Immuno-Oncology Resource Center

Immuno-Oncology Resource Center

January 31, 2018
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Leukemia disease burden impacts response with CAR T-cell therapy

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Michel Sadelain

Adults with relapsed B-cell acute lymphoblastic leukemia who received CD19-28z chimeric antigen receptor cells had an 83% complete remission rate and a median survival of nearly 13 months, according to long-term follow-up of a phase 1 study published in The New England Journal of Medicine.

“Following our early clinical results reported in 2013 and 2014, the FDA granted us breakthrough designation for the continuation of this trial,” Michel Sadelain, MD, PhD, director of the center for cell engineering and gene transfer and gene expression laboratory at Memorial Sloan Kettering Cancer Center, told HemOnc Today. “The chimeric antigen receptor (CAR) molecule 19-28z is a CD28-based second-generation CAR specific for CD19, a molecule we had previously identified as an attractive CAR target. We reported on 53 patients treated at Memorial Sloan Kettering, where CAR T cells were manufactured.”

Despite previous reports from other studies of CAR T-cell persistence correlating with remissions, researchers did not find a significant correlation between the persistence of CAR T cells and survival in all the subgroups of patients, which indicates that CD19-28z CAR T-cell persistence is not requisite for durable remissions.

In their study, Sadelain and colleagues assessed safety and long-term outcomes for 53 adults (median age, 44 years; range, 23-74) with relapsed B-cell ALL who received an infusion of manufactured autologous T cells expressing the 19-28z CAR from February 2010 through June 2016.

Sixty-eight percent of patients (n = 36) received CAR T-cell therapy as a third or later salvage treatment, 36% had undergone previous allogeneic hematopoietic stem cell transplant, 25% had previously received blinatumomab (Blincyto, Amgen) and 23% had primary refractory disease.

At the time of infusion, 60% of patients (n = 32) had high disease burden— defined as 5% or greater bone marrow blasts (n = 27) or extramedullary disease (n = 5) — 28% had minimal residual disease with bone marrow blasts of 0.01% to less than 5%, and 11% were minimal residual disease negative with less than 0.01% bone marrow blasts.

Median follow-up was 29 months (range, 1-65).

“Unlike earlier CAR trial reports in the field, which focused on response rates and early toxicities, we assessed long-term survival and its correlates,” Sadelain said.

Eighty-three percent of patients achieved complete remission. Of 48 patients with sufficient bone marrow samples, 32 (67%; 95% CI, 52-90) achieved minimal residual disease-negative complete remission.

Median EFS was 6.1 months (95% CI, 5-11.5) and median OS was 12.9 months (95% CI, 8.7-23.4).

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Patients with a low disease burden before treatment — defined as less than 5% bone marrow blasts — had markedly enhanced remission duration and survival, with a median EFS of 10.6 months (95% CI, 5.9 to not reached) and a median OS of 20.1 months (95% CI, 8.7 to not reached). In comparison, patients with a high disease burden had a median EFS of 5.3 months (95% CI, 3-9; P = .01 vs. low disease burden) and median OS of 12.4 months (95% CI, 5.9-20.7; P = .02).

After infusion, cytokine release syndrome occurred at any grade among 45 patients (85%; 95% CI, 72-93) and as grade 3 or worse among 14 patients (26%; 95% CI, 15-20). One patient died on the fifth day of treatment from multiorgan failure and severe cytokine release syndrome. Cytokine release syndrome manifested as fever, tachycardia, hypotension, respiratory distress or hypoxemia.

Forty-two percent of patients (n = 22) received supportive care for cytokine release syndrome. Six patients received anti-interleukin-6 receptor monoclonal antibody tocilizumab (Actemra, Genentech) alone, 13 received tocilizumab plus a glucocorticoid, and four received glucocorticoids alone.

Grade 2 neurotoxic effects occurred in one patient, grade 3 events occurred among 19 patients, and grade 4 events occurred among three patients. Neurologic adverse events included confusion, disorientation, aphasia, encephalopathy and seizure.

More patients with a high vs. low burden of disease before treatment experienced cytokine release syndrome (41% vs. 5%; P = .004) and neurotoxic events (59% vs. 14%; P = .002).

“The key finding is that patients with lower tumor burden experienced the highest long-term survival and the lowest toxicities — cytokine release syndrome and neurotoxicity,” Sadelain said. “Patients with a higher tumor burden were not only those who experienced higher toxicities, as we had previously reported, but they also were more likely to relapse. The study, thus, identified which patients were most likely to benefit with minimal risks.

“These findings very strongly support providing this treatment to adults with refractory ALL and a small tumor burden,” Sadelain added. “There is presently no approved CAR therapy for this patient population. These findings further indicate that CAR therapy should be given earlier in the course of disease, a conclusion that should be evaluated prospectively.”

A secondary finding is that allogeneic HSCT after CAR therapy did not increase OS, Sadelain added.

“Although this point is very important for guiding future medical practice — and for gauging the effectiveness of CAR therapy — this key point would, in principle, require a prospective study to be validated,” he said.

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Researchers noted the median OS of 12.9 months in this study compared favorably with the median OS of 7.7 months among adults with relapsed ALL treated with blinatumomab, even though this analysis included more heavily pretreated patients than the blinatumomab study (third or later salvage therapy, 68% vs. 24%).

“A complete response is obtained within a few weeks of treatment,” Sadelain said. “However, as with any kind of therapy, some patients will subsequently relapse. With some treatments, most patients respond but none enjoy long-term survival.”

Although CD19 CAR therapies prolong life and are curative for some patients, there is a need for improvement on two levels, according to Sadelain.

“One is to prevent relapse, so that most complete remissions remain in complete remission,” he said. “The other is to decrease short-term toxicities, such as cytokine release syndrome and neurotoxicity. In the interim, we have identified a group of very desperate patients — adults with low-burden refractory ALL — who can maximally benefit from treatment with the 19-28z CAR. This treatment should be made available to patients with ALL.” – by Chuck Gormley

 

For more information:

Michel Sadelain, MD, PhD, can be reached at m-sadelain@ski.mskcc.org.

 

Disclosures: Sadelain reports grant support from Juno Therapeutics, as well as patents licensed to Juno Therapeutics for nucleic acids encoding chimeric T-cell receptors (US 7446190), constitutive expression of costimulatory ligands on adoptively transferred T lymphocytes (PCT/US2008/004251), methods for off-the-shelf tumor immunotherapy using allogeneic T-cell precursors PCT/US2009/000606), and compositions and methods for immunotherapy (PCT/US2014/030671). Please see the study for all other authors’ relevant financial disclosures.