Practice Update: Haematology & Oncology

HAEMATOLOGY

11

JOURNAL SCAN Inotuzumab ozogamicin for acute lymphoblastic leukaemia The New England Journal of Medicine Take-home message

• This was an open-label randomised phase III trial. The authors compared inotuzumab ozogamicin, an anti-CD22 antibody conjugated to calicheamicin, with standard chemotherapy in 326 patients with relapsed or refractory acute lymphoblastic leukaemia. The rate of complete remission was significantly higher in the inotuzumab ozogamicin vs standard-therapy group (80.7% vs 29.4%). Progression-free survival (PFS) and overall survival (OS) were both longer in the inotuzumab ozogamicin group compared with the standard-therapy group (PFS, 5.0 vs 1.8 months; OS, 7.7 vs 6.7 months). Veno-occlusive liver disease occurred more commonly in the inotuzumab ozogamicin group than the standard therapy group (11% vs 1%). • Inotuzumab ozogamicin therapy was superior to standard therapy in patients with acute lymphoblastic leukaemia; however, there was a higher risk of veno-occlusive liver disease associated with it. Dr Jeremy Jones Expert comment We are highlighting this article because of the focus the imprimatur of The New England Journal of Medicine will bring to this provocative study. It presents the reader with an avalanche of data, the comprehension of which may require an hour to dissect, and includes data only presented as supplementary. Otherwise, one may find oneself confused. This international study randomised previously treated ALL patients with more than 5% marrow blasts between the anti-CD22 antibody conjugated to calicheamicin, given alone, and one of three investigator- choice chemotherapy regimens, all based on anthracycline-cytarabine. The majority of patients (63–69%) had had only one prior regimen, and less than 20% had prior transplants. It is unclear why AML-type regimens were selected that excluded vincristine/prednisone, one of the most effective treatments for ALL. Something else a bit confusing is safety Table 3, which appears to report almost no fever or infection in either protocol arm. The actual adverse events are enumerated in Supplementary Table S1. Of the remissions achieved with the study antibody, 39 of 109 (36%) were CR by standard criteria and 49 were ‘CR with incomplete haematologic recovery.’ This may not be evident to the rapid reader. Median remission on both arms was short (4.6 v 3.1 months), with none beyond a year. Even among remission patients who proceeded to transplants (41% of the antibody arm; 11% of control), median remission was only 5.5 months. As was seen in CD33-calicheamicin studies, veno-occlusive disease was a serious toxicity, particularly among patients after transplant. Salvage chemotherapy, with or without transplant, has cured many patients after first relapse of ALL. Although there are no successes among patients given the control regimens chosen in this study, intensive salvage chemotherapy remains an option. The decision to choose inotuzumab alone, even as a bridge to transplant, is not made easier by the data in this study. Its profound effect on MRD assessed within a month of remission did not translate into prolonged time to leukaemia regrowth. It is unknown if occult extramedullary disease in any patient was responsible for relapse, as search for it was limited to patients with obvious EMD before enrolment. It would be interesting to have had follow-up MRD studies to help us learn why disease relapses so quickly after negative result. The future of this antibody is unclear. It would be unusual that an antibody alone can ablate relapsed leukaemia, and it may have a place in combination with salvage chemotherapy. Dr Isabel Cunningham is Adjuct Associate Research Scientist, Division of Hematology Oncology, Columbia University College of Physicians and Surgeons. Abstract

RESULTS Of the 326 patients who underwent randomisation, the first 218 (109 in each group) were included in the primary intention-to-treat analysis of complete remission. The rate of complete remission was significantly higher in the inotuzumab ozogamicin group than in the standard-therapy group (80.7% [95% confidence interval {CI}, 72.1 to 88.7] vs 29.4% [95% CI, 21.0 to 38.8], P < 0.001). Among the patients who had complete remission, a higher percentage in the inotuzumab ozogamicin group had results below the threshold for minimal residual disease (0.01% marrow blasts) (78.4% vs 28.1%, P < 0.001); the dura- tion of remission was longer in the inotuzumab ozogamicin group (median, 4.6 months [95% CI, 3.9 to 5.4] vs 3.1 months [95% CI, 1.4 to 4.9]; hazard ratio, 0.55 [95% CI, 0.31 to 0.96]; P = 0.03). In the survival analysis, which included all 326 patients, progression-free survival was significantly longer in the inotuzumab ozogamicin group (median, 5.0 months [95% CI, 3.7 to 5.6] vs 1.8 months [95% CI, 1.5 to 2.2]; hazard ratio, 0.45 [97.5% CI, 0.34 to 0.61]; P < 0.001); the median overall survival was 7.7 months (95% CI, 6.0 to 9.2) versus 6.7 months (95% CI, 4.9 to 8.3), and the hazard ratio was 0.77 (97.5% CI, 0.58 to 1.03) (P = 0.04). In the safety population, the most frequent grade 3 or higher nonhematologic adverse events with inotuzumab ozogamicin were liver-related. Veno-occlusive liver disease of any grade occurred in 15 patients (11%) who received inotuzumab ozogamicin and in 1 patient (1%) who received standard therapy. CONCLUSIONS The rate of complete remission was higher with inotu- zumab ozogamicin than with standard therapy, and a higher percent- age of patients in the inotuzumab ozogamicin group had results below the threshold for minimal residual disease. Both progression-free and overall survival were longer with inotuzumab ozogamicin. Veno- occlusive liver disease was a major adverse event associated with inotuzumab ozogamicin. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukaemia. N Engl J Med 2016 Jun 12;[EPub Ahead of Print], Kantarjian HM, DeAngelo DJ, Stelljes M, et al

METHODS In this phase 3 trial, we randomly assigned adults with re- lapsed or refractory acute lymphoblastic leukaemia to receive either inotuzumab ozogamicin (inotuzumab ozogamicin group) or standard intensive chemotherapy (standard-therapy group). The primary end points were complete remission (including complete remission with incomplete haematologic recovery) and overall survival.

BACKGROUND The prognosis for patients with acute lymphoblastic leukaemia is poor. We sought to determine whether inotuzumab ozogamicin, an anti-CD22 antibody conjugated to calicheamicin, results in better outcomes in patients with relapsed or refractory acute lymphoblastic leukaemia than does standard therapy.

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VOL. 1 • No. 2 • 2016