseline and follow-up neurocognitive evaluations were available for 4 PR patients, and there were no significant differences between pre- and post-treatment evaluations ( P > .05 for language, memory, visual-spatial, attention, or motor functions). All patients who progressed or did not respond to chemotherapy and then received WBRT had died at a median time of 3.4 months. Patients who progressed or did not respond to chemotherapy had worse overall survival ( P = .001) and freedom from CNS relapse ( P = .005) compared with CR patients. Conclusions Among patients with a PR to induction chemotherapy, reduced-dose WBRT with a boost to residual PCNSL may be a viable treatment approach that merits further investigation.
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