PracticeUpdate: Haematology & Oncology

HAEMATOLOGY

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Ibrutinib effective for patients with relapsed or refractory chronic lymphocytic leukaemia with 17p deletion Comment by Isabel Cunningham, MD W ith our editors’ dedication to highlighting practice-changing trials for our readers, we point to this work detailing 2-year median

JOURNAL SCAN Daratumumab, bortezomib, and dexamethasone for multiple myeloma The New England Journal of Medicine Take-home message • This was a multicenter, randomized, open-label, phase III trial designed to compare the combination of daratumumab, bortezomib, and dexamethasone with that of bortezomib and dexamethasone in 498 patients with relapsed/ refractory multiple myeloma. Patients in the daratumumab arm had significantly longer progression-free survival compared with those who received bortezomib and dexamethasone alone (PFS, 7.2 months, vs NR; HR, 0.39 for Vd and BVd, respectively). Grade 3 or higher thrombocytopenia, neutropenia, and infusion reactions were all more common in the daratumumab group; however, only 7.4% of patients discontinued treatment due to adverse events. • Daratumumab with bortezomib and dexamethasone led to significantly increased progression-free survival, but also resulted in more frequent adverse events compared with bortezomib/dexamethasone alone. Abstract

and other adverse events are enumerated which should familiarise doctors with this inhibitor of Bru- ton’s tyrosine kinase, that is now being incorporated in upfront therapy protocols for

follow-up of open-label ibrutinib treatment of re- lapsed/refractory del17p CLL, for which there has been no effective therapy to date. Susan O’Brien shepherded a 40-site international study with rigor- ous requirements of central review, regular CT scans, and confirmation of response by two CTs 3 months apart. The 83% response rate and estimated 2-year PFS of 63% and OS 75% are noteworthy. Infectious

this difficult form of CLL. Dr Cunnigham is Adjunct Associate Research Scientist, Division of Hematology Oncology, Columbia University College of Physicians and Surgeons, New York.

daratumumab group than in the control group (82.9% vs 63.2%, P<0.001), as were the rates of very good partial response or better (59.2% vs 29.1%, P<0.001) and complete response or better (19.2% vs 9.0%, P=0.001). Three of the most common grade 3 or 4 adverse events reported in the daratumumab group and the control group were thrombocytopenia (45.3% and 32.9%, respectively), anemia (14.4% and 16.0%, respectively), and neutropenia (12.8% and 4.2%, respectively). Infusion-re- lated reactions that were associated with daratumumab treatment were reported in 45.3% of the patients in the daratumumab group; these reactions were mostly grade 1 or 2 (grade 3 in 8.6% of the patients), and in 98.2% of these patients, they occurred during the first infusion. CONCLUSIONS Among patients with re- lapsed or relapsed and refractory multiple myeloma, daratumumab in combination with bortezomib and dexamethasone resulted in significantly longer progres- sion-free survival than bortezomib and dexamethasone alone and was associ- ated with infusion-related reactions and higher rates of thrombocytopenia and neutropenia than bortezomib and dexa- methasone alone. Daratumumab, bortezomib, and dexamethasone for multiple myeloma . N Engl J Med 2 016 Aug 25;375:754-766, Palumbo A, Chanan-Khan A, Weisel K, et al.

BACKGROUND Daratumumab, a human IgGκ monoclonal antibody that targets CD38, induces direct and indirect antimyeloma activity and has shown substantial efficacy as monotherapy in heavily pretreated pa- tients with multiple myeloma, as well as in combination with bortezomib in patients with newly diagnosed multiple myeloma. METHODS In this phase 3 trial, we randomly assigned 498 patients with relapsed or relapsed and refractory multiple myeloma to receive bortezomib (1.3 mg per square meter of body-surface area) and dexa- methasone (20 mg) alone (control group) or in combination with daratumumab (16 mg per kilogram of body weight) (dara- tumumab group). The primary end point was progression-free survival. RESULTS A prespecified interim analysis showed that the rate of progression-free survival was significantly higher in the dara- tumumab group than in the control group; the 12-month rate of progression-free sur- vival was 60.7% in the daratumumab group versus 26.9% in the control group. After a median follow-up period of 7.4 months, the median progression-free survival was not reached in the daratumumab group and was 7.2 months in the control group (hazard ratio for progression or death with daratumumab vs control, 0.39; 95% confi- dence interval, 0.28 to 0.53; P<0.001). The rate of overall response was higher in the

Ibrutinib for patients with relapsed or refractory chronic lymphocytic leukaemia with 17p deletion (RESONATE-17): a phase 2, open-label, multicentre study Lancet Oncology Take-home message • The authors in this multicenter, single-arm, open-label study evaluated the safety and efficacy of ibrutinib in 145 patients with relapsed or refractory del17p chronic lymphocytic leukemia (CLL). Overall response rate at 27.6 months was 83%. Additionally, 2-year progression-free and overall survivals were 63% and 75%, respectively. Grade 3 or worse infection rate was 30%. • The authors conclude that ibrutinib offers significant clinical benefit in the most difficult-to-control CLL subgroup, warranting continued study to better establish its position in treatment algorithms. Abstract

JOURNAL SCAN Rituximab in B-lineage adult acute lymphoblastic leukaemia The New England Journal of Medicine Take-home message • This was an international, multicenter, randomized trial that assessed whether the addition of rituximab to standard chemotherapy results in improved event- free survival. The study enrolled 209 patients with CD20-positive, Ph-negative acute lymphoblastic leukemia. The addition of rituximab resulted in higher rates of 2-year event-free survival compared with standard therapy (65% vs 52% for rituximab and control groups, respectively). There was a trend toward prolonged overall survival in the rituximab-treated group (2-year OS, 71% vs 64%; P = 0.1). The addition of rituximab did not result in significantly more severe adverse events. • The results of this study suggest that the addition of rituximab to standard chemotherapy safely improves the survival outcomes for patients with CD20- positive, Ph-negative acute lymphoblastic leukemia. Abstract

review committee assessment; 119 patients (83%, 95% CI 76–88) had an overall response according to investigator assessment. In an extended analysis with median follow-up of 27.6 months (IQR 14.6–27.7), the investigator-assessed overall response was reported in 120 patients (83%, 95% CI 76–89). 24-month progression-free survival was 63% (95% CI 54–70) and 24-month overall survival was 75% (67–81). Sustained haematological improvement was noted in 72 (79%) of 91 patients with any baseline cytopenia. No clinically relevant changes were noted from baseline to 6 months or 24 months in IgA (median 0.4 g/L at baseline, 0.6 g/L at 6 months, and 0.7 g/L at 24 months), IgG (5.0 g/L, 5.3 g/L, and 4.9 g/L), or IgM (0•3 g/L at each timepoint) concentrations. Common reasons for treatment discontinu- ation were progressive disease in 34 (24%) patients and adverse events, unacceptable toxicity, or death in 24 (17%) patients. Major bleeding occurred in 13 (9%) patients (11 [8%] grade 3–4). Grade 3 or worse infections occurred in 43 (30%) patients, including pneumonia in 19 (13%) patients. In the extended analysis, 38 patients died, 18 as a result of adverse events (four pneumonia, three chronic lymphocytic leukaemia, two Richter’s syndrome, two sepsis, and one each of acutemyocardial infarction, septic shock, encepha- lopathy, general deterioration in physical health, abnormal hepatic function, myocardial infarction, and renal infarction). INTERPRETATION A high proportion of patients had an overall response to ibrutinib and the risk:benefit profile was favourable, providing further evidence for use of ibrutinib in the most difficult subset of patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma. Ibrutinib represents a clinical advance in the treatment of patients with del17p chronic lymphocytic leukaemia and has been incorporated into treatment algorithms as a primary treatment for these patients. Lancet Oncol 2016 Sep 13;[Epub ahead of print], O’Brien S, Jones JA, Coutre SE, et al

BACKGROUND The TP53 gene, encoding tumour suppres- sor protein p53, is located on the short arm of chromo- some 17 (17p). Patients with 17p deletion (del17p) chronic lymphocytic leukaemia have poor responses and survival after chemoimmunotherapy. We assessed the activity and safety of ibrutinib, an oral covalent inhibitor of Bruton’s tyrosine kinase, in relapsed or refractory patients with del17p chronic lymphocytic leukaemia or small lympho- cytic lymphoma. METHODS We did a multicentre, international, open-label, single-arm study at 40 sites in the USA, Canada, Europe, Australia, and New Zealand. Patients (age ≥18 years) with previously treated del17p chronic lymphocytic leukaemia or small lymphocytic lymphoma received oral ibrutinib 420 mg once daily until progressive disease or unacceptable toxicity. The primary endpoint was overall response in the all-treated population per International Workshop on Chronic Lymphocytic Leukaemia 2008 response criteria modified for treatment-related lymphocytosis. Preplanned exploratory analyses were progression-free survival, overall survival, sustained haematological improvement, and immunological improvement. Patient enrolment is complete, but follow-up is ongoing. Treatment discontinu- ation owing to adverse events, unacceptable toxicity, or death were collected as a single combined category. FINDINGS Between Jan 29, 2013, and June 19, 2013, 145 pa- tients were enrolled. The all-treated population consisted of 144 patients with del17p chronic lymphocytic leukaemia or small lymphocytic lymphoma who received at least one dose of study drug, with a median age of 64 years (IQR 57– 72) and a median of two previous treatments (IQR 1–3). At the prespecified primary analysis after a median follow-up of 11•5 months (IQR 11.1–13.8), 92 (64%, 95% CI 56–71) of 144 patients had an overall response according to independent

control group. After a median follow-up of 30 months, event-free survival was longer in the rituximab group than in the control group (hazard ratio, 0.66; 95% confidence interval [CI], 0.45 to 0.98; P=0.04); the es- timated 2-year event-free survival rates were 65% (95% CI, 56 to 75) and 52% (95% CI, 43 to 63), respectively. Treatment with rituximab remained associated with longer event-free survival in a multivariate analy- sis. The overall incidence rate of severe adverse events did not differ significantly between the two groups, but fewer al- lergic reactions to asparaginase were observed in the rituximab group. CONCLUSIONS Adding rituximab to the ALL chemotherapy protocol improved the outcome for younger adults with CD20- positive, Ph-negative ALL. Rituximab in B-lineage adult acute lymphoblastic leukemia. N Engl J Med 2016;375:1044-1053, Maury S, Chevret S, Thomas X, et al.

BACKGROUND Treatment with rituximab has improved the outcome for patients with non-Hodgkin’s lymphoma. Patients with B- lineage acute lymphoblastic leukemia (ALL) may also have the CD20 antigen, which is targeted by rituximab. Although single- group studies suggest that adding rituxi- mab to chemotherapy could improve the outcome in such patients, this hypothesis has not been tested in a randomized trial. METHODS We randomly assigned adults (18 to 59 years of age) with CD20-positive, Philadelphia chromosome (Ph)-negative ALL to receive chemotherapy with or without rituximab, with event-free survival as the primary end point. Rituximab was given during all treatment phases, for a total of 16 to 18 infusions. RESULTS From May 2006 through April 2014, a total of 209 patients were enrolled: 105 in the rituximab group and 104 in the

VOL. 1 • No. 4 • 2016