Haematology+Oncology_News

Vol. 9 • No. 1 • 2016 • H aematology & O ncology N ews 13 ASH 2015

More complete cytogenetic responses at 12 months with radotinib than imatinib

Prasugrel does not reduce vaso- occlusive crises in sickle cell anemia BY BIANCA NOGRADY Frontline Medical News P latelet inhibitor prasugrel has failed to show a significant re- duction in the rate of vaso-oc- clusive crises events in children and adolescents with sickle cell anaemia, according to data presented at the annual meeting of the American Society of Haematology. The phase III randomised placebo- controlled trial of 341 children and adolescents (aged 2–17 years), known as the Determining Effects of Platelet Inhibition on Vaso-Occlusive Events (DOVE) trial – simultane- ously published in the New England Journal of Medicine – showed the rate of vaso-occlusive crises was 2.30 per person-year in the prasugrel group and 2.77 in the placebo group (rate ratio 0.83, 95% confidence interval 0.66-1.05, P = 0.12), with a slightly greater but still nonsignificant reduc- tion among the older patients aged 12–17 years. Treatment with prasugrel did not achieve any significant reductions in secondary outcomes of hospi- talisations for vaso-occlusive crises, red-cell transfusions, pain rate or intensity, analgesic use, or school absences, compared with placebo. Platelet reactivity, however, was significantly lower in the prasugrel group ( N Engl J Med 2015, Dec 8. doi: 10.1056/NEJMoa1512021). “Sickle cell anaemia is a hetero- geneous and complex disease in which platelet activation is only one of several mechanisms of vascular injury, which perhaps explains why prasugrel was ineffective,” wrote Dr Matthew M. Heeney of Dana- Farber/Boston Children’s Cancer and Blood Disorders Centre, and his coauthors. “However, the nonsignificant ef- fect of prasugrel in the oldest age group may suggest that platelet ac- tivation is relatively more important in these older patients, a hypothesis that is consistent with the fact that endothelial dysfunction in sickle cell disease is progressive.” Daiichi Sankyo and Eli Lilly funded the study. Several authors disclosed ties with Eli Lilly or other pharmaceu- tical companies. Three authors were employees of Eli Lilly, and one was an employee of Daiichi Sankyo.

twice-daily group, and 82% (66/81) in the imatinib 400 mg once-daily group. The rates of major molecular response at 12 months were significantly higher in patients re- ceiving radotinib 300 mg b.i.d. (52%, P = 0.0044) and radotinib 400 mg b.i.d. (46%, P = 0.0342), compared with imatinib (30%), Dr Kwak reported at the annual meeting of the American Society of Haematology in Orlando. Among responders, the median times to major molecular response were shorter on radotinib 300 mg b.i.d. (5.7 months) and radotinib 400 mg b.i.d. (5.6 months) than on imatinib (8.2 months). The MR 4.5 rates by 12 months were also higher for both radotinib 300 mg b.i.d. (15%) and 400 mg b.i.d. (14%), compared with imatinib (9%). The complete cytogenetic response rates by 12 months were 91% for radotinib 300 mg b.i.d. (P = 0.0120), compared with imatinib (77%). None dyspnea, delirium, and prolonged thrombocyto- penia and all completely resolved. Both patients had much higher serum levels of interleukin-6 than the other patients, he noted. Both patients also received the highest dose level of anti-BCMA CAR T cells. Going forward, that dose will now only be administered to pa- tients with less than 50% bone marrow plasma cells, Dr Kochenderfer said. Other responses among the 12 patients treated thus far include 1 transient very good partial re- sponse of 8-week duration, 1 transient partial response lasting 2 weeks, and 8 responses of stable disease. While three new drugs (elotuzumab, dara- tumumab, ixazomib) were approved for the treatment of multiple myeloma in the month of November alone, this is early days for CAR T-cell therapy in multiple myeloma. “Almost all of the CAR T-cell work has been in B-cell malignancies, acute lymphocytic leukae- mia, and chronic lymphocytic leukaemia, so is this the right antigen, we don’t know? Is this the right construct, we don’t know? But there’s clearly activity and that is very exciting,” session comod- erator Dr David P. Steensma of the Dana-Farber Cancer Institute in Boston, said in an interview. Dana-Farber is conducting a CAR T cell trial in myeloma using a different target and NKG2D ligands. Other centres are also using CAR T cells with different targets. “So maybe other targets would have different results and a better safety profile,” he added. BCMA is an appropriate target for CAR T cell therapy for multiple reasons, Dr Kochenderfer said. Multiple myeloma is still an incurable dis- ease and BCMA, a member of the tumour necro- sis factor superfamily, is uniformly expressed in 60% to 70% of cases. Preclinical studies by the team also show that BCMA is not detectable in normal human tis- sues, but is selectively expressed only in bone marrow, lymphoid organs, and organs known to The rates of major molecular response at 12 months were significantly higher in patients receiving radotinib 300 mg b.i.d. and radotinib 400 mg b.i.d., compared with imatinib.

of the patients in the study had progressed to accelerated phase or blast crisis at 12 months. Drug discontinuation due to adverse events (AEs) or laboratory abnormalities occurred in 9% of patients on radotinib 300 mg b.i.d., 20% on radotinib 400 mg b.i.d., and 6% on imatinib. The major side effects included grade 3/4 thrombocytopenia in 16% of patients receiving radotinib 300 mg b.i.d., 14% on radotinib 400 mg b.i.d., and 20% receiving imatinib. Grade 3/4 neutropenia occurred in 19%, 24%, and 30% for radotinib 300 mg b.i.d., 400 mg b.i.d., and imatinib, respectively. Overall, grade 3/4 nonlaboratory AEs were uncommon in all groups. The most common nonlaboratory AEs in the radotinib groups were skin rash (about 33% in both), nausea/vomiting (about 23% in both), headache (19% and 31%), and pruritus (19% and 30%). In the imatinib group, the most common adverse events were oedema (35%), myalgia (28%), nausea/vomiting (27%), and skin rash (22%). Dr Kwak had no relevant disclosures. Some of his colleagues received research funding from IL-YANG Pharmaceutical Co. and Alexion Pharmaceuticals. have plasma cells in their lamina propria and by plasma cells and a small fraction of B cells. The investigators genetically modified autolo- gous T cells to express an anti-BCMA CAR and ligated it into a replication-incompetent gamma retrovirus. The T cells were stimulated with the anti-CD3 monoclonal antibody OKT3 before transduction, with the entire culture process tak- ing 9 days from start to finish. T cells expressing this CAR recognize BCMA with great specificity, Dr Kochenderfer observed. The 12 patients received 300 mg/m 2 of cyclo- phosphamide and 30 mg/m 2 of fludarabine daily for 3 days before a single infusion of anti-BCMA CAR at dose levels of 0.3 x 10 6 to 9 x 10 6 T cells/ kg. All patients had at least 3 prior therapies and normal organ function. Five had amyloid light chain only, 4 had immunoglobulin gamma disease, and 4 patients, including the complete responder, had immunoglobulin alpha disease. It’s unclear why only a few patients responded to the CAR T cells, but dose level was likely a big factor and there is a lot of patient variability with T-cell therapies, Dr Kochenderfer said at a press briefing. “I wish we knew exactly why some patients respond and some don’t,” he added. “The CAR T cells have shown remarkable activity against re- ally previously refractory diseases like acute lym- phocytic leukaemia,” noted Dr George Daley of Harvard Medical School, Boston, in an interview at the meeting. “There’s been a lot of excitement that maybe we can extend the principles that work in leukaemia to other types of diseases.” The study is still ongoing and accruing patients, but a multicentre trial is also being initiated in my- eloma with Bluebird Bio using “a closely related, but slightly different CAR,” Dr Kochenderfer said. leukaemia, so is this the right antigen, we don’t know? Is this the right construct, we don’t know? But there’s clearly activity and that is very exciting. Almost all of the CAR T-cell work has been in B-cell malignancies, acute lymphocytic leukaemia, and chronic lymphocytic

BY MARY JO DALES Frontline Medical News

R adotinib was associated with significantly higher complete cytogenetic responses and major molecular responses than imatinib was at a minimum 12 months of follow-up in a randomised, open-label, phase III clinical trial of patients with newly diagnosed chronic myeloid leukaemia-chronic phase (CML-CP). Radotinib, an investigational BCR-ABL1 ty- rosine kinase inhibitor developed by IL-YANG Pharmaceuticals, is approved in Korea for the treatment of CML-CP in patients who have failed prior TKIs. Dr Jae-Yong Kwak of Chonbuk National Uni- versity Medical School and Hospital, Jeonju, South Korea, and his colleagues randomised 241 patients to either radotinib 300 mg twice daily (n = 79), radotinib 400 mg twice daily (n = 81), or imatinib 400 mg once daily (n = 81). All three study groups were balanced in regard to baseline age, gender, race, and Sokal risk score. At a minimum follow-up of 12 months, the proportions of patients receiving a study drug were 86% (69/79) in the radotinib 300 mg twice- daily group, 72% (58/81) in the radotinib 400 mg C himeric antigen receptor (CAR) T cells tar- geting BCMA eradicated myeloma cells in a patient with a heavy burden of chemotherapy- resistant multiple myeloma. The patient had received three prior myeloma therapies and relapsed with myeloma making up more than 90% of his bone marrow cells just 3 months after autologous transplant. CD138-positive plasma cells were completely absent, however, one month after infusion of CAR T cells directed against the B-cell maturation anti- gen (BCMA), and remain undetectable 14 weeks after infusion. “We have demonstrated for the first time that CAR T cells can have powerful activity against measurable multiple myeloma,” Dr James N. Kochenderfer of the National Cancer Institute in Bethesda, Maryland, said at the annual meeting of the American Society of Haematology. A second patient, who had five prior lines of myeloma therapy and myeloma in 80% of his bone marrow cells, also experienced a dramatic reduction in myeloma, resulting so far in a partial response. The patient has returned to full-time work and myeloma cells continue to decrease 6 weeks after infusion. The two ongoing responses, however, were as- sociated with the most severe clinical signs of cytokine release syndrome in the late-breaking abstract study (LBA-1), Dr Kochenderfer said. The complete responder experienced cytokine release toxicities including fever, tachycardia, hy- potension, elevated liver enzymes, and elevated creatinine kinase that resolved. The patient was also platelet transfusion-dependent for 9 weeks after infusion and a baseline absolute neutrophil count of less than 500 microliters remained at that level for 40 days after infusion. All symptoms resolved within two weeks, he said. The ongoing partial responder experienced fe- ver, tachycardia, hypotension, acute kidney injury, BY PATRICE WENDLING Frontline Medical News

First shot across the bow for CAR T cells in multiple myeloma

By Prof Osaro Erhabor via Wikimedia Commons, Creative Commons license.