The long-term outcome for patients with relapsed or refractory acute lymphoblastic leukemia (ALL) is poor, with 5-year overall survival from first relapse being only approximately 10%.1,2 Patients with disease relapse following allogeneic transplant have the worse prognosis and are typically excluded from clinical trials. It is, therefore, with great excitement that we highlight a recently published clinical trial report in patients with relapsed or refractory ALL by Maude and colleagues.3 These researchers from the University of Pennsylvania once again stand at the front line in advancing our knowledge of CD19 chimeric antigen receptor (CAR)-modified T cells in treating patients with ALL.
CTL019 Study
In their seminal phase I/IIA study, reviewed in the December 1 issue of The ASCO Post, 25 children and 5 adults with relapsed or refractory ALL who were either ineligible for allogeneic hematopoietic stem cell transplant (alloHCT) or had prior alloHCT were treated with patient-derived CD19 CAR T cells. Complete remission was seen in 90% of patients. The 6-month event-free survival rate was 67% (95% confidence interval [CI] = 51%–88%), and 6-month overall survival was 78% (95% CI = 65%–95%). More than half of the patients (68%, 95% CI = 50%–92%) had detectable CAR T cells at 6 months. B-cell aplasia was found to be a surrogate marker for presence of persistent CAR T cells.
The major toxicities associated with CAR T-cell infusion included cytokine-release syndrome in all patients, with severe cytokine-release syndrome in 27%, neurotoxicity in 43%, and B-cell aplasia in all responders. C-reactive protein was identified as a good surrogate serum marker for following cytokine-release syndrome progression.
More important, severe cytokine-release syndrome was associated with higher disease burden prior to T-cell infusion, higher levels of CD8-positive CD19 CAR T cells, and higher levels of interleukin (IL)-6, and was ameliorated with the use of the anti–IL-6 receptor–blocking antibody tocilizumab (Actemra). No treatment-related deaths were reported.
This study is a nice follow-up to the group’s initial report of impressive complete responses to CTL019 in two pediatric patients and is the first study demonstrating durable remission. Indeed, it presents the first piece of convincing evidence that CD19 CAR T cells can lead to sustained remission of up to 24 months without further treatment. This definitely is an encouraging result and brings great hope for patients with relapsed and refractory ALL, especially those whose disease has relapsed after a prior alloHCT. None of the therapeutics currently approved by the U.S. Food and Drug Administration for this patient population has been shown to elicit such a dramatic clinical response.
Persistence of CAR T Cells
This study identified a positive association between duration of T-cell persistence and B-cell aplasia and sustained remission. The CD19 CAR in this study uses 4-1BB as the costimulatory domain. Davila et al4 observed a complete remission rate of 88% in 16 adult patients using a CD19 CAR, with CD28 as the costimulatory domain. Lee et al5 reported a 70% complete remission rate in 20 pediatric and young adult ALL patients using a slightly different CD19 CAR, with CD28 as the costimulatory domain. An accurate assessment of CAR T-cell persistence was not possible due to subsequent alloHCT in responders in the latter two trials.
It remains debatable which CAR has the highest short-term efficacy, and it remains unknown whether a deep remission obtained at day 28 is sufficient for a sustained remission. In addition, one has to consider the contribution of a graft-vs-leukemic effect to the maintenance of sustained remission seen in patients with a prior alloHCT in Maude et al’s study. Therefore, only a randomized side-by-side direct comparison of different CD19 CAR T cells would be able to clearly define the necessity of CAR T-cell persistence and duration of persistence. Unfortunately, such a trial is unlikely to be carried out in the current environment, as each of the three CD19 CAR T cells mentioned involves different sponsors—but individual studies with longer follow-up will still be informative.
Feasibility
The design of the current study did not include an intent-to-treat analysis. Therefore, the true feasibility of this approach is not known. The National Cancer Institute group led by Crystal L. Mackall, MD,5 recently reported the first intent-to-treat analysis using their version of CD19 CAR T cells for patients with ALL. The feasibility was 90%, with 19 of 21 patients receiving the intended doses.
However, a direct cross reference is not possible due to differences in CD19 CAR design, vector of choice, manufacturing platform, and lymphodepleting regimens. It is therefore of increasing importance for future CAR T-cell clinical trials to include intent-to-treat analysis so that it can be determined if this treatment will be available to the majority of, if not all, patients, and to determine if there are any limitations to producing a T-cell product, especially in the relapsed setting.
Post-AlloHCT Setting
A surprising finding of this study is that a history of alloHCT did not compromise the high treatment efficacy of these CD19 CAR T cells. Only 3 of 10 such patients treated by Kochenderfer et al6 and 3 of 7 patients treated by Lee et al5 achieved complete remission. Many differences among these trials might contribute to the differences in outcomes reported.
In addition, none of these studies is designed for a rigorous efficacy comparison between the pretransplant and post-transplant groups. Therefore, there are currently insufficient data to conclude whether the antitumor activities of the donor-derived CAR T cells match up to those of autologous CD19 CAR T cells in patients with no prior transplant. A prospective clinical trial in patients with prior alloHCT would certainly provide further information to this end.
It is, however, reassuring to conclude that infusion of donor-derived CD19 CAR T cells is safe and unlikely to cause graft-vs-host disease, since no incidence of this complication has been reported by five independent groups,3-7 regardless of whether the T cells were freshly collected from the donor host or from donor cells circulating in the recipient host. This makes the CAR T-cell treatment a very desirable immune-based therapy for ALL patients with relapsed disease following a prior allogeneic transplant.
Non-CD19 Malignancies
Many groups, including ours, have been devoting great efforts to expanding the CAR technology to non–CD19-positive malignancies. Distinct CARs are being tested in acute myeloid leukemia, multiple myeloma, brain tumors, prostate cancer, mesothelioma, and many other tumor types.
Combination therapy with immune checkpoint inhibitory blockade might be necessary to augment the efficacy in some tumors that are known to activate PD-1/PD-L1 and similar immunoinhibitory pathways that confer resistance to T-cell function when encountering tumors. Using different defined subsets of T cells, with regard to both number and phenotype, as the starting population is another exciting potential strategy that has sparked many research investigations.
The era of adoptive T-cell immunotherapy has just begun. We look forward to more exciting reports like the one from Maude et al and other groups in the near future. ■
Disclosure: Drs. Budde, Khaled, and Forman reported no potential conflicts of interest.
References
1. Forman SJ, Rowe JM: The myth of the second remission of acute leukemia in the adult. Blood 121:1077-1082, 2013.
2. Burke MJ, Gossai N, Wagner JE, et al: Survival differences between adolescents/young adults and children with B precursor acute lymphoblastic leukemia after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 19:138-142, 2013.
3. Maude SL, Frey N, Shaw PA, et al: Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 371:1507-1517, 2014.
4. Davila ML, Riviere I, Wang X, et al: Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med 6:224ra25, 2014.
5. Lee DW, Kochenderfer JN, Stetler-Stevenson M, et al: T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: A phase 1 dose-escalation trial. Lancet. October 10, 2014 (early release online).
6. Kochenderfer JN, Dudley ME, Carpenter RO, et al: Donor-derived CD19-targeted T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation. Blood 122:4129-4139, 2013.
7. Cruz CRY, Micklethwaite KP, Savoldo B, et al: Infusion of donor-derived CD19-redirected virus-specific T cells for B-cell malignancies relapsed after allogeneic stem cell transplant. Blood 122:2965-2973, 2013.
Dr. Budde is Assistant Professor, Dr. Khaled is Assistant Clinical Professor, and Dr. Forman is Francis and Kathleen McNamara Distinguished Chair in the Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California.
