To determine the efficacy and toxicity of chemoimmunotherapy followed by either whole-brain radiotherapy (WBRT) or intensive chemotherapy and autologous stem-cell transplantation (ASCT) as a ...first-line treatment of primary CNS lymphoma (PCNSL).
Immunocompetent patients (18 to 60 years of age) with untreated PCNSL were randomly assigned to receive WBRT or ASCT as consolidation treatment after induction chemotherapy consisting of two cycles of R-MBVP (rituximab 375 mg/m
day (D) 1, methotrexate 3 g/m
D1; D15, VP16 100 mg/m
D2, BCNU 100 mg/m
D3, prednisone 60 mg/kg/d D1-D5) followed by two cycles of R-AraC (rituximab 375 mg/m
D1, cytarabine 3 g/m
D1 to D2). Intensive chemotherapy consisted of thiotepa (250 mg/m
/d D9; D8; D7), busulfan (8 mg/kg D6 through D4), and cyclophosphamide (60 mg/kg/d D3; D2). WBRT delivered 40 Gy (2 Gy/fraction). The primary end point was 2-year progression-free survival. Cognitive outcome was the main secondary end point. Analysis was intention to treat in a noncomparative phase II trial.
Between October 2008 and February 2014, 140 patients were recruited from 23 French centers. Both WBRT and ASCT met the predetermined threshold (among the first 38 patients in each group, at least 24 patients were alive and disease free at 2 years). The 2-year progression-free survival rates were 63% (95% CI, 49% to 81%) and 87% (95% CI, 77% to 98%) in the WBRT and ASCT arms, respectively. Toxicity deaths were recorded in one and five patients after WBRT and ASCT, respectively. Cognitive impairment was observed after WBRT, whereas cognitive functions were preserved or improved after ASCT.
WBRT and ASCT are effective consolidation treatments for patients with PCNSL who are 60 years of age and younger. The efficacy end points tended to favor the ASCT arm. The specific risk of each procedure should be considered.
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.
Our objective was to identify the genetic changes involved in primary central nervous system lymphoma (PCNSL) oncogenesis and evaluate their clinical relevance.
We investigated a series of 29 newly ...diagnosed, HIV-negative, PCNSL patients using high-resolution single-nucleotide polymorphism (SNP) arrays (n = 29) and whole-exome sequencing (n = 4) approaches. Recurrent homozygous deletions and somatic gene mutations found were validated by quantitative real-time PCR and Sanger sequencing, respectively. Molecular results were correlated with prognosis.
All PCNSLs were diffuse large B-cell lymphomas, and the patients received chemotherapy without radiotherapy as initial treatment. The SNP analysis revealed recurrent large and focal chromosome imbalances that target candidate genes in PCNSL oncogenesis. The most frequent genomic abnormalities were (i) 6p21.32 loss (HLA locus), (ii) 6q loss, (iii) CDKN2A homozygous deletions, (iv) 12q12-q22, and (v) chromosome 7q21 and 7q31 gains. Homozygous deletions of PRMD1, TOX, and DOCK5 and the amplification of HDAC9 were also detected. Sequencing of matched tumor and blood DNA samples identified novel somatic mutations in MYD88 and TBL1XR1 in 38% and 14% of the cases, respectively. The correlation of genetic abnormalities with clinical outcomes using multivariate analysis showed that 6q22 loss (P = 0.006 and P = 0.01) and CDKN2A homozygous deletion (P = 0.02 and P = 0.01) were significantly associated with shorter progression-free survival and overall survival.
Our study provides new insights into the molecular tumorigenesis of PCNSL and identifies novel genetic alterations in this disease, especially MYD88 and TBL1XR1 mutations activating the NF-κB signaling pathway, which may be promising targets for future therapeutic strategies.
In 2011 we reported a rituximab plus miniCHOP (reduced-dose cyclophosphamide, doxorubicin, vincristine, and prednisone) combination for patients older than 80 years with diffuse large B-cell lymphoma ...(DLBCL). The 2-year overall survival was 59% (95% CI 49-67) with an excess of early toxicity. To improve those results we tested the same chemotherapy protocol in combination with ofatumumab and a pre-phase treatment.
For this open-label, multicentre, single-group, phase 2 trial, we recruited patients older than 80 years with untreated histologically-proven CD20-positive DLBCL, Ann Arbor stage I to IV, from 41 academic and hospital centres in France and Belgium. Patients received a pre-phase with oral vincristine (1 mg total dose 1 week before cycle 1 day -7) and oral prednisone (60 mg total dose starting 1 week before cycle 1, for 4 days day -7 to day -4) before the first cycle of the ofatumumab plus miniCHOP regimen. The regimen consisted of 1000 mg total dose of intravenous ofatumumab, 25 mg/m
of intravenous doxorubicin, 400 mg/m
of intravenous cyclophosphamide, and 1 mg of intravenous vincristine, on day 1 of each cycle; and 40 mg/m
of oral prednisone on days 1-5. Ofatumumab was administered with 1000 mg of paracetamol and 50 mg of diphenhydramine. The primary endpoint was overall survival in the intention-to-treat population. The statistical analysis has been done on an intention-to-treat principle. This study was registered with ClinicalTrials.gov, number NCT01195714.
Between June 2, 2010, and Nov 4, 2011, we enrolled 120 patients. Age-adjusted International Prognostic Index was 2-3 in 68 (57%) of them. The median follow-up time was 26·8 months (IQR 24·5-30·1). The 2-year overall survival was 64·7% (95% CI 55·3-72·7) and median overall survival was not reached (95% CI 30·2-not reached). 45 patients died during the treatment, of whom 28 (62%) died due to lymphoma. The most common side-effect was haematological toxicity. Among the 120 patients, grade 3-4 neutropenia was reported in 24 (21%) patients and thrombocytopenia in two (2%), during the treatment period. Grade 3-4 anaemia was reported in six (5%) patients; seven (6%) patients had one episode of febrile neutropenia. 17 (15%) of 115 patients in the modified intention-to-treat population had red blood cell transfusions and three (3%) had platelet transfusions.
Our result suggest that, in patients older than 80 years with DLBCL, ofatumumab and pre-phase treatment seem to improve overall survival compared with the previously reported data. The combination of pre-phase treatment, a monoclonal antibody against CD20, and miniCHOP can be considered a new treatment platform for use in randomised clinical trial design for DLBCL treatment in patients older than 80 years.
The Lymphoma Study Association, GlaxoSmithKline.
Most primary central nervous system lymphomas (PCNSLs) in immunocompetent patients are diffuse large B-cell lymphomas (DLBCLs), characterized by poor prognosis, compared with systemic forms. A ...germinal center B-cell–like (GCB) origin of PCNSL was hypothesized on the basis of BCL-6 expression and ongoing mutational activity. Our goal herein was to determine, for 83 PCNSLs, the percentages of GCB and activated B-cell–like (ABC) phenotypes and their prognostic significance. CD10, BCL-6, MUM1, BCL-2, and CD138 antigens were immunohistochemically labeled on paraffin-embedded sections; the first 4 were positive in 2.4%, 55.5%, 92.6%, and 55.5% of the tumors, respectively. None of the 56 tested samples expressed CD138. Among the 82 patients with complete information, 79 (96.3%) were classified as ABC; 42 (51.2%) expressed BCL-6+MUM1+, suggesting an “activated GCB” origin; 33 (40.2%) were exclusively MUM1+, and the remaining 4 (4.9%) were negative for all markers tested. These findings provide new insights into interpreting the poor PCNSL prognostic, which may, in part, be due to biologic aggressiveness associated with its activated B-cell–like pattern. We postulate assigning PCNSL a histogenetic “time-slot,” overlapping late GC and early post-GC, that could explain the predominant ABC phenotype observed.
Anti-CD20-containing chemotherapy regimens have become the standard of care for patients with follicular lymphoma needing cytotoxic therapy. Four randomized trials demonstrated a clinical benefit for ...patients treated with rituximab. However, no long-term follow up (i.e. > 5 years) of these trials is yet available. Between May 2000 and May 2002, 358 newly diagnosed patients with high tumor burden follicular lymphoma were randomized to receive cyclophosphamide, adriamycin, etoposide and prednisolone plus interferon-α2a or a similar chemotherapy-based regimen plus rituximab, and outcome was up-dated. With a median follow up of 8.3 years, addition of rituximab remained significantly associated with prolonged event-free survival (primary end point) (P=0.0004) with a trend towards a benefit for overall survival (P=0.076). The Follicular Lymphoma International Prognostic Index score was strongly associated with outcome for both event-free and overall survival in univariate analysis and its prognostic value remained highly significant after adjusting for other significant covariates in multivariate models (P<0.0001 and P=0.001, respectively). Considering long-term toxicity, the addition of rituximab in the first-line setting was confirmed as safe with regards to development of secondary malignancies. Long-term follow up of patients with follicular lymphoma treated in the FL2000 study confirms the sustained clinical benefit of rituximab without long-term toxicity.
Between 2011 and 2012, a phase II trial evaluated the use of the RiBVD (Rituximab, Bendamustine, Velcade and Dexamethasone) combination as first-line treatment for mantle cell lymphoma (MCL) patients ...aged over 65. We have now re-examined the classic prognostic factors, adding an assessment of the mutation status of TP53. Patients (n=74; median age 73 years) were treated with the RiBVD combination. Median Progression Free Survival (mPFS) was 79 months, and median Overall Survival (mOS) was 111 months. TP53 mutation status was available for 54/74 (73%) patients. TP53 mutations (TP53mt) were found in 12 patients (22.2%). In multivariate analysis, among the prognostic factors (PF) evaluated, only TP53mt and an albumin level below 3.6 g/dL (Alb<3.6 g/dL) were independently associated with a shorter mPFS. A hazard ratio (HR) of 3.16 (1.3-9.9, p=0.014) was obtained for TP53mt versus TP53wt, and 3.6 (1.39-9.5, p=0.009) for Alb<3.6 g/dL vs Alb≥3.6 g/dL. In terms of mOS, multivariate analysis identified three PFs: TP53mt (HR: 5.9 (1.77-19.5, p=0.004)), Alb<3.6 g/dL (HR: 5.2 (1.46-18.5, p=0.011)), and ECOG=2 (HR: 3.7 (1.31-10.6, p=0.014)). Finally, a score combining TP53 status and albumin level distinguished three populations based on the presence of 0, 1, or 2 PF. For these populations, mPFS was 7.8 years, 28 months and 2.5 months, respectively. Our prolonged follow-up confirmed the efficacy of the RiBVD regimen, comparing it favorably to other regimens. TP53mt and hypoalbuminemia emerge as strong PF that can be easily integrated into prognostic scores for older adult patients with MCL.
We analyzed detailed characteristics and salvage treatment in 175 follicular lymphoma patients from the FL2000 study who were in progression after first-line therapy with or without addition of ...rituximab to chemotherapy and interferon.
The impact of using autologous stem cell transplantation and/or rituximab administration at first progression was investigated, taking into account initial therapy. With a median follow up of 31 months, 3-year event free and overall survival rates after progression were 50% (95%CI 42-58%) and 72% (95%CI 64-78%), respectively.
The 3-year event free rate of rituximab re-treated patients (n=112) was 52% (95%CI 41-62%) versus 40% (95%CI 24-55%) for those not receiving rituximab second line (n=53) (P=0.075). There was a significant difference in 3-year overall survival between patients receiving autologous stem cell transplantation and those not: 92% (95%CI 78-97%) versus 63% (95%CI 51-72%) (P=0.0003), respectively. In multivariate analysis, both autologous stem cell transplantation and period of progression/relapse affected event free and overall survival.
Regardless of front-line rituximab exposure, this study supports incorporating autologous stem cell transplantation in the therapeutic approach at first relapse for follicular lymphoma patients.
No standard chemotherapy regimen exists for primary CNS lymphoma, reflecting an absence of randomised studies. We prospectively tested two promising methotrexate-based regimens, one more intensive ...and a milder regimen, for primary CNS lymphoma in the elderly population, who account for most patients.
In this open-label, randomised phase 2 trial, done in 13 French institutions, we enrolled immunocompetent patients who had neuroimaging and histologically confirmed newly diagnosed primary CNS lymphoma, were aged 60 years and older, and had a Karnofsky performance scale score of 40 or more. Participants were stratified by Karnofsky performance scale score (<60 vs ≥60) and treating institution and randomly assigned (1:1) to receive methotrexate (3·5 g/m(2)) with temozolomide (150 mg/m(2)) or methotrexate (3·5 g/m(2)), procarbazine (100 mg/m(2)), vincristine (1·4 mg/m(2)), and cytarabine (3 mg/m(2)). Neither regimen included radiotherapy; both included prophylactic G-CSF and corticosteroids. The primary endpoint was 1-year progression-free survival. Analysis was intent to treat, in a non-comparative phase 2 trial design. This study is registered with ClinicalTrials.gov, number NCT00503594.
Between July 16, 2007, and March 25, 2010, 98 patients were enrolled, of whom 95 were randomly assigned and analysed; 48 to methotrexate with temozolomide and 47 to methotrexate, procarbazine, vincristine, and cytarabine. 1-year progression-free survival was 36% (95% CI 22-50) in the methotrexate, procarbazine, vincristine, and cytarabine group and 36% (22-50) in the methotrexate with temozolomide group; median progression-free survival was 9·5 months (95% CI 5·3-13·8) versus 6·1 months (3·8-11·9), respectively. Objective responses were noted in 82% (95% CI 68-92) of patients in the methotrexate, procarbazine, vincristine, and cytarabine group versus 71% (55-84) of patients in the methotrexate with temozolomide group. Median overall survival was 31 months (95% CI 12·2-35·8) in the methotrexate, procarbazine, vincristine, and cytarabine group and 14 months (8·1-28·4) in the methotrexate with temozolomide group. No differences were noted in toxic effects between the two groups. The most common grades 3 and 4 toxicities in both groups were liver dysfunction (21 4% in the the methotrexate and temozolomide group and 18 38% in the methotrexate, procarbazine, vincristine, and cytarabine group), lymphopenia (14 29% and 14 30%), and infection (six 13% and seven 15%). To date, 33 (69%) patients in the methotrexate and temozolomide group have died, versus 31 (55%) in the methotrexate, procarbazine, vincristine and cytarabine group. Quality-of-life evaluation (QLQ-C30 and BN20) showed improvements in most domains (p=0·01-0·0001) compared with baseline in both groups. Prospective neuropsychological testing showed no evidence of late neurotoxicity.
In this study of two different methotrexate-based combination regimens in elderly patients, the efficacy endpoints tended to favour the methotrexate, procarbazine, vincristine, and cytarabine group. Both regimens were associated with similar, moderate toxicity, but quality of life improved with time, suggesting pursuing treatment in these poor prognosis patients is worthwhile. New alternatives are needed to improve response duration in this population.
Schering-Plough/Merck and French Government.
PDF