Rationales for Selecting CD19-Targeted Therapy in R/R B-Cell ALL – Cancer Therapy Advisor

Five real-life cases of adult patients with relapsed/refractory CD19-positiveB-cell acute lymphoblastic leukemia (ALL) were recently detailed in an articlein Blood along with the rationalesfor selecting CD19-directed CAR-T therapy or the CD3/CD19 bispecific antibody,blinatumomab, as the first CD19-targeted treatment approach for each patientcase.

While both blinatumomab and CD19-directed CAR-T therapy (ie,tisagenlecleucel in patients 25 years or younger) are approved by the US Foodand Drug Administration (FDA) for the treatment of relapsed/refractory B-cellALL, the mechanisms of action of these therapies are very different: the formerdrug activates T cells by linking them through their CD3 receptor to the CD19surface antigen on B cells, whereas CD19-directed CAR-T therapy uses autologousT cells that have been genetically modified to express the CD19 receptor.

Nevertheless, both treatment approaches are considered tolerable and potentiallycurative in the setting of relapsed/refractory B-cell ALL. Furthermore, it maybe possible to subsequently offer the alternative CD19-targeted treatment ifdisease progression occurs following treatment with either CD19-directed CAR-Ttherapy or blinatumomab. However, some patients will become ineligible for subsequenttreatment with the alternative approach due to loss of B-cell expression ofCD19.

Oncethe decision to use CD19-targeted immunotherapy to treat a patient withadvanced ALL has been made, the physician faces the challenge of selectingbetween blinatumomab and CAR T cells, the study authors noted, adding that itis crucial to weigh all considerations for each individual patient beforeselecting one immunotherapy over another.

Inthe patient cases highlighted in this article, multiple factors were consideredin making individualized treatment decisions.

Forexample, initial treatment with blinatumomab was selected for an older patientwith low-burden disease, given its FDA approval across all age groups, itslower associated risks of severe cytokine release syndrome and neurotoxicitycompared with CAR-T therapy, and its demonstrated efficacy in patients withlow-burden disease. Furthermore, because allogeneic hematopoietic stem celltherapy (allo-HCT) was planned for this patient who had a matched siblingdonor, another factor weighing in favor of blinatumomab was the avoidance of delaysassociated with CAR-T manufacturing.

Factorsassociated with selection of CD19-directed CAR-T therapy as the initialCD19-directed approach included the presence of extramedullary disease in the centralnervous system (CNS), as there is evidence supporting CNS penetration by CAR-Tcells, as well as promising antileukemic activity in patients with extramedullarydisease.

Inaddition, CAR-T therapy was preferred for a patient who experienced diseaseprogression following allo-HCT and was unlikely to receive a second allo-HCT,given evidence for long-lasting remissions even without consolidation allo-HCTfollowing treatment with CAR-T therapy.

Inthis context, the study authors stated that blinatumomab in this setting isbetter used as a bridging therapy rather than a definitivecurative treatment.

The study authors concluded that treatment with blinatumomab and CD19 CAR T cells holds promise in advanced ALL, allowing more patients to attain remission and possible cure with and without additional therapies. Both treatments have unique limitations and advantages, and the treating physician should be discerning when selecting treatment of each case.

Reference

Aldoss I, Forman SJ. How I treat adults with advanced acute lymphoblastic leukemia eligible for CD19-targeted immunotherapy.[published online March 12, 2020]. Blood. 2020;135:804-813. doi:10.1182/blood.2019002132

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Rationales for Selecting CD19-Targeted Therapy in R/R B-Cell ALL - Cancer Therapy Advisor

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