Thilo Zander

Summary: The randomized phase II SAKK 35/14 trial, conducted by the Swiss Group for Clinical Cancer Research (SAKK) and the Nordic Lymphoma Group (NLG), compared efficacy and safety of rituximab (375 mg/m ² intravenously for 4 weeks followed by maintenance every 2 months for 24 months) plus placebo (arm A) versus the same schedule of rituximab plus ibrutinib (560 mg daily for 24 months, arm B) in patients with advanced follicular lymphoma in need of systemic therapy. The primary end‐point, complete remission (CR) rate at 24 months, was 36% in arm A and 40% in arm B, with no statistically significant difference. Three‐year progression‐free survival (PFS) was 36% in arm A and 45% in arm B, with a hazard ratio of 0.64 ( p = 0.057). Three‐year overall survival was about 96% in both arms. A higher percentage of patients in arm B experienced grade ≥3 adverse events, but they were manageable. No toxic deaths were observed. Although the primary end‐point (CR rate at 24 months) was not met, a trend towards improved PFS with ibrutinib plus rituximab observed at the prespecified significance level of 0.1 may indicate a potential clinical benefit.

The Swiss Group for Clinical Cancer Research (SAKK) and the Nordic Lymphoma Group conducted the SAKK 35/10 randomized phase 2 trial to compare rituximab (R) alone vs R plus lenalidomide (L) as initial treatment for follicular lymphoma (FL). Patients with grade 1 to 3A FL, requiring systemic therapy, were randomized to either R (n = 77; 375 mg/m2 IV × 1, weeks 1-4) or rituximab-lenalidomide (RL) (n = 77; R on the same schedule and L at 15 mg daily continuously). Responders (evaluated at 10 weeks) repeated R during weeks 12 to 15 with or without L (for a total of 18 weeks). Both arms had 47% of patients with a poor risk score on the FL International Prognostic Index. The primary end point, complete response (CR)/CR unconfirmed rates at 6 months, was superior with the combination, and after a median follow-up of 9.5 years, this has translated into a longer duration of response (median, not reached vs 3.2 years; hazard ratio [HR], 0.42; 95% confidence interval [CI], 0.21-0.86; P = .014), progression-free survival (9.3 vs 2.3 years; HR, 0.57; 95% CI: 0.37-0.89; P = .0128), and time to next treatment (median, not reached vs 2.1 years; HR, 0.43; 95% CI, 0.27-0.67; P < .001). Over 60% of RL responders remained in first CR at 10 years. Overall survival was similar in both arms (77% vs 78% at 10 years; P = .881). Toxicity was more common with RL but manageable. The SAKK 35/10 trial's long-term results confirmed a durable benefit of a short-term chemotherapy-free first-line RL regimen in symptomatic FL. This trial was registered at www.clinicaltrials.gov as #NCT0137605.

High-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) is an option to consolidate remission in Waldenstrom’s macroglobulinemia (WM), particularly in selected younger patients with chemosensitive disease. BEAM, consisting of BCNU, etoposide, cytarabine, and melphalan, is often used as a conditioning regimen. However, problems with BCNU, including pneumotoxicity, tolerance, and availability, necessitate the search for alternatives. In this pilot study, we investigated high-dose chemotherapy with BeEAM, in which BCNU is replaced with high-dose bendamustine as an alternative conditioning regimen in six subsequent patients with WM. Bendamustine treatment was well tolerated without unexpected toxicities. The overall response rate was 6/6 patients (2 very good partial responses (VGPR) and 4 PR). After a median follow-up of 72 months, two (33%) patients relapsed. Median progression-free and overall survivals were not reached, and no severe late-onset toxicities were observed so far. In this pilot study, BeEAM conditioning before ASCT seems feasible, safe, and effective in patients with WM.

In patients with relapsed/refractory Burkitt lymphoma (r/r BL), overall survival (OS) is poor, and effective therapies and evidence for the best therapy are lacking. The monoclonal antibody blinatumomab may represent a novel option. However, only limited data on the use of blinatumomab in r/r BL are so far available. This multi-center, retrospective case series investigated nine patients with r/r BL treated with blinatumomab. The safety of blinatumomab was assessed with respect to frequency and severity of adverse effects (AEs) infections, cytokine release syndrome (CRS) and neurotoxicity. Progression-free survival (PFS), OS and overall response rate (ORR) were analyzed to assess efficacy. No AEs > grade 2 occurred, and AEs were generally treatable and fully reversible. The best response to blinatumomab was complete remission in 3/9 patients and partial remission in 2/9, whilst 4/9 presented with progressive disease. Median PFS and OS were 2 and 6 months, respectively, ranging from 5 days to 32 months and 11 days to 32 months, respectively. Blinatumomab treatment was a successful bridging treatment to stem cell transplantation in 3/9 patients. The response to blinatumomab varied widely, and only one patient survived longer term, but activity in patients with r/r BL was evident in some patients, with its use being safe, warranting its prospective investigation.

Definite cure remains exceptional in myeloma patients even after high-dose chemotherapy (HDCT) with melphalan (Mel) and autologous stem cell transplantation (ASCT). Thus, improving efficacy of HDCT in MM remains an unresolved issue. This randomized phase II trial compared standard 200 mg/m² Mel HDCT to experimental HDCT with 200 mg/m² bendamustine, given both at days −4 and −3, combined with 100 mg/m² melphalan at days −2 and −1 (BenMel) before ASCT as first-line consolidation in myeloma patients. The primary endpoint aimed to identify at least a 15% improvement in the complete remission rate (stringent CR + CR) after HDCT with BenMel compared with Mel alone. A total of 120 MM patients were 1:1 randomized. The rate of sCR/CR after ASCT was higher in BenMel than in Mel treated patients (70.0% vs. 51.7%; p = 0.039). Three patients in the BenMel group (5.0%) had reversible acute renal insufficiency compared with none in Mel patients. Minimal residual disease negativity (p = 0.375). Our data suggest that BenMel HDCT is safe and improves the sCR/CR rate compared with standard Mel alone.

PURPOSE: To address the role of consolidation treatment for newly diagnosed, transplant eligible patients with multiple myeloma in a controlled clinical trial. PATIENTS AND METHODS: The EMN02/HOVON95 trial compared consolidation treatment with two cycles of bortezomib, lenalidomide, and dexamethasone (VRD) or no consolidation after induction and intensification therapy, followed by continuous lenalidomide maintenance. Primary study end point was progression-free survival (PFS). RESULTS: Eight hundred seventy-eight eligible patients were randomly assigned to receive VRD consolidation (451 patients) or no consolidation (427 patients). At a median follow-up of 74.8 months, median PFS with adjustment for pretreatment was prolonged in patients randomly assigned to VRD consolidation (59.3 v 42.9 months, hazard ratio [HR] = 0.81; 95% CI, 0.68 to 0.96; P = .016). The PFS benefit was observed across most predefined subgroups, including revised International Staging System (ISS) stage, cytogenetics, and prior treatment. Revised ISS3 stage (HR, 2.00; 95% CI, 1.41 to 2.86) and ampl1q (HR, 1.67; 95% CI, 1.37 to 2.04) were significant adverse prognostic factors. The median duration of maintenance was 33 months (interquartile range 13-86 months). Response ≥ complete response (CR) after consolidation versus no consolidation before start of maintenance was 34% versus 18%, respectively ( P < .001). Response ≥ CR on protocol including maintenance was 59% with consolidation and 46% without ( P < .001). Minimal residual disease analysis by flow cytometry in a subgroup of 226 patients with CR or stringent complete response or very good partial response before start of maintenance demonstrated a 74% minimal residual disease–negativity rate in VRD-treated patients. Toxicity from VRD was acceptable and manageable. CONCLUSION: Consolidation treatment with VRD followed by lenalidomide maintenance improves PFS and depth of response in newly diagnosed patients with multiple myeloma as compared to maintenance alone.

The SAKK 35/10 phase-2 trial (NCT01307605), developed by the Swiss Group for Clinical Cancer Research (SAKK) and the Nordic Lymphoma Group (NLG), compared the activity of rituximab versus rituximab plus lenalidomide in untreated follicular lymphoma patients in need of systemic therapy. Patients were randomized to rituximab (375 mg/m² IV on day 1, weeks 1-4, repeated week 12-15 in responding patients) or to rituximab (same schedule) in combination with lenalidomide (15 mg PO daily for 18 weeks). Primary endpoint was complete response (CR/CRu) rate at 6 months. In total, 77 patients were allocated to rituximab monotherapy and 77 to the combination (47% poor-risk FLIPI in each arm). A significantly higher CR/CRu rate at 6 months was documented in the combination arm by the investigators (36%, 95% CI: 26-48% vs. 25%, 95% CI: 16-36%) and confirmed by an independent response review of only CT scans (61%, 95% CI: 49-72% vs. 36%, 95% CI: 26-48%). After a median follow-up of 4 years, significantly higher 30-month CR/CRu rates, longer progression-free survival (PFS) and time to next treatment (TTNT) were observed for the combination. Overall survival (OS) rates were similar in both arms (≥ 90%). Toxicity grade ≥3 was more common in the combination arm (56% vs. 22% of pts), mainly represented by neutropenia (23% vs. 7%). Addition of lenalidomide to rituximab significantly improved CR/CRu rates, PFS, and TTNT, with higher but expected and manageable toxicity. The excellent OS in both arms suggests that chemotherapy-free strategies should be further explored. Key points Compared with rituximab only, a short rituximab-lenalidomide regimen improved CR rate and PFS in untreated symptomatic follicular lymphomas. Excellent OS in both arms suggests that chemotherapy-free strategies should be further explored in follicular lymphoma.