In patients with relapsed or refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), treatment with lisocabtagene maraleucel (liso-cel) was associated with deep, rapid responses and manageable safety, according to results from the phase I/II TRANSCEND CLL 004 study published in Blood.
Tanya Siddiqi, MD, of City of Hope in Duarte, California, and colleagues enrolled 25 adult patients with relapsed/refractory CLL/SLL from January 2018 to January 2019 across eight U.S. sites. Patients were a median of 66 years of age and 48% male. Out of 25 patients, 91% had nodal disease, eight (35%) had bulky (>5 cm) lymph nodes, and 13 (57%) had disease present in the bone marrow. At baseline, hypogammaglobulinemia was reported in six patients. The median prognostic BALL risk score was 2 (range = 0-3). A majority of patients (83%) had high-risk genetic features, including mutated TP53, del(17p), complex karyotype, and/or unmutated immunoglobulin heavy chain variable (IGHV).
Among patients in the study, the median number of prior lines of therapy was four (range = 2-11). All 25 patients had previously received ibrutinib, 20 (87%) had prior treatment with chemoimmunotherapy, and 15 (65%) previously received both ibrutinib and venetoclax. Twenty-one patients had disease that was relapsed/refractory to ibrutinib, and four of those patients were also intolerant to prior ibrutinib. Prior to liso-cel re-infusion, 17 patients (74%) received bridging therapy.
Because of central nervous system disease, one patient discontinued the study prior to liso-cel infusion. Out of 24 patients for whom liso-cel was successfully manufactured, one patient was excluded from the safety-evaluable population after receiving nonconforming product.
The primary endpoint of this ongoing open-label, multicenter study was the modified toxicity probability interval-2 (mTPI-2) algorithm output of the type, frequency, and severity of adverse events (AEs) and laboratory abnormalities. Additional endpoints included overall response rate (ORR), complete response (CR) rate, and cellular kinetics.
For production of liso-cel, patients underwent leukapheresis. After a median washout period of seven days (range = 3-7), they received three days of lymphodepleting chemotherapy consisting of fludarabine 30 mg/m2/day plus cyclophosphamide (300 mg/m2/day). Patients received either of the following dose levels (DLs) of liso-cel:
- DL1 (50 × 106 CAR+ T cells [n=9])
- DL2 (100 × 106 CAR+ T cells [n=14])
Investigators assessed responses using International Workshop on Chronic Lymphocytic Leukemia criteria on day 30 of the study and periodically until disease progression, study discontinuation, or death. Minimal residual disease (MRD) was also assessed by flow cytometry in peripheral blood and next-generation sequencing in marrow. The researchers used validated quantitative polymerase chain reaction to detect the liso-cel transgene in peripheral blood. Safety, efficacy, subsequent anticancer therapies, and survival were evaluated for a total of two years after the patients’ last infusion of liso-cel.
One patient was excluded from the efficacy analysis after being diagnosed with Richter transformation following leukapheresis. For the 22 efficacy-evaluable patients, the median follow-up was 24 months (95% CI 17.9-24.4). The ORR was 82% (95% CI 59.7-94.8). The CR (including CR with incomplete marrow recovery [CRi]) rate was 45%. Median time to response was one month (range = 1-6) and median time to CR/CRi was two months (range = 1-12).
At the time of data cutoff on July 24, 2020, 11 patients had at least 18 months of follow-up. Among the 11 patients, one had progressed, with the other 10 remaining in response at 18 months. Out of seven patients who completed the 24-month study, five remained in CR and two remained in partial response. At a median follow-up of 24 months, the median PFS was 18 months and the median duration of response was not reached (95% CI 3.0-not reached).
Twenty of the 23 efficacy-evaluable patients were evaluable for MRD. At baseline, one patient from each DL group had disease only measurable by lymph node, with no detectable disease in peripheral blood or bone marrow. These two patients were excluded from the MRD analysis. Three-quarters of patients (n=15) achieved undetectable MRD (sensitivity <10-4) in blood. Thirteen of these patients also achieved undetectable MRD in bone marrow, and three of the 13 have progressed. By day 30, 13 and 12 patients had achieved undetectable MRD in blood and marrow, respectively.
Among 23 safety-evaluable patients, the most common grade 3/4 treatment-emergent AEs were cytopenias including anemia (74%), thrombocytopenia (70%), neutropenia/neutrophil count decrease (70%), leukopenia (43%), febrile neutropenia (26%), and lymphopenia (26%). Across both DLs, safety profiles were similar and serious treatment-emergent AEs were reported in 57% of patients.
Nine patients died during the study period. Progressive disease was the cause of death in seven patients. One patient from the DL1 group developed grade 3 pneumonia two months after receiving liso-cel and died two weeks later from grade 5 respiratory failure. The authors noted that lymphodepleting chemotherapy likely caused the pneumonia. One patient in the DL2 group with acute kidney injury and pneumonia died more than 90 days after treatment with liso-cel. The cause of death was septic shock considered unrelated to treatment with liso-cel.
The phase I portion of TRANSCEND CLL 004 is limited by its single-arm design, small sample size, and limited follow-up. “The ongoing phase II monotherapy expansion cohort, currently enrolling at DL2, will provide additional information on the safety and efficacy of liso-cel in patients with relapsed/refractory CLL/SLL,” the authors wrote.
Study authors report no relevant conflicts of interest.
Reference
Siddiqi T, Soumerai JD, Dorritie KA, et al. Phase I TRANSCEND CLL 004 study of lisocabtagene maraleucel in patients with relapsed/refractory CLL or SLL [published online ahead of print, 2021 Oct 26]. Blood. doi: 10.1182/blood.2021011895.
