Relapsed B-cell Lymphoma Research Articles

State of the Art on CAR T-Cell Therapies for Onco-Haematological Disorders and Other Conditions

The use of chimeric antigen receptors (CAR T-cells) for the treatment of patients with malignant haematological diseases has become a well-established application for conditions such as refractory or relapsed B-cell acute lymphoblastic leukaemia (B-ALL), B-cell lymphomas (BCL), and multiple myeloma (MM). Nearly 35,000 patients have received autologous CAR T-cells for the treatment of these conditions only in the USA. Since their approval by the Food and Drug Administration (FDA) in 2017, over 1200 clinical trials have been initiated globally and there are at least 10 different CAR T-cells with approval by different regulatory agencies around the globe. In the USA, the FDA has approved six commercial CAR T-cells that are widely distributed worldwide. At the time of writing, several clinical trials have been performed in patients with solid tumours such as glioblastoma, renal and pancreatic cancer, as well as in patients with autoimmune conditions such as systemic lupus erythematosus (SLE), idiopathic inflammatory myositis (IIM), and systemic sclerosis (SS). There are also several studies showing the potential benefit of CAR T-cells for other non-malignant diseases such as asthma and even fungal infections. In this review, without pretending to cover all current areas of treatments with CAR T-cells, we offer a brief summary of some of the most relevant aspects of the use of CAR T-cells for some of these conditions.

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...

Carfilzomib plus rituximab, ifosfamide, carboplatin and etoposide (C-RICE) led to higher response, OS, and PFS in patients with transplant-eligible relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL).

7042 Background: The CORAL study highlighted the need to develop novel salvage regimens for R/Rr/r DLBCL previously treated with R+CHOP. Overall response rate (ORR) to second line immuno-chemotherapy was 51% with a 3-year progression free survival (PFS) of 30% following high-dose chemotherapy and autologous stem cell support (HDC-ASCS). Optimal disease control (complete remission [CR] or partial remission [PR]) prior to HDC-ADCS and more recently to chimeric antigen receptor T-cell therapy (CAR T), correlates with improved outcomes. Dysregulation of Bcl-2 family members has been associated with acquired resistance to rituximab and chemotherapy which we have previously shown may be mitigated by co-treatment with proteasome inhibition in pre-clinical model. Subsequently, we conducted a Phase I/II clinical trial evaluating the safety and efficacy of CRICE as salvage therapy for R/R DLBCL (Blood Adv. 2023 7:1146-1155). Methods: Here we retrospectively compared the clinical outcomes of R/R DLBCL patients treated with CRICE (N=28) versus RICE (N=38) on our prior clinical trial (NCT01959698). Demographic, clinical, and pathological characteristics were collected for both groups (Table). Study endpoints consisted of differences in overall response rate (ORR), CR/PR rates, median progression free survival (PFS) and overall survival (OS) between the two cohorts. Results: The addition of Carfilzomib to RICE resulted in improved clinical outcomes. A higher ORR (92.9 vs 76.3, P=0.073) and CR rates (82.1 vs. 44.7, P=0.002) were observed in CRICE vs. RICE treated patients. Multivariate analysis confirmed the higher CR rates in CRICE vs. RICE when adjusted by DLBCL subtype (GCB vs. nNon-GCB, P=0.003). More CRICE patients proceeded to HDC-ASCS (52.6% vs. 47.4%, P=0.618). The 3yr PFS rate was higher in CRICE (54%, 32-72%) vs. RICE treated patients (35%, 19-51%). While the median PFS was longer in CRICE treated patients 36.8m (0.8, 73.2) vs. 3.2m (0.5, 54.2) (RICE), it did not reach statistical significance (P=0.714). No differences in OS were observed between CRICE & RICE patients, median OS 67.3m vs. 71.8m. Conclusions: The CRICE outcomes were more striking in patients with non-GCB r/r DLBCL (ORR 85%, mPFS and OS not reached). CRICE led to high CR rates and longer PFS among r/r DLBCL patients, especially in non-GCB DLBCL patients. CRICE could be an attractive regimen to achieve disease control in r/r DLBCL patients undergoing consolidation therapy with HDC-ASCT or CAR T-cell therapy. [Table: see text]

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]

Long-term Remissions Following CD20-Directed Chimeric Antigen Receptor-Adoptive T-cell Therapy.

Chimeric antigen receptor (CAR) T-cell therapy produces high response rates in refractory B-cell non-Hodgkin lymphoma, but long-term data are minimal to date. In this study, we present long-term follow-up of a pilot trial testing a CD20-targeting third-generation CAR in patients with relapsed B-cell lymphomas following cyclophosphamide-only lymphodepletion. Two of the three patients in the trial, with mantle cell lymphoma and follicular lymphoma, had remissions lasting more than 7 years, though they ultimately relapsed. The absence of B-cell aplasia in both patients suggested a lack of functional CAR T-cell persistence, leading to the hypothesis that endogenous immune responses were responsible for these long-term remissions. Correlative immunologic analyses supported this hypothesis, with evidence of new humoral and cellular antitumor immune responses proximal to clinical response time points. Collectively, our results suggest that CAR T-cell therapy may facilitate epitope spreading and endogenous immune response formation in lymphomas. Significance: Two of three patients treated with CD20-targeted CAR T-cell therapy had long-term remissions, with evidence of endogenous antitumor immune response formation. Further investigation is warranted to develop conditions that promote epitope spreading in lymphomas.

Phase II single-arm study of a combination of obinutuzumab and venetoclax in early relapsed or refractory diffuse large B-cell lymphoma—final results of the AGMT NHL15B study

BackgroundPatients with diffuse large B-cell lymphoma (DLBCL) relapsing early (within 12 months) or primary refractory to induction therapy with rituximab (R) and CHOP have a poor prognosis. We therefore initiated a study with obinutuzumab and venetoclax.Study design and methodsTwenty-one patients with DLBCL (relapsed within 12 months or primary refractory), detectable Bcl-2 protein expression, and CD20 positivity were included in this prospective single-arm study between 2016 and 2021. Obinutuzumab was administered i.v. at a dose of 1,000 mg on days 1, 8, and 15 in cycle 1 and on day 1 of each of the following 21-day cycles. Venetoclax was given at 800 mg daily p.o. continuously. Treatment was repeated for up to three cycles. Eligible patients were planned to either proceed to cellular therapies or receive up to nine cycles of maintenance. The primary endpoint was objective response rate (ORR) after three cycles (Eudract Nr. 2016-001760-10 and NCT02987400).ResultsTwenty-one patients (median age, 64 years) with refractory or early relapsed DLBCL after one (N = 11) to four previous lines of therapy were included. The majority of patients received three cycles of obinutuzumab/venetoclax (range, 1–8). The regimen was well tolerated with manageable cytopenias and infections. Severe adverse events related to treatment were observed in 9.5%. The ORR was 38.1% (8/21 patients) with a best response of five complete remissions (CRs; 23.8%) and three partial remissions (PRs; 14.2%). The primary endpoint (45% ORR) was not met. Response duration was 83.3% at 84 days, with a progression-free survival of 38.8% at 84 days and 25.9% at 168 days and a median overall survival of 169.1 weeks. All deaths were due to underlying disease. Seven patients became eligible for autologous transplant. Overall, nine patients (42.8%) received 11 cellular therapies (5 ASCT and 6 CAR-T). Three patients went directly from obinutuzumab/venetoclax to CAR-T therapy. All patients had successful peripheral stem cell or T-cell harvests. Characteristics of responders include relapsed disease (response rate, 6 of 11 = 54%), very good or good R-IPI (7 of 8), and low number of previous therapies (median = 1).ConclusionObinutuzumab/venetoclax represents an effective chemo-free relapse regimen with low toxicity that can be followed by cellular therapies, particularly CAR-T cells.

Multimodal machine learning models identify chemotherapy drugs with prospective clinical efficacy in dogs with relapsed B-cell lymphoma.

Dogs with B-cell lymphoma typically respond well to first-line CHOP-based chemotherapy, but there is no standard of care for relapsed patients. To help veterinary oncologists select effective drugs for dogs with lymphoid malignancies such as B-cell lymphoma, we have developed multimodal machine learning models that integrate data from multiple tumor profiling modalities and predict the likelihood of a positive clinical response for 10 commonly used chemotherapy drugs. Here we report on clinical outcomes that occurred after oncologists received a prediction report generated by our models. Remarkably, we found that dogs that received drugs predicted to be effective by the models experienced better clinical outcomes by every metric we analyzed (overall response rate, complete response rate, duration of complete response, patient survival times) relative to other dogs in the study and relative to historical controls.

STAT6 mutations enriched at diffuse large B-cell lymphoma relapse reshape the tumor microenvironment

Diffuse large B-cell lymphoma (DLBCL) relapses in approximately 40% of patients following frontline therapy. We reported that STAT6D419 mutations are enriched in relapsed/refractory DLBCL (rrDLBCL) samples, suggesting that JAK/STAT signaling plays a role in therapeutic resistance. We hypothesized that STAT6D419 mutations can improve DLBCL cell survival by reprogramming the microenvironment to sustain STAT6 activation. Thus, we investigated the role of STAT6D419 mutations on DLBCL cell growth and its microenvironment. We found that phospho-STAT6D419N was retained in the nucleus longer than phospho-STAT6WT following IL-4 stimulation, and STAT6D419N recognized a more restricted DNA-consensus sequence than STAT6WT. Upon IL-4 induction, STAT6D419N expression led to a higher magnitude of gene expression changes, but in a more selective list of gene targets compared with STATWT. The most significantly expressed genes induced by STAT6D419N were those implicated in survival, proliferation, migration, and chemotaxis, in particular CCL17. This chemokine, also known as TARC, attracts helper T-cells to the tumor microenvironment, especially in Hodgkin’s lymphoma. To this end, in DLBCL, phospho-STAT6+ rrDLBCL cells had a greater proportion of infiltrating CD4+ T-cells than phospho-STAT6− tumors. Our findings suggest that STAT6D419 mutations in DLBCL lead to cell autonomous changes, enhanced signaling, and altered composition of the tumor microenvironment.

Hypofractionated radiotherapy for refractory or relapsed aggressive B-cell lymphoma in the rituximab era

BackgroundRadiotherapy (RT) is an effective and available local treatment for patients with refractory or relapsed (R/R) aggressive B-cell lymphomas. However, the value of hypofractionated RT in this setting has not been confirmed.MethodsWe retrospectively analyzed patients with R/R aggressive B-cell lymphoma who received hypofractionated RT between January 2020 and August 2022 at a single institution. The objective response rate (ORR), overall survival (OS), progression-free survival (PFS) and acute side effects were analyzed.ResultsA total of 30 patients were included. The median dose for residual disease was 36 Gy, at a dose per fraction of 2.3–5 Gy. After RT, the ORR and complete response (CR) rates were 90% and 80%, respectively. With a median follow-up of 10 months (range, 2–27 months), 10 patients (33.3%) experienced disease progression and three died. The 1-year OS and PFS rates for all patients were 81.8% and 66.3%, respectively. The majority (8/10) of post-RT progressions involved out-of-field relapses. Patients with relapsed diseases, no response to systemic therapy, multiple lesions at the time of RT, and no response to RT were associated with out-of-field relapses. PFS was associated with response to RT (P = 0.001) and numbers of residual sites (P < 0.001). No serious non-hematological adverse effects (≥ grade 3) associated with RT were reported.ConclusionThese data suggest that hypofractionated RT was effective and tolerable for patients with R/R aggressive B-cell lymphoma, especially for those that exhibited localized residual disease.

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.

Polatuzumab vedotin plus rituximab and lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma: a cohort of a multicentre, single-arm, phase 1b/2 study

Diffuse large B-cell lymphoma comprises nearly 30% of non-Hodgkin lymphoma cases and patients with relapsed or refractory diffuse large B-cell lymphoma who are ineligible for stem-cell transplantation have few treatment options and poor prognoses. We aimed to determine whether the novel combination of polatuzumab vedotin in combination with rituximab and lenalidomide (Pola+R+Len) would provide a tolerable treatment option with enhanced antitumour response in patients with relapsed or refractory diffuse large B-cell lymphoma. This completed phase 1b/2, open-label, multicentre, single-arm study (GO29834) evaluated the safety and efficacy of Pola+R+Len in patients with relapsed or refractory diffuse large B-cell lymphoma at 19 sites in three countries (USA, Spain, and UK). Patients (≥18 years old) were eligible for inclusion if they had histologically documented CD20-positive relapsed or refractory diffuse large B-cell lymphoma and Eastern Cooperative Oncology Group performance status of 2 or lower, had received at least one previous line of chemoimmunotherapy, including an anti-CD20 agent, and were ineligible for stem-cell transplantation. The dose-escalation phase (1b) used escalating doses of lenalidomide to find the recommended phase 2 dose. Patients received six 28-day cycles of induction treatment with intravenous rituximab 375 mg/m2 and intravenous polatuzumab vedotin 1·8 mg/kg (all cohorts) plus oral lenalidomide at the following doses: 10 mg (cohort A); 15 mg (cohort B); and 20 mg (cohort C). Rituximab and polatuzumab vedotin were administered on day 1 and lenalidomide on days 1-21 of each 28-day cycle. During the dose-expansion phase (2), patients received six 28-day cycles of Pola+R+Len at the recommended phase 2 dose established during dose escalation. In both phases, patients with a complete response or partial response at the end of induction were eligible for post-induction therapy with rituximab 375 mg/m2 on day 1 and lenalidomide 10 mg/day on days 1-21 of each 28-day cycle for a maximum of 6 cycles. The primary safety objective of the dose-escalation phase was identification of the maximum tolerated dose through incidence of dose-limiting toxic effects. The primary efficacy outcome of the dose-expansion phase was Independent Review Committee-assessed complete response rate at end of induction, based on PET-CT. Analyses were conducted in the safety population, which included all patients who received at least one dose of any study drug, and the efficacy population, which included all patients who received at least one dose of any study drug at the recommended phase 2 dose. This study is registered with ClinicalTrials.gov, number NCT02600897. Between July 11, 2017 and Feb 3, 2020, 57 patients were enrolled (median age 71 years [IQR 60-75]; 38 [67%] were male and 19 (33%) were female; 47 [82%] were not Hispanic or Latino; and the median previous lines of therapy was 2 [IQR 1-3]). 18 participants were included in phase 1b and 39 were included in phase 2. Phase 1b confirmed a 20 mg recommended phase 2 dose for lenalidomide. After a median follow-up of 11·8 months (IQR 4·7-25·8), the complete response rate, as assessed by the Independent Review Committee, was 31% (90% CI 20-43). The most common grade 3-4 adverse events were neutropenia (35 [61%] of 57) and thrombocytopenia (eight [14%] of 57). Serious adverse events were reported in 23 (40%) of 57 patients and one patient died due to a treatment-related adverse event (neutropenic sepsis). Although the combination of Pola+R+Len did not meet the prespecified activity threshold, some patients derived clinical benefit and the regimen had a tolerable safety profile in patients with relapsed or refractory diffuse large B-cell lymphoma. Genentech/F Hoffmann-La Roche.

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.

Early failure is still a poor prognostic factor in patients with relapsed or refractory large B-cell lymphoma in the era of CAR T-cell therapy.

Patients with refractory or relapsed (R/R) large B-cell lymphoma (LBCL) refractory to first-line chemotherapy or with early relapse have poor outcomes. While chimeric antigen receptor (CAR) T-cell therapy has impressive efficacy after two or more lines of chemotherapy, it's still uncertain if these outcomes remain consistent in the context of third-line CAR T-cell therapy. We conducted a retrospective study of 107 R/R LBCL patients. Patients with relapse 12 months or more after their first-line chemoimmunotherapy (late failure: n = 25) had significantly longer overall survival (OS) than patients with refractory disease or relapse within 12 months (early failure: n = 82) (median OS: not achieved vs. 18.4 months; P < 0.001). Among patients who proceeded to autologous hematopoietic stem-cell transplantation (auto-HSCT), those with late failure had significantly longer event-free survival (EFS) than those with early failure (median EFS: 26.9 vs. 3.1 months; P = 0.012). However, no significant difference in EFS was detected among patients who underwent CAR T-cell therapy (median EFS: not reached vs. 11.8; P = 0.091). Cox regression with restricted cubic spline demonstrated that timing of relapse had significant impact on EFS in patients with auto-HSCT but not in patients with CAR T-cell therapy. Of patients who were scheduled for CAR T-cell therapy, those with late failure were significantly more likely to receive CAR T-cell therapy than those with early failure (90% vs. 57%; P = 0.008). In conclusion, patients with early failure still experienced poor outcomes after the approval of third-line CAR T-cell therapy.

Therapeutic options for large B-cell lymphoma relapsing after CD19-directed CAR T-cell therapy.

In recent years, chimeric antigen receptor T-cell therapy (CART) has revolutionized the treatment landscape for large B cell lymphoma (LBCL), demonstrating remarkable efficacy and ushering a new era of therapeutic possibilities. However, a subset of patients may not achieve the desired response with CAR T. This review examines strategies aimed at optimizing outcomes for patients who relapse or progress after CAR T. Available data on utilization of CD19-directed monoclonal antibodies and antibody drug conjugates have shown limited efficacy in this setting. Moreover, bispecific antibodies have also emerged as an alternative therapy in relapsed and or refractory LBCL, but long-term follow up treated cases post-CAR T failure are lacking. Several observational studies have shown efficacy of allogeneic hematopoietic cell transplantation, but attainment of a complete remission prior to allografting is a prerequisite to achieve durable remissions. As we navigate the intricate landscape of treatment of post CAR T failure, it becomes evident that this represents a therapeutic challenge which necessitates a multifaceted approach.

Gemcitabine and liposomal doxorubicin (GemDox) for the treatment of relapsed and refractory T-cell lymphomas

Aggressive T-cell lymphomas (TCL) account for 10–15% of non-Hodgkin lymphomas (NHL) with weaker responses and shorter durations to chemotherapy than other types of NHL. Current therapies for patients with relapsed/refractory Cutaneous T-cell lymphoma (CTCL) have limited efficacy, and short durations of response. Gemcitabine and liposomal doxorubicin have shown single-agent activity in TCL and combined have activity in relapsed B-cell lymphomas. We evaluated outcomes of 18 patients with relapsed/refractory aggressive TCL (13 CTCL, 5 PTCL) treated with a gemcitabine plus liposomal doxorubicin (GemDox) combination and evaluated outcomes with a specific focus on CTCL patients. Significant responses were observed in CTCL patients with an overall response rate of over 80%. In all patients, objective responses were seen in eight patients (50%), with six patients (5 CTCL) able to proceed to allogeneic stem cell transplant. Given limited treatment options for r/r CTCL, GemDox should be considered a therapeutic option in relapsed/refractory CTCL.

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 &amp;lt; 0.0001), disease burden (SPD; P &amp;lt; 0.0001), and LDH ( P &amp;lt; 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.

Hypofractionated Radiotherapy in Aggressive B-Cell Lymphoma

Background and purpose: Radiotherapy (RT) is an effective and available local treatment for patients with refractory or relapsed (R/R) aggressive B-cell lymphomas. However, the value of comprehensive hypofractionated RT in this setting has not been confirmed. Materials and methods : We retrospectively analyzed patients with R/R aggressive B-cell lymphoma who received comprehensive hypofractionated RT between January 2020 and August 2022 at a single institution. The objective response rate (ORR), overall survival (OS), progression-free survival (PFS) and acute side effects were analyzed. Results : A total of 30 patients were included. The median dose for residual disease was 36 Gy, at a dose per fraction of 2.3-5 Gy. After RT, the ORR and complete response (CR) rates were 90% and 80%, respectively. With a median follow-up of 10 months (range, 2-27 months), 10 patients (33.3%) experienced disease progression and three died. The 1-year OS and PFS rates for all patients were 81.8% and 66.3%, respectively. The majority (8/10) of post-RT progressions involved out-field relapses. Patients with relapsed diseases, no response to systemic therapy, multiple lesions at the time of RT, and no response to RT were associated with out-field relapses. PFS was associated with response to RT (P=0.001) and numbers of residual sites (P&amp;lt;0.001). No serious non-hematological adverse effects (≥grade 3) associated with RT were reported. Conclusion: These data suggest that comprehensive hypofractionated RT was effective and tolerable for patients with R/R aggressive B-cell lymphoma, especially for those that exhibited localized residual disease.

Impact of ARID1A and TP53 mutations in pediatric refractory or relapsed mature B-Cell lymphoma treated with CAR-T cell therapy

BackgroundChimeric antigen receptor (CAR)-T cell therapy has been used to treat pediatric refractory or relapsed mature B-cell non-Hodgkin lymphoma (r/r MB-NHL) with significantly improved outcomes, but a proportion of patients display no response or experience relapse after treatment. To investigate whether tumor-intrinsic somatic genetic alterations have an impact on CAR-T cell treatment, the genetic features and treatment outcomes of 89 children with MB-NHL were analyzed.Methods89 pediatric patients treated at multiple clinical centers of the China Net Childhood Lymphoma (CNCL) were included in this study. Targeted next-generation sequencing for a panel of lymphoma-related genes was performed on tumor samples. Survival rates and relapse by genetic features and clinical factors were analyzed. Survival curves were calculated using a log-rank (Mantel-Cox) test. The Wilcox sum-rank test and Fisher’s exact test were applied to test for group differences.ResultsA total of 89 driver genes with somatic mutations were identified. The most frequently mutated genes were TP53 (66%), ID3 (55%), and ARID1A (31%). The incidence of ARID1A mutation and co-mutation of TP53 and ARID1A was high in patients with r/r MB-NHL (P = 0.006; P = 0.018, respectively). CAR-T cell treatment significantly improved survival in r/r MB-NHL patients (P = 0.00081), but patients with ARID1A or ARID1A and TP53 co-mutation had poor survival compared to those without such mutations.ConclusionThese results indicate that children with MB-NHL harboring ARID1A or TP53 and ARID1A co-mutation are insensitive to initial conventional chemotherapy and subsequent CAR-T cell treatment. Examination of ARID1A and TP53 mutation status at baseline might have prognostic value, and risk-adapted or more effective therapies should be considered for patients with these high-risk genetic alterations.