SAN DIEGO—Although the treatment of chronic lymphocytic leukemia (CLL) has drastically changed over the past few years, with the increased use of orally dosed targeted inhibitors and novel combinations, complete response rates remain low, thus necessitating the use of continuous therapy. Consequently, the complete elimination of minimal residual disease (MRD) has become a crucial endpoint and an independent predictor for improved patient outcomes.
One investigational CD19-targeting CAR T-cell therapy is lisocabtagene maraleucel (liso-cel; JCAR017), which is administered in a defined ratio of CD8:CD4 CAR T cells. This therapy is currently being evaluated in TRANSCEND CLL-004 (NCT03331198), which is an open-label, phase I/II trial in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL).
At the 2018 ASH Annual Meeting, preliminary safety, pharmacokinetic (PK), and efficacy results were presented from the phase I monotherapy dose-finding portion of the study by the lead investigator, Tanya Siddiqi, MD, a hematologist/oncologist at City of Hope in Duarte, Calif. (Abstract 300).
Regarding the importance of disease eradication, Siddiqi noted, “In CLL, undetectable MRD correlates with improved outcomes for patients and is particularly difficult to achieve in patients who have progressed on ibrutinib.”
Patients with CLL or small lymphocytic lymphoma were deemed eligible if they had received 3 prior lines of therapy if they were at standard risk or 2 prior lines of therapy if they were at high risk (i.e., del(17p), TP53 mutation, unmutated IGVH, or complex karyotype).
Additionally, one of those prior lines of therapy had to be a Bruton's tyrosine kinase inhibitor unless medically contraindicated. Those with active untreated CNS disease, ECOG performance score of greater than 1, or Richter's transformation were excluded from participation.
After lymphodepletion with fludarabine (30 mg/m2) and cyclophosphamide (300 mg/m2) for 3 days, patients received liso-cel at either dose level 1 (5×107 CAR+ T cells) or dose level 2 (1×108 CAR+ T cells).
Response assessment was performed using International Workshop on Chronic Lymphocytic Leukemia 2008 criteria.
ASH 2018 Abstract 300
The initial data presented by Siddiqi for TRANSCEND CLL-004 included 16 patients from the ongoing phase I monotherapy dose-escalation portion of the study. The median number of lines of prior therapy was 4.5, with 75 percent of patients having high-risk cytogenetic features. All patients had previously received treatment with ibrutinib, with 81 percent having R/R CLL on ibrutinib and 50 percent receiving prior treatment with ibrutinib and venetoclax.
The most common treatment-emergent adverse events reported included anemia (88%); thrombocytopenia (81%); cytokine release syndrome (CRS) (75%); neutropenia (63%); leukopenia (56%); hypokalemia (50%); pyrexia (38%); lymphopenia (31%); nausea (31%); diarrhea (25%); febrile neutropenia (25%); headache (25%); insomnia (25%); and tremor (25%). One patient (6.3%) experienced grade 3 CRS, while three patients (18.8%) experienced grade 3 neurologic events (NEs). No patients experienced grade 4 CRS or NE. Significantly, no dose-limiting toxicities were identified.
The overall response rate was 81 percent, with 43 percent of patients demonstrating a complete response (CR). As of September 2018, five patients have 6-month follow-up, with all having maintained a response and undetectable MRD in their blood by flow cytometry. The median time-to-peak expansion was 16 days; additionally, CAR+ T cells remained detectable in patients at 3 months post-dosing.
The median maximum serum concentration (Cmax) was 219 CAR T cells/μL (range: 0.35-583.46 cells/ μL), while the median time to peak expansion was 15.5 days (range: 13-19 days). The median area under the time-concentration curve (AUC) was 1528 cells∗day/μL (range: 590-2847 cells∗day/μL). Minimal CAR T-cell expansion was observed in the one patient that experienced a best response of progressive disease.
The toxicities observed for liso-cel were manageable, including events of CRS and NE, in these heavily pretreated CLL patients. Both high-risk and standard-risk CLL patients who previously received ibrutinib rapidly attained CRs and undetectable MRD, with the majority also having had received venetoclax.
Regarding the study's initial results, Siddiqi commented, “The high response rates we observed in heavily pretreated patients in this initial dataset, along with undetectable MRD status that appears to be maintained over time, warrants further investigation of liso-cel in this area of high unmet need.”
Richard Simoneaux is a contributing writer.