GAUGUIN evaluated the safety and efficacy of obinutuzumab (GA101) monotherapy in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). In phase 1 (dose escalation), 13 patients ...received obinutuzumab 400 to 1200 mg (days 1 and 8 of cycle 1; day 1 of cycles 2-8). In phase 2, 20 patients received a fixed dose of 1000 mg (days 1, 8, and 15 of cycle 1; day 1 of cycles 2-8). Infusion-related reactions occurred in nearly all patients, but few were grade 3/4. Grade 3/4 neutropenia occurred in 7 patients in phase 1 (but was not dose-related) and in 4 patients in phase 2. Overall end-of-treatment response (all partial responses) was 62% (phase 1) and 15% (phase 2); best overall response was 62% and 30%, respectively. Phase 2 median progression-free survival was 10.7 months and median duration of response was 8.9 months. In summary, obinutuzumab monotherapy is active in patients with heavily pretreated relapsed/refractory CLL. GAUGUIN was registered at www.clinicaltrials.gov as #NCT00517530.
•In this phase 1/2 study, obinutuzumab (GA101) monotherapy was active in patients with relapsed or refractory CLL.•Best overall response was lower in phase 2 vs phase 1, possibly due to higher baseline tumor burden resulting in lower treatment exposure.
Obinutuzumab (GA101), a type II, glycoengineered, humanized anti-CD20 monoclonal antibody, was superior to rituximab in human diffuse large B-cell lymphoma (DLBCL) and mantle-cell lymphoma (MCL) ...xenograft models. In phase I of our study, obinutuzumab (GA101) exhibited encouraging activity but no clear dose-response relationship, and few patients had aggressive histologies. The efficacy and safety of two doses of obinutuzumab (GA101) were explored in our randomized phase II trial in patients with heavily pretreated DBLCL and MCL.
Patients were randomly assigned to receive eight cycles of obinutuzumab (GA101) either as a flat dose of 400 mg for all infusions (days 1 and 8 of cycle 1; day 1 of cycles 2 to 8) or 1,600 mg on days 1 and 8 of cycle 1 and 800 mg on day 1 of cycles 2 to 8.
Forty patients were enrolled: 21 patients in the 400/400-mg treatment arm (DLBCL, n = 10; MCL, n = 11) and 19 patients in the 1,600/800-mg arm (DLBCL, n = 15; MCL, n = 4). End-of-treatment response was 28% (32% and 24% in the 1,600/800-mg and 400/400-mg study arms, respectively). Best overall response rates were 37% in the 1,600/800-mg arm and 24% in the 400/400-mg study arm (DLBCL, eight 32% of 25 patients; MCL, four 27% of 15 patients). Five (20%) of 25 rituximab-refractory patients exhibited treatment response, including four of 12 in the 1,600/800-mg group. The most common adverse events were infusion-related reactions (IRRs), which were manageable. Three patients had grade 3/4 IRRs. Grade 3/4 neutropenia was seen in only one patient.
Obinutuzumab (GA101) 1,600/800 mg achieves early steady-state concentration and clinical activity with an acceptable safety profile in relapsed/refractory DLBCL and MCL, supporting further exploration.
Early identification of ultra-risk diffuse large B-cell lymphoma (DLBCL) patients is needed to aid stratification to innovative treatment. Previous studies suggested high baseline total metabolic ...tumor volume (TMTV) negatively impacts survival of DLBCL patients. We analyzed the prognostic impact of TMTV and prognostic indices in DLBCL patients, aged 60 to 80 years, from the phase 3 REMARC study that randomized responding patients to R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) into maintenance lenalidomide or placebo. TMTV was computed on baseline positron emission tomography/computed tomography using the 41% maximum standardized uptake value method; the optimal TMTV cutoff for progression-free (PFS) and overall survival (OS) was determined and confirmed by a training validation method. There were 301 out of 650 evaluable patients, including 192 patients classified as germinal center B-cell–like (GCB)/non-GCB and MYC/BCL2 expressor. Median baseline TMTV was 238 cm3; optimal TMTV cutoff was 220 cm3. Patients with high vs low TMTV showed worse/higher Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2, stage III or IV disease, >1 extranodal site, elevated lactate dehydrogenase, International Prognostic Index (IPI) 3-5, and age-adjusted IPI 2-3. High vs low TMTV significantly impacted PFS and OS, independent of maintenance treatment. Although the GCB/non-GCB profile and MYC expression did not correlate with TMTV/survival, BCL2 >70% impacted PFS and could be stratified by TMTV. Multivariate analysis identified baseline TMTV and ECOG PS as independently associated with PFS and OS. Even in responding patients, after R-CHOP, high baseline TMTV was a strong prognosticator of inferior PFS and OS. Moreover, TMTV combined with ECOG PS may identify an ultra-risk DLBCL population. This trial was registered at www.clinicaltrials.gov as #NCT01122472.
•Early identification of ultra-risk DLBCL patients is needed to aid stratification to alternative treatment approaches.•High baseline TMTV (±ECOG) was a strong prognosticator of inferior PFS and OS in REMARC patients post-R-CHOP, irrespective of maintenance.
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Treatment options for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) are limited, with no standard of care; prognosis is poor, with 4- to 6-month median survival. Avadomide (CC-122) ...is a cereblon-modulating agent with immunomodulatory and direct antitumor activities. This phase 1 dose-expansion study assessed safety and clinical activity of avadomide monotherapy in patients with de novo R/R DLBCL and transformed lymphoma. Additionally, a novel gene expression classifier, which identifies tumors with a high immune cell infiltration, was shown to enrich for response to avadomide in R/R DLBCL. Ninety-seven patients with R/R DLBCL, including 12 patients with transformed lymphoma, received 3 to 5 mg avadomide administered on continuous or intermittent schedules until unacceptable toxicity, disease progression, or withdrawal. Eighty-two patients (85%) experienced ≥1 grade 3/4 treatment-emergent adverse events (AEs), most commonly neutropenia (51%), infections (24%), anemia (12%), and febrile neutropenia (10%). Discontinuations because of AEs occurred in 10% of patients. Introduction of an intermittent 5/7-day schedule improved tolerability and reduced frequency and severity of neutropenia, febrile neutropenia, and infections. Among 84 patients with de novo R/R DLBCL, overall response rate (ORR) was 29%, including 11% complete response (CR). Responses were cell-of-origin independent. Classifier-positive DLBCL patients (de novo) had an ORR of 44%, median progression-free survival (mPFS) of 6 months, and 16% CR vs an ORR of 19%, mPFS of 1.5 months, and 5% CR in classifier-negative patients (P = .0096). Avadomide is being evaluated in combination with other antilymphoma agents. This trial was registered at www.clinicaltrials.gov as #NCT01421524.
•Avadomide monotherapy is well tolerated and demonstrates preliminary clinical efficacy in the treatment of R/R DLBCL patients.•Avadomide monotherapy resulted in mPFS of 6 months in classifier-positive vs 1.5 months in classifier-negative R/R DLBCL patients.
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Apart from localized gastric disease, there is no consensus on standard initial treatment of mucosa-associated lymphoid tissue lymphoma. The IELSG-19 study (Randomized Trial of Chlorambucil Versus ...Chlorambucil Plus Rituximab Versus Rituximab in MALT Lymphoma) was launched to compare chlorambucil alone versus chlorambucil plus rituximab in patients not previously given systemic anticancer therapy.
Patients not responding to or not suitable for local therapy were eligible. In arm A, chlorambucil was given daily 6 mg/m(2) orally (PO) for 6 weeks. Responding patients and those with stable disease continued to be given daily chlorambucil 6 mg/m(2) PO for 14 consecutive days every 28 days for four cycles. In arm B, intravenous rituximab 375 mg/m(2) per day was added on days 1, 8, 15, 22, 56, 84, 112, and 140. After completion of the planned accrual, the protocol was amended to introduce a third arm with rituximab alone. We report the planned final analysis of the first two arms (113 patients in arm A and 114 in arm B).
At a median follow-up of 62 months, the 5-year event-free survival (EFS) was significantly better for the patients treated in arm B (68% v 50%; P = .002) who, despite similar overall response rates (90% v 87%), achieved a higher complete remission rate (78% v 65%; P = .025). Progression-free survival was also improved but it did not reach statistical significance (P = .057). Five-year overall survival (OS) was 89% in both arms. Both treatments were well tolerated without unexpected toxicities.
Both treatments were active; the better response rate and EFS obtained with the addition of rituximab did not translate into improved OS.
The combination of carmustine, etoposide, cytarabine, and melphalan (BEAM) as conditioning regimen prior to autologous stem-cell transplantation (ASCT) remains the standard of care for patients with ...mantle cell lymphoma (MCL) who are eligible for transplantation. The replacement of carmustine with bendamustine (BeEAM) was described as a promising alternative in non-Hodgkin lymphoma. The aim of this retrospective study was to compare the BeEAM with the BEAM regimen in MCL patients in the frontline setting. Sixty and 108 patients were included in the BeEAM and the BEAM groups, respectively. At 3 years, progression-free survival (PFS) was significantly higher in the BeEAM than in the BEAM group (84% 73-96 vs. 63% 51-79, p = 0.03). The overall survival was not statistically different between the two groups (p = 0.2). In multivariable analysis, BeEAM regimen remained associated with higher PFS (HR = 0.377, 95% CI, 0.146-0.970; p = 0.043). Subgroup analyses in patients treated with prior rituximab-aracytine induction alone showed that BeEAM improved the PFS compared with BEAM regimen (p = 0.04). Despite the high rate of acute renal failure KDIGO III (32%), treatment-related mortality was not increased with the BeEAM regimen. A prospective randomized trial will be necessary to confirm the beneficial effect of the BeEAM regimen in MCL patients undergoing ASCT.
Histone deacetylase inhibitors are members of a class of epigenetic drugs that have proven activity in T-cell malignancies, but little is known about their efficacy in B-cell lymphomas. Abexinostat ...is an orally available hydroxamate-containing histone deacetylase inhibitor that differs from approved inhibitors; its unique pharmacokinetic profile and oral dosing schedule, twice daily four hours apart, allows for continuous exposure at concentrations required to efficiently kill tumor cells. In this phase II study, patients with relapsed/refractory non-Hodgkin lymphoma or chronic lymphocytic leukemia received oral abexinostat at 80 mg BID for 14 days of a 21-day cycle and continued until progressive disease or unacceptable toxicity. A total of 100 patients with B-cell malignancies and T-cell lymphomas were enrolled between October 2011 and July 2014. All patients received at least one dose of study drug. Primary reasons for discontinuation included progressive disease (56%) and adverse events (25%). Grade 3 or over adverse events and any serious adverse events were reported in 88% and 73% of patients, respectively. The most frequently reported grade 3 or over treatment-emergent related adverse events were thrombocytopenia (80%), neutropenia (27%), and anemia (12%). Among the 87 patients evaluable for efficacy, overall response rate was 28% (complete response 5%), with highest responses observed in patients with follicular lymphoma (overall response rate 56%), T-cell lymphoma (overall response rate 40%), and diffuse large B-cell lymphoma (overall response rate 31%). Further investigation of the safety and efficacy of abexinostat in follicular lymphoma, T-cell lymphoma, and diffuse large B-cell lymphoma implementing a less dose-intense week-on-week-off schedule is warranted. (
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While bone marrow (BM) grafts were initially used for T-replete HLA-haploidentical related donors transplantation (Haplo-SCT) with post-transplantation cyclophosphamide (PT-Cy), the use of peripheral ...blood stem cell (PBSC) remains debated. We thus conducted a detailed analysis evaluating the incidence, risk factors, and prevalence of GVHD after PBSC Haplo-SCT with PT-Cy. One hundred and eighty-one patients with hematological diseases were included. Median time for neutrophil and platelet recovery was 21 and 30 days, respectively. The cumulative incidence of grade 3-4 acute GVHD and severe chronic GVHD were 8% and 4%, respectively, approaching what was observed after BM Haplo-SCT. NRM at 2 years was 21%, and 41% of the non-relapse deaths were caused by GVHD. The cumulative incidence of relapse at 2 years was 17% in the whole cohort, and 13% among AML patients (n = 54), suggesting a high GVL effect. As surrogate markers for good quality of life, we observed a 2-year GVHD-relapse-free survival probability of 50% and found that 6% and 2% of disease-free patients at 2 years were still living with GVHD and immunosuppressive treatments, respectively. Haplo-SCT with PT-Cy using PBSC grafts results in low incidence GVHD and promising disease control, making PBSCs a valuable alternative to BM graft in this setting.
It is now widely recognized that cancer development is a protracted process requiring the stepwise acquisition of multiple oncogenic events. In humans, this process can take decades, if not a ...lifetime, blurring the notion of 'healthy' individuals. Follicular lymphoma exemplifies this multistep pathway of oncogenesis. In recent years, variants of follicular lymphoma have been recognized that appear to represent clonal B-cell expansions at an early stage of follicular lymphoma lymphomagenesis. These include follicular lymphoma in situ, duodenal follicular lymphoma, partial involvement by follicular lymphoma, and in the blood circulating follicular lymphoma-like B cells. Recent genetic studies have identified similarities and differences between the early lesions and overt follicular lymphoma, providing important information for understanding their biological evolution. The data indicate that there is already genomic instability at these early stages, even in instances with a low risk for clinical progression. The overexpression of BCL2 in t(14;18)-positive B cells puts them at risk for subsequent genetic aberrations when they re-enter the germinal center and are exposed to the influences of activation-induced cytidine deaminase and somatic hypermutations. The emerging data provide a rationale for clinical management and, in the future, may identify genetic risk factors that warrant early therapeutic intervention.
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