Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy approved for the treatment (Tx) of patients (pts) with R/R LBCL with ≥ 2 prior systemic therapies. In Cohorts 1+2 ...(C1+2) of the ZUMA-1 study, Grade ≥ 3 cytokine release syndrome (CRS) and neurologic events (NEs) occurred in 11% and 32% of pts, respectively (Locke FL et al, Lancet Oncol 2019). A nonrandomized safety expansion cohort (Cohort 4 C4) evaluated the impact of earlier steroid use on CRS and NE rates. Here we present the primary analysis of ZUMA-1 C4 with a greater number of pts and longer follow-up (F/U).
Eligible pts were leukapheresed, could receive optional bridging chemotherapy (not allowed in C1+2), and received conditioning chemotherapy before axi-cel infusion at a targeted 2 × 106 anti-CD19 CAR T cells/kg. C4 pts received early steroid intervention at Grade 1 NE and at Grade 1 CRS after 3 days of supportive care. Primary endpoints were incidence and severity of CRS and NEs. ORR and CAR T cell levels were compared across quartiles of tumor burden (TB).
As of May 6, 2019, 41 pts had received axi-cel, with a median F/U of 8.7 mo. Pts who received bridging therapy prior to axi-cel (68%) all had evidence of disease after bridging, documented by a new baseline PET/CT scan. The median age was 61 y (range, 19 – 77 y; 32% ≥ 65 y). The majority of pts (63%) had DLBCL; 49% had an ECOG 1; 70% had disease stage III/IV; 68% were refractory to ≥ 2nd-line therapy; 63% had ≥ 3 prior lines of therapy; and 20% had relapsed after ASCT. C4 pts had a lower median TB by sum of product diameters (SPD; C4: 2100 mm2; C1+2: 3723 mm2) and lower pre-Tx serum LDH level than C1+2 pts.
A greater proportion of C4 pts received steroids and tocilizumab vs C1+2 (73% and 76% vs 27% and 43%). Fewer C4 pts experienced Grade ≥ 3 CRS (2%) and NE (17%) than C1+2 pts. The ORR in C4 was 73% with a CR rate of 51%. Response was ongoing in C4 54% of pts with ≥ 6 mo F/U vs the 44% ongoing response rate at the primary analysis of C1+2 (also ≥ 6 mo F/U). Although most pts in C4 had lower SPDs than those in C1+2, responses were comparable when evaluated by TB. Median DOR was 8.9 mo, consistent with that observed for C1+2 (8.1 mo; Locke, AACR 2017; Figure). Median PFS was 11.7 mo; median OS was not reached. Peak CAR T cell levels were 42 cells/µL blood in C1+2 vs 59 cells/µL in C4. C1+2 had a median CAR AUC of 462 cells/µL × days vs 512 cells/µL in C4. CAR T cell expansion was comparable between cohorts when adjusted by TB. Levels of key NE-associated biomarkers including ferritin (pre- and post-Tx) and IL-2 (post-Tx) appeared lower in C4 than in C1+2.
Earlier steroid use may reduce the rates of CAR T cell Tx-related CRS and NEs without affecting efficacy. Conclusions are limited by the nonrandomized study design and differences in population sizes and baseline characteristics between cohorts. Optimizing AE management is important to improve the benefit–risk profile of CAR T cell therapy.
Background. Transformation to diffuse large cell lymphoma (DLCL) is a frequent event in patients with follicular lymphoma (FL), occurring in approximately 30–50% of patients. Upon transformation the ...prognosis of these patients is dismal, with a median overall survival of 1–2 years. However, a subset of patients does respond to aggressive chemotherapy regimens, including autologous stem cell transplantation and can achieve long-term disease-free survival. Currently, there are no prognostic factors reliably predicting response to treatment. We used gene expression profiling to identify a profile which can predict responsiveness to chemotherapy and long-term survival at transformation.
Patients and methods. From the pathology archives of the 4 participating institutions, 46 cases with transformation of FL were identified for whom frozen tissue was available. 11 cases were excluded from the analysis: 4 because of insufficient clinical information and 7 because the patients were not treated with aggressive chemotherapy regimens (defined as containing at least CHOP-like chemotherapy). RNA was extracted from frozen tissue. All samples were hybridized to cDNA microarray slides prepared at the Central Microarray Facility at the Netherlands Cancer Institute. The arrays contain 18336 biological transcripts as well as 864 control probes. Samples were cohybridized with a tonsil reference. Data analysis was performed in the statistical package R as well as with BrB array tools.
Results. Of the 35 patients, 62% was male. The median interval between the initial diagnosis of FL and transformation was 27 months (range 0–252; 4 patients had transformed FL at initial diagnosis). Median age at transformation was 52 years (range 32–78). Using hierarchical clustering, no clear separation of the cases was obtained. Of the 35 cases, 13 reached a CR or Cru and had an overall survival of >24 months (range 37–134+, median 60 months). 6 patients achieved a partial remission and had an overall survival of 12–24 months, and 16 patients had stable or progressive disease and died within 13 months (range 3–13, median 5.5 months). Using supervised analysis on patients grouped based on survival, a classifier with an accuracy of up to 88% accuracy could be reached in an LOOCV procedure.
An analysis of the most differentially expressed genes related to survival identified mostly genes involved in cell cycle, metabolism and immune related genes.
Conclusions. Using gene expression profiling a classifier can be constructed that can separate transformed FL with a long survival from transformed FL with a short survival. This classifier can help to identify patients who benefit from intensive chemotherapy. Functional annotation of the differentially expressed genes identified mostly genes involved in cell cycle control and metabolism, and immune related genes. We plan to validate this approach using immunohistochemistry.
Non-Hodgkin's lymphoma (NHL) forms a heterogeneous group of diseases. Tumor markers may help to identify high-risk patients who might benefit from more aggressive therapy. Serum soluble CD27 (sCD27) ...and thymidine kinase (TK) are potentially valuable markers, since sCD27 has previously been shown to be related to tumor load and TK to proliferation of malignant cells. We determined serum sCD27, TK, beta-2-microglobulin (beta(2)M) and lactic dehydrogenase (LD) levels at diagnosis in 79 lymphoma patients and correlated these parameters with the stage of disease, the International Prognostic Index (IPI) score and survival. Receiver operator characteristic (ROC) curve analysis showed an excellent ability for sCD27 to discriminate between low- and high-stage disease (p < 0.001), especially in indolent lymphomas. No discriminative value for TK, beta(2)M or LD was found. For aggressive NHL, sCD27, TK, beta(2)M and LD did predict survival in the univariate analyses. However, LD was found to be the most independent prognostic factor in a multivariate Cox regression model. In indolent lymphomas, sCD27 proved to be a powerful marker to predict progression-free survival (p = 0.008). Taken together, the results of the ROC curve and survival analysis suggest that substitution of LD by sCD27 in the IPI may be considered for indolent lymphomas to enhance the prognostic value. A study in a larger cohort of patients is required to validate this approach.
Tisagenlecleucel, a chimeric antigen receptor T-cell therapy, has demonstrated efficacy and manageable safety in adult patients (pts) with relapsed/refractory diffuse large B-cell lymphoma (r/r ...DLBCL) in the global, multicenter, pivotal, phase 2, JULIET trial (NCT02445248). The primary endpoint, overall response rate (ORR), was met at the interim analysis (ORR: 59% CR, 43%; PR, 16%). Here, we report an updated analysis with a median 19 mo follow-up.
Adult pts ≥18 y with r/r DLBCL that had progressed after ≥2 lines of therapy including rituximab and an anthracycline and who were ineligible for or failed autologous stem cell transplant (ASCT) were enrolled. Tisagenlecleucel was manufactured from autologous T cells at 2 facilities (Morris Plains, NJ, USA main cohort. and Leipzig, Germany cohort A) and provided to pts at 27 treatment centers in 10 countries across the globe. Efficacy analyses include all pts with ≥3 mo of follow-up or earlier discontinuation. Safety analyses include all infused pts.
In the JULIET study, 115 pts (99 in main cohort; 16 in cohort A) received a single dose of tisagenlecleucel infusion as of 21 May 2018. Prior to infusion, 90% of infused pts received bridging chemotherapy and 93% received lymphodepletion chemotherapy. Pts were a median 56 y (range, 22-76 y); 77% of pts had stage III/IV and 17% had double/triple-hit disease at the time of entry. Approximately half (51%) of pts had received ≥3 prior lines of chemotherapy (range, 1-6); 49% received prior ASCT. ORR was 54% (40% CR, 13% PR; 95% CI, 43%-64%) with a median follow-up of 19.3 mo post-infusion. Median duration of response (DOR) was not reached. The relapse-free probability was 66% (95% CI, 51%-78%) at 6 mo and 64% (95% CI, 48%-76%) at 12 or 18 mo. Consistent ORR was reported across prognostic subgroups (eg, prior ASCT; double/triple-hit lymphoma) and DOR was similar among age groups and disease status (Figure). Median OS was not reached for pts in CR and was 11.1 mo (95% CI, 6.6 mo-NE) for all infused pts. The probability of OS was 48% (95% CI, 38%-57%) at 12 mo and 43% (95% CI, 33%-53%) at 18 mo (max follow-up, 29 mo). No pts proceeded to allogeneic SCT or ASCT while in remission. During the first 8 wks post-infusion, grade 3/4 adverse events of special interest were cytopenias lasting >28 days (34%), cytokine release syndrome (CRS; 23%, by the Penn scale), infections (19%), febrile neutropenia (15%), neurologic events (11%; 1 case of grade 2 cerebral edema), and tumor lysis syndrome (2%). Tocilizumab was administered to 16% of pts with CRS, and no treatment-related death was reported.
This updated analysis with longer follow-up confirms earlier findings. Tisagenlecleucel produced a durable high ORR, consistent efficacy across all predefined subgroups, and had a manageable safety profile in pts with r/r DLBCL.
Follicular lymphoma (FL) is characterized by an indolent clinical course and frequent relapses. Transformation to more aggressive disease is common and one of the main causes of death. The time to ...transformation may vary widely and some patients show early transformation and a poor prognosis. Main questions in FL center on markers to predict transformation (and prognosis) at the time of diagnosis and to accurately assess the transformed phase to tailor the choice of therapy. Currently, prognostic stratification for actual aggressiveness and overall survival is based on histological grading and clinical criteria; however, in up to 30% of all cases these methods prove to be insufficient. Using 18k cDNA arrays, we analyzed gene-expression patterns of 135 cases of FL addressing both issues.
1) Using supervised classification on a training set of paired samples from the indolent and aggressive disease episodes and on an independent validation set, a 81-gene-expression profile was established that could, with an accuracy of 100% and 93% respectively distinguish indolent from aggressive disease. Importantly, in a third series of FL with ambiguous histological grade, precluding meaningful morphological guidance, the profile showed a 94% classification accuracy supporting the value of this method for practical clinical use. The profile consists of genes involved in cell cycle control, DNA synthesis and metabolism (upregulated in high-grade disease), T-cell related genes (upregulated in low-grade disease) and T-cell and macrophage activation markers, that are significantly upregulated upon transformation. This profile, however, did not predict future transformation in FL samples at diagnosis.
2) A separate analysis was performed in a selection of the biopsy samples of not previously treated patients with grade 1 and 2 FL with transformation to DLBCL within 7–22 months after diagnosis and no transformation with a minimum follow-up of 108 months. Supervised and unsupervised cluster analysis showed no differences between both groups exceeding the threshold of significance to construct a predictor profile with a validated significance, underlining the biological homogeneity of the study cohort. Direct comparison analysis on the basis of signal-to-noise ratio's suggested a discriminative role of the immune response with enhanced cytokine- and chemokine-mediated T-cell activation and antigen-processing in the extremes of the spectrum. However, differences were slight and the immune-response seemed to play a less distinctive role in patients with transformed disease after more than 3 years.
In conclusion, actual indolent and aggressive clinical behavior can be more reliably distinguished using a FL-stratification profile than the currently used histological grading and clinical criteria, and may provide an important alternative to guide the choice of therapy in FL patients both at presentation and at relapse. Although there may be subtle differences between rapidly transforming disease and long-term stable indolent disease, possible inherent variations are insufficient to reliably predict future transformation.
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