乌鸦传媒

SAN DIEGO -- Targeted agents such as ibrutinib (Imbruvica) or checkpoint inhibitors could bolster outcomes in patients with hematologic malignancies treated with CAR T-cell therapies, researchers reported here.

Among 43 consecutive patients with relapsed or refractory chronic lymphocytic leukemia (CLL), 83% of those who continued on ibrutinib responded to an investigational CAR T-cell therapy, JCAR014, compared with 65% of patients who halted ibrutinib before getting JCAR014, reported Jordan Gauthier, MD, of the Fred Hutchinson Cancer Research Center in Seattle.

In the second study, which included 13 young acute lymphoblastic leukemia (ALL) patients with limited initial responses to CAR T-cell therapy and one B-cell lymphoblastic lymphoma patient, 50% achieved either partial responses (PRs) or complete responses (CRs) with the addition of PD-1 inhibition, according to Shannon Maude, MD, PhD, of the Children's Hospital of Philadelphia.

The studies were presented here at a press briefing dedicated to CAR T-cell therapy at the American Society of Hematology meeting.

Ibrutinib Plus CAR T-Cell Therapy in CLL

For the main response analysis in this retrospective study, Gauthier's group used the International Workshop Group on CLL 2018 criteria. Other analyses of response -- flow cytometry or deep sequencing to detect no disease in marrow -- were similar or also favored patients who received concurrent ibrutinib.

• Flow cytometry: 72% with continuous ibrutinib vs 74%
• Deep sequencing: 85% vs 50%

"Concurrent administration of ibrutinib with CD19-specific CAR-T cells was feasible in most patients, induced high response rates and deep responses -- early on, at 4 weeks," Gauthier said, adding that it was also associated with "higher in vivo expansion of CD4+ CAR T cells and lower rates of severe toxicity."

Notably, while there were similar overall rates of cytokine release syndrome between groups (74% vs 92%, respectively, P=0.21), severe episodes were significantly less common in the concurrent group (0% vs 25%, P=0.03). Any neurologic toxicity (32% vs 42%) and severe neurologic toxicity (26% vs 29%) were similar between groups.

The groups were well balanced with no significant differences seen for age, sex, and performance status, as well as chromosome 17p deletion status, complex karyotype, bulky adenopathy, and other disease characteristics. However, time to initial ibrutinib resistance was significantly longer in the cohort receiving concurrent ibrutinib plus CAR T-cell therapy (24 vs 19 months, P=0.02).

A prospective phase I/II study, TRANSCEND-CLL, will attempt to validate these findings.

CAR T-cell therapy in CLL, should it be approved, would enter a crowded field of effective drugs, and there would likely only be a small subset of patients appropriate for the treatment following various lines of available treatments such as ibrutinib, venetoclax (Venclexta), and duvelisib (Copiktra).

"CAR T seem ready to replace the role of allo-transplant in the minority of patients who would have needed it should they have failed all of the standards of care," Anthony Mato, MD, of Memorial Sloan Kettering Cancer Center in New York City, told 乌鸦传媒. "If it were commercially available, that's the patient population I would be targeting."

Adding PD-1 Inhibition

This small study used either pembrolizumab (Keytruda) or nivolumab (Opdivo) in young patients with limited or no response to CAR T-cell therapy. The researchers had hypothesized that inhibiting PD-1/PD-L1 could decrease T-cell exhaustion and thereby improve CAR T-cell persistence.

Among six patients who responded to CAR T-cell therapy but had poor persistence, three had a return of B-cell aplasia, sustained CR with B-cell aplasia, and continued persistence following checkpoint blockade.

Four patients showing no initial response in their bulky extramedullary disease achieved PR or CR (two for each) following checkpoint inhibition.

"We show that PD-1 checkpoint inhibitors can be safely combined with CD19 CAR T-cell therapy, and that this mechanism may be useful to improve CAR T-cell persistence," Maude said during the briefing.

No benefit with the strategy was seen among four patients that had only achieved a PR or failed to respond to CAR T-cell therapy. These patients continued to have disease progression after treatment with the PD-1 inhibitor, one of whom had reduced CD19 expression -- the likely mode of resistance.

"This combination resulted in few adverse events and was well tolerated," Maude noted.

Adverse events included fever, grade 2 cytokine release syndrome, and cytopenia, but none were considered serious.

Patients in the study were 4 to 17 years old, had heavily pretreated, relapsed disease and were treated with pembrolizumab or nivolumab within 2 weeks from the CAR T-cell infusion. Doses of the PD-1 inhibitor could be repeated every 3 weeks.