1. May, Brandon

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SAN DIEGO-Tisagenlecleucel, a CD19-targeted CAR T-cell therapy, was associated with sustained relapse-free survival and overall survival (OS) in children and young adults with relapsed/refractory acute lymphoblastic leukemia (ALL), according to an update of the ELIANA trial presented by Stephan A. Grupp, MD, PhD, at the 2018 ASH Annual Meeting (Abstract 895). He is Director of the Cancer Immunotherapy Program, Director of Translational Research for the Center for Childhood Cancer Research, and Medical Director of the Stem Cell Laboratory at Children's Hospital of Philadelphia.

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"We were looking to see that if pediatric ALL patients who go into remission following treatment with tisagenlecleucel were able to keep that remission," Grupp told Oncology Times. "And the answer was, it's pretty darn good. We're seeing two-thirds of the patients at 12 and 18 months remain in remission after they receive their initial remission from CAR T-cell therapy. The median follow-up is 2 years, which is pretty significant."


When asked what surprised him and his colleagues on the updated findings, Grupp stated that, from a toxicity standpoint, the most surprising finding was that they didn't find anything. "If you follow these patients for another year, you're not seeing these patients running into trouble," he added. "There is long-term toxicity that we knew about-particularly that, in the process of killing all the leukemia B cells, the bystander effect also gets rid of normal B cells. This results in the need for IV immunoglobulin. Some of these patients need this for a long period of time, but they can get it at home, and these patients don't get infections."


Study Details

Using data from the phase II ELIANA clinical trial of tisagenlecleucel, Grupp and colleagues analyzed overall response rate (ORR) in a total of 97 patients with >=5 percent leukemic blasts in bone marrow. All patients were aged >=3 years at time of screening and <=21 years at time of diagnosis (median age, 11 years (range, 3-24 years). Cryopreserved apheresed mononuclear cells, central production facilities, and a global supply chain were used to provide tisagenlecleucel to patients at 25 different treatment centers in 11 countries on four continents.


Two sites centrally manufactured tisagenlecleucel "by lentiviral transduction of autologous T cells with a vector encoding for a second generation 4-1BB anti-CD19 CAR and expanded ex vivo." An independent review committee assessed the primary outcome, which was comprised of an ORR within a 3-month period that was maintained for >=28 days. Additionally, the researchers assessed duration of remission (DOR), safety, OS, and cellular kinetics.


A total of 18 patients were not included in the updated analysis due to manufacturing failures and either death or adverse events (AEs) that prevented infusion. The majority of patients underwent lymphodepleting chemotherapy (n=76) followed by a single median tisagenlecleucel dose of 3.0x106 (range, 0.2-5.4x106) CAR-positive viable T cells/kg. All patients had >=3 months of follow-up data available for analysis and a median time from infusion to data cutoff of 24 months (range, 4.5-35 months). At time of enrollment, approximately 61 percent of the cohort had previously received hematopoietic stem cell transplant (SCT).


The majority of patients with a complete response or CRi (n=65) achieved minimal residual disease negativity within a 3-month period (98%). While the median DOR was not reached, a total of 29 patients had responses that were ongoing (maximum DOR, 29 months and ongoing). Relapse prior to additional anticancer treatment was observed in 19 patients, and mortality occurred in 13 of these patients. While in remission, eight patients underwent SCT, eight received anticancer therapy, and one discontinued treatment. The 18-month probability of relapse-free survival in these patients was 66 percent (95% CI, 52%-77%), whereas the 18-month probability of OS was 70 percent (95% CI, 58%-79%).


Although it was noted that the majority of patients (77%) experienced grade 3/4 cytokine release syndrome (CRS), all cases were reversible. Tocilizumab, a medication indicated for CRS, and care in the intensive care unit were required for CRS in 39 percent and 48 percent of patients, respectively.


"We learned with our very first pediatric patient how to manage CRS, and we understand the mechanisms with CRS and that the central molecular-interleukin 6-we know how to block that," Grupp added. "It can be very significant in patients with very high disease burden because the amount of T-cell proliferation it takes to get on top of all that leukemia is significant. The good news is that the T cells grow and put the patient in remission, but the bad news is that for about a week, you might be pretty sick. Fortunately, we can manage that."


Frequently reported grade 3/4 nonhematologic AEs that occurred in >15 percent of the cohort included neutropenia within 8 weeks of therapy infusion (body temperature >38.3[degrees]C, 62%), hypoxia (20%), and hypotension (20%). Grade 3 neurological events were reported in 13 percent of patients, and grade 3/4 thrombocytopenia and neutropenia that did not resolve by 28 days, yet most of the observed AEs were resolved to grade <=2 at 3 months. Post-infusion mortality was observed in 25 patients, with the majority of these deaths observed after 30 days (n=23; range, 53-859 days).


"With a single targeted therapy, there are some leukemia cells that try to evade that target, which is CD19," Grupp commented when asked about the study's limitations. "While two-thirds of patients remain in remission, most of the patients that do experience relapse do so because the leukemia learned how to hide CD19. So, that's something we need to fix." He also emphasized that this was a post hoc analysis that requires replication in larger trials.


"The amazing thing for me is that you treat multiple relapsed or who relapsed after transplant and are on death's door, you get them into remission, and these are kids...that get back to their lives," Grupp concluded. "They get back to doing everything they want. We're not seeing long-term functional impact of having CAR T-cell therapy in the same way in patients who've had a bone marrow transplant. It's actually the lack of side effects of tisagenlecleucel that's incredibly gratifying."


Brandon May is a contributing writer.