Terry J. Fry, MD
Anti-CD22 chimeric antigen receptor (CAR) T-cell therapy induced an 80% complete remission (CR) rate among children and young adults with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL), many of whom had prior anti-CD19 CAR T-cell therapy.
The high remission rate occurred in patients who received biologically active dose levels of the treatment. According to the findings, which were presented at the 2016 ASH Annual Meeting, the remissions were sustained, with 3 patients in ongoing remission now at 3 months, 6 months, and >1 year.
“This is the first successful salvage CAR T-cell therapy for CD19 negative B-ALL. Preliminary experience suggests that what we have seen is at least comparable to the phase I experience with CD19 at the same dose level,” said study author Terry J. Fry, MD, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health.
Fry noted that despite the tremendous success with anti-CD-19 CAR T-Cell therapy in pre–B-cell (pre-B) ALL, there are remaining challenges.
“We’re learning now that one of the limitations of this approach is loss of CD-19 expression, which potentially occurs in a substantial number of patients, although that has not yet been systematically analyzed. CD22 is a well-defined alternative target in B-ALL.”
Fry et al’s phase I dose-escalation study examined anti-CD22 CAR T-cell therapy in patients with relapsed/refractory CD22-positive hematologic malignancies. The results Fry presented at ASH were for 16 patients with ALL. The median age was 19.5 years (range, 7-30) and 56% (n = 9) of patients were male.
All patients had prior hematopoietic stem cell transplantation, 69% (n = 11) had prior anti-CD19 CAR T-cell therapy, and 31% (n = 5) had prior blinatumomab (Blincyto). Fifty-six percent of patients (n = 9) were CD19-negative or had reduced expression of CD19 on the surface of their ALL. Seventy-five percent (n = 12) of patients had ≥M2 marrow at enrollment and 19% (n = 3) had extramedullary disease. Patients with CNS3 disease were excluded from enrollment.
All patients received initial treatment with 25 mg/m2
daily of fludarabine for 3 days and 900 mg/m2
daily of cyclophosphamide for 1 day on days -4 to -2.
The 3 dose levels of transduced CAR T cells/kg examined were 3 x 10e5 (6 patients), 1 x 10e6 (8 patients), and 3 x 10e6 (2 patients).
“Dose level 2 (1 x 10e6) is the dose that has been used in most of the CD19 CAR trials, we started half a log lower than that as part of the safety protocol of the trial,” said Fry.
Eight of 10 patients treated at the 2 higher dose levels achieved a CR, including 7 patients (88%) at the 1 x 10e6 dose and 1 patient (50%) at the 3 x 10e6 dose. Only 1 patient (17%) achieved a CR at the 3 x 10e5 dose.
“There was a suggestion that response tended to correlated with dose level,” said Fry.
Five patients relapsed, 1 with CAR cell loss and 4 with changes in CD22 expression. Among the latter, 3 had a decrease in site density and 1 had antigen loss.
At the lowest dose level, there was a dose-limiting toxicity (DLT) of grade 3 diarrhea that was self-limiting. Among patients receiving the highest dose level, there was 1 patient with a DLT of grade 4 hypoxia that required early initiation of steroids.
Among the initial patients receiving the middle dose of 1 x 10e6, there were no DLTs; however, in the expansion cohort of patients receiving this dose, there was 1 death due to sepsis that occurred after resolution of cytokine release syndrome (CRS). Fry said that thus far, all instances of CRS in the study have been a maximum of grade 2.
Going forward, Frey is optimistic about earlier use of anti-CD22 therapy, including opportunities for bispecific and multispecific CAR targeting.
“At least our bias is that this may not be best used as a salvage therapy—we are beginning to think about how this could be potentially included with CD19 in the upfront setting,” said Frey.
Shah, NN, Stetler-Stevenson M, Yuan CM, et al. Minimal residual disease negative complete remissions following anti-CD22 chimeric antigen receptor (CAR) in children and young adults with relapsed/refractory acute lymphoblastic leukemia (ALL). Presented at: 58th ASH Annual Meeting and Exposition; San Diego, California; December 2-6, 2016. Abstract 650.<<< View more from the 2016 ASH Annual Meeting