Optimizing Chimeric Antigen Receptor T-Cell Therapy for Adults With Acute Lymphoblastic Leukemia

Noelle V. Frey, MD; Pamela A. Shaw, PhD; Elizabeth O. Hexner, MD; Edward Pequignot, MS; Saar Gill, MD, PhD; Selina M. Luger, MD; James K. Mangan, MD, PhD; Alison W. Loren, MD; Alexander E. Perl, MD; Shannon L. Maude, MD, PhD; Stephan A. Grupp, MD, PhD; Nirav N. Shah, MD; Joan Gilmore, BS; Simon F. Lacey, PhD; Jos J. Melenhorst, PhD; Bruce L. Levine, PhD; Carl H. June, MD; David L. Porter, MD


J Clin Oncol. 2020;38(5):415-422. 

In This Article

Abstract and Introduction


Purpose: The anti-CD19 chimeric antigen receptor T-cell therapy tisagenlecleucel (CTL019) has an 81% response rate in children with relapsed or chemotherapy refractory (r/r) B-cell acute lymphoblastic leukemia (ALL). Cytokine release syndrome (CRS) is a life-threatening treatment-related toxicity that limits the full therapeutic potential in adults. We report outcomes for adults with r/r ALL treated with an optimized CTL019 dosing and CRS management strategy.

Methods: Adults with r/r B-cell ALL received CTL019 in 1 of 2 trials. Patients received lymphodepletion followed by CTL019 as either a one-time infusion or fractionated infusions split over 3 days (day 1, 10%; day 2, 30%; day 3, 60%), which allowed for day 2 and day 3 doses to be held for early CRS. Total planned CTL019 dose varied with adaptive protocol modifications in response to efficacy and CRS toxicity.

Results: Thirty-five adults with r/r ALL received CTL019 in 1 of 3 dosing cohorts. The low-dose cohort (n = 9) received single or fractionated dosing and had manageable toxicity with a 33% complete remission (CR) rate. In the high-dose single infusion cohort, 3 of 6 patients with refractory CRS concurrent with culture-positive sepsis died, and 3 achieved CR. The 20 patients in the high-dose fractionated (HDF) cohort had a 90% CR rate and manageable CRS. The HDF cohort had the highest survival, with a 2-year overall survival of 73% (95% CI, 46% to 88%) and event-free survival of 49.5% (95% CI, 21% to 73%).

Conclusion: Fractionated dosing of CTL019 with intrapatient dose modification optimizes safety without compromising efficacy in adults with r/r ALL.


T cells engineered to express a chimeric antigen receptor (CAR) that targets CD19 have generated high remission rates in pediatric and adult patients with relapsed or chemotherapy refractory (r/r) acute lymphoblastic leukemia (ALL).[1–6] The immune activation on which this efficacy depends is also responsible for the life-threatening toxicity of cytokine release syndrome (CRS). CRS correlates with the activation and expansion of anti-CD19 CAR T cells and clinically manifests with fevers that can progress to life-threatening vasodilatory shock and capillary leak with hypoxic respiratory failure.[7] With efficacy clearly established, a better understanding of treatment-related toxicities and evaluation of CRS mitigation strategies are critical.

On August 30, 2017, the US Food and Drug Administration approved the first CD19-directed CAR T-cell therapy tisagenlecleucel (formerly CTL019) for the treatment of pediatric and young adult patients up to age 25 years with B-cell precursor ALL that is refractory or in second or greater relapse. We now report outcomes using CTL019 in 35 older adult patients with r/r ALL. Compared with the pediatric cohort, we have observed significant toxicity in adults, with 3 CRS-related deaths. We then modified the protocol to ask whether mitigation strategies, including a fractionated dosing scheme, could maintain high response rates with acceptable tolerability in adult patients with ALL.