The Canadian Cancer Trials Group (CCTG) LY.17 is an ongoing multi-arm randomized phase II trial evaluating novel salvage therapies compared with R-GDP (rituximab, gemcitabine, dexamethasone and cisplatin) in autologous stem cell transplantation (ASCT)-eligible patients with relapsed/refractory diffuse large B-cell lymphoma (RR-DLBCL). This component of the LY.17 trial evaluated a dose-intensive chemotherapy approach using a single cycle of inpatient R-DICEP (rituximab, dose-intensive cyclophosphamide, etoposide and cisplatin) to achieve both lymphoma response and stem cell mobilization, shortening time to ASCT. This report is the result of the protocol-specified second interim analysis of the 67 patients who were randomized to either 1 cycle of R-DICEP or to 3 cycles of R-GDP. The overall response rate (ORR) was 65.6% for R-DICEP and 48.6% for R-GDP. The ASCT rate was 71.9% versus 54.3%, and 1-year progression-free survival rate was 42% versus 32%, respectively, for R-DICEP versus R-GDP. Although the improvement in ORR for R-DICEP versus R-GDP exceeded the pre-specified 10% threshold to proceed to full accrual of 64 patients/arm, higher rates of grade 3-5 toxicities, and the need for hospitalization led to the decision to stop this arm of the study. CCTG LY.17 will continue to evaluate different salvage regimens that incorporate novel agents.

Venetoclax is a first-in-class B-cell lymphoma-2 (BCL-2) inhibitor approved as continuous monotherapy and in combination with rituximab as fixed-treatment duration for relapsed and refractory chronic lymphocytic leukemia (R/R CLL). DEVOTE was a 24-week, multicenter observational study (NCT03310190) evaluating the safety, healthcare resource utilization (HCRU) and health-related quality of life (HRQoL) of patients initiating venetoclax for R/R CLL in Canada. Overall, 89 patients received 1 dose of venetoclax; 80% had prior exposure (42% resistant) to ibrutinib. Biochemical tumor lysis syndrome (TLS) occurred in five patients. We observed differences in hospitalization across Canadian provinces including in patients at low risk for TLS with no clear impact on TLS incidence. Additionally, a rapid and sustained improvement in several domains of HRQoL was observed during venetoclax initiation. Early adoption of venetoclax was mainly for R/R CLL patients with few treatment options; nonetheless, acceptable toxicity and a positive impact on HRQoL were observed.

BACKGROUND:Iron deficiency is highly prevalent worldwide and is an issue of health inequity. Despite its high prevalence, uncertainty on the clinical applicability and evidence-base of iron-related lab test cut-offs remains. In particular, current ferritin decision limits for the diagnosis of iron deficiency may not be clinically appropriate nor scientifically grounded.METHODS:A modified Delphi study was conducted with various clinical experts who manage iron deficiency across Canada. Statements about ferritin decision limits were generated by a steering committee, then distributed to the expert panel to vote on agreement with the aim of achieving consensus and acquiring feedback on the presented statements. Consensus was reached after two rounds, which was defined as 70% of experts rating their agreement for a statement as 5 or higher on a Likert scale from 1 to 7.RESULTS:Twenty-six clinical experts across 10 different specialties took part in the study. Consensus was achieved on 28 ferritin decision limit statements in various populations (including patients with multiple comorbid conditions, pediatric patients, and pregnant patients). For example, there was consensus that a ferritin <30 μg/L rules in iron deficiency in all adult patients (age ≥ 18 years) and warrants iron replacement therapy.CONCLUSION:Consensus statements generated through this study corresponded with current evidence-based literature and guidelines. These statements provide clarity to facilitate clinical decisions around the appropriate detection and management of iron deficiency.

Following the recent publication of Canadian evidence-based guidelines for frontline treatment of chronic lymphocytic leukemia (CLL), the same group of clinicians developed guidelines for CLL in the relapsed/refractory (R/R) setting. The treatment of R/R CLL has changed significantly in the past few years, with many novel therapeutics available to hematologists across the country. These guidelines aim to standardize the management of CLL in the relapsed/refractory setting, using the best evidence currently available.

Chronic lymphocytic leukemia (cll) is the most common adult leukemia in North America. In 2018, the first unified national guideline in Canada was developed for the front-line treatment of cll that helped guide treatment across the country. As an update in 2022, a group of clinical experts from across Canada came together to provide input and guidance that included new and innovative treatments and approaches that will continue to provide health care professionals with clear guidance on the first-line management of cll. Recommendations were provided in consensus based on available evidence for the first-line treatment of cll.

Background: Although von Willebrand disease (VWD) is inherited by men and women equally, women are more likely to experience bleeding symptoms due to the challenges of menstruation and childbirth. Heavy menstrual bleeding (HMB) is the most common symptom observed in women and girls with VWD, and increases risk of iron deficiency anemia, blood transfusion, hospitalization and decreased health-related quality of life. While replacement therapy with von Willebrand factor (VWF) is recommended for prophylaxis in patients with VWD with severe and frequent bleeding, recommendations on its use for prophylaxis of HMB are limited due the lack of clinical trial data. Aims: The EMPOWER pilot trial will determine the feasibility of the trial design, as well as explore assay sensitivity to inform the determination of the primary outcome for the definitive randomized trial which will evaluate the effect of prophylaxis with plasma-derived VWF/FVIII (1:1; pdVWF:FVIII) concentrate compared with placebo on HMB in women with VWD. Methods: EMPOWER is a pilot, randomized, placebo-controlled, crossover, double-blind (patient and outcome assessor blinded), 2-year trial in female outpatients with VWD and HMB. We will evaluate the effect of 2-3 doses of prophylaxis with 40-60 IU VWF:RCo/kg pdVWF/FVIII concentrate when provided on the 2 heaviest days within the first 4 days of menstruation compared with placebo (normal saline). For the first treatment period, participants will be randomized to receive either pdVWF/FVIII concentrate or placebo for 4 cycles, crossing over to the comparator treatment during the second treatment period (see Figure 1). Non-pregnant female patients, ≥18 years of age with a diagnosis of inherited VWD (any type) with HMB defined as a modified pictorial blood assessment chart (mPBAC) score >100, on stable treatment for HMB and iron-deficiency anemia will be eligible. Patients with diagnosis of another bleeding disorder or the presence of >2 risk factors for venous thromboembolism will be excluded. The pilot trial viability outcomes include blinding index scores and participant drop-out rates. Feasibility outcomes include data completeness and rate of enrolment. The proposed primary clinical efficacy outcome is the mPBAC score and the key secondary efficacy outcome is the need for rescue therapy (i.e. >2 days of oral tranexamic acid use, additional treatment with pdVWF:FVIII concentrate, additional hormonal therapy for HMB, urgent/emergent gynecological surgery for HMB, treatment with intravenous iron, red blood cell transfusion, or hospital admission for HMB). Other secondary outcomes include major bleeding, clinically relevant non-major bleeding, red blood cell transfusion, fatigue and quality of life scores. Given the uncertainty in this area of research and the relative comparable clinical importance of proposed clinical efficacy outcomes, we will evaluate assay sensitivity to determine the outcome that has the greatest chance of detecting a difference between treatment periods. Assay sensitivity is defined as the ability of a scale to distinguish an effective from a less effective intervention or placebo. Assay sensitivity along with the proportion of missing data per clinical efficacy outcome and sample size considerations will influence the choice of primary outcome for the definitive trial. Safety will be evaluated by monitoring for hypersensitivity reactions, thromboembolic events and VWF inhibitors. The pilot trial will recruit 20 participants from Hemophilia Treatment Centres in Canada over 2 years. Results: The pilot trial is aiming to launch by the fall 2022. If the pilot trial is deemed feasible and viable, we will subsequently conduct a definitive international randomized controlled trial. Conclusion: Data from the EMPOWER trial will fill an important knowledge gap to facilitate evidence-based management of HMB in women with VWD. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Patients with hematological malignancies have an increased risk of serious outcomes following COVID-19 infection, suggesting broader protection is needed beyond vaccination. Monoclonal antibodies such as sotrovimab, casirivimab–imdevimab, and bamlanivimab have provided valuable options for the treatment of COVID-19 disease. More recently, monoclonal antibodies have been examined for the prevention of COVID-19 infection. The monoclonal antibody combination, tixagevimab–cilgavimab, was recently approved by Health Canada as pre-exposure prophylaxis against COVID-19 in individuals who are immunocompromised or where vaccination is not recommended. Prophylactic approaches such as the use of tixagevimab–cilgavimab, in addition to COVID-19 vaccination, may provide additional protection for patients with hematological malignancies who are at greater risk of serious outcomes from COVID-19 infection.

Summary The manageable toxicity profile of obinutuzumab (GA101; G) alone or with chemotherapy in first‐line (1L; fit and non‐fit) and relapsed/refractory (R/R) patients with chronic lymphocytic leukaemia (CLL) was established in the primary analysis of the Phase IIIb GREEN trial (Clinicaltrials.gov: NCT01905943). The final analysis (cut‐off, 31 January 2019) is reported here. Patients received G (1000 mg) alone (G‐mono; fit and non‐fit patients) or with chemotherapy [fludarabine and cyclophosphamide (FC; fit patients); chlorambucil (non‐fit patients); bendamustine (any patient)]. Study endpoints were safety (primary) and efficacy (secondary). Subgroup analyses were performed on prognostic biomarkers in 1L CLL. Overall, 630 patients received 1L and 341 received R/R CLL treatment. At the final analysis, no new safety signals were observed [Grade ≥ 3 adverse events (AEs): 1L 82·7%, R/R 84·5%; serious AEs: 1L 58·1%, R/R 62·5%]. Neutropenia (1L 50·5%, R/R 53·4%) and thrombocytopenia (1L 14·6%, R/R 19·1%) were the most common Grade 3–5 AEs. G‐mono‐, G‐bendamustine and G‐FC‐treated patients with unmutated immunoglobulin heavy chain trended towards shorter progression‐free survival. Achievement of minimal residual disease negativity was greatest in 1L patients treated with G‐FC. In this final analysis of the GREEN trial, the safety profile of G was consistent with current risk management strategies. Biomarker analyses supported efficacy in the specific subgroups.

It has been another busy year for Canadian Cancer Trials Group at the American Society of Clinical Oncology Annual Meeting. This conference brings together oncology professionals from around the world to discuss state-of-the-art treatments, new therapies with the best minds in the field of cancer research. CCTG is well represented on this world stage with three recognition awards, fifteen poster presentations, and four oral abstracts. See below for more details. For more information on the event see the ASCO 2017 website or you can follow the conversation on our twitter account @CDNCancerTrial #ASCO17

Buparlisib is an orally available pan-Class I PI3K inhibitor, that is more potent than idelalisib in vitro. Its distinct toxicities include hyperglycemia, hypertension, and mood disturbance. IND216 is a single arm phase II trial of buparlisib in Relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Fourteen patients were enrolled, 13 were evaluable for response and toxicity. Six of 13 patients had a partial response (46%) with a median duration of response of 15.5 months, all 11 patients with tumor assessment experienced tumor shrinkage. The most common adverse events (>= 15%) were hyperglycemia, fatigue, anxiety, and gastrointestinal toxicities; all were < grade 3 except for fatigue. Three patients stopped therapy for alterations in mood. Lower levels of raptor were significantly associated with greater tumor shrinkage, suggesting that raptor could be a biomarker for response. This requires further validation in a larger CLL patient cohort. The clinical activity of buparlisib is comparable to other phosphatidylinositol-3-kinase inhibitors, with a different toxicity profile.Novelty and impact Buparlisib, an oral, pan PI3 kinase inhibitor, is associated with a 46% partial response rate among patients with relapse chronic lymphocytic leukemia (CLL). This is a similar clinical activity to other phosphatidylinositol-3-kinase inhibitors tested. However, buparlisib has a distinct toxicity profile, characterized by hyperglycemia, hypertension, and mood alteration. In agreement with our previous preclinical study, our results suggest that basal raptor expression in CLL correlates with clinical response to buparlisib.

Background Venetoclax plus obinutuzumab has been established as a fixed-duration treatment regimen for patients with chronic lymphocytic leukaemia. We compared the long-term efficacy after treatment cessation of the combination of venetoclax plus obinutuzumab with chlorambucil plus obinutuzumab in patients with previously untreated chronic lymphocytic leukaemia. Methods CLL14 is a multicentre, randomised, open-label, phase 3 trial done at 196 sites in 21 countries. Eligible patients were aged 18 years or older, had untreated chronic lymphocytic leukaemia, and coexisting conditions with a cumulative illness rating scale greater than 6, a creatinine clearance of 30-69 mL/min, or both. Patients were randomly assigned (1:1) via a web and voicemail system with allocation concealment and based on a computer generated randomisation schedule with a block size of six and stratified by Binet stage and geographical region. Patients received either venetoclax plus obinutuzumab (oral venetoclax initiated on day 22 of cycle 1 [28-day cycles], with a 5-week dose ramp-up [20 mg, 50 mg, 100 mg, and 200 mg, then 400 mg daily for 1 week], thereafter continuing at 400 mg daily until completion of cycle 12; combined with intravenous obinutuzumab for six cycles starting with 100 mg on day 1 and 900 mg on day 2 [or 1000 mg on day 1], 1000 mg on days 8 and day 15 of cycle 1, and subsequently 1000 mg on day 1 of cycles 2 through 6) or chlorambucil plus obinutuzumab (oral chlorambucil at 0.5 mg/kg bodyweight on days 1 and 15 of each cycle for 12 cycles combined with the same obinutuzumab regimen). The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. Patient enrolment is complete, and the study is registered with ClinicalTrails.gov, NCT02242942. Findings Between Aug 7, 2015, and Aug 4, 2016, 432 patients were enrolled and randomly assigned to receive either venetoclax plus obinutuzumab (n=216) or chlorambucil plus obinutuzumab (n=216). All patients had been off treatment for at least 24 months at data collection. At a median follow-up of 39.6 months (IQR 36.8-43.0), patients given venetoclax plus obinutuzumab had a significantly longer progression-free survival than did patients given chlorambucil plus obinutuzumab (HR 0.31, 95% CI 0.22-0.44; p<0.0001). Median progression-free survival was not reached (95% CI not estimable to not estimable) in the venetoclax plus obinutuzumab group vs 35.6 months (33.7-40.7) in the chlorambucil plus obinutuzumab group. The most common grade 3 or 4 adverse event in both groups was neutropenia (112 [53%] of 212 patients in the venetoclax plus obinutuzumab group versus 102 [48%] of 214 patients in the chlorambucil plus obinutuzumab group). Serious adverse events occurred in 115 (54%) of 212 patients in the venetoclax plus obinutuzumab group and 95 (44%) of 214 patients in the chlorambucil plus obinutuzumab group. Venetoclax or chlorambucil treatment-related deaths were reported in one (1%) of 212 patients in the venetoclax plus obinutuzumab group (n=1 sepsis) and two (1%) of 214 patients in the chlorambucil plus obinutuzumab group (n=1 septic shock, n=1 metastatic skin squamous carcinoma). Interpretation 2 years after treatment cessation, venetoclax plus obinutuzumab continues to significantly improve progression-survival compared with chlorambucil plus obinutuzumab, thereby providing a limited duration treatment option for patients with previously untreated chronic lymphocytic leukaemia. Copyright (C) 2020 Elsevier Ltd. All rights reserved.

Background:The multinational, open‐label, phase 3 CLL14 trial (NCT02242942) compared fixed‐duration targeted venetoclax plus obinutuzumab (VenG) treatment with chlorambucil‐obinutuzumab (ClbG) treatment in previously untreated patients (pts) with chronic lymphocytic leukemia (CLL) and comorbidities.Aims:We present endpoint analyses with particular emphasis on progression‐free survival (PFS) and minimal residual disease (MRD)‐negativity.Methods:Pts with a CIRS score >6 and/or an estimated creatinine clearance <70 mL/min were randomized 1:1 to receive equal duration treatment with 12 cycles of standard Clb or Ven 400 mg daily in combination with G for the first 6 cycles. The primary endpoint was PFS. MRD‐negativity in peripheral blood (PB) or bone marrow (BM) 3 months after treatment completion was a key secondary endpoint. MRD was analyzed serially from Cycle 4 every 3 months by an allele‐specific oligonucleotide polymerase chain reaction assay (ASO‐PCR; cut‐off, 10−4) and by next generation sequencing (NGS; cut‐offs, 10−4, 10−5, 10−6).Results:In total, 432 pts were enrolled; 216 in each treatment group (intent‐to‐treat population). Median age, total CIRS score, and CrCl at baseline were 72 years, 8, and 66.4 ml/min respectively. After 29 months median follow‐up, superior PFS was observed with VenG vs ClbG (Figure 1a). Median PFS was not reached in either group: at Month 24, PFS rates were 88% with VenG and 64% with ClbG (hazard ratio [HR] 0.35; 95% confidence interval [CI] 0.23–0.53; P < 0.0001). MRD‐negativity by ASO‐PCR was significantly higher with VenG vs ClbG in both PB (76% vs 35% [P < 0.0001]) and BM (57% vs 17% [P < 0.0001]) 3 months after treatment completion. Overall, 75% of VenG MRD‐negative pts in PB were also MRD‐negative in BM vs 49% in the ClbG group. Landmark analysis for this timepoint by PB MRD status showed that MRD‐negativity was associated with longer PFS. MRD‐negativity rates were more sustainable with VenG: 81% (VenG) vs 27% (ClbG) of pts were MRD‐negative 12 months after treatment completion; HR for MRD conversion 0.19; 95% CI 0.12–0.30 (median time off‐treatment: 19 months) (Figure 1b). MRD‐negativity rates by NGS confirmed these results; 78% (VenG) vs 34% (ClbG) of pts had MRD‐negative status at <10−4, 35% vs 15% at ≥10−6–<10−5 and 31% vs 4% at <10−6, respectively.Summary/Conclusion:Fixed‐duration VenG induced deep, high (<10−4 in 3/4 of pts and <10−6 in 1/3 of pts), and long lasting MRD‐negativity rates (with a low rate of conversion to MRD‐positive status 1 year after treatment) in previously untreated pts with CLL and comorbidities, translating into improved PFS.image

Introduction: The multinational, open-label, phase 3 CLL14 trial (NCT02242942) compared fixed-duration targeted venetoclax plus obinutuzumab (VenG) treatment with chlorambucil-obinutuzumab (ClbG) treatment in previously untreated patients (pts) with chronic lymphocytic leukemia (CLL) and comorbidities. We present endpoint analyses with particular emphasis on progression-free survival (PFS) and minimal residual disease (MRD)-negativity. Methods: Pts with a CIRS score >6 and/or an estimated creatinine clearance <70 mL/min were randomized 1:1 to receive equal duration treatment with 12 cycles of standard Clb or Ven 400 mg daily in combination with G for the first 6 cycles. The primary endpoint was PFS. MRD-negativity in peripheral blood (PB) or bone marrow (BM) 3 months after treatment completion was a key secondary endpoint. MRD was analyzed serially from Cycle 4 every 3 months by an allele-specific oligonucleotide polymerase chain reaction assay (ASO-PCR; cut-off, 10-4) and by next generation sequencing (NGS; cut-offs, 10-4, 10-5, 10-6). Results: 432 pts were enrolled (216 in each treatment group; intent-to-treat population). Median age, total CIRS score, and CrCl at baseline were 72 years, 8, and 66.4 mL/min respectively. After 29 months' median follow-up, superior PFS was observed with VenG vs ClbG (Figure 1a). Median PFS was not reached in either group: at Month 24, PFS rates were 88% with VenG and 64% with ClbG (hazard ratio [HR] 0.35; 95% confidence interval [CI] 0.23–0.53; P<0.0001). MRD-negativity by ASO-PCR was significantly higher with VenG vs ClbG in both PB (76% vs 35% [P<0.0001]) and BM (57% vs 17% [P<0.0001]) 3 months after treatment completion. Overall, 75% of VenG MRD-negative pts in PB were also MRD-negative in BM vs 49% in the ClbG group. Landmark analysis for this timepoint by PB MRD status showed that MRD-negativity was associated with longer PFS. MRD-negativity rates were more sustainable with VenG: 81% (VenG) vs 27% (ClbG) of pts were MRD-negative 12 months after treatment completion (Figure 1b). MRD-negativity rates by NGS confirmed these results; 78% (VenG) vs 34% (ClbG) of pts had MRD-negative status at <10-4, 35% vs 15% at ≥10-6–<10-5 and 31% vs 4% at <10-6, respectively. Conclusions: Fixed-duration VenG induced deep, high (<10-4 in 3/4 of pts and <10-6 in 1/3 of pts), and long lasting MRD-negativity rates (with a low rate of conversion to MRD-positive status 1 year after treatment) in previously untreated pts with CLL and comorbidities, translating into improved PFS. Funding: This study was funded by F. Hoffmann-La Roche Ltd and Abbvie Inc. Third-party editing and administrative support was provided by Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd. This abstract has been previously submitted in part to ASCO 2019 and EHA 2019. Keywords: chronic lymphocytic leukemia (CLL); obinutuzumab; venetoclax. Disclosures: Fischer, K: Other Remuneration: Expenses: Roche. Porro Lurà, M: Employment Leadership Position: Roche; Stock Ownership: Roche. Al-Sawaf, O: Other Remuneration: Other relationship: AbbVie, Roche, Gilead, Janssen. Bahlo, J: Honoraria: Roche; Other Remuneration: Expenses: Roche. Fink, A: Consultant Advisory Role: Janssen. Tandon, M: Employment Leadership Position: Roche. Dixon, M: Employment Leadership Position: Roche; Stock Ownership: Roche. Warburton, S: Employment Leadership Position: Roche. Humphrey, K: Employment Leadership Position: Roche; Stock Ownership: Roche. Liberati, A: Other Remuneration: Personal Fees: Abbvie. Pinilla-Ibarz, J: Consultant Advisory Role: Janssen, Gilead, Abbvie, Pharmacyclics, Millenium Pharmaceuticals/Takeda, TEVA, TG Therapeutics; Research Funding: TG Therapeutics; Other Remuneration: Speakers' Bureau: Janssen, Gilead, Abbvie, Pharmacyclics, Millenium Pharmaceuticals/Takeda, TEVA, Bayer. Opat, S: Consultant Advisory Role: Roche, AbbVie; Honoraria: Roche, AbbVie; Research Funding: Roche; Other Remuneration: Speakers' Bureau: Roche. Utoft Niemann, C: Consultant Advisory Role: Abbvie, Janssen, Gilead, AstraZeneca, Sunesis, Acerta, CSL Behring, Roche; Research Funding: Abbvie, Janssen; Other Remuneration: Expenses: Novartis, Gilead, Roche; Other relationship: Roche - Payment for trial enrollment/patient management of the trial, indirectly through GCLLSG. Weinkove, R: Consultant Advisory Role: Abbvie; Honoraria: Abbvie; Other Remuneration: Other relationship: Capital & Coast District Health Board - Institution received reimbursement of the costs of conducting trial-related clinical procedures. Robinson, S: Consultant Advisory Role: Roche, AbbVie. Kipps, T: Employment Leadership Position: UC, San Diego Health, Moores Cancer Center; Consultant Advisory Role: AbbVie, Genentech-Roche, Gilead, Pharmacyclics, Celgene; Honoraria: Gilead, AbbVie, Pharmacyclics, Janssen, Verastem; Research Funding: AbbVie, Genentech-Roche, Pharmacyclics, Oncternal; Other Remuneration: Membership on an entity's board of directors, speaker's bureau, or its advisory committees: AbbVie, Pharmacyclics, Janssen, Verastem. Boettcher, S: Honoraria: Roche, AbbVie, Janssen; Research Funding: Celgene, Roche, AbbVie, Janssen; Other Remuneration: Personal Fees: Janssen, Abbvie. Tausch, E: Consultant Advisory Role: Roche; Other Remuneration: Speakers' Bureau: Roche; Expert testimony: Abbvie; Expenses: Abbvie. Schary, W: Employment Leadership Position: AbbVie; Stock Ownership: AbbVie. Eichhorst, B: Consultant Advisory Role: Abbvie, Roche; Honoraria: Abbvie, Roche; Research Funding: Abbvie, Roche; Other Remuneration: Speakers' Bureau and expenses: Abbvie, Roche. Wendtner, C: Honoraria: F. Hoffmann La-Roche Ltd, Abbvie, Janssen-Cilag, Gilead, MorphoSys, Mundipharma, Novartis; Research Funding: F. Hoffmann La-Roche Ltd, Abbvie, Janssen-Cilag, Gilead, MorphoSys, Mundipharma, Novartis. Langerak, A: Consultant Advisory Role: AbbVie; Research Funding: Roche-Genentech, Gilead. Kreuzer, K: Consultant Advisory Role: Roche, Abbvie; Other Remuneration: Expert Testimony: Roche, Abbvie. Goede, V: Consultant Advisory Role: Roche, Janssen, Gilead, AbbVie; Other Remuneration: Speakers' Bureau: Roche, Janssen, Gilead. Stilgenbauer, S: Research Funding: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann La-Roche, Janssen, Novartis, Pharmacyclics, Sunesis; Other Remuneration: Personal Fees: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann La-Roche, Janssen, Novartis, Pharmacyclics, Sunesis. Mobasher, M: Employment Leadership Position: Genentech/F. Hoffmann-La Roche Ltd, Corvus; Stock Ownership: Genentech/F. Hoffmann-La Roche Ltd, Corvus; Other Remuneration: Expenses: Genentech/F. Hoffmann-La Roche Ltd, Corvus. Ritgen, M: Consultant Advisory Role: Roche, Abbvie; Research Funding: Roche, Abbvie; Other Remuneration: Personal Fees – Roche. Hallek, M: Consultant Advisory Role: Roche, Abbvie; Honoraria: Roche, Abbvie, Gilead, Janssen, Celgene, Boehringer Ingelheim; Research Funding: Roche, Abbvie; Other Remuneration: Speakers' Bureau: Roche, Abbvie.

BACKGROUND The BCL2 inhibitor venetoclax has shown activity in patients with chronic lymphocytic leukemia (CLL), but its efficacy in combination with other agents in patients with CLL and coexisting conditions is not known. METHODS In this open-label, phase 3 trial, we investigated fixed-duration treatment with venetoclax and obinutuzumab in patients with previously untreated CLL and coexisting conditions. Patients with a score of greater than 6 on the Cumulative Illness Rating Scale (scores range from 0 to 56, with higher scores indicating more impaired function of organ systems) or a calculated creatinine clearance of less than 70 ml per minute were randomly assigned to receive venetoclax-obinutuzumab or chlorambucil-obinutuzumab. The primary end point was investigator-assessed progression-free survival. The safety of each regimen was also evaluated. RESULTS In total, 432 patients (median age, 72 years; median Cumulative Illness Rating Scale score, 8; median creatinine clearance, 66.4 ml per minute) underwent randomization, with 216 assigned to each group. After a median follow-up of 28.1 months, 30 primary end-point events (disease progression or death) had occurred in the venetoclax-obinutuzumab group and 77 had occurred in the chlorambucil-obinutuzumab group (hazard ratio, 0.35; 95% confidence interval [CI], 0.23 to 0.53; P<0.001). The Kaplan-Meier estimate of the percentage of patients with progression-free survival at 24 months was significantly higher in the venetoclax-obinutuzumab group than in the chlorambucil-obinutuzumab group: 88.2% (95% CI, 83.7 to 92.6) as compared with 64.1% (95% CI, 57.4 to 70.8). This benefit was also observed in patients with TP53 deletion, mutation, or both and in patients with unmutated immunoglobulin heavy-chain genes. Grade 3 or 4 neutropenia occurred in 52.8% of patients in the venetoclax-obinutuzumab group and in 48.1% of patients in the chlorambucil-obinutuzumab group, and grade 3 or 4 infections occurred in 17.5% and 15.0%, respectively. All-cause mortality was 9.3% in the venetoclax-obinutuzumab group and 7.9% in the chlorambucil-obinutuzumab group. These differences were not significant. CONCLUSIONS Among patients with untreated CLL and coexisting conditions, venetoclax-obinutuzumab was associated with longer progression-free survival than chlorambucil-obinutuzumab. (Funded by F. Hoffmann-La Roche and AbbVie; ClinicalTrials.gov number, NCT02242942.).

The conditional survival of patients after frontline therapy for diffuse large B-cell lymphoma (DLBCL) approaches that of the general population once patients have survived disease free for 2 years. We sought to determine the conditional survival of patients among patients with relapsed de novo DLBCL successfully undergoing an autologous stem-cell transplant (ASCT) after first relapse. A total of 478 patients with de novo DLBCL, relapsed after 1 treatment from the Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL) and LY.12, were included. Patients were followed prospectively after ASCT for a median of 5.3 and 8.2 years, respectively. Individual patient data were analyzed for event-free survival (EFS) and overall survival. Standardized mortality ratios (SMRs) were estimated using French and Canadian life tables. The EFS estimates declined with each year of follow-up after ASCT and were 50.1% (95% confidence interval [CI]: 43.7% to 56.3%) and 43.4% (95% CI: 36.7% to 49.9%) at 5 years in CORAL and LY.12, respectively. The rate of death stabilized once patients achieved at least 4 years of EFS. Compared with the age- and sex-matched population, the SMR was significantly higher until 5 years after ASCT, when values were no longer statistically significant. Patients undergoing ASCT for relapsed DLBCL continue to have a higher rate of death at least until they have survived event free for 5 years. These observations can help to determine endpoints for future clinical trials in this population and for patient counseling. This trial was registered at www.clinicaltrials.gov as #NCT00078949.

Prior to novel targeted agents for chronic lymphocytic leukemia (CLL), the best chemoimmunotherapy regimen in patients with non-del(11q) disease was unclear. The role of lenalidomide was also not defined. This phase 2 study randomized 342 untreated patients with non-del(11q) CLL requiring therapy to fludarabine plus rituximab (FR; n=123), FR plus lenalidomide consolidation (FR+L; n=109), or FR plus cyclophosphamide (FCR; n=110) and compared 2-year progression-free survival (PFS) rates of each to the historical control rate with FC (60%). Patients with del(11q) in at least 20% of pretreatment cells continued with FCR (n=27) or were reassigned to FCR+L (n=31) and excluded from the primary analysis. Among non-del(11q) patients, 2-year PFS rates were 64% (90% confidence interval [CI], 57-71; FR), 72% (90% CI, 65-79; FR+L), and 74% (90% CI, 66-80; FCR); FR+L and FCR had rates significantly greater than historical control. Median PFS was significantly shorter with FR compared with FR+L (P=.04) and FCR (P<.001): 43 (95% CI, 33-50), 61 (95% CI, 45-71), and 97 (95% CI, 61 to not reached) months, respectively. Median follow-up was 73 months and median overall survival (OS) was only reached with FCR (101 months; 95% CI, 96 to not reached). With FR+L, the risk of death decreased over time and was lower than with FR at later time points (P=.01), but not significantly different from FCR (P=.21). Future studies incorporating short courses of lenalidomide into other novel treatment regimens are justified.

Introduction: Inhibition of the phospho-inositol 3 kinase (PI3K) delta isoform is effective in the treatment of relapsed and refractory chronic lymphocytic leukemia (CLL) (Pongas G, et al. Semin Oncol 2016; 43: 647). The efficacy of this class of drugs is limited by the potency of the inhibitor and its toxicity profile. Buparlisib is an orally available pan-Class I PI3K inhibitor which has greater potency than idelalisib in vitro . Low P70S6k and raptor levels, both of which are downstream regulators of the PI3K/mTOR pathway, correlate with sensitivity to PI3K inhibitor activity in CLL lymphocytes in vitro (Amrein L, et al. Int J Cancer 2013; 133: 247-52). The recommended phase II dose of buparlisib is 100 mg daily po and the main toxicities in Phase I were hyperglycemia, hypertension and mood disturbance (Bendell JC, et al. J Clin Oncol. 2012;30:282-90). We conducted a single arm phase II trial of buparlisib in patients with relapsed and refractory CLL (NCT02340780) and attempted to correlate response with P70S6k and raptor levels.