Community Oncologists Critical to Success of CAR T-cell Therapy in R/R Large B-Cell Lymphoma
April 28, 2020 05:45pm
By Jared Kaltwasser
“This randomized phase III study for the first time provides prospective long-term results on survival and other end points of interest after standard treatment with CHOP in patients with PTCL beyond 60 years who represent the majority of [patients with] PTCL, generally less eligible for more intense therapies like autologous and allogeneic transplantation."
Response rates improved in elderly patients with peripheral T-cell lymphoma (PTCL) when alemtuzumab (Lemtrada) was added to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), but survival was not improved overall due to treatment-related toxicities, according to results of the phase III DSHNHL2006-1B/ACT-2 trial (NCT00725231).
Overall, objective responses were observed in 42 of the 58 patients in the alemtuzumab plus CHOP (A-CHOP) arm (72%; 95% CI, 59%-83%) versus in 38 of 58 patients in the control arm (66%; 95% CI, 52%-78%; P = .422).
“This randomized phase III study for the first time provides prospective long-term results on survival and other end points of interest after standard treatment with CHOP in patients with PTCL beyond 60 years who represent the majority of [patients with] PTCL, generally less eligible for more intense therapies like autologous and allogeneic transplantation,” the study authors wrote. “Moreover, it verifies data from retrospective analyses suggesting a significant impact of the IPI on survival also for patients with PTCL.”
Sixty percent of patients achieved a complete response (CR) with the addition of alemtuzumab to CHOP (95% CI, 47%-73%) versus 43% with CHOP alone (95% CI, 30%-57%; P = .063), and 12% versus 13% of patients had achieved a partial response, respectively. Stable disease was observed in 5% of patients in each arm, and progressive disease was observed more frequently in the control arm (29%) compared with the A-CHOP arm (19%).
Event-free survival (EFS) rate at 3 years was 27% in the experimental arm (95% CI, 15%-39%) versus 24% in the control arm (95% CI, 12%-35%; P = .248). Progression-free survival (PFS) rate at 3 years was 28% in those who received the addition of alemtuzumab (95% CI, 15%-40%) compared with 29% with CHOP alone (95% CI, 17%-41%; P = .537), and the 3-year overall survival (OS) rate was 37% (95% CI, 23%-50%) versus 56% (95% CI, 44%-69%; P = .079), respectively. However, these differences in PFS and OS were not significant.
Five-year EFS was 21% in the A-CHOP arm (95% CI, 9%-33%) versus 10% in the CHOP arm (95% CI, 0%-20%), PFS was 22% (95% CI, 10%-34%) versus 13% (95% CI, 1%-24%), and OS was 25% (95% CI, 12%-38%) versus 39% (95% CI, 23%-56%), respectively.
In terms of OS, Kaplan-Meier estimates suggested worse outcomes for patients who received the addition of alemtuzumab, and these results were confirmed in a multivariate Cox regression model adjusted for International Prognostic Index (IPI) factors for EFS (HR, 0.8; 95% CI, 0.5-1.2; P = .293), PFS (HR, 0.9; 95% CI, 0.6-1.4; P = .620), and OS (HR, 1.6; 95% CI, 1.0-2.7; P = .044). This was also confirmed in multivariate analyses with adjustments for IPI factors, age >70 years, bulky disease, and gender in terms of EFS (HR, 0.8; 95% CI, 0.5-1.1; P = .094), PFS (HR, 0.8; 95% CI, 0.5-1.2; P = .271), and OS (HR, 1.4; 95% CI, 0.9-2.4; P = .154).
Other prominent and significant risk factors for EFS, PFS, and OS included male sex for EFS (HR, 2.5; P<.001) and bulky disease for EFS (HR, 2.2; P =.019). No differences were observed for EFS, PFS, and OS among patients treated with alemtuzumab.
Thirty-nine patients in the A-CHOP arm versus 30 in the control arm died during the study; causes of death were lymphoma-related in 64% of patients versus 73% of patients, respectively.
Hematologic toxicities of grade 3/4 in severity were more common in the A-CHOP arm compared with the control, including grade 4 leukocytopenia observed in 70% versus 54% and grade 3/4 thrombocytopenia in 19% versus 13%, respectively. Alemtuzumab led to significant peripheral blood lymphocyte depletion after 3 courses of therapy, which was associated with more grade ≥3 infections in the A-CHOP arm (40%) than the control (21%; P = .026), mostly due to an increase in cytomegalovirus infections either alone or in combination with bacterial or fungal infections in the experimental arm.
The most common non-hematologic adverse event of grade 3 to 5 in severity was infections, occurring in 40% of patients in the experimental arm and 21% in the control arm, and others included diarrhea (9% vs 3%), neuropathy sensory (9% vs 7%), and cardiac general events (7% vs 2%), respectively.
Treatment-related deaths occurred in 5 patients, which were all caused by infections, including 4 patients in the experimental arm. The causes of death during therapy in 2 patients were due to hepatic failure due to systemic adenoviral infection and stenotrophomonas maltophilia pneumonia. Both lethal events had occurred late in the course of treatment following at least 5 rounds of A-CHOP.
The 3 other treatment-related deaths occurred early on during follow-up. Two deaths happened within the first 3 months of follow-up where 1 in the A-CHOP arm was due to combined candida pneumonia and stenotrophomonas septicemia and 1 in the CHOP arm due to CMV infection associated with hemophagocytic syndrome. The third patient who was in the A-CHOP arm died at 6 months of follow-up, which was due to CMV septicemia/encephalitis. Overall, 3 of 4 patients who died because of infectious complications after A-CHOP therapy had received 300, 300, and 360 mg doses of alemtuzumab, respectively, and the fourth patient had received 100 mg of the study drug.
Overall, 116 patients who were 61 to 80 years old with PTCL were randomized to receive either CHOP alone or in combination with alemtuzumab. Patients received alemtuzumab on day 1 at a dose of 360 mg in 21 patients or 120 mg in 37 patients in addition to the standard CHOP regimen for the experimental arm.
These data are in line with what has been previously reported in a prior small phase II study, but unfortunately the primary end point of the study, EFS, was not met in this trial. The addition of this therapy to the CHOP regimen was able to increase the response rates among elderly patients with PTCL, but survival due to treatment-related toxici was not improved.
Wulf GG, Altmann B, Ziepert M, et al; ACT-2 study investigators. Alemtuzumab plus CHOP versus CHOP in elderly patients with peripheral T-cell lymphoma: the DSHNHL2006-1B/ACT-2 trial [Published online May 7, 2020]. Leukemia. doi:10.1038/s41375-020-0838-5