PracticeUpdate: Haematology & Oncology

HAEMATOLOGY

26

JOURNAL SCAN Long-term follow-up of the French Stop Imatinib (STIM1) Study in CML Journal of Clinical Oncology Take-home message

JOURNAL SCAN R-CHOP vs high- dose sequential chemotherapy in high-risk DLBCL Journal of Clinical Oncology Take-home message • In this randomized phase III trial, the authors compared R-CHOP with rituximab plus high-dose sequential chemotherapy (R-HDS) with autologous stem-cell transplantation (ASCT) in high- risk patients with diffuse large B-cell lymphomas. The clinical response rate, failure rate, and early treatment-related mortality rate were similar after R-CHOP and R-HDS. Although more hematologic toxicity and infectious complications were observed in the R-HDS arm, there were no significant differences in overall survival or progression-free survival. • The study authors concluded that R-HDS with ASCT does not offer a significant improvement in outcome in high-risk patients with diffuse large B-cell lymphomas. Abstract PURPOSE The benefit of high-dose chemotherapy with autologous stem-cell transplantation (ASCT) as first-line treatment in patients with diffuse large B-cell lymphomas is still a matter of debate. To address this point, we designed a randomized phase III trial to compare rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP)-14 (eight cycles) with rituximab plus high- dose sequential chemotherapy (R-HDS) with ASCT. PATIENTS AND METHODS From June 2005 to June 2011, 246 high-risk patients with a high-intermediate (56%) or high (44%) International Prognostic Index score were randomly assigned to the R-CHOP or R-HDS arm, and 235 were analyzed by intent to treat. The primary efficacy end point of the study was 3-year event-free survival, and results were analyzed on an intent-to-treat basis. RESULTS Clinical response (complete response, 78% v 76%; partial response, 5% v 9%) and failures (no response, 15% v 11%; and early treatment-related mortality, 2% v 3%) were similar after R-CHOP versus R-HDS, respectively. After a median follow-up of 5 years, the 3-year event-free survival was 62% versus 65% (P = 0.83). At 3 years, compared with the R-CHOP arm, the R-HDS arm had better disease-free survival (79% v 91%, respectively; P = 0.034), but this subsequently vanished because of late-occurring treatment-related deaths. No difference was detected in terms of progression-free survival (65% v 75%, respectively; P = 0.12), or overall survival (74% v 77%, respectively; P = 0.64). Significantly higher hematologic toxicity (P < 0.001) and more infectious complications (P < 0.001) were observed in the R-HDS arm. CONCLUSION In this study, front-line intensive R-HDS chemotherapy with ASCT did not improve the outcome of high-risk patients with diffuse large B-cell lymphomas. Randomized trial comparing R-CHOP versus high-dose sequential chemotherapy in high-risk patients with diffuse large B-cell lymphomas. J Clin Oncol 2016 Oct 03;[Epub ahead of print], Cortelazzo S, Tarella C, Gianni AM, et al.

• This study was a long-term follow up (median, 77 months) of a previously reported study in which 100 patients with CML with undetectable minimal residual disease (MRD) after 2 years of therapy had imatinib discontinued and were followed. Only 61 of 100 patients developed molecular recurrence during the prolonged follow-up. The 5-year molecular relapse-free survival was 38%. Of the 61 patients who relapsed, 57 restarted therapy. As many as 97% of retreated patients achieved a second undetectable MRD status. • Patients with CML who achieve undetectable MRD can safely discontinue imatinib with close molecular surveillance. Although most will relapse, some patients will have sustained molecular responses without therapy. Abstract

Molecular recurrence-free survival was 43% (95% CI, 33% to 52%) at 6 months and 38% (95% CI, 29% to 47%) at 60 months. Treatment was restarted in 57 of 61 patients with MR, and 55 patients achieved a second UMRD with a median time of 4 months (range, 1 to 16 months). None of the patients experienced a CML progression. Analyses of the characteristics of the study population identified that the Sokal risk score and duration of IM treatment were significantly associated with the probability of MR. CONCLUSION With a median follow-up of more than 6 years after treatment dis- continuation, the STIM1 study demonstrates that IM can safely be discontinued in patients with a sustained deep molecular response with no late MR. Long-term follow-up of the French Stop Imatinib (STIM1) study in patients with chronic myeloid leukemia. J Clin Oncol 2016 Oct 03;[Epub ahead of print], Etienne G, Guilhot J, Rea D, et al.

PURPOSE Imatinib (IM) can safely be discontinued in patients with chronic myeloid leukemia (CML) who have had undetectable minimal residual disease (UMRD) for at least 2 years. We report the final results of the Stop Imatinib (STIM1) study with a long follow-up. PATIENTS AND METHODS IM was prospectively discontinued in 100 patients with CML with UMRD sustained for at least 2 years. Molecular recurrence (MR) was defined as positivity of BCR-ABL transcript in a quantitative reverse transcriptase polymerase chain reaction assay confirmed by a second analysis point that indicated an increase of one log in relation to the first analysis point at two successive assessments or loss of major molecular response at one point. RESULTS The median molecular follow-up after treatment discontinuation was 77 months (range, 9 to 95 months). Sixty-one patients lost UMRD after a median of 2.5 months (range, 1 to 22 months), and one patient died with UMRD at 10 months.

JOURNAL SCAN Overall survival of patients with relapsed multiple myeloma treated with panobinostat or placebo plus bortezomib and dexamethasone The Lancet Haematology Take-home message

months (95% CI 35.0–44.8) in those who received panobinostat, bortezomib, and dexamethasone versus 35.8 months (29.0–40.6) in those who received pla- cebo, bortezomib, and dexamethasone (hazard ratio [HR] 0.94, 95% CI 0.78–1.14; p=0.54). Of patients who had received at least two previous regimens including bortezomib and an immunomodulatory drug, median overall survival was 25.5 months (95% CI 19.6–34.3) in 73 patients who received panobinostat, bortezomib, and dexamethasone versus 19.5 months (14.1–32.5) in 74 who received placebo (HR 1.01, 95% CI 0.68–1.50). INTERPRETATION The overall survival ben- efit with panobinostat over placebo with bortezomib and dexamethasone was modest. However, optimisation of the regimen could potentially prolong treat- ment duration and improve patients’ outcomes, although further trials will be required to confirm this. Overall survival of patients with relapsed multiple myeloma treated with panobinostat or placebo plus bortezomib and dexamethasone (the PANORAMA 1 trial): a randomised, placebo-controlled, phase 3 trial. Lancet Haematol 2016 Nov 01;3:e506-e515, San-Miguel JF, Hun- gria VT, Yoon SS, et al.

• This was a final overall survival analysis of a randomized, placebo-controlled, double-blind, prospective multicenter phase III study comparing panobinostat vs placebo in combination with bortezomib and dexamethasone in 768 patients with relapsed, refractory multiple myeloma (rrMM). Median overall survival in the treatment and placebo groups was 40.3 vs 35.8 months, respectively (P = 0.54). • The authors concluded that, while panobinostat offers a PFS benefit in combination with bortezomib and dexamethasone, no clear OS benefit was observed, warranting further study to optimize this regimen. Abstract

placebo on days 1, 3, 5, 8, 10, and 12; bortezomib on days 1, 4, 8, and 11; and dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12. During treatment phase 2 (four 6-week cycles with a 2 weeks on, 1 week off schedule), panobinostat or placebo was given three times a week, bortezomib was administered once a week, and dexamethasone was given on the days of and following bortezomib administration. The primary endpoint was progression-free survival; overall survival was a key secondary endpoint. FINDINGS Between Jan 21, 2010, and Feb 29, 2012, 768 patients were enrolled into the study and randomly assigned to receive either panobinostat (n=387) or placebo (n=381), plus bortezomib and dexamethasone. At data cutoff (June 29, 2015), 415 patients had died. Median overall survival was 40.3

BACKGROUND Panobinostat plus borte- zomib and dexamethasone significantly increased median progression-free survival compared with placebo plus bortezomib and dexamethasone in the phase 3 PANORAMA 1 trial. Here, we present the final overall survival analysis for this trial. METHODS PANORAMA 1 is a randomised, placebo-controlled, double-blind, phase 3 trial of patientswith relapsedor relapsed and refractory multiplemyeloma with one to three previous treatments. Patients were randomly assigned (1:1) to receive panobinostat (20 mg orally) or placebo, with bortezomib (1.3mg/m 2 intravenously) and dexamethasone (20 mg orally), over two distinct treatment phases. In treatment phase 1 (eight 3-week cycles), patients received: panobinostat or

JOURNAL SCAN Ixazomib and dexamethasone in patients with relapsed multiple myeloma not refractory to bortezomib Blood Take-home message • The authors of this phase II randomized trial sought to determine the efficacy and toxicity of ixazomib in combination with dexamethasone in relapsed myeloma. Patients (N = 70) were randomly assigned to receive either 4 mg or 5.5 mg of ixazomib in combination with 40 mg dexamethasone. In total, 43% of patients achieved confirmed partial response or better; 31% were responsive in the 4-mg group, and 54% were responsive in the 5.5-mg group. A grade 3 or 4 adverse event considered at least possibly related to treatment was observed in 32% of patients at the 4-mg dose and 60% of patients at the 5.5-mg dose. • The authors conclude that ixazomib with dexamethasone has good efficacy in relapsed myeloma and is generally well-tolerated. Notably, both response rate and toxicity are higher at 5.5 mg.

Advertisers Novartis Tasigna

6–7

Melanoma

16–17

Seqirus Palexia SR

median event free survival (EFS) for the entire study population was 8.4 months and 1-year overall survival was 96%. The EFS was 5.7 months for patients with prior bortezomib exposure and 11.0 months for bortezomib naïve patients. A grade 3 or 4 adverse event considered at least possibly related to treatment was seen in 11 (32%) patients at 4 mg and in 21 (60%) at 5.5 mg. Dose reductions were more frequent with 5.5 mg dose. Overall, the ixazomib with dexamethasone has good efficacy in relapsed myeloma, is well tolerated and with higher response rate at 5.5 mg, albeit with more toxicity. Randomized phase 2 trial of ixazomib and dexamethasone in relapsed multiple myeloma not refractory to bortezomib. Blood 2016 Oct 04;[Epub ahead of print], Kumar SK, LaPlant BR, Reeder CB, et al.

ABSTRACT Proteasome inhibitors have become an integral part of myeloma therapy. Considerable efforts have gone into optimizing this therapeutic approach in order to obtainmaximal proteasome inhibition with least toxicity. Ixazomib is the first oral proteasome inhibitor to enter the clinic and has been studied as a single agent as well as in various combinations. The current trial was designed to examine the efficacy and toxicity of combining two different doses of ixazomib (4 mg and 5.5 mg given weekly for 3 of 4 weeks) with 40 mg weekly of dexamethasone, in relapsed myeloma. Seventy patients were enrolled, 35 patients randomly assigned to each Ixazomib dose. Overall, 30 (43%, 95%CI: 31–55) of the patients achieved a confirmed partial response or better, with 31% achieving a response with 4 mg and 54% with 5.5 mg of ixazomib. The

10–11

AstraZeneca Lynparza

14

Sanofi Gaucher disease

19

Bristol-Myers Squibb Opdivo

20–21

Mylan Glivec Soliris Alexion

23

28

PRACTICEUPDATE HAEMATOLOGY & ONCOLOGY