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ASH 2018: CAR-T
CAR T-Cell Therapy in Lymphomas and Acute Lymphoblastic Leukemia: Exciting Data From ASH 2018

Released: April 29, 2019

Expiration: April 27, 2020

Daniel J. DeAngelo
Daniel J. DeAngelo, MD, PhD
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CAR T‑cell therapy is an exciting new approach to the treatment of leukemia and lymphoma. Currently, the FDA has approved 2 CAR T‑cell therapies, both directed to CD19: tisagenlecleucel, for patients aged up to 25 years with acute lymphoblastic leukemia (ALL) that is refractory or in at least second relapse and for adult patients with relapsed/refractory (R/R) large B-cell lymphoma after 2 or more lines of therapy; and axicabtagene ciloleucel, also for adults with R/R large B-cell lymphoma after at least 2 lines of therapy. At ASH 2018, we saw important updates to the registration trials for these products, along with data on their postcommercial availability use.

Updates From ASH 2018 on CAR T-Cell Registration Trials
The FDA approved tisagenlecleucel for pediatric and young adult patients with R/R ALL based on the phase II ELIANA trial. At ASH 2018, Grupp and colleagues presented updated data from ELIANA on 79 patients infused with tisagenlecleucel. The ORR was 82%, and 98% achieved measurable residual disease negativity. The 12-month relapse-free survival was 76%, with most relapses occurring in the first year. Tisagenlecleucel was approved for adults with large B-cell lymphoma based on the phase II JULIET trial. The update on JULIET presented at ASH 2018 reported sustained response in the 99 patients from the main cohort who were infused, with an ORR of 54% and a stable 64% probability of being relapse free at 12 and 18 months.

We also saw a 2-year follow-up report of the ZUMA-1 trial, the results of which led to the FDA approval of axicabtagene ciloleucel for high‑grade B-cell lymphoma. The update reported an ORR of 83%, including 58% achieving CR. These are impressive data in patients with highly refractory disease.

“Real-World” Use of CAR T-Cell Therapies
ASH 2018 also included analyses on the commercially approved use of CAR T-cell therapies in patients meeting less stringent eligibility criteria (eg, older, worse performance status) than for the clinical trials, but who are still being treated in the large centers that participated in the early-phase trials. In an analysis of axicabtagene ciloleucel treatment reported by Nastoupil and colleagues, 165 patients with R/R aggressive B-cell lymphoma achieved comparable safety and efficacy results to the registration trial—a remarkable ORR of 79% at Day 30 and with 59% having ongoing responses at Day 100—despite that approximately one half of the patients would not have been eligible for the ZUMA‑1 trial. Similar results were reported by Jacobson and colleagues in a retrospective study of 76 patients with R/R aggressive B-cell lymphoma also treated with this agent. These data affirm that clinical benefit with these agents is not limited to patients meeting the narrow eligibility requirements for clinical trials.

Integration of CAR T-Cell Therapies Into Patient Care
With this growing body of evidence suggesting that CAR T-cell therapies should play an increasing role in the care of patients with ALL and aggressive B-cell lymphomas, which patients should we be considering for this approach?

I would recommend searching for an ongoing clinical trial of CAR T-cell therapy for any patient who is in first relapse of their disease (either ALL or aggressive B-cell lymphoma). If the patient is in second or later relapse or refractory to at least 2 lines of therapy—and meets the criteria for FDA-approved indications—then I would recommend looking for a center nearby that can provide the appropriate CAR T-cell therapy. Fortunately, these centers generally correspond to the transplant centers to which clinicians already refer their patients. In fact, many patients will have already received stem cell transplants at these centers and, therefore, are in the center’s system.

It is important to bear in mind that CAR T-cells are autologous, requiring harvesting of T-cells from the patient and 2‑4 weeks for production. Consequently, the patient needs to have some stability of disease or treatment options during that wait time. So, timely discussion of CAR T-cell therapy with patients and the treatment center is necessary rather than waiting until after a patient has failed multiple lines of therapy and their disease is getting out of control.

Regarding post–CAR T-cell management, although the center administering the CAR T-cell therapy will manage short-term toxicities (ie, cytokine-release syndrome, neurologic toxicity), referring clinicians should be aware that CD19-targeted CAR T-cell therapies are associated with the potential for B-cell aplasia that may require long‑term intravenous IgG administration.

Future Directions
CAR T-cell therapy is an exciting area of research. First are the efforts directed toward developing prepackaged “off-the-shelf” allogeneic CAR T-cells to avoid the challenges of generating autologous CAR T-cells from sick patients. At ASH 2018, there were data presented on the first allogeneic CAR directed against CD19 showing a manageable safety profile and evidence of preliminary efficacy in patients with R/R ALL.

Second are efforts to develop CAR T-cells directed against targets other than CD19 because some leukemia and lymphoma patients lose CD19 as a mechanism of resistance. Alternative targets include CD22 or even double targets, such as CD19 plus CD22; indeed, at ASH 2018 we saw a very early but interesting study on a bispecific CAR against CD19 and CD22.

Finally, there are also ongoing investigations to expand the use of CAR T-cell therapy into adult patients with R/R ALL, which is an exciting opportunity. At ASH 2018, the phase I ZUMA‑3 trial administered axicabtagene ciloleucel to adults with R/R ALL to determine the recommended phase II dosing and evaluate toxicity; early results were promising and this trial has now entered phase II testing.

Your Thoughts?
For which settings do you think CAR T-cell therapies offer the most promise? In what patient populations would you have concerns about using these products? Please share your thoughts in the comments box!

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