Relapsed Large B-cell Lymphoma Research Articles

CD19 CAR-T With Axicabtagene Ciloleucel in R/R Large B-Cell Lymphoma With/Without Prior Autologous Stem Cell Transplant.

Anti-CD19 CAR-T therapy has been a breakthrough in treatment of primary refractory or relapsed large B-cell lymphoma (r/r LBCL) and is poised to supplant previous second line of high dose chemotherapy and autologous stem cell transplantation (HDT/ASCT). However, in clinical practice, high risk patients with chemoimmunotherapy sensitive disease continue to receive salvage chemoimmunotherapy or cannot access CAR-T in a timely manner and thus may still proceed to HDT/ASCT. Little is known about clinical outcomes of CAR-T in patients who receive HDT/ASCT compared to those who are transplant-naïve. We conducted a retrospective study of patients with r/r LBCL who previously underwent HDT/ASCT or were transplant-naïve (n = 97) and received axicabtagene ciloleucel after at least 2 prior therapy lines between 1/1/2018 to 12/31/2021. Primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), nonrelapse mortality (NRM), and cumulative incidence of relapse/progression. 82 (84.5%) patients were transplant-naïve and 15 (15.5%) previously received HDT/ASCT. No differences were found in the incidence of high-grade cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome, length of hospital admission, or incidence of cytopenia at day 30. 90-day response, PFS, OS, cumulative incidence of relapse/progression, and NRM were not different. Factors that adversely affected outcomes were prior bridging therapy, elevated LDH or thrombocytopenia at time of lymphodepleting chemotherapy, and worse ECOG performance status. Prior treatment with HDT/ASCT does not compromise the safety and efficacy of anti-CD19 CAR-T therapy, suggesting a continued role for HDT/ASCT in treatment of select patients with r/r DLBCL.

ABCL-185 Mosunetuzumab wWth Polatuzumab Vedotin: Subgroup Analyses in Patients (pts) With Primary Refractory or Early Relapsed Large B-Cell Lymphoma (LBCL)

ABCL-185 Mosunetuzumab wWth Polatuzumab Vedotin: Subgroup Analyses in Patients (pts) With Primary Refractory or Early Relapsed Large B-Cell Lymphoma (LBCL)

Mosunetuzumab With Polatuzumab Vedotin: Subgroup Analyses in Patients (pts) With Primary Refractory or Early Relapsed Large B-Cell Lymphoma (LBCL)

Mosunetuzumab With Polatuzumab Vedotin: Subgroup Analyses in Patients (pts) With Primary Refractory or Early Relapsed Large B-Cell Lymphoma (LBCL)

Bendamustine is a safe and effective lymphodepletion agent for axicabtagene ciloleucel in patients with refractory or relapsed large B-cell lymphoma

BackgroundFludarabine in combination with cyclophosphamide (FC) is the standard lymphodepletion regimen for CAR T-cell therapy (CAR T). A national fludarabine shortage in 2022 necessitated the exploration of alternative regimens with...

Mosunetuzumab with polatuzumab vedotin: Subgroup analyses in patients (pts) with primary refractory or early relapsed large B-cell lymphoma (LBCL).

7021 Background: The primary analysis of mosunetuzumab with polatuzumab vedotin (mosun-pola) in the Phase Ib/II study (NCT03671018) demonstrated durable responses and manageable safety in pts with relapsed or refractory (R/R), transplant-ineligible LBCL (Budde et al. Nat Med 2023). Here, we present results for primary refractory (refr) or early relapse (rel) subgroups from this study after a median follow-up of 23.9 months. Methods: Pts with R/R LBCL (diffuse LBCL not otherwise specified [NOS], high-grade B-cell lymphoma [HGBCL], transformed follicular lymphoma (FL), and FL grade 3b) and who received ≥1 prior line of therapy (including an anti-CD20 antibody) were treated with mosun-pola. Refr was defined as SD, PD, PR, or CR with relapse <3 months after first-line (1L) therapy. Rel was defined as CR with relapse ≥3 and ≤12 months after 1L therapy. The primary endpoint was best overall response rate (ORR) by IRC using Lugano 2014 response criteria. Key secondary endpoints included CR rate, duration of response (DOR), duration of CR (DOCR), progression-free survival (PFS), overall survival (OS), and safety. Results: As of July 6, 2023, of the 98 pts in the overall population, 45 (46%) and 27 (28%) pts had refr or rel LBCL, respectively. At baseline, the median age in the refr and rel subgroups was 68 and 70 years respectively; 23/45 pts (51%) and 6/27 pts (22%) were treated with mosun-pola as second-line, respectively. The majority of refr/rel pts had DLBCL NOS (71%; 78%) or HGBCL (24%; 19%), Ann Arbor stage III/IV (80%; 89%), elevated LDH (55%; 48%), and extranodal involvement (67%; 59%). In refr pts, the ORR was 49%, which was generally consistent with the overall population (59%); although the sample size was limited, higher responses (ORR: 74%) were observed in rel pts. Additional clinical outcomes are reported (Table). The safety profile was consistent with the overall population. Grade 3 CRS occurred in one pt in each subgroup. Treatment-related ICANS-like events occurred in 2/45 pts (4%; refr) and 3/27 pts (11%; rel). Conclusions: Mosun-pola demonstrated durable benefits in ORR and CR rates irrespective of a poor response to 1L treatment. Outcomes for pts with refr or rel LBCL are encouraging. Clinical trial information: NCT03671018 . [Table: see text]

Treatment strategies for relapse after CAR T-cell therapy in B cell lymphoma.

Clinical trials of anti-CD19 chimeric antigen receptor T (CART19) cell therapy have shown high overall response rates in patients with relapsed/refractory B-cell malignancies. CART19 cell therapy has been approved by the US Food and Drug Administration for patients who relapsed less than 12 months after initial therapy or who are refractory to first-line therapy. However, durable remission of CART19 cell therapy is still lacking, and 30%-60% of patients will eventually relapse after CART19 infusion. In general, the prognosis of patients who relapse after CART19 cell therapy is poor, and various strategies to treat this patient population have been investigated extensively. CART19 failures can be broadly categorized by the emergence of either CD19-positive or CD19-negative lymphoma cells. If CD19 expression is preserved on the lymphoma cells, a second infusion of CART19 cells or reactivation of previously infused CART19 cells with immune checkpoint inhibitors can be considered. When patients develop CD19-negative relapse, targeting different antigens (e.g., CD20 or CD22) with CAR T cells, investigational chemotherapies, or hematopoietic stem cell transplantation are potential treatment options. However, salvage therapies for relapsed large B-cell lymphoma after CART19 cell therapy have not been fully explored and are conducted based on clinicians' case-by-case decisions. In this review, we will focus on salvage therapies reported to date and discuss the management of relapsed/refractory large B-cell lymphomas after CART19 cell therapy.

Re-examining the role of hematopoietic stem cell transplantation in relapsed large B-cell lymphoma in the era of chimeric antigen receptor (CAR) T-cell therapy.

Historically, salvage chemoimmunotherapy with consolidative autologous hematopoietic stem cell transplantation (ASCT) was the only potentially curative therapeutic option for patients with relapsed/refractory large B-cell lymphoma (LBCL). Treatment options were few and outcomes poor for patients whose lymphoma failed to respond to salvage chemotherapy/ASCT and for patients not eligible for ASCT. The approval of chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory LBCL revolutionized the treatment landscape with unprecedented response rates and durability of responses. As a result, earlier intervention with CAR T-cell therapy has been explored, and the enthusiasm for CAR T-cell therapy has overshadowed ASCT. In this article, we will review the data available for ASCT and CAR T-cell therapy in relapsed LBCL and will examine the role for ASCT in relapsed/refractory LBCL in the era of CAR T-cell therapy.

Circulating Tumor DNA Dynamics as Early Outcome Predictors for Lisocabtagene Maraleucel as Second-Line Therapy for Large B-Cell Lymphoma from the Phase 3 TRANSFORM Study

Background: While the prognostic value of MRD using ultrasensitive circulating tumor DNA (ctDNA) assays after first-line immunochemotherapy for DLBCL has been shown (Roschewski M, et al. Blood 2022;140[suppl 1]:785), its relevance to outcomes after second-line (2L) treatment with CD19-directed CAR T cell therapy remains unclear. The phase 3 TRANSFORM study (NCT03575351) showed statistically significant and clinically meaningful improvements in event-free survival (EFS), CR rate, and PFS for lisocabtagene maraleucel (liso-cel) compared with standard of care (SOC) for patients (pts) with primary refractory or early relapsed large B-cell lymphoma (LBCL) eligible for autologous HSCT (Kamdar M, et al. Lancet 2022; Abramson JS, et al. Blood 2023). Here, we report longitudinally measured ctDNA levels from TRANSFORM as a prospective measure of disease burden and describe the predictive value of ctDNA after 2L liso-cel therapy for LBCL. Methods: From the original randomized population (n = 184), 551 plasma samples from 160 pts (liso-cel, n = 79; SOC, n = 81) were used for ctDNA assessment in a blinded manner by Phased Variant (PV) Enrichment and Detection Sequencing (PhasED-Seq) at Foresight Diagnostics. Tumor-derived PVs were identified directly from baseline plasma samples taken at screening without use of tumor tissue; matched DNA from peripheral blood mononuclear cells was used to censor germline variants and clonal hematopoiesis. PVs were used to longitudinally assess ctDNA on the day of liso-cel infusion; at Day 15; and Months 1, 2, 3, and 12 after infusion. For the SOC arm, only pretreatment samples were evaluated. ctDNA levels were compared with baseline characteristics, responses by Lugano 2014 criteria, and EFS. Pts/samples were reported as having detectable MRD when ctDNA levels exceeded a detection threshold (≈1:10 6 cell-free DNA molecules) corresponding to 98% specificity. Results: PVs were identified from 136 of 160 pts (85%) with evaluable pretreatment samples from the liso-cel and SOC treatment arms. The remaining samples had lower disease burden (sum of product of diameters[SPD]; 13%) or failed quality check (2%). Pretreatment ctDNA levels varied widely (median [IQR]: 136 [35‒696] haploid genome equivalents/mL) and were correlated with disease indices portraying higher-risk disease, including stage ( P = 0.02), age-adjusted International Prognostic Index ( P < 0.0001), disease burden (SPD; P < 0.0001), and LDH ( P < 0.0001). Serial ctDNA levels were evaluated after liso-cel infusion in 63 pts. Achieving undetectable ctDNA was associated with achieving CR and longer EFS at all time points after liso-cel infusion. ctDNA levels decreased rapidly in pts who achieved CR at Month 3, with 50% (17/34) having undetectable ctDNA by Day 15 after liso-cel infusion. Conversely, 89% of pts (16/18) with PD at Month 3 still had detectable ctDNA at Day 15 with lower levels of ctDNA clearance. These results highlight significant enrichment of undetectable ctDNA observed as early as Day 15 after infusion between pts with Month 3 CR versus PD ( P = 0.006). ctDNA clearance in pts who achieved CR at Month 3 continued to deepen further over time, with undetectable ctDNA rates of 63%, 74%, and 86% at 1, 3, and 12 months after liso-cel infusion, respectively. Furthermore, most pts in CR by PET/CT had undetectable ctDNA at paired time points (71%), confirming that pts achieving CR also achieved durable molecular remission. In the cases with discordant CR and ctDNA results, detection of residual ctDNA was significantly prognostic for shorter EFS at all respective response assessments (fraction of CR cases with residual ctDNA at 1 month and Log-rank test P value for EFS: 47% [15/32], P = 0.011; 3 months: 26% [9/34], P = 0.025; 12 months: 13% [4/31], P = 0.003). Conclusions: Achieving undetectable ctDNA in the first 3 months and as early as 15 days after liso-cel infusion was significantly associated with durable clinical benefit. Conversely, detectable ctDNA captured relapse risk unmeasured by imaging. These results demonstrate the potential clinical value of ctDNA monitoring as a biomarker for disease surveillance and as an early predictor of clinical benefit of liso-cel treatment for LBCL, which could guide and accelerate future clinical trials.

Total Body Irradiation Versus Chemotherapy-Only Conditioning in Autologous Hematopoietic Stem Cell Transplantation for Large B-Cell Lymphoma

Introduction Recent data suggest that compared with high-dose chemotherapy conditioning and autologous stem cell transplant (ASCT), CD19-chimeric antigen receptor (CAR) T-cell therapy as second-line therapy improves outcomes in patients with primary refractory or early relapsed large B-cell lymphoma (LBCL). However, more than half of patients will not attain a long-term remission with CAR T-cell therapy, and may subsequently be considered for ASCT, indicating an unmet need for alternative therapies including strategies to improve ASCT outcomes. Given that LBCL is radioresponsive, we evaluated whether total body irradiation (TBI)-based conditioning may improve outcomes compared to chemotherapy-only conditioning among LBCL patients who underwent peripheral blood ASCT at our institution. Methods We reviewed the records of adults with relapsed/refractory LBCL who underwent ASCT at Fred Hutch Cancer Center between 2012-2021. LBCL was categorized as de novo DLBCL, transformed DLBCL, and double-hit lymphoma (DHL). Patients with primary CNS lymphoma were excluded. Given that TBI is generally reserved for younger patients (≤ 60 years), we excluded patients in the chemo-only group older than the oldest patient in the TBI group (58.7 years) to reduce the bias due to age differences. The hazards for failure for progression-free survival (PFS) and for overall mortality (OM) were compared between TBI-based and chemo-only groups using Cox regression with adjustment for clinically important variables including age, sex, histology, LDH at ASCT, conditioning type, PET positivity at the time of ASCT and year of ASCT. LDH at ASCT, age and year of ASCT were modeled as continuous linear variables. Results Among 225 patients, we excluded 121 patients in the chemo-only group who were older than 58.7 years, leaving 104 patients for the analysis ( Table 1). A total of 48 (46%) patients received TBI-based and 56 (54%) received chemo-only conditioning. All patients in the TBI group received 12 Gy in 6-8 fractions. Most patients (n=46, 82.14%) in the chemo-only group received BEAM conditioning. Patients receiving TBI-based conditioning had more adverse features including male sex (72.9% vs 58.9%), DHL histology (31.3% vs 7.1%), and PET-positive disease at the time of ASCT (39.6% vs 23.2%). With a median follow-up of 51.2 months (range 1.3-134.2) among survivors, point estimates of PFS at 2 and 5 years were 74.3% and 66.3%, respectively among TBI patients and 68.5% and 64.0%, respectively among the chemo-only patients ( Figure 1). Time to engraftment was similar between the groups. On multivariable analysis, compared to chemo-only conditioning, TBI was not associated with improved PFS (TBI vs chemo-only: HR 1.02, 95%CI 0.45-2.31, P=0.96) or OS (HR 0.85, 95%CI 0.37-1.98, P=0.7). Predictors of worse PFS were PET positivity at the time of ASCT (HR 3.39, 95%CI 1.61-7.17, P < 0.01) and higher LDH (HR 1.0011, 95%CI 1.0002-1.0020, P=0.02). Similarly, both PET positivity (HR 3.12, 95%CI 1.47-6.63, P<0.01) and higher LDH (HR 1.0013, 95%CI 1.0003-1.0022, P <0.01) were associated with worse OS. Age, sex, histology and year of ASCT were not significant. Conclusions Despite worse prognostic factors, TBI-based conditioning yielded similar outcomes compared to chemo-only conditioning for patients with relapsed/refractory LBCL undergoing ASCT. These results confirm prior findings from a registry-based study. Although a proportion of patients may achieve a long-term remission with ASCT, other strategies are needed to improve ASCT outcomes.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Central nervous system (CNS) involvement in patients with refractory or relapsed large B-cell lymphoma (LBCL) is associated with an extremely poor prognosis. Autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is an approved treatment for patients with refractory or relapsed (R/R) LBCL that has changed the prognosis of patients with chemoresistant LBCL. However, data regarding efficacy and safety of CART cell treatment in patients with active CNS involvement are limited since they are excluded from most of clinical trials. Methods: We retrospectively collected data from 75 patients with LBCL, treated with CART cells from January 2020 to January 2023 in Henri Mondor Hospital. We identified 13 patients with active CNS involvement at the time of CAR-T cell treatment decision: 12/13 had abnormal neurological examination, 8/11 had head and/or medullar MRI abnormalities consistent with lymphoma and 9/10 had detectable lymphoma cells in the cerebrospinal fluid. We compared the characteristics of the 13 patients with CNS involvement (CNS+) with 62 patients without evidence of active CNS disease (CNS-). Median age was 69 and 59 years, respectively (p = 0.05). CNS+ patients received a median of 2 previous lines of treatment versus 3 for CNS- patients (p = 0.34). Performance status prior to CART-cell injection was 2 or more in 9/13 (69%) and 11/62 (18%) p < 0.001, respectively. 5/13 (38%) CNS+ patients had high grade B-cell lymphomas versus 11/62 (18%) CNS- (p = 0.13). CAR-T-cell was axi-cel in 10/13 (77%) CNS+ patients versus 42/62 (68%) CNS– (p = 0.74). It is noteworthy that 7/13 (54%) CNS+ patients had pre-existing low-grade B-cell lymphomas versus 15/62 (24%) CNS- (p = 0.046). Results: The best overall response rate was identical in both groups: 12/13 (92%) in CNS+ patients versus 51/61 (92%) in CNS-, including 11/13 (85%) and 44/61(72%) complete metabolic response. As shown in the figure, median progression free survival and overall survival was 5.5 and 8.4 months, respectively in CNS+ patients versus 11.5 and 21 months in CNS- patients (not significant). Regarding safety, 13/13 (100%) CNS+ patients had a cytokine release syndrome (10 grade 1–2 and 3 grade 3) versus 54/62 (87%) CNS- (49 grade 1–2 and 5 grade 3–4) and 10/13 (77%) experienced ICANS (6 grade 1–2 and 4 grade 3–4) versus 28/62 (45%) CNS- (27 grade 1–2 and 1 grade 3–4) (p = 0.06 and 0.02 for grade 3–4). Transfer into an intensive care unit occurred in 4/13 (31%) CNS+ patients versus 9/62 (15%) CNS- (p = 022). Median time of hospitalization was 37 days for CNS+ patients versus 20 days for CNS- patients (p = 0.007). Six CNS+ patients died from which 5 died of progression and 1 of infection. Keywords: Aggressive B-cell non-Hodgkin lymphoma, Cellular therapies, Immunotherapy Conflicts of interests pertinent to the abstract. F. Lemonnier Consultant or advisory role: BMS, Kiowa, Miltenyi Educational grants: Gilead, Janssen, Roche L. Roulin Educational grants: Kite gilead, Novartis, Bristol myers squibb

Survival Outcomes for High Risk Primary Refractory and Relapsed Large B-Cell Lymphoma (LBCL) within the Veterans Health Administration (VHA)

Introduction: Even in the Rituxan era, patients with primary refractory or relapsed LBCL have poor outcomes. The standard of care for these patients is salvage therapy (ST) as second-line treatment followed by high dose therapy with autologous stem cell transplant (ASCT) in chemosensitive patients with an estimated 30-40% of ST responders deemed eligible to undergo transplant (PMID: 28774879). Currently, chimeric antigen receptor (CAR) T-cell therapy is the standard of care for high risk LBCL (high International Prognostic Index (IPI), HIT status) who do not respond to ST and have manageable safety profiles and high efficacy. Promising CAR T data is also emerging for early chemotherapy failure and as alternative second-line therapy (PMID: 35314842). The purpose of this study is to analyze the treatment patterns and survival outcomes of primary refractory and relapsed population of LBCL within the VHA. Methods: This is a retrospective chart review of 5199 randomly selected patients with an ICD code for lymphoma treated within the VHA between 01/01/2011 and 12/31/2019. Data abstractors included patients with LBCL who completed first-line chemotherapy treatment and had documented post-treatment scans (PET, CT). We defined primary refractory as either stable disease (SD) or progressive disease (PD) based on post-treatment scans and relapsed disease as recurrence of disease within 12 months of post treatment scans. Median overall survival (OS) was calculated using the Wilcoxon-Mann-Whitney test. Results: A total of 2288 patients met inclusion criteria who received or completed treatment at the VHA. Baseline characteristics are outlined in Table 1. From our analysis, 299 (13.1%) of patients were primary refractory. Median age was 68.9 years and 97% were male. European Cooperative Oncology Group (ECOG) was 0-2 (81.3%). Stage at diagnosis was III-IV (83.9%). Most patients had an IPI score ≥3 (85%). Germinal center B-Cell (GCB) accounted for 48.2% while Activated B-Cell (ABC) was 24.4%. Gene rearrangement was present in 26% of the patients with available data. Of the 119 (63.9%) patients who received second line treatment, only 19 (6.4%) were able to receive high dose chemotherapy and underwent an ASCT and only 3 (1%) of patients received CAR T-cell therapy. One year and two year overall survival was 47.8% and 24.7% respectively. Median OS for this population was 11.0 months. There were 105 (4.6%) relapsed patients in our cohort. Median age was 64.7 years and 96.2% were male. ECOG was 0-2 (85.7%). Stage at diagnosis was III-IV at 84.8%. Most patients had an IPI score ≥3 (80%). GCB accounted for 37.1% while ABC was 35.2%. Gene rearrangement was present for 20% of the patients with available data. In this group, 16 (15.2%) of patients received high dose chemotherapy and ASCT and only 3 (2.9%) received CAR T-cell therapy. One year and two year overall survival was 72% and 41% respectively. Median OS for this population was 21.3 months. 1403 (61%) of patients had complete response (CR) with a 1 and 2 year survival rate of 97 % and 93 % respectively and median OS of 69.3 months. Conclusion: This is one of largest data sets studying the rate of primary refractory and relapsed LBCL in the VHA and shows that more than two-thirds of these patients have high risk disease. Furthermore, a significant portion of these veterans did not receive second-line therapy including ASCT as compared to previously reported real world and clinical trial data. It is possible that our patient populations had higher rates of chemoresistance, were deemed ineligible for transplant due to age or performance status, or had higher comorbidities. Emerging data on newer antibodies and CAR T-cell therapy for early chemotherapy failure or second-line therapy might be a more appropriate option for our veteran population. In conclusion, CAR T-Cell therapy will likely replace the treatment paradigm for primary refractory or relapsed disease for early treatment failures in patients with LBCL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Lymphoma tumor burden before chimeric antigen receptor T-Cell treatment: RECIL vs. Lugano vs. metabolic tumor assessment.

PurposeHigh tumor burden has emerged as a negative predictor of efficacy in chimeric antigen receptor T-cell therapy (CART) in patients with refractory or relapsed large B-cell lymphoma. This study analyzed the deviation among imaging-based tumor burden (TB) metrics and their association with progression-free (PFS) and overall survival (OS).Materials and methodsIn this single-center observational study, we included all consecutively treated patients receiving CD19 CART with available baseline PET-CT imaging. Imaging-based TB was determined based on response evaluation criteria in lymphoma (RECIL), the Lugano criteria, and metabolic tumor volume. Total, nodal and extranodal TB were represented, according to the respective criteria, by sum of longest diameters (TBRECIL), sum of product of perpendicular diameters (TBLugano), and metabolic tumor volume (TBMTV). Correlation statistics were used for comparison. Proportional Cox regression analysis studied the association of TB metrics with PFS and OS.Results34 consecutive patients were included (median age: 67 years, 41% female) with total median baseline TBRECIL of 12.5 cm, TBLugano of 4,030 mm2 and TBMTV of 330 mL. The correlation of TBRECIL and TBLugano with TBMTV was strong (ρ=0.744, p<0.001 and ρ=0.741, p<0.001), with lowest correlation for extranodal TBRECIL with TBMTV (ρ=0.660, p<0.001). Stratification of PFS was strongest by total TBMTV>50% (HR=2.915, p=0.042), whereas total TBRECIL>50% and total TBLugano>50% were not significant (both p>0.05). None of the total TB metrics were associated with OS (all p>0.05).ConclusionPre-CART TB metrics vary significantly based on the assessment method, impacting their association with survival outcomes. The correlation between TBRECIL, TBLugano and TBMTV was influenced by disease phenotype and prior bridging therapy. TB method of assessment must be considered when interpreting the impact of TB on outcomes in clinical trials. Considering the heterogeneity, our results argue for standardization and harmonization across centers.

Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): results from an interim analysis of an open-label, randomised, phase 3 trial

Patients with large B-cell lymphoma (LBCL) primary refractory to or relapsed within 12 months of first-line therapy are at high risk for poor outcomes with current standard of care, platinum-based salvage immunochemotherapy and autologous haematopoietic stem cell transplantation (HSCT). Lisocabtagene maraleucel (liso-cel), an autologous, CD19-directed chimeric antigen receptor (CAR) T-cell therapy, has previously demonstrated efficacy and manageable safety in third-line or later LBCL. In this Article, we report a prespecified interim analysis of liso-cel versus standard of care as second-line treatment for primary refractory or early relapsed (within 12 months after response to initial therapy) LBCL. TRANSFORM is a global, phase 3 study, conducted in 47 sites in the USA, Europe, and Japan, comparing liso-cel with standard of care as second-line therapy in patients with primary refractory or early (≤12 months) relapsed LBCL. Adults aged 18-75 years, Eastern Cooperative Oncology Group performance status score of 1 or less, adequate organ function, PET-positive disease per Lugano 2014 criteria, and candidates for autologous HSCT were randomly assigned (1:1), by use of interactive response technology, to liso-cel (100 × 106 CAR+ T cells intravenously) or standard of care. Standard of care consisted of three cycles of salvage immunochemotherapy delivered intravenously-R-DHAP (rituximab 375 mg/m2 on day 1, dexamethasone 40 mg on days 1-4, two infusions of cytarabine 2000 mg/m2 on day 2, and cisplatin 100 mg/m2 on day 1), R-ICE (rituximab 375 mg/m2 on day 1, ifosfamide 5000 mg/m2 on day 2, etoposide 100 mg/m2 on days 1-3, and carboplatin area under the curve 5 [maximum dose of 800 mg] on day 2), or R-GDP (rituximab 375 mg/m2 on day 1, dexamethasone 40 mg on days 1-4, gemcitabine 1000 mg/m2 on days 1 and 8, and cisplatin 75 mg/m2 on day 1)-followed by high-dose chemotherapy and autologous HSCT in responders. Primary endpoint was event-free survival, with response assessments by an independent review committee per Lugano 2014 criteria. Efficacy was assessed per intention-to-treat (ie, all randomly assigned patients) and safety in patients who received any treatment. This trial is registered with ClinicalTrials.gov, NCT03575351, and is ongoing. Between Oct 23, 2018, and Dec 8, 2020, 232 patients were screened and 184 were assigned to the liso-cel (n=92) or standard of care (n=92) groups. At the data cutoff for this interim analysis, March 8, 2021, the median follow-up was 6·2 months (IQR 4·4-11·5). Median event-free survival was significantly improved in the liso-cel group (10·1 months [95% CI 6·1-not reached]) compared with the standard-of-care group (2·3 months [2·2-4·3]; stratified hazard ratio 0·35; 95% CI 0·23-0·53; stratified Cox proportional hazards model one-sided p<0·0001). The most common grade 3 or worse adverse events were neutropenia (74 [80%] of 92 patients in the liso-cel group vs 46 [51%] of 91 patients in the standard-of-care group), anaemia (45 [49%] vs 45 [49%]), thrombocytopenia (45 [49%] vs 58 [64%]), and prolonged cytopenia (40 [43%] vs three [3%]). Grade 3 cytokine release syndrome and neurological events, which are associated with CAR T-cell therapy, occurred in one (1%) and four (4%) of 92 patients in the liso-cel group, respectively (no grade 4 or 5 events). Serious treatment-emergent adverse events were reported in 44 (48%) patients in the liso-cel group and 44 (48%) in the standard-of-care group. No new liso-cel safety concerns were identified in the second-line setting. There were no treatment-related deaths in the liso-cel group and one treatment-related death due to sepsis in the standard-of-care group. These results support liso-cel as a new second-line treatment recommendation in patients with early relapsed or refractory LBCL. Celgene, a Bristol-Myers Squibb Company.

Abstract CT166: Pretreatment (PreTx) immune cell phenotypes in peripheral blood associated with the tumor immune contexture, product attributes, and durable clinical efficacy in patients with large B-cell lymphoma (LBCL) treated with axicabtagene ciloleucel (axi-cel)

Abstract Background: Conventional prognostic factors for LBCL were not associated with outcomes in the pivotal ZUMA-1 study of axi-cel in relapsed LBCL (Neelapu et al. NEJM. 2017); however, other attributes like chimeric antigen receptor (CAR) T-cell fitness and composition (CCR7+CD45RA+ T cells), reduced preTx tumor burden, and immune tumor microenvironment (TME) with presence of activated CD8+PD-1+LAG-3+/-TIM-3- T cells were associated with efficacy (Locke et al. Blood Adv. 2020; Galon et al. ASCO 2020. #3022). Here, we evaluated preTx immune cell phenotypes in premanufacturing apheresis (premfg aph) material, comprising peripheral blood mononuclear cells, to determine associations with product attributes, immune TME features, and clinical efficacy in ZUMA-1. Methods: Evaluable samples from patients (pts) in Phase (Ph) 1 and Ph2 Cohorts (C) 1-3 were analyzed (NCT02348216; Ph1 and Ph2 C1+2, ≥2-y follow-up; C3, ≥6-mo follow-up). Memory T, myeloid, NK, NKT, and B cells in premfg aph material (n=101, excluding C3) were characterized by flow cytometry (FC). PreTx immune TME was analyzed by multiplex IHC (n=18) and gene expression analysis (n=30) as previously described (Rossi et al. AACR 2018. #LB-016; Galon et al. ASCO 2020. #3022). CAR T-cell fitness was analyzed by doubling time, viability during manufacturing, and product T-cell phenotypes by FC (n=145). Associations between these covariates, and with routine hematology tests, were performed by Spearman rank correlation or Wilcoxon tests. Effects on survival were assessed by Kaplan-Meier with optimized cutpoint selection. Results: The percentage (%) of naive (CCR7+CD45RA+) T helper (Th; CD4+CD127+CD25low) cells coexpressing CD27 and CD28 (median, 1%; range, 0.01%-15.8%; IQR, 0.3%-3.8%) in aph associated positively with axi-cel efficacy. The % of intermediate monocytes (IMs; CD14+CD16+; median, 1.8%; range, 0.003%-16.7%; IQR, 1%-3%) in aph associated negatively with efficacy. The % of circulating CD27+CD28+ naive Th cells associated positively with an enriched preTx immune TME T-cell signature, % CCR7+CD45RA+ product T cells, objective response rate, PFS, and OS. An increased % of IMs associated directly with negative predictive markers (preTx serum levels of LDH, IL-6, and CRP) and inversely with TME T-cell signature, PFS, and OS. The premfg ratio of CD27+CD28+ naive Th cells/IMs associated directly with CAR T-cell expansion and efficacy. Conclusions: This work points to a link between the pre-existing state of the immune system, reflected in premfg aph, and immune TME, as well as product attributes influencing axi-cel efficacy in LBCL. These data bear practical implications towards the development of predictive biomarkers for axi-cel efficacy. [JB and JC contributed equally.] Citation Format: Justin Budka, Justin Chou, Vicki Plaks, Francesca Milletti, Zixing Wang, Frederick L. Locke, Sattva S. Neelapu, David B. Miklos, Caron A. Jacobson, Lazaros J. Lekakis, Yi Lin, Armin Ghobadi, Zahid Bashir, Nathalie Scholler, Jérôme Galon, John M. Rossi, Adrian Bot. Pretreatment (PreTx) immune cell phenotypes in peripheral blood associated with the tumor immune contexture, product attributes, and durable clinical efficacy in patients with large B-cell lymphoma (LBCL) treated with axicabtagene ciloleucel (axi-cel) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT166.

Immune reconstitution and infectious complications following axicabtagene ciloleucel therapy for large B-cell lymphoma

Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 has significantly improved outcomes in the treatment of refractory or relapsed large B-cell lymphoma (LBCL). We evaluated the long-term course of hematologic recovery, immune reconstitution, and infectious complications in 41 patients with LBCL treated with axicabtagene ciloleucel (axi-cel) at a single center. Grade 3+ cytopenias occurred in 97.6% of patients within the first 28 days postinfusion, with most resolved by 6 months. Overall, 63.4% of patients received a red blood cell transfusion, 34.1% of patients received a platelet transfusion, 36.6% of patients received IV immunoglobulin, and 51.2% of patients received growth factor (granulocyte colony-stimulating factor) injections beyond the first 28 days postinfusion. Only 40% of patients had recovered detectable CD19+ B cells by 1 year, and 50% of patients had a CD4+ T-cell count <200 cells per μL by 18 months postinfusion. Patients with durable responses to axi-cel had significantly longer durations of B-cell aplasia, and this duration correlated strongly with the recovery of CD4+ T-cell counts. There were significantly more infections within the first 28 days compared with any other period of follow-up, with the majority being mild-moderate in severity. Receipt of corticosteroids was the only factor that predicted risk of infection in a multivariate analysis (hazard ratio, 3.69; 95% confidence interval, 1.18-16.5). Opportunistic infections due to Pneumocystis jirovecii and varicella-zoster virus occurred up to 18 months postinfusion in patients who prematurely discontinued prophylaxis. These results support the use of comprehensive supportive care, including long-term monitoring and antimicrobial prophylaxis, beyond 12 months after axi-cel treatment.

Expression of B and T Lymphocyte Attenuator (BTLA) Correlates with CNS Metastasis and Adverse Prognosis in Activated B-Cell Lymphoma and Acute Lymphoblastic Leukemia

Background. The genetic factors that contribute to dissemination and relapse in aggressive lymphomas and acute lymphoblastic leukemia (ALL) are incompletely defined. We tested the hypothesis that shared molecular pathways contribute to drug resistance and metastasis in three distinct types of lymphoid neoplasms: large B-cell lymphoma, primary central nervous system lymphoma (PCNSL, DLBCL) and ALL.Methods. We used a variety of approaches involving high-resolution array-based comparative genomic hybridization, patient-derived cell lines, murine tumor models, diagnostic tumor specimens, and clinical outcome data sets to interrogate the biological significance of candidate mediators of relapse and CNS metastasis.Results. We first tested the hypothesis that genomic aberrations may contribute to the refractory phenotype in aggressive B-cell lymphoma. To pursue this, we compared DNA copy number aberrations in relapsed large B-cell lymphoma that had metastasized to the brain (3 cases, each isolated by resection) with the genomic changes identified in large B-cell lymphoma at diagnosis (15 cases: 12 PCNSL and 3 nodal lymphomas; all DLBCL). We identified a focal recurrent copy number gain at chromosome 3q encoding two candidate proteins: SIDT1, a mediator of microRNA transport, and BTLA, a member of the CD28 superfamily and modifier of both B-cell receptor signaling as well as T-cell responses. Elevated BTLA transcript and protein expression in relapsed specimens was confirmed. We also demonstrated by immunohistochemistry that tumor cell expression of BTLA but not SIDT1 correlated with short overall survival in an independent set of 40 patients with PCNSL treated uniformly with an immunochemotherapy protocol. Using independent databases of systemic DLBCL (n=203 and 69 respectively, Lenz et al. PNAS 2008; Shaknovich et al. Blood 2010), we determined that expression of both BTLA and SIDT1 were significantly higher in ABC compared to GCB DLBCL (p<0.0001) and, in an independent cohort of 73 ABC DLBCL cases, high BTLA expression was associated with a trend towards shorter overall survival (P=0.059). Finally, high BTLA transcript levels, but not SIDT1, correlated with significantly shorter overall survival in both ALL and Ph+ALL in ECOG E2993 (n=215, Geng el al. Cancer Discovery 2012), and with minimal residual disease in COG P9906 (n=207, Harney et al. Blood 2010). In addition, we used flow-cytometry to demonstrate that BTLA was strongly expressed by patient-derived cell lines of primary and secondary CNS lymphoma as well as Ph+ALL. In a murine model of spontaneous CNS metastasis involving patient-derived ABC DLBLC cells, we demonstrated that tumor cell clones that homed to the CNS meninges after flank implantation displayed higher BTLA expression compared to lymphoma cells that metastasized to spleen. Finally, we demonstrated that in a murine model of ALL, genetic deletion of BTLA was associated with impaired ALL cell proliferation and colony formation in vitro. By contrast, BTLA deficiency had no functional consequences in a murine model of CML.Conclusions. Taken together these data suggest for the first time that BTLA expression may contribute to metastasis and CNS progression of activated B-cell lymphoma and to resistance in ALL and Ph+ ALL. Our data suggest that BTLA may not only be a useful biomarker in these aggressive neoplasms, but also a potential therapeutic target. Additional studies are needed to deduce the mechanisms by which BTLA contributes to resistance and metastasis in ABC DLBCL and in ALL.Supported by the Leukemia and Lymphoma Society and the National Cancer Institute DisclosuresRubenstein:Celgene: Research Funding; Genentech: Research Funding.

Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up