Summary Background Patients with indolent non-Hodgkin lymphoma who fail to achieve adequate disease control with rituximab-based treatment have few treatment options and a poor prognosis. We aimed to ...assess a combination of obinutuzumab (GA101), a novel glyco-engineered type II anti-CD20 monoclonal antibody, and bendamustine in this patient population. Methods In this open-label, randomised, phase 3 study (GADOLIN), patients aged 18 years or older with histologically documented, CD20-positive indolent non-Hodgkin lymphoma refractory to rituximab were enrolled at 83 hospital and community sites in 14 countries in Europe, Asia, and North and Central America. Patients were randomly assigned (1:1) using a hierarchical dynamic randomisation scheme stratified by indolent non-Hodgkin lymphoma subtype, rituximab-refractory type, number of previous therapies, and geographical region, to receive induction treatment (six 28-day cycles) with obinutuzumab plus bendamustine or bendamustine monotherapy, both given intravenously. Obinutuzumab plus bendamustine dosing was obinutuzumab 1000 mg (days 1, 8, and 15, cycle 1; day 1, cycles 2–6) plus bendamustine 90 mg/m2 per day (days 1 and 2, cycles 1–6), and bendamustine monotherapy dosing was 120 mg/m2 per day (days 1 and 2, all cycles). Non-progressing patients in the obinutuzumab plus bendamustine group received obinutuzumab maintenance (1000 mg every 2 months) for up to 2 years. The primary endpoint was progression-free survival in all randomised patients, as assessed by an independent review committee. Safety was assessed in all patients who received any amount of obinutuzumab or bendamustine. This study is registered with ClinicalTrials.gov , number NCT01059630 , and has stopped recruiting patients. Findings Between April 15, 2010, and Sept 1, 2014, when the study was stopped after a pre-planned interim analysis, 396 patients were randomly assigned (194 to obinutuzumab plus bendamustine and 202 to bendamustine monotherapy). After a median follow-up time of 21·9 months (IQR 12·1–31·0) in the obinutuzumab plus bendamustine group and 20·3 months (9·5–29·7) in the bendamustine monotherapy group, progression-free survival was significantly longer with obinutuzumab plus bendamustine (median not reached 95% CI 22·5 months–not estimable) than with bendamustine monotherapy (14·9 months 12·8–16·6; hazard ratio 0·55 95% CI 0·40–0·74; p=0·0001). Grade 3–5 adverse events occurred in 132 (68%) of 194 patients in the obinutuzumab plus bendamustine group and in 123 (62%) of 198 patients in the bendamustine monotherapy group. The most frequent grade 3 or worse adverse events were neutropenia (64 33% in the obinutuzumab plus bendamustine group vs 52 26% in the bendamustine monotherapy group), thrombocytopenia (21 11% vs 32 16%), anaemia (15 8% vs 20 10%) and infusion-related reactions (21 11% vs 11 6%). Serious adverse events occurred in 74 patients (38%) in the obinutuzumab plus bendamustine group and in 65 patients (33%) in the bendamustine monotherapy group, and deaths due to adverse events occurred in 12 patients (6%) and 12 patients (6%), respectively. Three (25%) of 12 adverse event-related deaths in the obinutuzumab plus bendamustine group and five (42%) of 12 in the bendamustine monotherapy group were treatment related. Interpretation Obinutuzumab plus bendamustine followed by obinutuzumab maintenance has improved efficacy over bendamustine monotherapy in rituximab-refractory patients with indolent non-Hodgkin lymphoma, with manageable toxicity, and is a new treatment option for patients who have relapsed after or are no longer responding to rituximab-based therapy. Funding F Hoffmann-La Roche Ltd.
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Summary Background Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality after allogeneic haematopoietic cell transplantation from unrelated donors. Anti-T-cell globulins ...(ATGs) might lower the incidence of GVHD. We did a prospective, randomised, multicentre, open-label, phase 3 trial to compare standard GVHD prophylaxis with ciclosporin and methotrexate with or without anti-Jurkat ATG-Fresenius (ATG-F). Methods Between May 26, 2003, and Feb 8, 2007, 202 patients with haematological malignancies were centrally randomly assigned using computer-generated centre-stratified block randomisation between treatment groups receiving ciclosporin and methotrexate with or without additional ATG-F. One patient in the ATG-F group did not undergo transplantation, thus 201 patients who underwent transplantation with peripheral blood (n=164; 82%) or bone marrow (n=37; 18%) grafts from unrelated donors after myeloablative conditioning were included in the full analysis set, and were analysed according to their randomly assigned treatment (ATG-F n=103, control n=98). The primary endpoint was severe acute GVHD (aGVHD) grade III–IV or death within 100 days of transplantation. The trial is registered with the numbers DRKS00000002 and NCT00655343. Findings The number of patients in the ATG-F group who had severe aGVHD grade III–IV or who died within 100 days of transplantation was 12 and 10 (21·4%, 95% CI 13·4–29·3), respectively, compared with 24 and nine (33·7%, 24·3–43·0) patients, respectively, in the control group (adjusted odds ratio 0·59, 95% CI 0·30–1·17; p=0·13). The cumulative incidence of aGVHD grade III–IV was 11·7% (95% CI 6·8–19·8) in the ATG-F group versus 24·5% (17·3–34·7) in the control group (adjusted hazard ratio HR 0·50, 95% CI 0·25–1·01; p=0·054), and cumulative incidence of aGVHD grade II–IV was 33·0% (n=34; 95% CI 25·1–43·5) in the ATG-F group versus 51·0% (n=50; 95% CI 42·0–61·9) in the control group (adjusted HR 0·56, 0·36–0·87; p=0·011). The 2-year cumulative incidence of extensive chronic GVHD was 12·2% (n=11; 95% CI 7·0–21·3) versus 42·6% (n=34; 95% CI 33·0–55·0; adjusted HR 0·22, 0·11–0·43; p<0·0001). There were no differences between treatment groups with regard to relapse, non-relapse mortality, overall survival, and mortality from infectious causes. Interpretation The addition of ATG-F to GVHD prophylaxis with ciclosporin and methotrexate resulted in decreased incidence of acute and chronic GVHD without an increase in relapse or non-relapse mortality, and without compromising overall survival. The use of ATG-F is safe for patients who are going to receive a haematopoietic cell transplantation from matched unrelated donors. Funding Fresenius Biotech GmbH.
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Summary Background Bortezomib and rituximab have shown additive activity in preclinical models of lymphoma, and have been shown to be active and generally well tolerated in a randomised phase 2 study ...in patients with follicular and marginal zone lymphoma. We compared the efficacy and safety of rituximab alone or combined with bortezomib in patients with relapsed or refractory follicular lymphoma in a phase 3 setting. Methods In this multicentre phase 3 trial, rituximab-naive or rituximab-sensitive patients aged 18 years or older with relapsed grade 1 or 2 follicular lymphoma were randomly assigned (1:1) to receive five 35-day cycles consisting of intravenous infusions of rituximab 375 mg/m2 on days 1, 8, 15, and 22 of cycle 1, and on day 1 of cycles 2–5, either alone or with bortezomib 1·6 mg/m2 , administered by intravenous injection on days 1, 8, 15, and 22 of all cycles. Randomisation was stratified by FLIPI score, previous use of rituximab, time since last therapy, and region. Treatment assignment was based on a computer-generated randomisation schedule prepared by the sponsor. Patients and treating physicians were not masked to treatment allocation. The primary endpoint was progression-free survival analysed by intention to treat. This trial has been completed and is registered with ClinicalTrials.gov , number NCT00312845. Findings Between April 10, 2006, and Aug 12, 2008, 676 patients were randomised to receive rituximab (n=340) or bortezomib plus rituximab (n=336). After a median follow-up of 33·9 months (IQR 26·4–39·7), median progression-free survival was 11·0 months (95% CI 9·1–12·0) in the rituximab group and 12·8 months (11·5–15·0) in the bortezomib plus rituximab group (hazard ratio 0·82, 95% CI 0·68–0·99; p=0·039). The magnitude of clinical benefit was not as large as the anticipated prespecified improvement of 33% in progression-free survival. Patients in both groups received a median of five treatment cycles (range 1–5); 245 of 339 (72%) and 237 of 334 (71%) patients in the rituximab and bortezomib plus rituximab groups, respectively, completed five cycles. Of patients who did not complete five cycles, most discontinued early because of disease progression (77 23% patients in the rituximab group, and 56 17% patients in the bortezomib plus rituximab group). Rates of adverse events of grade 3 or higher (70 21% of 339 rituximab-treated patients vs 152 46% of 334 bortezomib plus rituximab treated patients), and serious adverse events (37 11% patients vs 59 18% patients) were lower in the rituximab group than in the combination group. The most common adverse events of grade 3 or higher were neutropenia (15 4% patients in the rituximab group and 37 11% patients in the bortezomib plus rituximab group), infection (15 4% patients and 36 11% patients, respectively), diarrhoea (no patients and 25 7% patients, respectively), herpes zoster (one <1% patient and 12 4% patients, respectively), nausea or vomiting (two <1% patients and 10 3% patients, respectively) and thrombocytopenia (two <1% patients and 10 3% patients, respectively). No individual serious adverse event was reported by more than three patients in the rituximab group; in the bortezomib plus rituximab group, only pneumonia (seven patients 2%) and pyrexia (six patients 2%) were reported in more than five patients. In the bortezomib plus rituximab group 57 (17%) of 334 patients had peripheral neuropathy (including sensory, motor, and sensorimotor neuropathy), including nine (3%) with grade 3 or higher, compared with three (1%) of 339 patients in the rituximab group (no events of grade ≥3). No patients in the rituximab group but three (1%) patients in the bortezomib plus rituximab group died of adverse events considered at least possibly related to treatment. Interpretation Although a regimen of bortezomib plus rituximab is feasible, the improvement in progression-free survival provided by this regimen versus rituximab alone was not as great as expected. The regimen might represent a useful addition to the armamentarium, particularly for some subgroups of patients. Funding Johnson & Johnson Pharmaceutical Research & Development and Millennium Pharmaceuticals, Inc.
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In many patients with chronic lymphocytic leukaemia requiring treatment, induction therapy with rituximab plus chemotherapy improves outcomes compared with chemotherapy alone. In this study we aimed ...to investigate the potential of rituximab maintenance therapy to prolong disease control in patients who respond to rituximab-containing induction regimens.
In this randomised, international, multicentre, open-label, phase 3 clinical trial, we enrolled patients who had achieved a complete response (CR), CR with incomplete bone marrow recovery (CRi), or partial response (PR) to first-line or second-line rituximab-containing chemoimmunotherapy and randomly assigned them in a 1:1 ratio (central block randomisation in the electronic case report form system) to either intravenous rituximab 375 mg/m(2) every 3 months, or observation alone, for 2 years. Stratification was by country, line of treatment, type of chemotherapy added to the rituximab backbone, and degree of remission following induction. The primary endpoint was progression-free survival. Efficacy analysis was done in the intention-to-treat population. This is the final, event-triggered analysis. Final analysis was triggered by the occurrence of 92 events. This trial is registered with ClinicalTrials.gov, number NCT01118234.
Between April 1, 2010, and Dec 23, 2013, 134 patients were randomised to rituximab and 129 to observation alone. Median observation times were 33·4 months (IQR 25·7-42·8) for the rituximab group and 34·0 months (25·4-41·9) for the observation group. Progression-free survival was significantly longer in the rituximab maintenance group (47·0 months, IQR 28·5-incalculable) than with observation alone (35·5 months, 95% CI 25·7-46·3; hazard ratio HR 0·50, 95% CI 0·33-0·75, p=0·00077). The incidence of grade 3-4 haematological toxicities other than neutropenia was similar in the two treatment groups. Grade 3-4 neutropenia occurred in 28 (21%) patients in the rituximab group and 14 (11%) patients in the observation group. Apart from neutropenia, the most common grade 3-4 adverse events were upper (five vs one 1% patient in the observation group) and lower (three 2% vs one 1%) respiratory tract infection, pneumonia (nine 7% vs two 2%), thrombopenia (four 3% vs four 3%), neoplasms (five 4% vs four 3%), and eye disorders (four 3% vs two 2%). The overall incidence of infections of all grades was higher among rituximab recipients (88 66% vs 65 50%).
Rituximab maintenance therapy prolongs progression-free survival in patients achieving at least a PR to induction with rituximab plus chemotherapy, and the treatment is well tolerated overall. Although it is associated with an increase in infections, there is no excess in infection mortality, suggesting that remission maintenance with rituximab is an effective and safe option in the management of chronic lymphocytic leukaemia in early treatment phases.
Arbeitsgemeinschaft Medikamentöse Tumortherapie gemeinnützige GmbH (AGMT), Roche.
Summary Background Lenalidomide, an immunomodulatory drug with antineoplastic and antiproliferative effects, showed activity in many single-group studies in relapsed or refractory mantle cell ...lymphoma. The aim of this randomised study was to examine the efficacy and safety of lenalidomide versus best investigator's choice of single-agent therapy in relapsed or refractory mantle cell lymphoma. Methods The MCL-002 (SPRINT) study was a randomised, phase 2 study of patients with mantle cell lymphoma aged 18 years or older at 67 clinics and academic centres in 12 countries who relapsed one to three times, had Eastern Cooperative Oncology Group performance status of 0–2, at least one measurable lesion to be eligible, and who were ineligible for intensive chemotherpy or stem-cell transplantation. Using a centralised interactive voice response system, we randomly assigned (2:1) patients in a permuted block size of six to receive lenalidomide (25 mg orally on days 1–21 every 28 days) until progressive disease or intolerability, or single-agent investigator's choice of either rituximab, gemcitabine, fludarabine, chlorambucil, or cytarabine. Randomisation was stratified by time from diagnosis, time from last anti-lymphoma therapy, and previous stem-cell transplantation. Individual treatment assignment between lenalidomide and investigator's choice was open label, but investigators had to register their choice of comparator drug before randomly assigning a patient. Patients who progressed on investigator's choice could cross over to lenalidomide treatment. We present the prespecified primary analysis results in the intention-to-treat population for the primary endpoint of progression-free survival, defined as the time from randomisation to progressive disease or death, whichever occurred first. Patient enrolment is complete, although treatment and collection of additional time-to-event data are ongoing. This study is registered with ClinicalTrials.gov , number NCT00875667. Findings Between April 30, 2009, and March 7, 2013, we enrolled 254 patients in the intention-to-treat population (170 67% were randomly assigned to receive lenalidomide, 84 33% to receive investigator's choice monotherapy). Patients had a median age of 68·5 years and received a median of two previous regimens. With a median follow-up of 15·9 months (IQR 7·6–31·7), lenalidomide significantly improved progression-free survival compared with investigator's choice (median 8·7 months 95% CI 5·5–12·1 vs 5·2 months 95% CI 3·7–6·9) with a hazard ratio of 0·61 (95% CI 0·44–0·84; p=0·004). In the 167 patients in the lenalidomide group and 83 patients in the investigator's choice group who received at least one dose of treatment the most common grade 3–4 adverse events included neutropenia (73 44% of 167 vs 28 34% of 83) without increased risk of infection, thrombocytopenia (30 18% vs 23 28%), leucopenia (13 8% vs nine 11%), and anaemia (14 8% vs six 7%). Interpretation Patients with relapsed or refractory mantle cell lymphoma ineligible for intensive chemotherapy or stem-cell transplantation have longer progression-free survival, with a manageable safety profile when treated with lenalidomide compared with monotherapy investigator's choice options. Funding Celgene Corporation.
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Available therapies for myelofibrosis can exacerbate cytopenias and are not indicated for patients with severe thrombocytopenia. Pacritinib, which inhibits both JAK2 and FLT3, induced spleen ...responses with limited myelosuppression in phase 1/2 trials. We aimed to assess the efficacy and safety of pacritinib versus best available therapy in patients with myelofibrosis irrespective of baseline cytopenias.
This international, multicentre, randomised, phase 3 trial (PERSIST-1) was done at 67 sites in 12 countries. Patients with higher-risk myelofibrosis (with no exclusions for baseline anaemia or thrombocytopenia) were randomly assigned (2:1) to receive oral pacritinib 400 mg once daily or best available therapy (BAT) excluding JAK2 inhibitors until disease progression or unacceptable toxicity. Randomisation was stratified by risk category, platelet count, and region. Treatment assignments were known to investigators, site personnel, patients, clinical monitors, and pharmacovigilance personnel. The primary endpoint was spleen volume reduction (SVR) of 35% or more from baseline to week 24 in the intention-to-treat population as assessed by blinded, centrally reviewed MRI or CT. We did safety analyses in all randomised patients who received either treatment. Here we present the final data. This trial is registered with ClinicalTrials.gov, number NCT01773187.
Between Jan 8, 2013, and Aug 1, 2014, 327 patients were randomly assigned to pacritinib (n=220) or BAT (n=107). Median follow-up was 23·2 months (IQR 14·8-28·7). At week 24, the primary endpoint of SVR of 35% or more was achieved by 42 (19%) patients in the pacritinib group versus five (5%) patients in the BAT group (p=0·0003). 90 patients in the BAT group crossed over to receive pacritinib at a median of 6·3 months (IQR 5·8-6·7). The most common grade 3-4 adverse events through week 24 were anaemia (n=37 17%), thrombocytopenia (n=26 12%), and diarrhoea (n=11 5%) in the pacritinib group, and anaemia (n=16 15%), thrombocytopenia (n=12 11%), dyspnoea (n=3 3%), and hypotension (n=3 3%) in the BAT group. The most common serious adverse events that occurred through week 24 were anaemia (10 5%), cardiac failure (5 2%), pyrexia (4 2%), and pneumonia (4 2%) with pacritinib, and anaemia (5 5%), sepsis (2 2%), and dyspnoea (2 2%) with BAT. Deaths due to adverse events were observed in 27 (12%) patients in the pacritinib group and 14 (13%) patients in the BAT group throughout the duration of the study.
Pacritinib therapy was well tolerated and induced significant and sustained SVR and symptom reduction, even in patients with severe baseline cytopenias. Pacritinib could be a treatment option for patients with myelofibrosis, including those with baseline cytopenias for whom options are particularly limited.
CTI BioPharma Corp.
Summary Background Most patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma relapse after initial therapy. Bendamustine plus rituximab is often used in the relapsed or ...refractory setting. We assessed the efficacy and safety of adding ibrutinib, an oral covalent inhibitor of Bruton's tyrosine kinase (BTK), to bendamustine plus rituximab in patients with previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma. Methods The HELIOS trial was an international, double-blind, placebo-controlled, phase 3 study in adult patients (≥18 years of age) who had active chronic lymphocytic leukaemia or small lymphocytic lymphoma with measurable lymph node disease (>1·5 cm) by CT scan, and had relapsed or refractory disease following one or more previous lines of systemic therapy consisting of at least two cycles of a chemotherapy-containing regimen, an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1, and adequate bone marrow, liver, and kidney function. Patients with del(17p) were excluded because of known poor response to bendamustine plus rituximab. Patients who had received previous treatment with ibrutinib or other BTK inhibitors, refractory disease or relapse within 24 months with a previous bendamustine-containing regimen, or haemopoietic stem-cell transplant were also excluded. Patients were randomly assigned (1:1) by a web-based system to receive bendamustine plus rituximab given in cycles of 4 weeks' duration (bendamustine: 70 mg/m2 intravenously on days 2–3 in cycle 1, and days 1–2 in cycles 2–6; rituximab: 375 mg/m2 on day 1 of cycle 1, and 500 mg/m2 on day 1 of cycles 2–6 for a maximum of six cycles) with either ibrutinib (420 mg daily orally) or placebo until disease progression or unacceptable toxicity. Patients were stratified according to whether they were refractory to purine analogues and by number of previous lines of therapy. The primary endpoint was independent review committee (IRC)-assessed progression-free survival. Crossover to ibrutinib was permitted for patients in the placebo group with IRC-confirmed disease progression. Analysis was by intention-to-treat and is continuing for further long-term follow-up. The trial is registered with ClinicalTrials.gov , number NCT01611090. Findings Between Sept 19, 2012, and Jan 21, 2014, 578 eligible patients were randomly assigned to ibrutinib or placebo in combination with bendamustine plus rituximab (289 in each group). The primary endpoint was met at the preplanned interim analysis (March 10, 2015). At a median follow-up of 17 months (IQR 13·7–20·7), progression-free survival was significantly improved in the ibrutinib group compared with the placebo group (not reached in the ibrutinib group (95% CI not evaluable) vs 13·3 months (11·3–13·9) in the placebo group (hazard ratio HR 0·203, 95% CI 0·150–0·276; p<0·0001). IRC-assessed progression-free survival at 18 months was 79% (95% CI 73–83) in the ibrutinib group and 24% (18–31) in the placebo group (HR 0·203, 95% CI 0·150–0·276; p<0·0001). The most frequent all-grade adverse events were neutropenia and nausea. 222 (77%) of 287 patients in the ibrutinib group and 212 (74%) of 287 patients in the placebo group reported grade 3–4 events; the most common grade 3–4 adverse events in both groups were neutropenia (154 54% in the ibrutinib group vs 145 51% in the placebo group) and thrombocytopenia (43 15% in each group). A safety profile similar to that previously reported with ibrutinib and bendamustine plus rituximab individually was noted. Interpretation In patients eligible for bendamustine plus rituximab, the addition of ibrutinib to this regimen results in significant improvements in outcome with no new safety signals identified from the combination and a manageable safety profile. Funding Janssen Research & Development.
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