However, there are still many hurdles to overcome. For example, unanswered questions surround the optimization of lymphodepletion regimens prior to CAR T infusion, the optimal dosing of CAR T cells, and the most effective CAR T product. The optimal combinations and therapeutic sequences are also currently unknown.

For example, the success of an adoptive immunotherapy approach was demonstrated in a 2013 trial that tested immune reconstitution following fludarabine-based therapy using autologous CD3/CD28 costimulated T cells.3 The treatment was found to be feasible and well tolerated and resulted in acceleration of CD4-positive and CD8-positive cell recovery. Moreover, in a 2015 follow-up to the 2011 trial mentioned above, researchers found a high overall response rate among heavily pretreated relapsed or refractory patients and a correlation between treatment with CAR T cells and positive clinical outcomes.4

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Adverse effects resulting from CAR T therapy must be considered as well. Cytokine release syndrome is the most serious adverse effect encountered in patients treated with CAR T cells. Symptoms of this syndrome include fever, cardiac dysfunction, neurologic toxicity, renal or hepatic failure, and disseminated intravascular coagulation; management strategies include supportive care and treatment with anti-interleukin-6 antibodies or corticosteroids. Research on management of other adverse effects is ongoing.


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Randall Davis, MD, a professor in the division of hematology and oncology at the University of Alabama at Birmingham, told Hematology Advisor there has not been adequate follow-up to determine precisely how beneficial CAR T therapy is for patients with CLL. Currently, this treatment is reserved for relapsed and refractory patients in a clinical trial setting. “These patients are challenging to treat and have more aggressive features. Most CAR T studies for CLL have been small [in size]. It is still not clear how durable these responses are,” Dr Davis said.

He added that there a large number of new treatment options, such as immunotherapies and small molecule kinase inhibitors, are targeted, less toxic, and better tolerated compared with classical nonspecific conventional chemotherapy. “Over the next few years we will learn more about what single [agents] or combinations of agents yield the best long-term responses.”

Future Directions

Matthew H Carabasi, MD, of the Sidney Kimmel Cancer Center and a professor at Thomas Jefferson University in Philadelphia, Pennsylvania, told Hematology Advisor that although considerable work remains to be done, the fact that some patients with advanced disease refractory to all other treatment options may be cured with CAR T therapy suggests we are entering a new era in the treatment of CLL.

“It is important to recognize that these results are being obtained with the first generation of CAR T cells broadly used in clinical trials,” Dr Carabasi told Hematology Advisor. “It would not be unreasonable to expect better efficacy and less toxicity in the future as newer constructs become available. This in turn would allow this approach to be used earlier in the disease course for appropriate patients, perhaps providing a better starting product for CAR T cell production as well as a better response after CAR T cell infusion in less heavily pretreated patients.”

Over the next 2 years, new and ongoing clinical trials will continue to clarify the best approach for different subgroups of patients with CLL, especially when balancing risks and benefits. However, Dr Carabasi noted, agents such as ibrutinib and venetoclax, alone or in combination with other agents, are also favorably altering the treatment landscape of CLL by improving survival and decreasing toxicity. “Although not curative, these agents, as well as other proven approaches, will remain the mainstays of CLL therapy until the toxicities, and perhaps the cost, of CAR T cells have been mitigated,” he said.

References

1.     Mato AR, Thompson MC, Nabhan C, Svoboda J, Schuster SJ. Chimeric antigen receptor T-cell therapy for chronic lymphocytic leukemia: a narrative review [published online July 21, 2017]. Clin Lymphoma Myeloma Leuk. doi: 10.1016/j.clml.2017.07.007

2.     Porter D, Levine B, Kalos M, Bagg A, June C. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011;365:725-733. doi: 10.1056/NEJMoa1103849

3.     Schuster SJ, Hosing CM, Shpall EJ, et al. Adoptive immunotherapy with autologous CD3/CD28-costimulated T-cells after fludarabine-based chemotherapy in patients with chronic lymphocytic leukemia. Blood. 2013;122:2874.

4.     Porter D, Hwang W, Frey N, et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med. 2015;7:303ra139. doi: 10.1126/scitranslmed.aac5415