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CLINICAL NEWS However, she noted, progress in cell manufac- turing suggests that CAR products could be gener- ated for nearly all patients who need them. At the National Cancer Institute, for example, 94 percent of patients were able to receive manufactured cell products. “We will find a time where, at least from a technical standpoint, this product could be made for every child who would need it. The economics of it, I think, will still need to be demonstrated,” Dr. Mackall said. Inotuzumab Ozogamicin Inotuzumab ozogamicin, a CD22-directed antibody- drug conjugate, was approved as the first antibody- drug conjugate for adult patients with CD22-positive relapsed or refractory ALL. The decision was based on results from the phase III INO-VATE 1022 trial, reported Tanya Wroblewski, MD, clinical reviewer at the FDA. The CR rate in the inotuzumab arm was 36 percent, versus 17 percent in the investigator choice of chemotherapy arm. Duration of CR also was longer in the inotuzumab arm, at 8.0 months versus 4.9 months in the control arm. However, overall survival in the total number of patients enrolled and treated in the INO-VATE ALL study did not reach statistical significance, “which is surprising given the CR rate, MRD-negativity rate, and the number of patients who proceeded to subsequent transplantation in the inotuzumab arm,” Dr. Wroblewski added. “The antibody drug conjugate class of thera- peutics embodies the principle of Ehrlich’s magic bullet – something that cancer researchers have been working toward for many, many years,” Dr. Mackall said during her discussion of this anti-CD22 therapy. “There have been substantial technological improve- ments in engineering antibodies and in refining the chemistry needed to link the chemotherapy agent to the antibody,” she noted, which is resulting in more of these agents entering clinical trials. While inotuzumab ozogamicin showed “im- pressive” remission rates in adults with relapsed or refractory B-cell ALL, Dr. Mackall mentioned that her excitement over the new agent is tempered by toxicity concerns. The drug carries a boxed warning for hepatotoxicity, including hepatic veno-occlusive disease (VOD). In patients who received inotuzumab ozogamicin in the INO-VATE trial, 14 percent devel- oped VOD overall, and 23 percent who underwent subsequent allogeneic hematopoietic cell transplanta- tion (alloHCT) developed VOD. Previous experiences with a related compound, gemtuzumab ozogamicin, also raise concerns, she said. “[Gemtuzumab ozogamicin] previously similarly demonstrated activity in acute myeloid leukemia, but clinical benefit was diminished by the risk of VOD in those patients, many of whom go on to get alloHCT,” she said. NHL Axicabtagene Ciloleucel Axicabtagene ciloleucel was the second CAR T-cell therapy approved by the FDA in 2017, and it is indicated for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy. This includes adults with diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from FL, but is not indicated for ASHClinicalNews.org primary central nervous system (CNS) lymphoma, said Yvette Kasamon, MD, clinical reviewer at the FDA. Approval was based on results from the single- arm, multicenter ZUMA-1 trial, which enrolled more than 100 adult patients with aggressive B-cell NHL. Following conditioning with low-dose cytarabine and fludarabine, 72 percent of patients responded to axicabtagene ciloleucel, with a CR rate of 51 percent. “Only patients who achieved CR tended to have durable remissions. In patients with the best overall response of CR, the median duration of response was not reached after approximately eight months of follow-up,” Dr. Kasamon said. “In contrast, in patients who achieved only partial remission, the median duration of response was two months.” The overall risk-benefit ratio is favorable in the approved population, she added. However, as with tisagenlecleucel, this CAR T-cell therapy carries boxed warnings for CRS and CNS neurotoxicity, and is only available through a REMs. In ZUMA-1, 52 percent of patients experienced a serious AE, the most common of which (occurring in ≥10% of pa- tients) included febrile neutropenia CRS, encepha- lopathy, and infections. “This is a ‘living drug’ with significant side ef- fects,” noted Helen Heslop, MD, DSc (Hon), Dan L. Duncan Ch