Julia von Tresckow

Bendamustine in Combination With Rituximab for Previously Untreated Patients With Chronic Lymphocytic Leukemia: A Multicenter Phase II Trial of the German Chronic Lymphocytic Leukemia Study Group

PURPOSE We investigated the safety and efficacy of bendamustine and rituximab (BR) in previously untreated patients with chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS In all, 117 patients, age 34 to 78 years, 46.2% of patients at Binet stage C, and 25.6% of patients age 70 years or older received BR chemoimmunotherapy for first-line treatment of CLL. Bendamustine was administered at a dose of 90 mg/m(2) on days 1 and 2 combined with 375 mg/m(2) rituximab on day 0 of the first course and 500 mg/m(2) on day 1 during subsequent courses for up to six courses. RESULTS Overall response rate was 88.0% (95% CI, 80.7% to 100.0%) with a complete response rate of 23.1% and a partial response rate of 64.9%. Ninety percent of patients with del(11q), 94.7% with trisomy 12, 37.5% with del(17p), and 89.4% with unmutated IGHV status responded to treatment. After a median observation time of 27.0 months, median event-free survival was 33.9 months, and 90.5% of patients were alive. Grade 3 or 4 severe infections occurred in 7.7% of patients. Grade 3 or 4 adverse events for neutropenia, thrombocytopenia, and anemia were documented in 19.7%, 22.2%, and 19.7% of patients, respectively. CONCLUSION Chemoimmunotherapy with BR is effective and safe in patients with previously untreated CLL.

Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial

Despite promising results with targeted drugs, chemoimmunotherapy with fludarabine, cyclophosphamide (FC), and rituximab (R) remains the standard therapy for fit patients with untreated chronic lymphocytic leukemia (CLL). Herein, we present the long-term follow-up of the randomized CLL8 trial reporting safety and efficacy of FC and FCR treatment of 817 treatment-naïve patients with CLL. The primary end point was progression-free survival (PFS). With a median follow-up of 5.9 years, median PFS were 56.8 and 32.9 months for the FCR and FC group (hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.50-0.69, P < .001). Median overall survival (OS) was not reached for the FCR group and was 86.0 months for the FC group (HR, 0.68; 95% CI, 0.54-0.89, P = .001). In patients with mutated IGHV (IGHV MUT), FCR improved PFS and OS compared with FC (PFS: HR, 0.47; 95% CI, 0.33-0.68, P < .001; OS: HR, 0.62; 95% CI, 0.34-1.11, P = .1). This improvement remained applicable for all cytogenetic subgroups other than del(17p). Long-term safety analyses showed that FCR had a higher rate of prolonged neutropenia during the first year after treatment (16.6% vs 8.8%; P = .007). Secondary malignancies including Richters transformation occurred in 13.1% in the FCR group and in 17.4% in the FC group (P = .1). First-line chemoimmunotherapy with FCR induces long-term remissions and highly relevant improvement in OS in specific genetic subgroups of fit patients with CLL, in particular those with IGHV MUT. This trial was registered at www.clinicaltrials.gov as #NCT00281918.

Minimal Residual Disease Assessment Improves Prediction of Outcome in Patients With Chronic Lymphocytic Leukemia (CLL) Who Achieve Partial Response: Comprehensive Analysis of Two Phase III Studies of the German CLL Study Group

Purpose To determine the value of minimal residual disease (MRD) assessments, together with the evaluation of clinical response in chronic lymphocytic leukemia according to the 2008 International Workshop on Chronic Lymphocytic Leukemia criteria. Patients and Methods Progression-free survival (PFS) and overall survival of 554 patients from two randomized trials of the German CLL Study Group (CLL8: fludarabine and cyclophosphamide [FC] v FC plus rituximab; CLL10: FC plus rituximab v bendamustine plus rituximab) were analyzed according to MRD assessed in peripheral blood at a threshold of 10-4 and clinical response. The prognostic value of different parameters defining a partial response (PR) was further investigated. Results Patients with MRD-negative complete remission (CR), MRD-negative PR, MRD-positive CR, and MRD-positive PR experienced a median PFS from a landmark at end of treatment of 61 months, 54 months, 35 months, and 21 months, respectively. PFS did not differ significantly between MRD-negative CR and MRD-negative PR; however, PFS was longer for MRD-negative PR than for MRD-positive CR ( P = .048) and for MRD-positive CR compared with MRD-positive PR ( P = .002). Compared with MRD-negative CR, only patients with MRD-positive PR had a significantly shorter overall survival (not reached v 72 months; P = .001), whereas there was no detectable difference for patients with MRD-negative PR or MRD-positive CR ( P = 0.612 and P = 0.853, respectively). Patients with MRD-negative PR who presented with residual splenomegaly had only a similar PFS (63 months) compared with patients with MRD-negative CR (61 months; P = .354), whereas patients with MRD-negative PR with lymphadenopathy showed a shorter PFS (31 months; P < .001). Conclusion MRD quantification allows for improved PFS prediction in both patients who achive PR and CR, which thus supports its application in all responders. In contrast to residual lymphadenopathy, persisting splenomegaly does not impact outcome in patients with MRD-negative PR.

CLL2-BXX Phase II trials: sequential, targeted treatment for eradication of minimal residual disease in chronic lymphocytic leukemia

AIM Four Phase II trials (clinical trials numbers: NCT02345863, NCT02401503, NCT02445131 and NCT02689141) evaluate a different combination of targeted agents in an all-comer population of approximately 60 patients with chronic lymphocytic leukemia irrespective of prior treatment, physical fitness and genetic risk factors. Patients with a higher tumor load start with a debulking treatment with bendamustine. The subsequent induction and maintenance treatment with an anti-CD20 antibody (obinutuzumab or ofatumumab) and a targeted oral agent (ibrutinib, idelalisib or venetoclax) are continued until achievement of a complete response and minimal residual disease negativity. CONCLUSION This strategy represents a new era of chronic lymphocytic leukemia therapy where chemotherapy is increasingly replaced by targeted agents and treatment duration is tailored to the patients individual tumor load and response.

Bendamustine followed by obinutuzumab and venetoclax in chronic lymphocytic leukaemia (CLL2-BAG): primary endpoint analysis of a multicentre, open-label, phase 2 trial

BACKGROUND Targeted agents such as the type II anti-CD20 antibody obinutuzumab and the B-cell lymphoma-2 antagonist venetoclax have shown impressive therapeutic activity in chronic lymphocytic leukaemia. The CLL2-BAG trial was initiated to investigate the combination of these two agents in patients with chronic lymphocytic leukaemia. METHODS In this ongoing multicentre, open-label, investigator-initiated phase 2 trial, patients (aged ≥18 years) with chronic lymphocytic leukaemia requiring treatment according to the 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria and an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled at 16 sites in Germany. Patients with a relevant tumour load (absolute lymphocyte count ≥25 000 cells per μL or lymph nodes with a diameter of ≥5 cm) received sequential treatment of debulking with two cycles of bendamustine (70 mg/m2 intravenously on days 1 and 2 of each of the two 28-day cycles), followed by induction and maintenance with obinutuzumab (1000 mg intravenously on days 1-2, 8, and 15 of the first induction cycle, every 4 weeks in induction cycles 2-6, and every 12 weeks in the maintenance phase) and oral venetoclax (starting in induction cycle 2 with 20 mg/day, with a weekly dose escalation over 5 weeks to the target dose of 400 mg/day). The primary endpoint was the proportion of patients achieving an overall response by investigator assessment at the end of induction treatment. All patients who received at least two induction cycles were included in the efficacy analyses and all patients who received at least one dose of study drug were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT02401503. FINDINGS Between May 6, 2015, and Jan 4, 2016, 66 patients were enrolled (35 treatment naive and 31 with relapsed or refractory disease), three of whom were excluded from the efficacy analysis because they received fewer than two induction cycles. Of the remaining 63 patients in the efficacy-evaluable population, 34 patients (54%) were treatment naive and 29 (46%) had relapsed or refractory disease. At data cutoff (Feb 28, 2017), all patients had completed induction treatment. At the end of the induction, 60 (95%) of 63 patients (95% CI 87-99) had responded, including all 34 patients in the treatment-naive cohort and 26 [90%] of 29 relapsed or refractory patients. The most common grade 3-4 adverse events during debulking were neutropenia and anaemia (five [11%] of 47 patients each), and thrombocytopenia and infection (three [6%] each). The most common grade 3-4 adverse events during induction were neutropenia (29 [44%] of 66 patients), infection (nine [14%]), thrombocytopenia (eight [12%]), infusion-related reactions (five [8%]), and secondary primary malignancy (four [6%]). 89 serious adverse events, including 69 related to study treatment, were reported. These serious adverse events were also mainly infections (four cases in four patients during debulking and 18 cases in 11 patients during induction) and cytopenia (four cases in four patients during debulking and ten cases in seven patients in induction). Five relapsed or refractory patients died: three cases of sepsis were deemed related to study treatment, whereas two deaths from Richters transformation were not. INTERPRETATION The sequential application of bendamustine and obinutuzumab combined with venetoclax caused no unexpected or cumulative toxicities. The high proportion of patients who achieved overall responses, both treatment-naive and relapsed or refractory patients irrespective of physical fitness and genetic risk factors, compare favourably to established chronic lymphocytic leukaemia therapies. Further follow-up will help to define whether the remissions with eradication of minimal residual disease achieved with this combination are durable after treatment discontinuation. FUNDING F Hoffmann-La Roche and AbbVie.