Safety of bendamustine for the treatment of indolent non-Hodgkin lymphoma: a UK real-world experience.

ABSTRACT: Bendamustine is among the most effective chemotherapeutics for indolent B-cell non-Hodgkin lymphomas (iNHL), but trial reports of significant toxicity, including opportunistic infections and excess deaths, led to prescriber warnings. We conducted a multicenter observational study evaluating bendamustine toxicity in real-world practice. Patients receiving at least 1 dose of bendamustine with/without rituximab (R) for iNHL were included. Demographics, lymphoma and treatment details, and grade 3 to 5 adverse events (AEs) were analyzed and correlated. In total, 323 patients were enrolled from 9 National Health Service hospitals. Most patients (96%) received bendamustine-R, and 46%, R maintenance. Overall, 21.7% experienced serious AEs (SAE) related to treatment, including infections in 12%, with absolute risk highest during induction (63%), maintenance (20%), and follow-up (17%) and the relative risk highest during maintenance (54%), induction (34%), and follow-up (28%). Toxicity led to permanent treatment discontinuation for 13% of patients, and 2.8% died of bendamustine-related infections (n = 5), myelodysplastic syndrome (n = 3), and cardiac disease (n = 1). More SAEs per patient were reported in patients with mantle cell lymphoma, poor preinduction performance status (PS), poor premaintenance PS, and abnormal preinduction total globulins and in those receiving growth factors. Use of antimicrobial prophylaxis was variable, and 3 of 10 opportunistic infections occurred despite prophylaxis. In this real-world analysis, bendamustine-related deaths and treatment discontinuation were similar to those of trial populations of younger, fitter patients. Poor PS, mantle cell histology, and maintenance R were potential risk factors. Infections, including late onset events, were the most common treatment-related SAE and cause of death, warranting extended antimicrobial prophylaxis and infectious surveillance, especially for maintenance-treated patients.

Outcomes of Patients Treated With RCHOP With a PET-Adapted Approach for Consolidative Radiotherapy: A Retrospective Single-Center Study at the Royal Marsden Hospital.

BACKGROUND: Treatment with CHOP-based chemotherapy with consolidative radiotherapy (CRT) for primary mediastinal B cell lymphoma (PMBCL) has been the standard approach in the pre-rituximab era. Overtreatment with CRT for patients who may have already been cured by primary immunochemotherapy in the rituximab era is a significant concern due to the long-term toxicity associated with radiotherapy. Positron emission tomography (PET) may help to identify patients who may not benefit from further CRT. METHODS: We conducted a retrospective review of patients treated at the Royal Marsden Hospital between 2003 and 2020 for PMBCL to assess CRT use and survival outcomes. RESULTS: Forty-three patients were identified, with 95% of the patients receiving R-CHOP. CRT was given in 5 patients. Five-year event-free survival was 79% (95% confidence interval: 64%-89%) and 5-year overall survival was 88% (95% confidence interval: 73%-95%). Seven of 9 patients with DS4 did not receive CRT and instead monitored with serial PET scans. None of these 7 patients relapsed in the mediastinum. CONCLUSION: CRT may be omitted in patients with a negative end of treatment PET scans; however, careful observation may also obviate the need for CRT in PET positive patients.

Outcomes in grade 3B follicular lymphoma: an international study led by the Australasian Lymphoma Alliance.

Grade (G) 3B follicular lymphoma (FL) is a rare FL subtype which exists on a histological continuum between 'lowgrade' (Grade 1, 2 and 3A FL) and diffuse large B-cell lymphoma (DLBCL) appearing to share features with each. Clinical characteristics and outcomes are poorly understood due to lack of adequate representation in prospective trials and large-scale analyses. We analyzed 157 G3BFL cases from 18 international centers, and two comparator groups; G3AFL (n=302) and DLBCL (n=548). Composite histology with DLBCL or low-grade FL occurred in approximately half of the G3BFL cases. With a median of 5 years follow-up, the overall survival and progression-free survival of G3BFL patients was better than that of DLBCL patients (P<0.001 and P<0.001, respectively); however, G3BFL patients were younger (P<0.001) with better performance status (P<0.001), less extranodal disease (P<0.001) and more frequently had normal lactate dehydrogenase (P<0.001) at baseline. The overall and progression-free survival of patients with G3BFL and G3AFL were similar (P=0.83 and P=0.80, respectively). After frontline immunochemotherapy, 24% of G3BFL relapsed; relapse rates were 63% in the DLBCL cohort and 19% in the low-grade FL cohort. Eight percent of relapses occurred beyond 5 years. In this G3BFL cohort, the revised International Prognostic Index successfully delineated risk groups, but the Follicular Lymphoma International Prognostic Index did not. We conclude that patients with immunochemotherapy-treated G3BFL have similar survival outcomes to those with G3AFL, yet a favorable baseline profile and distinctly superior prognosis compared to patients with DLBCL.

Comparison of the diagnostic performance and impact on management of 18F-FDG PET/CT and whole-body MRI in multiple myeloma.

PURPOSE: Comparative data on the impact of imaging on management is lacking for multiple myeloma. This study compared the diagnostic performance and impact on management of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) and whole-body magnetic resonance imaging (WBMRI) in treatment-naive myeloma. METHODS: Forty-six patients undergoing 18F-FDG PET/CT and WBMRI were reviewed by a nuclear medicine physician and radiologist, respectively, for the presence of myeloma bone disease. Blinded clinical and imaging data were reviewed by two haematologists in consensus and management recorded following clinical data ± 18F-FDG PET/CT or WBMRI. Bone disease was defined using International Myeloma Working Group (IMWG) criteria and a clinical reference standard. Per-patient sensitivity for lesion detection was established. McNemar test compared management based on clinical assessment ± 18F-FDG PET/CT or WBMRI. RESULTS: Sensitivity for bone lesions was 69.6% (32/46) for 18F-FDG PET/CT (54.3% (25/46) for PET component alone) and 91.3% (42/46) for WBMRI. 27/46 (58.7%) of cases were concordant. In 19/46 patients (41.3%) WBMRI detected more focal bone lesions than 18F-FDG PET/CT. Based on clinical data alone, 32/46 (69.6%) patients would have been treated. Addition of 18F-FDG PET/CT to clinical data increased this to 40/46 (87.0%) patients (p = 0.02); and WBMRI to clinical data to 43/46 (93.5%) patients (p = 0.002). The difference in treatment decisions was not statistically significant between 18F-FDG PET/CT and WBMRI (p = 0.08). CONCLUSION: Compared to 18F-FDG PET/CT, WBMRI had a higher per patient sensitivity for bone disease. However, treatment decisions were not statistically different and either modality would be appropriate in initial staging, depending on local availability and expertise.

Prognostic indices in diffuse large B-cell lymphoma in the rituximab era: an analysis of the UK National Cancer Research Institute R-CHOP 14 versus 21 phase 3 trial.

We compared the International Prognostic Index (IPI), Revised (R)-IPI and age-adjusted (aa)-IPI as prognostic indices for patients with diffuse large B-cell lymphoma (DLBCL) in the UK National Cancer Research Institute (NCRI) R-CHOP 14 versus 21 trial (N = 1080). The R-IPI and aa-IPI showed no marked improvement compared to the IPI for overall and progression-free survival, in terms of model fit or discrimination. Similar results were observed in exploratory analyses incorporating the Grupo Español de Linfomas/Transplante de Médula Ósea (GELTAMO)-IPI, where baseline ß2-microglobulin data were available (N = 655). Although our findings support current use of the IPI, a novel prognostic tool to better delineate a high-risk DLBCL group in the rituximab era is needed.

Factors Affecting COVID-19 Outcomes in Cancer Patients: A First Report From Guy's Cancer Center in London.

Background: There is insufficient evidence to support clinical decision-making for cancer patients diagnosed with COVID-19 due to the lack of large studies. Methods: We used data from a single large UK Cancer Center to assess the demographic/clinical characteristics of 156 cancer patients with a confirmed COVID-19 diagnosis between 29 February and 12 May 2020. Logistic/Cox proportional hazards models were used to identify which demographic and/or clinical characteristics were associated with COVID-19 severity/death. Results: 128 (82%) presented with mild/moderate COVID-19 and 28 (18%) with a severe case of the disease. An initial cancer diagnosis >24 months before COVID-19 [OR: 1.74 (95% CI: 0.71-4.26)], presenting with fever [6.21 (1.76-21.99)], dyspnea [2.60 (1.00-6.76)], gastro-intestinal symptoms [7.38 (2.71-20.16)], or higher levels of C-reactive protein [9.43 (0.73-121.12)] were linked with greater COVID-19 severity. During a median follow-up of 37 days, 34 patients had died of COVID-19 (22%). Being of Asian ethnicity [3.73 (1.28-10.91)], receiving palliative treatment [5.74 (1.15-28.79)], having an initial cancer diagnosis >24 months before [2.14 (1.04-4.44)], dyspnea [4.94 (1.99-12.25)], and increased CRP levels [10.35 (1.05-52.21)] were positively associated with COVID-19 death. An inverse association was observed with increased levels of albumin [0.04 (0.01-0.04)]. Conclusions: A longer-established diagnosis of cancer was associated with increased severity of infection as well as COVID-19 death, possibly reflecting the effects a more advanced malignant disease has on this infection. Asian ethnicity and palliative treatment were also associated with COVID-19 death in cancer patients.

CHOP versus GEM-P in previously untreated patients with peripheral T-cell lymphoma (CHEMO-T): a phase 2, multicentre, randomised, open-label trial.

BACKGROUND: Outcomes with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) or CHOP-like chemotherapy in peripheral T-cell lymphoma are poor. We investigated whether the regimen of gemcitabine, cisplatin, and methylprednisolone (GEM-P) was superior to CHOP as front-line therapy in previously untreated patients. METHODS: We did a phase 2, parallel-group, multicentre, open-label randomised trial in 47 hospitals: 46 in the UK and one in Australia. Participants were patients aged 18 years and older with bulky (tumour mass diameter >10 cm) stage I to stage IV disease (WHO performance status 0-3), previously untreated peripheral T-cell lymphoma not otherwise specified, angioimmunoblastic T-cell lymphoma, anaplastic lymphoma kinase-negative anaplastic large cell lymphoma, enteropathy-associated T-cell lymphoma, or hepatosplenic γδ T-cell lymphoma. We randomly assigned patients (1:1) stratified by subtype of peripheral T-cell lymphoma and international prognostic index to either CHOP (intravenous cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1·4 mg/m2 [maximum 2 mg] on day 1, and oral prednisolone 100 mg on days 1-5) every 21 days for six cycles; or GEM-P (intravenous gemcitabine 1000 mg/m2 on days 1, 8, and 15, cisplatin 100 mg/m2 on day 15, and oral or intravenous methylprednisolone 1000 mg on days 1-5) every 28 days for four cycles. The primary endpoint was the proportion of patients with a CT-based complete response or unconfirmed complete response on completion of study chemotherapy, to detect a 20% superiority of GEM-P compared with CHOP, assessed in all patients who received at least one cycle of treatment and had an end-of-treatment CT scan or reported clinical progression as the reason for stopping trial treatment. Safety was assessed in all patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov (NCT01719835) and the European Clinical Trials Database (EudraCT 2011-004146-18). FINDINGS: Between June 18, 2012, and Nov 16, 2016, we randomly assigned 87 patients to treatment, 43 to CHOP and 44 to GEM-P. A planned unmasked review of efficacy data by the independent data monitoring committee in November, 2016, showed that the number of patients with a confirmed or unconfirmed complete response with GEM-P was non-significantly inferior compared with CHOP and the trial was closed early. At a median follow-up of 27·4 months (IQR 16·6-38·4), 23 patients (62%) of 37 assessable patients assigned to CHOP had achieved a complete response or unconfirmed complete response compared with 17 (46%) of 37 assigned to GEM-P (odds ratio 0·52, 95% CI 0·21-1·31; p=0·164). The most common adverse events of grade 3 or worse in both groups were neutropenia (17 [40%] with CHOP and nine [20%] with GEM-P), thrombocytopenia (4 [10%] with CHOP and 13 [30%] with GEM-P, and febrile neutropenia (12 [29%] with CHOP and 3 [7%] with GEM-P). Two patients (5%) died during the study, both in the GEM-P group, from lung infections. INTERPRETATION: The number of patients with a complete response or unconfirmed complete response did not differ between the groups, indicating that GEM-P was not superior for this outcome. CHOP should therefore remain the reference regimen for previously untreated peripheral T-cell lymphoma. FUNDING: Bloodwise and the UK National Institute of Health Research.

Outcomes following front-line chemotherapy in peripheral T-cell lymphoma: 10-year experience at The Royal Marsden and The Christie Hospital.

We evaluated the outcomes for patients with peripheral T-cell lymphoma (PTCL) undergoing front-line chemotherapy at our institutions between 2002 and 2012. One hundred and fifty-six patients were eligible, comprising PTCL not otherwise specified (NOS) (n = 50, 32.0%), angioimmunoblastic T-cell lymphoma (AITL) (n = 44, 28.2%), anaplastic large-cell lymphoma (ALCL) ALK negative (n = 23, 14.7%), ALCL ALK positive (n = 16, 10.3%), and other (n = 23, 14.7%). Most patients received CHOP (66.0%) and 13.0% received an autologous hematopoietic progenitor cell transplant (HPCT). With a median follow-up of 63.4 months, 5-year overall survival (OS) and progression-free survival (PFS) was 38.8% and 19.8% respectively. Independent risk factors for inferior OS were age >60 years, International Prognostic Index (IPI) ≥ 2 and lack of complete response to induction. When responding patients were compared by receipt of an autologous HPCT versus not, HPCT was associated with improved PFS (p = .001) and OS (p = .046) and remained significant for PFS in multivariate analysis suggesting a possible therapeutic benefit.

Outcomes for transformed follicular lymphoma in the rituximab era: the Royal Marsden experience 2003-2013.

Survival for transformed follicular lymphoma (tFL) has improved in the rituximab era and the need for upfront stem cell transplantation (SCT) is unclear. We evaluated the outcomes for all patients treated with first-line chemotherapy for histologically-proven tFL at our institution from 2003-2013 (n = 87). The majority of patients (89.7%) did not receive a SCT as part of first-line management. With a median follow-up of 7.8 years the 5-year overall survival (OS) for all patients was 61.7%. Patients treated with R-CHOP without upfront SCT (n = 55/87) had a 5-year OS of 64.3%. In a Cox regression analysis of the entire cohort (n = 87) International Prognostic Index (IPI) risk group and presence of B symptoms at transformation were independently associated with OS in multivariate analysis (MVA). Our analysis confirms the improved survival of tFL in the rituximab era even in the absence of upfront SCT consolidation.

Rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) in the management of primary mediastinal B-cell lymphoma: a subgroup analysis of the UK NCRI R-CHOP 14 versus 21 trial.

We performed a subgroup analysis of the phase III UK National Cancer Research Institute R-CHOP-14 versus R-CHOP-21 (two- versus three-weekly rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone) trial to evaluate the outcomes for 50 patients with World Health Organization 2008 classified primary mediastinal B-cell lymphoma identified from the trial database. At a median follow-up of 7·2 years the 5-year progression-free survival and overall survival was 79·8% and 83·8%, respectively. An exploratory analysis raised the possibility of a better outcome in those who received R-CHOP-14 and time intensification may still, in the rituximab era, merit testing in a randomised trial in this subgroup of patients.

Bromodomain inhibitor OTX015 in patients with lymphoma or multiple myeloma: a dose-escalation, open-label, pharmacokinetic, phase 1 study.

BACKGROUND: The first-in-class small molecule inhibitor OTX015 (MK-8628) specifically binds to bromodomain motifs BRD2, BRD3, and BRD4 of bromodomain and extraterminal (BET) proteins, inhibiting them from binding to acetylated histones, which occurs preferentially at super-enhancer regions that control oncogene expression. OTX015 is active in haematological preclinical entities including leukaemia, lymphoma, and myeloma. We aimed to establish the recommended dose of OTX015 in patients with haematological malignancies. We report the results from a cohort of patients with lymphoma or multiple myeloma (non-leukaemia cohort). METHODS: In this dose-escalation, open-label, phase 1 study, we recruited patients from seven university hospital centres (in France [four], Switzerland [one], UK [one], and Italy [one]). Adult patients with non-leukaemia haematological malignancies who had disease progression on standard therapies were eligible to participate. Patients were treated with oral OTX015 once a day continuously over five doses (10 mg, 20 mg, 40 mg, 80 mg, and 120 mg), using a conventional 3 + 3 design, with allowance for evaluation of alternative administration schedules. The primary endpoint was dose-limiting toxicity (DLT) in the first treatment cycle (21 days). Secondary objectives were to evaluate safety, pharmacokinetics, and preliminary clinical activity of OTX015. The study is ongoing and is registered with ClinicalTrials.gov, number NCT01713582. FINDINGS: Between Feb 4, 2013, and Sept 5, 2014, 45 patients (33 with lymphoma and 12 with myeloma), with a median age of 66 years (IQR 55-72) and a median of four lines of prior therapy (IQR 3-5), were enrolled and treated. No DLTs were observed in the doses up to and including 80 mg once a day (first three patients). We then explored a schedule of 40 mg twice a day (21 of 21 days). DLTs were reported in five of six patients receiving OTX015 at this dose and schedule (all five patients had grade 4 thrombocytopenia). We explored various schedules at 120 mg once a day but none was tolerable, with DLTs of thrombocytopenia, gastrointestinal events (diarrhoea, vomiting, dysgeusia, mucositis), fatigue, and hyponatraemia in 11 of 18 evaluable patients. At this point, the Safety Monitoring Committee decided to establish the feasibility of 80 mg once a day on a continuous basis, and four additional patients were enrolled at this dose. DLTs (grade 4 thrombocytopenia) was noted in two of the patients. In light of these DLTs and other toxicities noted at 120 mg, the dose of 80 mg once a day was selected, although on a schedule of 14 days on, 7 days off. Common toxic effects reported in the study were thrombocytopenia (43 [96%] patients), anaemia (41 [91%]), neutropenia (23 [51%]), diarrhoea (21 [47%]), fatigue (12 [27%]), and nausea (11 [24%]). Grade 3-4 adverse events were infrequent other than thrombocytopenia (26 [58%]). OTX015 plasma peak concentrations and areas under the concentration versus time curve increased proportionally with dose. Trough concentrations increased less than proportionally at lower doses, but reached or exceeded the in-vitro active range at 40 mg twice a day and 120 mg once a day. Three patients with diffuse large B-cell lymphoma achieved durable objective responses (two complete responses at 120 mg once a day, and one partial response at 80 mg once a day), and six additional patients (two with diffuse large B-cell lymphoma, four with indolent lymphomas) had evidence of clinical activity, albeit not meeting objective response criteria. INTERPRETATION: The once-daily recommended dose for oral, single agent oral OTX015 in patients with lymphoma is 80 mg on a 14 days on, 7 days off schedule, for phase 2 studies. OTX015 is under evaluation in expansion cohorts using this intermittent administration (14 days every 3 weeks) to allow for recovery from toxic effects. FUNDING: Oncoethix GmbH (a wholly owned subsidiary of Merck Sharp & Dohme Corp).

Rituximab, Gemcitabine, Cisplatin and Methylprednisolone (R-GEM-P) is an effective regimen in relapsed diffuse large B-cell lymphoma.

BACKGROUND: Patients with relapsed diffuse large B-cell lymphoma (DLBCL) have a poor prognosis. Gemcitabine, methylprednisolone, cisplatin +/- rituximab (GEM-P+/-R) is a salvage regimen with limited overlap in toxicity with first-line therapy and short duration of inpatient delivery. METHODS: We assessed the efficacy and safety of GEM-P+/-R in a retrospective single-centre analysis including patients meeting criteria of ≥ 18 yr of age, histologically proven DLBCL, treated between 2001 and 2011 in second-line with gemcitabine 1000 mg/m(2) day 1, 8 and 15, methylprednisolone 1000 mg day 1-5, cisplatin 100 mg/m(2) day 15 (replaced with carboplatin AUC5 if contraindication/toxicity) +/- rituximab 375 mg/m(2) day 1 and 15, every 28 d. RESULTS: Forty-five patients aged 25-74 received a median of three cycles of GEM-P+/-R; 64% received rituximab. In 44 evaluable patients receiving GEM-P+/-R, overall response rate (ORR) was 48%; in 28 evaluable patients treated with rituximab + GEM-P (R-GEM-P), ORR was 61%. With median follow-up of 50.5 months (95% CI: 28.3-72.7), 3-yr overall survival (OS) from start of GEM-P+/-R was 31.4% (95% CI: 16.5-46.3); in patients treated with R-GEM-P, 3-yr OS was 49.1% (95% CI: 28.7-69.5). Predominant grade ≥ 3 toxicities were haematological; thrombocytopenia 69%, neutropenia 60% and febrile neutropenia 7%. CONCLUSION: R-GEM-P is a deliverable regimen with useful activity in second-line treatment of DLBCL. Our data suggest that rituximab should be given concurrently.

Successful treatment with rituximab and mycophenolate mofetil of refractory autoimmune hemolytic anemia post-hematopoietic stem cell transplant for dyskeratosis congenita due to TINF2 mutation.

AIHA following allogeneic HSCT is appearing more frequently in the literature. It occurs as a result of donor cell-derived antibodies targeting donor red cell antigens. Little guidance exists on the management of such patients, particularly in the pediatric setting. First-line conventional treatment is corticosteroids and/or immunoglobulin therapy with monoclonal antibody therapy reserved for treatment failure. We report our experience of a child refractory to immunoglobulin and steroid therapy who required several infusions of rituximab and immunomodulatory therapy to obtain a clinically significant response.