Alexander E. Perl, MD, associate professor of medicine, University of Pennsylvania, Perelman School of Medicine, discusses the promise of using chimeric antigen receptor (CAR) T cells for the treatment of patients with pediatric leukemia.

CAR T-cell therapy has made a significant impact in pediatric acute lymphoblastic leukemia (ALL), and Perl hopes that similar success will be seen with this approach in pediatric acute myeloid leukemia (AML). Although this therapy has demonstrated significant activity, it also has substantial toxicity that needs to be mitigated, Perl adds. Therefore, it is important to understand the toxicity profile of CAR T cells and to develop a plan to deal with adverse events. The biggest challenge with manufacturing an effective CAR T cell in AML is the fact that AML blasts are very similar to normal elements of the bone marrow that are critical to hematopoiesis. However, investigators are hopeful that this challenge can be overcome in time.

At the 2018 ASH Annual Meeting, data were presented demonstrating the sustained efficacy of this therapy in pediatric ALL. For example, after a long-term follow-up, the CD19-directed CAR T-cell therapy tisagenlecleucel (Kymriah) showed durable rates of relapse-free survival and overall survival at 24 and 18 months, respectively, for pediatric and young adult patients with relapsed or refractory ALL.

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Alexander E. Perl, MD, associate professor of medicine, University of Pennsylvania, Perelman School of Medicine, discusses the promise of CAR T cells in the treatment of pediatric leukemia.

Dr. Perl on CAR T Cells in Pediatric Leukemia

Alexander E. Perl, MD, an assistant professor of medicine at the University of Pennsylvania, discusses recent advances made in the treatment of patients with acute myeloid leukemia (AML).

Everything is changing rapidly in AML, but it was not too long ago that patients were treated with a “one-size-fits-all” approach, Perl says. All patients deemed fit for intensive chemotherapy would receive the same regimen, and all patients deemed unfit would receive the same low-dose regimen to avoid toxicity.

The recent implementation of targeted agents allows for a more effective treatment approach in patients with certain genomic or historical characteristics in their disease. It is now known that 

 is a targetable mutation, he explains, and 2 drugs have recently been approved by the FDA for those with 

This paradigm shift has all happened within the past year, Perl explains, and he expects at least 4 more drugs to receive FDA approval in the near future. Although researchers have known the biology of the disease for a while, it has taken a long time to apply that knowledge to the development of more effective treatments that can improve patient outcomes.

Alexander E. Perl, MD, assistant professor of medicine, University of Pennsylvania, discusses the evolving treatment landscape in acute myeloid leukemia.

Dr. Perl on Evolving Treatment in AML

Alexander E. Perl, MD, associate professor of medicine, University of Pennsylvania, discusses remaining challenges with chimeric antigen receptor (CAR) T-cell therapy.

Perl says that the big problems are figuring out how to make CAR T-cell therapy safe for patients, and to make it more widely available. This has been challenging due to the rate of cytokine release syndrome, which can be traumatic and life-threatening. The neurotoxicity is unpredictable, and there currently is no appropriate therapy to fully mitigate its complications. The products can be associated with cerebral edema where the neurotoxicity can be quite dangerous, Perl adds.

Additionally, Perl says that clinicians are still trying to figure out the best supportive care practices for managing patients who receive CAR T-cell therapy. This involves determining how to optimize patients to reduce the risk of toxicities.

Lastly, Perl says that achieving durable responses in each patient remains a challenge. There are patients who receive CAR T-cell therapy and respond, then lose that response. There are also patients who never get a response in the first place.

Dr. Perl on Remaining Challenges with CAR T-Cell Therapy

Alexander E. Perl, MD, associate professor of medicine, University of Pennsylvania, discusses potential chimeric antigen receptor (CAR) T-cell therapies in hematologic malignancies.

CAR T-cell therapy is being explored in acute myeloid leukemia (AML), but investigators have not determined which antigen is best to target, says Perl. There were data presented at the 2017 ASH Annual Meeting looking at CD123 and CD33-directed CARs, and other antigens that are on AML blasts. Perl says that it is hard to define an epitope to design a CAR against that is unique to the leukemia, and that is not shared with normal tissue or hematopoietic cells.

There is interest in other forms of B-cell lymphoma other than diffuse large B-cell lymphoma for which there is already a CAR T-cell therapy approval. Additionally, there is also interest in developing CAR T-cell therapies for multiple myeloma, says Perl.

Alexander E. Perl, MD, associate professor of medicine, University of Pennsylvania, discusses potential chimeric antigen receptor (CAR) T-cells in hematologic malignancies.
 

Dr. Perl on Potential CAR T-Cell Therapies in Hematologic Malignancies

Alexander E. Perl, MD, associate professor of medicine, University of Pennsylvania, discusses the impact of the ELIANA trial in acute lymphoblastic leukemia (ALL).

In August 2017, the FDA approved the chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel (Kymriah) for the treatment of patients up to 25 years of age with B-cell precursor ALL that is refractory or in second or later relapse. This approval was based off findings from the ELIANA trial of 63 patients who received a single dose of tisagenlecleucel. The overall remission rate was 82.5% (95% CI, 70.9-91.0) in treated subjects, and 40 patients (63%) had complete remission.

Perl says that the most exciting thing about the ELIANA trial is that this therapy can be done at any center that is properly equipped. The fact that the toxicities were uniform between the single-center data and the multi-center data was encouraging, Perl adds. There is a learning curve to CAR T-cell therapy, and physicians should refer their patients to centers that have experience administering it.

Alexander E. Perl, MD, associate professor of medicine, University of Pennsylvania, discusses the impact of the ELIANA trial in acute lymphoblastic leukemia (ALL).
 

Dr. Perl Discusses the Impact of the ELIANA Trial

Alexander E. Perl, MD, associate professor of medicine, University of Pennsylvania, discusses upcoming chimeric antigen receptor (CAR) T-cell therapies for patients with acute lymphoblastic leukemia (ALL).

There has been interest in patients who lose response to CAR T-cell therapy, says Perl. One mechanism of resistance has been the loss of expression of the target of the CAR T cells. Many of those patients lack CD19, which has been the target of the cells that were generated.

Investigators have begun investigating whether 2 CAR T cells are needed, one directed against an antigen like CD19, the other against a second antigen, or whether a fallback option for the cells that do grow despite the T-cell therapy be better? Early data have looked at CD22, which is also commonly expressed in patients with ALL, but they are not as far along as data with CD19.

The development of CAR T-cell therapy has been particularly interesting in myeloma, says Perl. There has been some development of CAR T cells targeting CD19, but B-cell maturation agent (BCMA) has been the main area of development.

Dr. Perl Discusses Upcoming CAR T-Cell Therapies for ALL

Alexander E. Perl, MD, associate professor of medicine, University of Pennsylvania, discusses the impact of chimeric antigen receptor (CAR) T-cell therapy on the treatment of patients with acute lymphoblastic leukemia (ALL).  

Historically, there has not been an effective salvage therapy for patients with ALL. The CD19-directed therapies have changed that process, whether it is with blinatumomab (Blincyto) or CAR T-cell therapies, explains Perl.  

There are high rates of response and durable responses with CD19-directed therapies. With CAR T-cell therapy, not all patients with ALL need a subsequent transplant because patients who achieve durable responses and persistence of their CAR T cells can live in sustained remissions without additional therapy.  

According to Perl, patients who have had salvage therapy and have not responded continue to respond to CAR T-cell therapy. Having a different mechanism of modality has changed the treatment landscape for this patient population. 

The FDA approved tisagenlecleucel (Kymriah) in patients with ALL back in August 2017. Investigators concluded that tisagenlecleucel was associated with clinically meaningful remissions. The estimated relapse-free rate among responders at month 6 was 75.4% (95% CI, 57.2-86.7). The median duration of response was not reached at a median follow-up of 4.8 months. 

Alexander E. Perl, MD, associate professor of medicine, University of Pennsylvania, discusses the impact of chimeric antigen receptor (CAR) T-cell therapy on the treatment of patients with acute lymphoblastic leukemia (ALL).

Dr. Perl Discusses the Impact of CAR T-Cell Therapy on ALL

Alexander E. Perl, MD, associate professor of medicine, University of Pennsylvania, discusses the outlook of FLT3 inhibitors for acute myeloid leukemia.

The first FLT3 inhibitor, midostaurin, is not potent enough against FLT3 and is more like a multikinase inhibitor. As a result, the newer FLT3 inhibitors are more potent and selective, explains Perl.

Perl says he is optimistic about patients with 

 mutations, as ongoing phase III trials have either completed or will soon complete accrual in relapsed or refractory patients with 

Alexander E. Perl, MD

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