SAN DIEGO—Fludarabine is “very important” for lymphodepletion prior to CD30-directed chimeric antigen receptor (CAR) T-cell therapy, according to a presentation at the 2018 ASH Annual Meeting.
A phase 1/2 study showed that bendamustine alone was not sufficient as lymphodepletion.
However, adding fludarabine to bendamustine could enhance responses to CD30.CAR T-cell therapy and improve progression-free survival (PFS) in patients with Hodgkin or non-Hodgkin lymphoma.
Natalie S. Grover, MD, of the University of North Carolina in Chapel Hill, presented these results as abstract 681.*
This trial (NCT02690545) included patients with relapsed/refractory, CD30+ Hodgkin lymphoma or T-cell non-Hodgkin lymphoma.
Twenty-four adult patients have been treated thus far. Twenty-two had classical Hodgkin lymphoma, one had Sézary syndrome, and one had enteropathy-associated T-cell lymphoma.
The patients’ median age at baseline was 34.5 years (range, 23-69), and they had received a median of 7.5 prior lines of therapy (range, 3-17).
Prior treatments included brentuximab vedotin (n=23), checkpoint inhibitors (n=16), autologous transplant (n=17), and allogeneic transplant (n=7).
In this trial, patients could receive bridging therapy while their T cells were being processed. They then underwent lymphodepletion and received CAR T-cell therapy at one of two doses.
Eight patients received lymphodepletion with 2 days of bendamustine at 90 mg/m2. Three of these patients received CD30.CAR T-cell therapy at 1×108 cells/m2, and all three progressed.
Of the five patients who received CAR T-cell therapy at a dose of 2×108 cells/m2, one progressed, one had stable disease, and three had a complete response (CR).
However, all three complete responders were in CR prior to lymphodepletion as a result of bridging therapy.
“Responses were more modest than what we were hoping for with lymphodepletion,” Dr. Grover noted. “We looked at the cytokine levels in patients getting bendamustine lymphodepletion and saw that bendamustine wasn’t supporting an ideal cytokine milieu. IL-7 and IL-15 are important for T-cell expansion, and these levels were not increased in patients post-bendamustine.”
When the researchers added fludarabine to the lymphodepleting regimen, they observed an increase in T-cell expansion.
Bendamustine plus fludarabine
Sixteen patients received bendamustine plus fludarabine prior to CAR T-cell therapy. The regimen consisted of 3 days of bendamustine at 70 mg/m2 and fludarabine at 30 mg/m2.
All 16 patients received CAR T cells at 2×108 cells/m2, which was the recommended phase 2 dose.
“Responses were more impressive in the bendamustine-fludarabine cohort,” Dr. Grover noted.
Twelve of the 16 patients achieved a CR, although two patients were already in CR prior to lymphodepletion.
Two patients had a partial response, one had stable disease, and one progressed.
PFS and toxicity
Dr. Grover and her colleagues also assessed PFS. At a median follow-up of 100 days, the median PFS was 164 days for the entire cohort, excluding patients who were in CR prior to lymphodepletion.
The median PFS was 396 days for the bendamustine-fludarabine cohort and 55 days for patients in the bendamustine-alone cohort (P=0.001).
There was no neurotoxicity in this trial.
Three patients developed cytokine release syndrome (CRS). Two patients had grade 1 CRS that resolved spontaneously, and one patient had grade 2 CRS, which responded to tocilizumab. Two of the patients with CRS had T-cell lymphoma. The Sézary patient had grade 2 CRS.
Eight patients had a mild rash, one of whom had a rash at baseline.
“CAR T cells against CD30 preceded by lymphodepletion with bendamustine and fludarabine have promising efficacy and a good safety profile in treating patients with relapsed/refractory, CD30+ lymphomas,” Dr. Grover said in closing.
“Fludarabine is very important in enhancing cytokines for improved growth and persistence of CAR T cells.”
This trial was sponsored by UNC Lineberger Comprehensive Cancer Center. Dr. Grover reported consulting for Seattle Genetics.
*Data in the abstract differ from the presentation.