Practice Update: Haematology & Oncology

HAEMATOLOGY

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EXPERT OPINION DR ANDRE GOY Haematology practice implications fromASCO: Chronic lymphocytic leukaemia Dr Farzanna Haffizulla spoke with Dr Andre Goy about new research presented at ASCO on treatments for chronic lymphocytic leukaemia and the implications for clinical practice.

rituximab plus placebo with an additional 2 years of follow-up showed that the benefit of the combination with ibrutinib continues to get better in terms of CR, PFS, but also mo- lecular CR. So, this is really, really important. There is a study about a second-generation BTK inhibitor, acalabrutinib, with 96% over- all response rates with no A-fib and very easy toxicity profiles; 4 this is something that’s going to be very relevant. There’s update on veneto- clax. 5 Venetoclax was the first BCL-2 inhibitor approved in the context of CLL and deletion 17p. There are data that were presented at ASCO showing that the response is very im- pressive in many patients who failed ibrutinib or idelalisib. So this is important. I think in CLL what is interesting is the CAR- T cells, which we mentioned; this is something that’s going to be definitely part of the treat- ment landscape. There are a number of other small molecules that have been tested in CLL. The landscape continues to be very exciting. We’ll see as we combine some of these small molecules if potentially we could shy away from chemotherapy in that disease. References 1. Dartigeas C, Van Den Neste E, Maisonneuve H, et al. Paper presented at 2016 Annual Meeting of the American Society of Clinical Oncology; Abstract 7505. 2. Turtle CJ, Hanafi L-A, Berger C, et al. Paper pre- sented at 2016 Annual Meeting of the American Society of Clinical Oncology; Abstract 102. 3. Fraser G, Cramer P, Demirkan D, et al. Paper pre- sented at 2016 Annual Meeting of the American Society of Clinical Oncology; Abstract 7525. 4. Byrd JC, Jones JA, Furman RR, et al. Paper pre- sented at 2016 Annual Meeting of the American Society of Clinical Oncology; Abstract 7521. 5. Jones JA, Wierda WG, Choi MY, et al. Paper pre- sented at 2016 Annual Meeting of the American Society of Clinical Oncology; Abstract 7519.

Dr Haffizulla: Dr Goy, a study was presented this year at ASCO on the results of rituximab main- tenance after induction with FCR in elderly patients with CLL. 1 What is your opinion of these data? There are a number of other small molecules that have been tested in CLL. We’ll see as we combine some of these small molecules if potentially we could shy away from chemotherapy in that disease. Dr Goy: In CLL, there are interesting data on approaching maintenance after induction chemotherapy with FCR. One of the problems with FCR and CLL is the toxicity in the elderly patient; so, there have been several attempts to try to do mini FCR or reduce the number of cycles. This particular study looked at four FCR cycles, and, as expected, the majority of patients responded well. Then they were ran- domised to maintenance rituximab 500 mg/m 2 every 2 months for 2 years or to observation. None of these patients had deletion 17p – this was an exclusion criterion. The data presented at ASCO show that the maintenance actu- ally prolonged the duration of response and delayed a relapse in those patients by almost a year. So this is something that is interesting. One of the questions that remain, though, is that there will be more myelotoxicity and infection, and that’s not surprisingly either in the context of maintenance rituximab. It’s important in CLL, where often there’s a lot of infection already, but there are also cost issues. This is an interesting concept. Maybe we should look at less induction therapy and try to gain benefit with the maintenance. Although, when you look at toxicity and cost, potentially overall, maybe it’s going to be important to try to look more at MRD (minimal residual disease) data in those patients. Who are the patients who will benefit from that? They don’t

have the data yet in that study, and they will present them later. Dr Haffizulla: There is also great deal of excite- ment about CAR-T cell therapy in this disease. Can you summarise some of the results pub- lished thus far? Dr Goy: CAR-T cell therapy is really exciting and, as you know, the first generation is anti- CD19 CAR-T cells that were tested in ALL, CLL, and non-Hodgkin’s lymphoma. The results have been really astounding in CLL, a very durable response; so, we were starting to see at this ASCO meeting how we can learn more. A study that looked at different levels of dosing in the context of CLL 2 showed that one gives better responses and better results, with more easily solved intolerance – not worse

intolerance, I should say. And then there is a study that is looking at early data, at CLL post induction as a consolidation. This was not as impressive because maybe the chemotherapy that was given for lymphodepletion before the infusion was actually very minimal. There are additional studies that are trying to understand better what we can do, the next step; what should we combine with the CAR-T cells to try to make this response very durable. Dr Haffizulla: That is excellent. It sounds prac- tice-changing. Any other studies in CLL that you feel are worth mentioning? Dr Goy: What is also very exciting is a confir- mation of the HELIOS study with ibrutinib. 3 Ibrutinib in combination with bendamustine and rituximab versus bendamustine and not masked from study investigators or patients. The primary endpoint was time from randomisa- tion to progression to symptomatic myeloma. The primary analysis was based on the per-protocol population, restricted to patients who fulfilled the protocol in terms of eligibility. Safety assessments were based on the intention-to-treat population. FINDINGS Between Nov 8, 2007, and June 9, 2010, 125 patients were enrolled and underwent ran- domisation. 119 patients comprised the per-protocol population and were randomly assigned to receive either lenalidomide plus dexamethasone (n = 57) or observation (n = 62). The cutoff date for this update was June 30, 2015. Median follow-up for surviving patients was 75 months (IQR 67–85). Lenalidomide plus dexamethasone continued to provide a benefit on time to progression compared with observation (median time to progression not reached [95% CI 47 months-not reached] vs 23 months [16–31]; hazard ratio [HR] 0.24 [95% CI 0.14–0.41]; P < 000001). Pro- gression to multiple myeloma occurred in 53 (86%) of 62 patients in the observation group compared with 22 (39%) of 57 patients in the treatment group. At data cutoff, ten (18%) patients had died in the treatment group and 22 (36%) patients had died in the observation group; median overall survival from the time of study entry had not been reached in either group (95% CI 65 months-not reached vs 53 months-not reached; HR 0.43 [95% CI 0.21–0.92], P = 0.024). Survival in patients who had received

Dr Andre Goy is on the advisory board of PracticeUpdate and is Chairman and Director of the John Theurer Cancer Center at Hackensack University Medical Center.

JOURNAL SCAN Lenalidomide plus dexamethasone vs observation in patients with high-risk smoldering multiple myeloma The Lancet Oncology Take-home message • This was a multicentre, open-label, randomised phase III study evaluating the clinical utility of early treatment with lenalidomide plus dexamethasone (Rd) vs observation in 125 patients with high-risk smoldering multiple myeloma (SMM). Rate of progression to symptomatic MMwas 39% vs 86%, with median time to progression (TTP) not reached vs 23 months in the Rd and observation groups, respectively (P < 0.001). • The authors conclude that early treatment with Rd in selected high-risk SMM patients offers TTP benefit, arguing against observation alone in this population. Dr Brandt Esplin

subsequent treatments at the time of progression to active disease did not differ between groups (HR 1.34 [95% CI 0.54–3.30]; P = 0.50). The most frequently reported grade 3 adverse events in patients given lenalidomide plus dexamethasone were infection (four [6%]), asthenia (four [6%]), neu- tropenia (three [5%]), and skin rash (two [3%]); these events all occurred during induction therapy. No grade 4 adverse events occurred, but one (2%) patient in the lenalidomide plus dexamethasone group died from a respiratory infection during in- duction therapy The frequency of second primary malignancies was higher in patients in the treatment group than in those in the observation group (six [10%] of 62 patients vs one [2%] of 63 patients), but the cumulative risk of development did not differ significantly between the groups (P = 0.070). INTERPRETATION This study is, to our knowledge, the first randomised trial in which early treatment has been assessed in selected patients with high-risk smouldering multiple myeloma. Positive results from ongoing trials would support the use of early treatment for patients with high-risk disease in the near future. Lenalidomide plus dexamethasone versus observation in patients with high-risk smoulder- ing multiple myeloma (quiredex): Long-term follow-up of a randomised, controlled, phase 3 trial. Lancet Oncol 2016 Jul 08;[EPub Ahead of Print], Mateos MV, Hernández MT, Giraldo P, et al.

random number generator, to receive either early treatment with lenalidomide plus dexamethasone or observation, with dynamic balancing to maintain treatment balance within the two groups. Ran- domisation was stratified by time from diagnosis of smouldering multiple myeloma to study enrol- ment (≤6 months vs >6 months). Patients in the treatment group received nine 4-week induction cycles (lenalidomide 25 mg per day on days 1–21, plus dexamethasone 20 mg per day on days-1–4 and days 12–15), followed by maintenance therapy (lenalidomide 10 mg per day on days 1–21 of each 28-day cycle) up to 2 years. Group allocation was

BACKGROUND The standard of care for smoulder- ing multiple myeloma is observation. We did the QuiRedex study to compare early treatment with lenalidomide plus dexamethasone with observa- tion in patients with high-risk smouldering multiple myeloma. Here we report the long-term follow-up results of the trial. METHODS We did this open-label, randomised, con- trolled phase 3 study at 19 centres in Spain and three centres in Portugal. Patients aged 18 years or older with high-risk smouldering multiple myeloma were randomly assigned (1:1), via a computerised

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