2 research outputs found
Recommended from our members
Post-CAR-T Checkpoint Inhibition Can Result in Durable Responses in a Minority of Patients with Multiple Myeloma (MM) or Non-Hodgkin's Lymphoma (NHL): Results of a Phase 2 Study of Nivolumab after CAR-T Failure
While checkpoint inhibition may theoretically improve T-cell effector function following CAR-T failure, a prospective trial of pembrolizumab following CAR-T in non-Hodgkin lymphoma (NHL) showed an ORR of only 25% (Chong Blood 2022). Nivolumab (nivo) has not been studied prospectively in this setting, and the efficacy of post-CAR-T checkpoint inhibition in multiple myeloma (MM) has not been characterized.
We conducted a single-center phase 2 trial (NCT04205409) of nivo 480mg IV every 4 weeks for MM or NHL pts with relapse following any CAR-T product as last line of therapy. The primary endpoint was overall response rate (ORR). Secondary endpoints included AEs, immune-related AEs (irAEs), and CRS/ICANS. Other endpoints included PFS, CAR-T expansion following first nivo dose, and PD-L1/PD-1 IHC expression on tumor biopsies.
We enrolled 20 pts (11 MM, 9 NHL) as shown in Table 1. Prior to nivo, the best response to CAR-T had been CR in 64% of MM pts and 44% of NHL pts, while 1 MM pt and 1 NHL pt had had PD as best response. Median time from infusion to post-CAR-T relapse was 537 days (range 30-1100) in MM and 134 days (range 28-434) in NHL. Median time between CAR-T infusion & C1D1 nivo was 624 days (range 59-1211) in MM and 149 days (range 34-506) in NHL. The ORR was 15% overall: 18% (2/11) for MM and 11% (1/9) for NHL. In all 3 responders (Table 2), clinical benefit was evident following a single nivo dose. Both MM patients achieved VGPR by light chains within 4 weeks, with one also showing rapid resolution of an 8.6-cm plasmacytoma. For these two patients, median duration of response is 15 months (Table 2). The responding NHL patient [who had had a pre-enrollment Deauville Score (DS) 5 response at Day +60 following axi-cel] – achieved a complete response (DS3) one month following nivo initiation. Conversely, in all non-responders, PD was evident within one month of nivo as well. Two irAEs (one Gr2 pneumonitis, one Gr2 rash) occurred in non-responders, both of which resolved with brief courses of prednisone. CRS or ICANS did not occur following nivo initiation. There were 3 deaths within 100 days, all unrelated to treatment and all in non-responders: PD (n = 2) and hypotensive cardiac arrest without myocarditis (n = 1). The results of ongoing analyses with CAR T-cell expansion and PD-1 staining will be presented at the meeting.
To our knowledge, this is the first prospective evaluation of nivo following CAR-T failure. While our study's 18% ORR in MM was numerically higher than the 4% figure previously described with nivo monotherapy in R/R MM (Lesokhin JCO 2016), responses to PD-1 blockade following CAR-T failure in NHL were rare. irAEs were relatively uncommon and manageable with steroids, while CRS and ICANS did not occur. The durable responses achieved by a subset of MM patients is of interest, and further correlative analyses are ongoing to better understand the mechanism of response
Recommended from our members
Identification and Prediction of Severe Hematologic Toxicity after CAR T-Cell Therapy Using Machine Learning-Based Time-Series Clustering
Severe hematologic toxicity is a significant complication associated with CAR T-cell therapy, leading to infections, transfusion dependency, and mortality. Using data from >400 CAR T-cell patients (pts), we hypothesized a time-series clustering-based approach could: i) automate the identification of pts with impaired absolute neutrophil count (ANC) recovery, ii) enable the identification of factors associated with ANC recovery, and iii) assess predictive models of hematologic toxicity after CAR T-cell therapy.
Adults who received their first infusion of CAR T cells for hematologic malignancies with commercial or investigational products at our center (2013-2023) were included. ANC trajectories were clustered using non-supervised longitudinal k-means based on Euclidean distances. Sensitivity and specificity were computed based on the Youden criteria.
403 pts were included. The most common disease types were aggressive NHL (n = 161; 40%), indolent NHL (n = 82; 20%), ALL (n = 74; 18%), and MM/PCL (n = 44; 11%). The most common CAR T-cell products were investigational CD19 or CD20 CAR T-cell products (n = 174; 43%), axi-cel (n = 101; 25%), and liso-cel (n = 46; 11%).
The longitudinal ANC data clustered into 4 distinct trajectories: 1) very good recovery (high nadir followed by rapid recovery), n = 294 (73%); 2) good recovery (low nadir followed by rapid recovery), n = 87 (22%); 3) poor recovery (low nadir followed by intermittent recovery), n = 13 (3%); 4) very poor recovery (aplastic phenotype), n = 9 (2%) (Figure 1). Pts with poor/very poor ANC recovery had significantly shorter overall survival than those with good/very good recovery (median 3 vs. 19 months, p < 0.001; Figure 2). 100-day mortality in pts with in very good/good vs. poor/very poor recovery was 62% vs. 11%, respectively (p < 0.001). In univariate logistic regression, predictors of poor/very poor recovery included disease type and inflammatory biomarkers (Table 1).
Next, we assessed the ability of the CAR-HEMATOTOX score (high vs. low risk; Rejeski, Blood 2021) to predict poor/very poor ANC recovery. Due to missing data, day +0 rather than pre-lymphodepletion (LD) values were used for CRP and ferritin. The specificity and sensitivity of the CAR-HEMATOTOX were 31% and 100%, respectively. A logistic regression model using restricted cubic splines and including pre-LD ANC, peak CRP, and peak ferritin showed high discrimination (C-index: 0.91) with 74% specificity and 95% sensitivity.
We introduce an automated and scalable framework that successfully identifies pts with the most severe hematologic toxicity after CAR T-cell therapy, and specifically those displaying an “aplastic” trajectory. We identified key factors associated with poor ANC recovery. A new model including peak inflammatory biomarkers showed improved performance compared to the CAR-HEMATOTOX score