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Leukemias
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Over the past year, several new drugs, including blinatumomab, a bispecific T-cell engaging (BiTE) antibody, which binds simultaneously to CD3-positive cytotoxic T-cells and to CD19-positive B-cells, enabling the patient’s T-cells to recognize and eliminate CD19-positive lymphoblasts, have been licensed in an effort to induce sustainable second and subsequent remissions for patients with relapsed/refractory ALL.54 Inotuzumab ozagamicin, an anti-CD22 antibody conjugated to calicheamicin, was approved after it was found to accord MRD negativity with improved OS, which was improved further by allo-SCT.55 Tisagenlecleucel, an adoptive immunotherapy using autologous T-cells genetically engineered to express a CAR, was approved in 2017 for younger patients with relapsed/refractory ALL after it was noted to confer 70–90% response rates.56,57 As with all CAR T-cell therapy, rapid and durable responses occur but are often associated with significant acute toxicities, which can be severe and even fatal. Cytokine release syndrome is the most common side effect, affecting over 50% of patients, and ranges from low-grade constitutional symptoms to life-threatening, multi-organ failure. The second most common acute toxicity is neurotoxicity, comprising confusion, delirium, seizures, and encephalopathy (termed CAR T-cell related encephalopathy syndrome).58
Acute Lymphoblastic Leukaemia
Published in Tariq I. Mughal, Precision Haematological Cancer Medicine, 2018
Perhaps the most palpable enthusiasm follows the US Food and Drug Administration’s (FDA) approval of tisagenlecleucel (Novartis), an adoptive immunotherapy using autologous T-cells genetically engineered to express a chimeric antigen receptor (CAR), in August 2017, for patients up the age of 25 years of age with relapsed or refractory ALL. Like all CAR T-cell therapy, rapid and durable responses are noted, but often associated with significant acute toxicities, which can be severe, and even fatal. Indeed, in September 2017, the USFDA placed a full hold on two phase I studies investigating an allogeneic CAR T-cell therapy (Cellectis). Cytokine release syndrome is the most common side effect, affecting over 50% of patients, and ranges from low-grade constitutional symptoms to life-threatening, multi-organ failure. The second most common acute toxicity is neurotoxicity, comprising of confusion, delirium, seizures and encephalopathy (termed CAR T-cell related encephalopathy syndrome). Despite the serious toxicity, there remains much current interest in developing this immunotherapy approach, not only for B-cell ALL but also for a variety of other haematological and non-haematological malignancies. In this regard, multidisciplinary guidelines, such as those proposed by the MD Anderson Cancer Center (Houston, Texas), for monitoring and managing such serious adverse effects are now being integrated in treatment algorithms.
Immunomodulatory Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
CAR-T cells target the surface antigens of malignant cells in an MHC-independent manner, thus tumor antigen escape by down-regulation of MHC molecules is of no consequence. The majority of clinical trials that have been undertaken with CAR-T therapies have been in the hematological setting. For example, anti-CD19 CAR-T cells have been the most studied in the clinic as CD19 expression is restricted to healthy B cells, their precursors, and to malignant B cells. The most advanced clinical trials, including those completed for approved therapies, have evaluated anti-CD19 CAR-T cells for the treatment of relapsed and refractory B-cell malignancies, such as Chronic Lymphoblastic Leukemia (CLL). In one of the initial studies at the University of Pennsylvania (USA), it was reported that two of the three enrolled patients experienced rapid and complete remission during the first six months. Crucially, these patients had already exhausted all other treatment options. A follow-up study of these patients revealed that they maintained a continued CR (complete response) for over five years with B-cell aplasia, suggesting that infused CAR-T cells can persist are administration. This result, along with another success in clinical trials involving young adults, solidified the interest of pharmaceutical companies such as Novartis in commercializing CAR-T therapies, and led to the approval of tisagenlecleucel (KymriahTM) for the treatment of B-cell Acute Lymphoblastic Leukemia (ALL) in patients up to 25 years old with refractory or relapsed disease. Later, an objective response rate of 53.1% was observed in a clinical trial of adult patients with relapsed/refractory DLBCL. Based on these results, in 2017 tisagenlecleucel became the first FDA-approved treatment to include a gene therapy step. The same year, the FDA granted approval to a second CAR-T therapy, axicabtagene ciloleucel (YescartaTM), developed by Kite Pharma for the treatment of patients with relapsed/refractory DLBCL. The approval was based on clinical studies demonstrating an objective response rate for axicabtagene ciloleucel of 82%.
Axicabtagene ciloleucel for the treatment of relapsed or refractory follicular lymphoma
Published in Expert Review of Anticancer Therapy, 2022
Tisagenlecleucel (Kymriah, Novartis) was evaluated in the phase 2 ELARA trial in adult patients with relapsed or refractory FL who have failed at least two prior lines of therapy [33]. ORR and CR rates were 86% and 69%, respectively, while at a median follow-up of 16.9 months, median DOR, PFS, and OS were not reached (1-year PFS was 67%). No patients experienced grade ≥3 CRS, and only 3% experienced grade ≥3 neurotoxicity. Based on these favorable results, tisagenlecleucel received accelerated FDA approval in May 2022 for use in relapsed or refractory FL in patients who have failed at least 2 prior lines of therapy. Although a direct comparison of tisagenlecleucel and axicabtagene ciloleucel has not been evaluated in a clinical trial, cross-trial comparison suggests that the former may be associated with a more favorable toxicity profile but inferior effectiveness. Individual aspects pertaining to the biochemistry, mechanism of action, efficacy, and toxicities of tisagenlecleucel and axicabtagene ciloleucel are discussed below.
Personalized patient care with aggressive hematological malignancies in non-responders to first-line treatment
Published in Expert Review of Precision Medicine and Drug Development, 2021
Katsuhiro Miura, Noriyoshi Iriyama, Yoshihiro Hatta, Masami Takei
Currently, tisagenlecleucel, a CD19-directed CAR-T product, is widely approved for patients with refractory B-ALL and aged ≤25 years. Engineered T-cells express CAR, which binds to CD19, and they have activatory domains of a CD3-zeta and costimulatory domain of 4-1BB. In a pivotal nonrandomized phase 2 study, 75 B-ALL children and young adults who did not respond to the treatment or relapsed two or more times received a single infusion of tisagenlecleucel. Within three months, their overall remission rate was 81%. One-year event-free survival (EFS) and OS rates were 50% and 76%, respectively. The significant toxicities associated with tisagenlecleucel were cytokine release syndrome and neurological toxicities [49]. To date, an increasing number of patients with refractory B-ALL were treated with tisagenlecleucel in clinical practice, and such real-world data show comparable efficacies and manageable toxicities [50].
Cost utility analysis of tisagenlecleucel vs salvage chemotherapy in the treatment of relapsed/refractory diffuse large B-cell lymphoma from Singapore’s healthcare system perspective
Published in Journal of Medical Economics, 2020
Boon Piang Cher, Kar Yee Gan, Mohamed Ismail Abdul Aziz, Liang Lin, William Ying Khee Hwang, Li Mei Poon, Kwong Ng
Patients were assumed to receive either tisagenlecleucel or salvage chemotherapy. Treatment with tisagenlecleucel starts with obtaining a patient’s T cells through leukapheresis. The harvested cells would be sent to an overseas manufacturing facility for enrichment and activation. The entire process takes at least 3–4 weeks before infusion of final product could take place. During this period, patients require bridging chemotherapy to stabilize the disease. Prior to the infusion, patients would also receive lymphodepleting therapy to create a favorable immune environment for CAR-T persistence. However, a small proportion of patients could experience deaths (10%) or other events (23%) such as manufacturing failures and adverse events during the manufacturing time lapse. We assumed that these patients would have undergone leukapheresis and some of them would have received bridging chemotherapy (50%) or lymphodepleting therapy (50%) but were no longer eligible for tisagenlecleucel infusion in the model to reflect real-life clinical practice. Patients who remained alive following infusion failure would accrue outcomes and costs similar to those who were treated with chemotherapy instead. About 6.3% of patients who were successfully infused with tisagenlecleucel did not have a response and underwent SCT in JULIET trial; this was also accounted for in the decision tree. As their OS and progression free survival (PFS) results were not reported separately, this group of patients were assumed to achieve the same outcomes as the overall trial population.