A multicentre phase II clinical experience with the novel aza-epothilone Ixabepilone (BMS247550) in patients with relapsed or refractory indolent non-Hodgkin lymphoma and mantle cell lymphoma

The epothilones represent a novel group of microtubule stabilization agents that appear to retain activity even in chemotherapy-resistant cell lines and animal models. Because of their ability to overcome chemotherapy resistance, we conducted a phase II study of Ixabepilone in patients with indolent non-Hodgkin lymphoma and mantle cell lymphoma (MCL). Ixabepilone was given at a dose of 25 mg/m(2) weekly for three of four consecutive weeks. Patients were required to have received < or =4 prior chemotherapy regimens, with an interval of at least one month since the last treatment, 3 months from prior rituximab, and 7 d from prior steroids, an absolute neutrophil count >1 x 10(9)/l and a platelet count >50 x 10(9)/l. Dose reductions were allowed. The overall response rate in assessable patients was 27% in this otherwise heavily treated population. One patient with chemotherapy-refractory follicular lymphoma attained a complete remission that lasted approximately 8 months. Three responses were also seen in refractory MCL and one in small lymphocytic lymphoma. The duration of response ranged from 2 to 8 months. Major toxicities included fatigue, myelosuppression and neuropathy. These data suggest that Ixabepilone has activity in chemotherapy-refractory lymphoma.     

Results of a phase I‐II study of fenretinide and rituximab for patients with indolent B‐cell lymphoma and mantle cell lymphoma

Fenretinide, a synthetic retinoid, induces apoptotic cell death in B‐cell non‐Hodgkin lymphoma (B‐NHL ) and acts synergistically with rituximab in preclinical models. We report results from a phase I‐II study of fenretinide with rituximab for B‐NHL s. Eligible diagnoses included indolent B‐NHL or mantle cell lymphoma. The phase I design de‐escalated from fenretinide at 900 mg/m² PO BID for days 1–5 of a 7‐day cycle. The phase II portion added 375 mg/m² IV rituximab weekly on weeks 5–9 then every 3 months. Fenretinide was continued until progression or intolerance. Thirty‐two patients were treated: 7 in phase I, and 25 in phase II of the trial. No dose‐limiting toxicities were observed. The phase II component utilized fenretinide 900 mg/m² twice daily with rituximab. The most common treatment‐related adverse events of grade 3 or higher were rash (n  = 3) and neutropenia (n  = 3). Responses were seen in 6 (24%) patients on the phase II study, with a median duration of response of 47 months (95% confidence interval, 2–56). The combination of fenretinide and rituximab was well tolerated, yielded a modest overall response rate, but with prolonged remission durations. Further study should focus on identifying the responsive subset of B‐NHL .     

Monotherapy with pixantrone in histologically confirmed relapsed or refractory aggressive B‐cell non‐Hodgkin lymphoma: post‐hoc analyses from a phase III trial

This post hoc analysis of a phase 3 trial explored the effect of pixantrone in patients (50 pixantrone, 47 comparator) with relapsed or refractory aggressive B‐cell non‐Hodgkin lymphoma (NHL) confirmed by centralized histological review. Patients received 28‐d cycles of 85 mg/m² pixantrone dimaleate (equivalent to 50 mg/m² in the approved formulation) on days 1, 8 and 15, or comparator. The population was subdivided according to previous rituximab use and whether they received the study treatment as 3rd or 4th line. Median number of cycles was 4 (range, 2–6) with pixantrone and 3 (2–6) with comparator. In 3rd or 4th line, pixantrone was associated with higher complete response (CR) (23·1% vs. 5·1% comparator, P = 0·047) and overall response rate (ORR, 43·6% vs. 12·8%, P = 0·005). In 3rd or 4th line with previous rituximab (20 pixantrone, 18 comparator), pixantrone produced better ORR (45·0% vs. 11·1%, P = 0·033), CR (30·0% vs. 5·6%, P = 0·093) and progression‐free survival (median 5·4 vs. 2·8 months, hazard ratio 0·52, 95% confidence interval 0·26–1·04) than the comparator. Similar results were found in patients without previous rituximab. There were no unexpected safety issues. Pixantrone monotherapy is more effective than comparator in relapsed or refractory aggressive B‐cell NHL in the 3rd or 4th line setting, independently of previous rituximab.     

A phase 2 study of inotuzumab ozogamicin in patients with indolent B‐cell non‐Hodgkin lymphoma refractory to rituximab alone,rituximab and chemotherapy,or radioimmunotherapy

This phase 2 study evaluated the efficacy and safety of inotuzumab ozogamicin (InO) in patients with indolent B‐cell non‐Hodgkin lymphoma (NHL) refractory to rituximab alone, rituximab plus chemotherapy or anti‐CD20 radioimmunotherapy. Patients received InO 1·8 mg/m² intravenously on a 28‐d cycle for a planned 4–8 cycles. The initial InO dose and schedule could be adjusted for tolerability and patients were allowed to receive 2 additional cycles (up to 8 total) after achieving a complete response (CR). The primary endpoint was overall response. Eighty‐one patients were enrolled, among whom 48 (59%) received ≥3 InO cycles and 13 (16%) completed the treatment phase. The overall response rate was 67% (CR, 31%). Median (95% confidence interval) progression‐free survival was 12·7 (8·9–26·9) months; median overall survival was not reached. Haematological adverse events (AEs) were common, particularly thrombocytopenia (74%) and neutropenia (56%). These were also the most common AEs leading to treatment discontinuation (37% and 11%, respectively); 58% of patients reported AEs leading to treatment discontinuation. InO demonstrated robust activity in these heavily pretreated patients, although treatment duration was limited by haematological toxicities. Additional studies may determine dosing regimens that allow for reduced toxicity.     

A multicentre,phase II trial of ofatumumab monotherapy in relapsed/progressive diffuse large B‐cell lymphoma

This international, multicentre phase II study was conducted to assess ofatumumab, a human anti‐CD20 monoclonal antibody, in patients with relapsed/progressive diffuse large B‐cell lymphoma (DLBCL) who were ineligible for autologous stem cell transplantation (TI) or who had relapse/progression after transplantation (PT). Eighty‐one patients received ofatumumab 300 mg intravenously (IV) on Day 1, followed by seven weekly IV infusions of 1000 mg. Patients in the TI and PT groups had received a median of 3 (range, 1–7) and 5 (range, 2–7) prior therapies, respectively. One‐third of patients did not respond to the last prior therapy, and 53% had failed two or more rituximab‐containing therapies. Overall response rate was 13% for the TI group (seven partial responses) and 8% for the PT group (two complete responses). Median progression‐free survival was 2·6 months, and median duration of response was 9·5 months. The most common Grade 3–4 adverse events were neutropenia (11%), leucopenia (6%), lymphopenia (6%) and thrombocytopenia (6%). Sixteen deaths have been reported, with disease progression as the most common cause of death. In conclusion, ofatumumab monotherapy was well tolerated and provided clinical benefit to some DLBCL patients in this study. This trial was registered at www.clinicaltrials.gov (NCT00622388).     

Phase IA/II,multicentre, open‐label study of the CD40 antagonistic monoclonal antibody lucatumumab in adult patients with advanced non‐Hodgkin or Hodgkin lymphoma

Despite advancements in the treatment of non‐Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL), patients continue to relapse and thus a need for new targeted therapies remains. The CD40 receptor is highly expressed on neoplastic B cells and activation leads to enhanced proliferation and survival. Lucatumumab (HCD122) is a fully human antagonistic CD40 monoclonal antibody. A phase IA/II study was designed to determine the maximum tolerated dose (MTD) and activity of lucatumumab in patients with relapsed/refractory lymphoma. Determination of the MTD was the primary objective of the phase IA dose escalation portion and clinical response was the primary objective of the phase II dose expansion portion. Patients received escalating doses of lucatumumab administered intravenously once weekly for 4 weeks of an 8‐week cycle. MTD was determined at 4 mg/kg of lucatumumab. A total of 111 patients with NHL (n = 74) and HL (n = 37) were enrolled. Responses were observed across various lymphoma subtypes. The overall response rate by computed tomography among patients with follicular lymphoma (FL) and marginal zone lymphoma of mucosa‐associated lymphatic tissue (MZL/MALT) was 33·3% and 42·9%, respectively. Lucatumumab demonstrates modest activity in relapsed/refractory patients with advanced lymphoma, suggesting that targeting of CD40 warrants further investigation.     

Rituximab extended schedule or retreatment trial for low tumour burden non‐follicular indolent B‐cell non‐Hodgkin lymphomas: Eastern Cooperative Oncology Group Protocol E4402

The rituximab extended schedule or retreatment trial (RESORT; E4402) was a phase 3 randomized prospective trial comparing maintenance rituximab (MR) versus a retreatment (RR) dosing strategy in asymptomatic, low tumour burden indolent lymphoma. A planned exploratory sub‐study compared the two strategies for small lymphocytic (SLL) and marginal zone lymphomas (MZL). Patients responding to rituximab weekly × 4 were randomized to MR (single dose rituximab every 3 months until treatment failure) or RR (rituximab weekly × 4) at the time of each progression until treatment failure. The primary endpoint was time to treatment failure (TTTF). Patients with SLL (n = 57), MZL (n = 71) and unclassifiable small B‐cell lymphoma (n = 3) received induction rituximab. The overall response rate (ORR) was 40% [95% confidence interval (CI) 31–49%; SLL ORR 22·8%; MZL ORR 52·1%]; all 52 responders were randomized. At a median of 4·3 years from randomization, treatment failure occurred in 18/23 RR and 15/29 MR. The median TTTF was 1·4 years for RR and 4·8 years for MR (P = 0·012); median time to first cytotoxic therapy was 6·3 years for RR and not reached for MR (P = 0·0002). Survival did not differ (P = 0·72). In low tumour burden SLL and MZL patients responding to rituximab induction, MR significantly improved TTTF as compared with RR.     

Rituximab combined with DexaBEAM followed by high dose therapy as salvage therapy in patients with relapsed or refractory B‐cell lymphoma: mature results of a phase II multicentre study

Salvage therapy followed by high‐dose therapy (HDT) remains a mainstay for patients with relapsed lymphoma, however no optimal regimen has been defined. Here we report on the results of R‐DexaBEAM (rituximab, dexamethasone, carmustine, etoposide, cytarabine, melphalan) followed by HDT. Patients aged 18–65 years, Eastern Cooperative Oncology Group performance score 0–2, with relapsed/refractory B‐cell non‐Hodgkin lymphoma (NHL) were eligible. R‐Dexa‐BEAM was given for two cycles followed by stem cell mobilization and HDT. Primary endpoint of the trial was progression‐free‐survival (PFS). One hundred and three patients were included: aggressive NHL (aNHL): diffuse large B‐cell lymphoma 55, mantle cell lymphoma 7, follicular lymphoma (FL) grade 3: 5, indolent Lymphoma (iNHL): FL grade 1–2: 29, marginal zone lymphoma 6, Immunocytoma 1. The overall response rate after salvage therapy was 62% for aNHL and 78% for iNHL patients. 66% of patients with aNHL and 86% with iNHL underwent HDT. Treatment‐related mortality for HDT was 1·3%. For aNHL patients, the median PFS was 0·83 years with 44% alive at the median follow‐up of 7·3 years. Corresponding figures for iNHL were: median PFS 3·7 years and 72% alive after 8 years. The combination of rituximab with DexaBEAM followed by HDT resulted in high response rates and sustained remissions in responders. R‐DexaBEAM followed by HDT can be considered a valid salvage option for NHL.     

Open‐label,single‐arm,phase II study of enzastaurin in patients with follicular lymphoma

This open‐label, phase II study investigated whether enzastaurin, a protein kinase C‐beta (PKCβ) inhibitor, had activity in patients with grade 1 or 2 follicular lymphoma (FL). Adults with grade 1 or 2 FL who had no more than one prior treatment received oral enzastaurin continuously for up to 3 years. Of the 66 patients who received enzastaurin, 53 were evaluable for response. Overall response rate (ORR, primary efficacy endpoint) was 26·4% (3·8% complete response). Median (95% confidence interval) progression‐free survival, time to response, and duration of response were 18·1 (11·5–28·3), 4·9 (2·8–8·1), and 22·3 (8·8‐not applicable) months, respectively. In patients with tumour tissue available for biomarker analysis, ORRs in low versus high PKCβ2 expression groups were 41·7% and 8·3%, respectively (P = 0·041). The most common, mainly low‐grade drug‐related adverse events were fatigue (25·8%), diarrhoea (25·8%), nausea (18·2%), and chromaturia (18·2%). Four (6·1%) patients had Grade 3 toxicity and one (1·5%) patient had Grade 4 toxicity. Enzastaurin demonstrated limited clinical activity in grade 1 or 2 FL. Patients with low PKCβ2 expression in tumours had higher ORR than those with high PKCβ2 expression. Enzastaurin was well tolerated with mostly grade 1 or 2 toxicities. Further studies may be warranted in select patient populations.     

Overall survival of children and adolescents with mature B cell non‐Hodgkin lymphoma who had refractory or relapsed disease during or after treatment with FAB/LMB 96: A report from the FAB/LMB 96 study group

We determined the risk factors associated with poor survival in children and adolescents with de novo mature B cell non‐Hodgkin lymphoma (B‐NHL) who had refractory or relapsed disease during or after the French‐American‐British mature lymphoma B (FAB/LMB) 96 multi‐agent chemotherapy. Among the 1 111 registered on study, 104 patients (9·4%) had refractory disease or disease relapse after first complete remission. Among these 104 patients, 28 (27%) patients had refractory disease and 76 (73%) had relapsed disease. The estimated 1‐ and 2‐year overall survival (OS) (95% confidence interval) was 31·5% (23·3–41·0%) and 22·3% (15·3–31·4%), respectively. Prognostic analysis of OS using a Cox multivariate model showed that factors independently associated with OS included lactate dehydrogenase ≥2 upper normal limit [hazard ratio (HR) = 2·86 (1·57–5·2), P = 0·0006]; time to failure (>6 months) [HR = 0·59 (0·36–0·97), P = 0·038]; and failure in bone marrow [HR = 2·78 (1·65–4·68), P = 0·0001]. New therapeutic strategies are required to significantly reduce refractory disease and disease relapse in patients with newly diagnosed mature B‐NHL and, more importantly, there is a critical need to develop novel retrieval approaches in patients with chemotherapy‐resistant disease.     

Prospective subgroup analyses of the randomized MCL‐002 (SPRINT) study: lenalidomide versus investigator's choice in relapsed or refractory mantle cell lymphoma

In the mantle cell lymphoma (MCL)‐002 study, lenalidomide demonstrated significantly improved median progression‐free survival (PFS) compared with investigator's choice (IC) in patients with relapsed/refractory MCL. Here we present the long‐term follow‐up data and results of preplanned subgroup exploratory analyses from MCL‐002 to evaluate the potential impact of demographic factors, baseline clinical characteristics and prior therapies on PFS. In MCL‐002, patients with relapsed/refractory MCL were randomized 2:1 to receive lenalidomide (25 mg/day orally on days 1–21; 28‐day cycles) or single‐agent IC therapy (rituximab, gemcitabine, fludarabine, chlorambucil or cytarabine). The intent‐to‐treat population comprised 254 patients (lenalidomide, n = 170; IC, n = 84). Subgroup analyses of PFS favoured lenalidomide over IC across most characteristics, including risk factors, such as high MCL International Prognostic Index score, age ≥65 years, high lactate dehydrogenase (LDH), stage III/IV disease, high tumour burden, and refractoriness to last prior therapy. By multivariate Cox regression analysis, factors associated with significantly longer PFS (other than lenalidomide treatment) included normal LDH levels (P < 0·001), nonbulky disease (P = 0·045), <3 prior antilymphoma treatments (P = 0·005), and ≥6 months since last prior treatment (P = 0·032). Overall, lenalidomide improved PFS versus single‐agent IC therapy in patients with relapsed/refractory MCL, irrespective of many demographic factors, disease characteristics and prior treatment history.     

Phase I/II trial of vorinostat with rituximab,cyclophosphamide, etoposide and prednisone as palliative treatment for elderly patients with relapsed or refractory diffuse large B‐cell lymphoma not eligible for autologous stem cell transplantation

The standard treatment of relapsed/refractory diffuse large B‐cell lymphoma (DLBCL) in frail elderly patients has not been established. A variation was made on rituximab (R), cyclophosphamide (C), etoposide (E), procarbazine and prednisone (P), substituting vorinostat (V) for procarbazine. Patients ≥aged 60 years with relapsed/refractory DLBCL, not candidates for autologous stem cell transplantation, were treated R‐CVEP [R 375 mg/m² intravenously (IV), day 1; C 600 mg/m² IV days 1, 8: E 70 mg/m² IV day 1, 140 mg/m² days 2, 3 orally (PO); V (300 vs. 400 mg) PO and P 60 mg/m² PO days 1–10] every 28 d for six cycles. Quality of life (QoL) was assessed in addition to response. Thirty patients (median age 76 years, 69–88) were enrolled (one died before treatment). Maximum tolerated dose (MTD) for V was 300 mg. For 23 patients at MTD (six phase I + 17 phase II), two were discontinued for toxicity, one withdrew consent, eight achieved complete response (35%), five achieved partial response (22%) and seven progressed (25%). Median overall survival was 17·5 months. Median progression‐free survival was 9·2 months. Nine patients are alive. QoL declined during treatment but improved above baseline for patients who completed treatment. In conclusion, R‐CVEP was tolerated at MTD and produced durable responses with improved QoL.     

The potential benefit of allogeneic over autologous transplantation in patients with very early relapsed and refractory follicular lymphoma with prior remission duration of ≤12 months

Early relapsed or refractory follicular lymphoma (FL) warrants consolidation with transplantation, though graft source modality remains controversial. We analysed the outcomes of 44 patients transplanted with either autologous or allogeneic graft sources in the post‐rituximab era. No difference in event‐free (EFS) or overall survival (OS) was observed between allogeneic (81% and 81%) and autologous transplantation (64% and 70%) at 3 years. There was a significant difference in EFS between allogeneic and autologous transplantation patients with previous remission duration of ≤12 months (80% and 42% at 3 years, P < 0·015). Very early relapsed FL may warrant consideration of allogeneic over autologous transplantation in the appropriate setting.     

Front‐line management of indolent non‐Hodgkin lymphoma in Australia. Part 2: mantle cell lymphoma and marginal zone lymphoma

Mantle cell lymphoma (MCL) and the marginal zone lymphoma (MZL) subtypes (nodal MZL, extra‐nodal MZL of mucosa‐associated lymphoid tissue (MALT lymphoma) and splenic MZL) are uncommon lymphoma subtypes, accounting for less than 5–10% of all non‐Hodgkin lymphoma. The evidence base for therapy is therefore limited and enrolment into clinical trials is preferred. Outcomes for patients with MCL have been steadily improving mainly due to the adoption of more intense strategies in younger patients, the use of rituximab maintenance and the recent introduction of bendamustine in older patients. MZL is a more heterogeneous group of cancer with both nodal, extra‐nodal and splenic subtypes. Extranodal MZL may be associated with autoimmune or infectious aetiologies, and can respond to eradication of the causative pathogen. Proton pump inhibitor plus dual antibiotics in Helicobacter pylori positive gastric MALT lymphoma is curative in many patients. Watchful waiting is appropriate in most patients with asymptomatic advanced stage disease, which tends to behave in a particularly indolent manner. Other options for symptomatic disease include splenectomy, chemoimmunotherapy with rituximab and, more recently, targeted therapies.     

An audit of patients with mature T‐cell non‐Hodgkin lymphoma by transplant status in Tasmania

This retrospective audit of patients diagnosed with mature T‐cell lymphoma across a 10‐year period provides contemporary information on the outcomes and treatment patterns of an Australian cohort. Forty‐two patients diagnosed with mature T‐cell lymphoma were identified from the Tasmanian Cancer Registry and analysed using medical records and simple statistical analysis. The demographics and outcomes of patients in this cohort were comparable to large international studies with treatment patterns in line with the best available evidence.     

A phase 2 study of mocetinostat,a histone deacetylase inhibitor,in relapsed or refractory lymphoma

Deregulation of histone deacetylase (HDAC) is important in the pathogenesis of follicular lymphoma (FL) and diffuse large B‐cell lymphoma (DLBCL). Mocetinostat, an isotype‐selective HDAC inhibitor, induces accumulation of acetylated histones, cell cycle arrest and apoptosis in several cancers. This phase 2 study evaluated mocetinostat in patients with relapsed/refractory (R/R) DLBCL and FL. Seventy‐two patients received mocetinostat (starting doses: 70–110 mg TIW, 4‐week cycles). The best overall response rate (95% CI) was 18·9% (7·2, 32·2) for the DLBCL cohort (n = 41), and 11·5% (1·7, 20·7) for the FL cohort (n = 31). Responses were durable (≥90 days in 7 of 10 responses). Overall, 54·1% and 73·1% of patients derived clinical benefit (response or stable disease) from mocetinostat in the DLBCL and FL cohorts, respectively. Progression‐free survival ranged from 1·8 to 22·8 months and 11·8 to 26·3 months in responders with DLBCL and FL, respectively. The most frequent treatment‐related adverse events were fatigue (75·0%), nausea (69·4%) and diarrhoea (61·1%). Although mocetinostat had limited single‐agent activity in R/R DLBCL and FL, patients with clinical benefit had long‐term disease control. The safety profile was acceptable. This drug class warrants further investigation, including identifying patients more likely to respond to this agent, or in combination with other agents.