How to optimize the CAR-T Cell therapy process? A group concept mapping analysis of preconditions for a frictionless process from a German multistakeholder perspective.

Introduction: Treatment with chimeric antigen receptor T (CAR-T) cells involves a large number of interdisciplinary stakeholders and is associated with complex processes ranging from patient-specific production to follow-up care. Due to the complexity, maximum process optimization is required in order to avoid efficiency losses. This study aimed at systematically determining the preconditions for a frictionless flow of the CAR-T process by surveying the stakeholders involved. Methods: A Group Concept Mapping (GCM) analysis, a mixed-methods participatory research, was conducted. CAR-T experts from different professional backgrounds went through three steps: 1) Brainstorming relevant aspects (statements) for a frictionless process, 2) Sorting the collected statements based on their similarity, and 3) Rating the importance and feasibility of each statement. A cluster map reflecting the overarching topics was derived, and mean ratings per statement and cluster were calculated. Results: Overall, 20 CAR-T experts participated. A total of 80 statements were collected, resulting in a map of the following 10 clusters (mean importance/feasibility): Information for patients and physicians (4.16/3.77), Supportive network (4.03/3.53), Eligibility of patients (4.41/3.63), Evidence, transparency and communication (4.01/3.33), Paperwork (4.1/2.52), Interface with pharmaceutical manufacturer (4.03/2.85), Reimbursement (4.29/2.31), Quality Management (4.17/3.18), Infrastructure of CAR-T clinics (4.1/2.93), and Patient-oriented processes (4.46/3.32). Discussion: The 80 statements underlined the complex and manifold nature of the CAR-T treatment process. Our results reflect the first step in overcoming hurdles: identifying potential hurdles and required preconditions. Decision-makers and stakeholders can use the results to derive strategies and measures to further promote a frictionless process.

Human immunodeficiency virus-associated Lymphomas: EHA-ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up.

This EHA-ESMO Clinical Practice Guideline provides key recommendations for managing HIV-associated lymphomas.The guideline covers clinical, imaging and pathological diagnosis; staging and risk assessment; treatment and follow-up.The author group encompasses a multidisciplinary group of experts from different institutions and countries in Europe.Recommendations are based on available scientific data and the authors' collective expert opinion.

Circulating Tumor DNA Sequencing for Biologic Classification and Individualized Risk Stratification in Patients With Hodgkin Lymphoma.

PURPOSE: Current clinical challenges in Hodgkin lymphoma (HL) include difficult-to-treat relapsed/refractory disease and considerable long-term toxicities of treatment. Since clinical risk factors lack discriminatory power, intensity of therapy is mainly based on tumor burden. Exploring HL genetics and tumor microenvironment (TME) might provide valuable insights for improved risk stratification. MATERIALS AND METHODS: In this study, we applied circulating tumor DNA sequencing to 243 patients obtained from pivotal German Hodgkin Study Group trials to identify subtypes of HL. Independent validation of the subtypes was performed in 96 patients treated in the EuroNet-PHL-C2 study. Outcome differences of subtypes were assessed in an event-enriched clinical validation cohort comprising 72 patients from the HD21 trial, using a refined, validated, and clinically feasible assay. RESULTS: We propose a biologic classification of HL consisting of three distinct subtypes: inflammatory immune escape HL is characterized by frequent copy-number variations including immune escape variants such as high-level amplifications of the PD-L1 locus and an inflammatory TME. Virally-driven HL is associated with Epstein-Barr virus and/or human herpesvirus 6 and an inflammatory TME with neutrophils and macrophages, while the tumor mutational burden (TMB) is low. Oncogene-driven HL is defined by a high TMB, recurrent mutations in oncogenic drivers such as TNFAIP3, ITPKB, and SOCS1, and a cold TME. A refined and validated assay version aiming at clinically feasible risk stratification showed significant progression-free survival differences between subtypes. In addition, assessment of minimal residual disease (MRD) allowed for the detection of patients at very high risk of relapse within the subtypes. CONCLUSION: We propose a clinically feasible, noninvasive method for individualized risk stratification and MRD monitoring in patients with HL on the basis of circulating tumor DNA sequencing.

Assessing the efficacy and tolerability of PET-guided BrECADD versus eBEACOPP in advanced-stage, classical Hodgkin lymphoma (HD21): a randomised, multicentre, parallel, open-label, phase 3 trial.

BACKGROUND: Intensified systemic chemotherapy has the highest primary cure rate for advanced-stage, classical Hodgkin lymphoma but this comes with a cost of severe and potentially life long, persisting toxicities. With the new regimen of brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone (BrECADD), we aimed to improve the risk-to-benefit ratio of treatment of advanced-stage, classical Hodgkin lymphoma guided by PET after two cycles. METHODS: This randomised, multicentre, parallel, open-label, phase 3 trial was done in 233 trial sites across nine countries. Eligible patients were adults (aged ≤60 years) with newly diagnosed, advanced-stage, classical Hodgkin lymphoma (ie, Ann Arbor stage III/IV, stage II with B symptoms, and either one or both risk factors of large mediastinal mass and extranodal lesions). Patients were randomly assigned (1:1) to four or six cycles (21-day intervals) of escalated doses of etoposide (200 mg/m2 intravenously on days 1-3), doxorubicin (35 mg/m2 intravenously on day 1), and cyclophosphamide (1250 mg/m2 intravenously on day 1), and standard doses of bleomycin (10 mg/m2 intravenously on day 8), vincristine (1·4 mg/m2 intravenously on day 8), procarbazine (100 mg/m2 orally on days 1-7), and prednisone (40 mg/m2 orally on days 1-14; eBEACOPP) or BrECADD, guided by PET after two cycles. Patients and investigators were not masked to treatment assignment. Hierarchical coprimary objectives were to show (1) improved tolerability defined by treatment-related morbidity and (2) non-inferior efficacy defined by progression-free survival with an absolute non-inferiority margin of 6 percentage points of BrECADD compared with eBEACOPP. An additional test of superiority of progression-free survival was to be done if non-inferiority had been established. Analyses were done by intention to treat; the treatment-related morbidity assessment required documentation of at least one chemotherapy cycle. This trial was registered at ClinicalTrials.gov (NCT02661503). FINDINGS: Between July 22, 2016, and Aug 27, 2020, 1500 patients were enrolled, of whom 749 were randomly assigned to BrECADD and 751 to eBEACOPP. 1482 patients were included in the intention-to-treat analysis. The median age of patients was 31 years (IQR 24-42). 838 (56%) of 1482 patients were male and 644 (44%) were female. Most patients were White (1352 [91%] of 1482). Treatment-related morbidity was significantly lower with BrECADD (312 [42%] of 738 patients) than with eBEACOPP (430 [59%] of 732 patients; relative risk 0·72 [95% CI 0·65-0·80]; p<0·0001). At a median follow-up of 48 months, BrECADD improved progression-free survival with a hazard ratio of 0·66 (0·45-0·97; p=0·035); 4-year progression-free survival estimates were 94·3% (95% CI 92·6-96·1) for BrECADD and 90·9% (88·7-93·1) for eBEACOPP. 4-year overall survival rates were 98·6% (97·7-99·5) and 98·2% (97·2-99·3), respectively. INTERPRETATION: BrECADD guided by PET after two cycles is better tolerated and more effective than eBEACOPP in first-line treatment of adult patients with advanced-stage, classical Hodgkin lymphoma. FUNDING: Takeda Oncology.

Time-dependent cost comparison and health economic impact analysis of second-line interventions for transplant-ineligible patients with relapsed or refractory diffuse large B cell lymphoma.

OBJECTIVES: Novel interventions (axicabtagene ciloleucel [axi-cel], lisocabtagene maraleucel [liso-cel], tafasitamab-lenalidomide [Tafa-L], polatuzumab-rituximab-bendamustine [pola-BR]) improve clinical outcomes in second-line (2 L) treatment of transplant-ineligible patients with early relapse or refractory (R/R) diffuse large B cell lymphoma (DLBCL). The costs vary depending on the respective treatment regimen and the treatment duration, difficult comparability in reimbursement decisions. The objective was to analyze the health economic impacts of novel 2 L interventions and conventional immunochemotherapies (bendamustine-rituximab [BR], rituximab-gemcitabine-oxaliplatin [R-GemOx]) from a German healthcare payer's perspective as a function of treatment duration. METHODS: An economic model was developed to compare treatment costs of 2 L interventions depending on the treatment duration. Treatment duration was measured by progression-free survival (PFS), identified based on a systematic review. Total and average costs were calculated over 5 years to evaluate incremental costs at median PFS for each intervention. RESULTS: Average costs per month at median PFS ranged from €2846 (95% CI: 5067-1641) to €40 535 (95% CI: 91180-N/A) for BR and liso-cel, respectively. Incremental costs at the lowest median PFS (R-GemOx: 5.3 months) revealed -€664, €5560, €11 817, €53 145, and €67 745 for BR, Tafa-L, pola-BR, axi-cel, and liso-cel as compared to R-GemOx, respectively. CONCLUSIONS: Analyses uncovered a variation of incremental costs of 2 L transplant-ineligible DLBCL interventions as a function of time leading to amortization of high-priced interventions.

Human leukocyte antigen (HLA) class I expression on Hodgkin-Reed-Sternberg cells is an EBV-independent major determinant of microenvironment composition in classic Hodgkin lymphoma.

Hodgkin-Reed-Sternberg cells (HRSCs) in classic Hodgkin Lymphoma (HL) frequently lack expression of human leukocyte antigen class I (HLA-I), considered to hamper activation of cytotoxic T cells in the tumor microenvironment (TME). Here, we demonstrate HLA-I expression on HRSCs to be a strong determinant of TME composition whereas expression of HLA-II was associated with only minor differential gene expression in the TME. In HLA-I-positive HL the HRSC content and expression of CCL17/TARC in HRSCs are low, independent of the presence of Epstein-Barr virus in HRSCs. Additionally, HLA-I-positive HL shows a high content of CD8+ cytotoxic T cells. However, an increased expression of the inhibitory immune checkpoint LAG3 on CD8+ T cells in close proximity to HRSCs is observed. Suggesting interference with cytotoxic activity, we observed an absence of clonally expanded T cells in the TME. While HLA-I-positive HL is not associated with an unfavorable clinical course in our cohorts, they share features with the recently described H2 subtype of HL. Given the major differences in TME composition, immune checkpoint inhibitors may differ in their mechanism of action in HLA-I-positive compared to HLA-I-negative HL.

[T-cell recruiting immunotherapies in B-cell lymphoma - the future backbone for all therapy lines?] / T-Zell-rekrutierende Immuntherapien des B-Zell-Lymphoms ­ bald in allen Therapielinien?

The introduction of immunologically targeted therapies has represented a significant advancement in the treatment of B-cell lymphomas, particularly aggressive B-cell lymphoma. CD19 CAR-T cells such as Axicabtagen-Ciloleucel (Axi-cel) and Lisocabtagen Maraleucel (Liso-cel) have been approved since 2022 and 2023, respectively, for second-line therapy of Diffuse Large B-Cell Lymphomas (DLBCL), when there is primary refractory disease or relapse within 12 months after the end of first-line therapy. These therapies result in a significant improvement in progression-free survival compared to the previous standard therapy (salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation). Especially in elderly patients or patients with underlying medical conditions, CAR-T cell therapies like Axi-cel and Liso-cel demonstrate acceptable tolerability and high efficacy.Furthermore, bispecific T-cell-engaging antibodies ("bispecifics") such as Glofitamab, Epcoritamab, and Mosunetuzumab also represent promising treatment options for patients with relapsed disease after failure of second- or later line therapy and show efficacy even in a subset of patients relapsing after CD19 CAR-T cells. However, randomized study results for these substances are not yet available. They are expected to be used in earlier lines of therapy in the future, especially in combination with standard chemotherapy regimens. Common side effects of bispecific antibody therapies are cytokine release syndrome (CRS) and immune-mediated cytopenias, whereas immune-cell associated neurotoxicity syndrome (ICANS) is relatively rare compared to CD19 CAR T cells. In summary, bispecifics represent a novel, highly effective immunotherapy for the treatment of lymphomas with a very favourable toxicity profile.

Prognostic Implications of 68Ga-FAPI-46 PET/CT-Derived Parameters on Overall Survival in Various Types of Solid Tumors.

Tumoral fibroblast activation protein expression is associated with proliferation and angiogenesis and can be visualized by PET/CT. We examined the prognostic value of [68Ga]Ga-fibroblast activation protein inhibitor (FAPI) (68Ga-FAPI)-46 PET/CT for different tumor entities in patients enrolled in 2 prospective imaging studies (NCT05160051, n = 30; NCT04571086, n = 115). Methods: Within 4 wk, 145 patients underwent 68Ga-FAPI-46 and [18F]FDG (18F-FDG) PET/CT. The association between overall survival (OS) and sex, age, tumor entity, total lesion number, highest SUVmax, and the presence of each nodal, visceral, and bone metastasis was tested using univariate Cox regression analysis. Multivariate analyses were performed for prognostic factors with P values of less than 0.05. Results: In the univariate analysis, shorter OS was associated with total lesion number and the presence of nodal, visceral, and bone metastases on 68Ga-FAPI-46 PET/CT (hazard ratio [HR], 1.06, 2.18, 1.69, and 2.05; P < 0.01, < 0.01, = 0.04, and = 0.02, respectively) and 18F-FDG PET/CT (HR, 1.05, 2.31, 1.76, and 2.30; P < 0.01, < 0.01, = 0.03, and < 0.01, respectively) and with SUVmax on 68Ga-FAPI-46 PET/CT (HR, 1.03; P = 0.03). In the multivariate analysis, total lesion number on 68Ga-FAPI-46 PET/CT was an independent risk factor for shorter OS (HR, 1.05; P = 0.02). In patients with pancreatic cancer, shorter OS was associated with total lesion number on 68Ga-FAPI-46 PET/CT (HR, 1.09; P < 0.01) and bone metastases on 18F-FDG PET/CT (HR, 31.39; P < 0.01) in the univariate analysis and with total lesion number on 68Ga-FAPI-46 PET/CT (HR, 1.07; P = 0.04) in the multivariate analyses. In breast cancer, total lesion number on 68Ga-FAPI-46 PET/CT (HR, 1.07; P = 0.02), as well as bone metastases on 18F-FDG PET/CT (HR, 9.64; P = 0.04), was associated with shorter OS in the univariate analysis. The multivariate analysis did not reveal significant prognostic factors. In thoracic cancer (lung cancer and pleural mesothelioma), the univariate and multivariate analyses did not reveal significant prognostic factors. Conclusion: Disease extent on 68Ga-FAPI-46 PET/CT is a predictor of short OS and may aid in future risk stratification by playing a supplemental role alongside 18F-FDG PET/CT.

Involved-site Radiation Therapy is Equally Effective and Less Toxic Than Involved-field Radiation Therapy in Patients Receiving Combined Modality Treatment for Early-stage Unfavorable Hodgkin Lymphoma-An Analysis of the Randomized Phase 3 HD17 Trial of the German Hodgkin Study Group.

PURPOSE: Combined modality treatment with chemotherapy followed by consolidation radiation therapy (RT) provides excellent outcomes for patients with early-stage Hodgkin lymphoma. The international standard of care for consolidation RT, involved-site/involved-node radiation therapy (ISRT/INRT), has never been evaluated in a randomized phase 3 trial against the former standard involved-field radiation therapy (IFRT). METHODS AND MATERIALS: In the multicenter phase 3 GHSG (German Hodgkin Study Group) HD17 trial, patients with early-stage unfavorable Hodgkin lymphoma were randomized between the standard Combined modality treatment group and a positron-emission tomography (PET)-guided group. In the standard group, patients received 2 cycles of escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (eBEACOPP) and 2 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by 30 Gy IFRT. In the experimental group, patients received no further therapy if postchemotherapy PET was negative and 30 Gy GHSG INRT, comparable to and therefore termed here ISRT, if PET was positive. Here, we analyze the interim PET-positive patients in a post hoc analysis, and therefore the randomized comparison of IFRT versus INRT/ISRT. RESULTS: A total of 1100 patients were randomized, of which 311 had a positive PET after chemotherapy. Kaplan-Meier estimates of 4-year progression-free survival were 96.8% (95% CI, 91.6%-98.8%) in the IFRT group and 95.4% (95% CI, 89.9%-97.9%; HR, 1.40; 95% CI, 0.44-4.42) in the ISRT group. The pattern of recurrence analyses indicated that none of the cases of disease progression or recurrence in the ISRT group would have been prevented by the use of IFRT. Acute grade 3/4 toxicities occurred in 8.5% of IFRT patients and 2.6% of ISRT patients (P = .03). CONCLUSIONS: For the first time, consolidation INRT/ISRT was randomly compared with IFRT in a phase 3 trial. Regarding progression-free survival, no advantage of IFRT could be demonstrated. In summary, our data confirm the status of INRT/ISRT as the current standard of care.

Cellular therapies in older adults with hematological malignancies: A case-based, state-of-the-art review.

Cellular therapies, including autologous stem cell transplant (ASCT), allogeneic hematopoietic cell transplantation (alloHCT), and chimeric antigen receptor- (CAR-) T cell therapies are essential treatment modalities for many hematological malignancies. Although their use in older adults has substantially increased within the past decades, cellular therapies represent intensive treatment approaches that exclude a large percentage of older adults due to comorbidities and frailty. Under- and overtreatment in older adults with hematologic malignancy is a challenge and many treatment decisions are influenced by chronologic age. The advent of efficient and well-tolerated newer treatment approaches for multiple myeloma has challenged the role of ASCT. In the modern era, there are no randomized clinical trials of transplant versus non-transplant strategies for patients ≥65 years. Nonetheless, ASCT is feasible for selected older patients and does not result in long-term compromise in quality of life. AlloHCT is the only curative approach for acute myeloid leukemia of intermediate and unfavourable risk but carries a significant risk for non-relapse mortality depending on comorbidities, general fitness, and transplant-specific characteristics, such as intensity of conditioning and donor choice. However, alloHCT is feasible in appropriately-selected older adults. Early referral for evaluation is strongly encouraged as this is the most obvious barrier. CAR-T cell therapies have shown unprecedented clinical efficacy and durability in relapsed and refractory diffuse large B cell lymphoma. Its use is well tolerated in older adults, although evidence comes from limited case numbers. Whether patients who are deemed unfit for ASCT qualify for CAR-T cell therapy remains elusive, but the tolerability and efficacy of CAR-T cell therapy appears promising, especially for older patients. The evidence from randomized trials is strong in favor of using a comprehensive geriatric assessment (CGA) to reduce treatment-related toxicities and guide treatment intensity in the care for solid tumors; its use for evaluation of cellular therapies is less evidence-based. However, CGA can provide useful information on patients' fitness, resilient mechanisms, and reveal potential optimization strategies for compensating for vulnerabilities. In this narrative review, we will discuss key questions on cellular therapies in older adults based on illustrative patient cases.

Diagnostic Accuracy of 68Ga-FAPI Versus 18F-FDG PET in Patients with Various Malignancies.

To assess the diagnostic accuracy of 68Ga-labeled fibroblast activation protein inhibitor (FAPI) and 18F-labeled FDG PET for the detection of various tumors, we performed a head-to-head comparison of both imaging modalities across a range of tumor entities as part of our ongoing 68Ga-FAPI PET observational trial. Methods: The study included 115 patients with 8 tumor entities who received imaging with 68Ga-FAPI for tumor staging or restaging between October 2018 and March 2022. Of those, 103 patients received concomitant imaging with 68Ga-FAPI and 18F-FDG PET and had adequate lesion validation for accuracy analysis. Each scan was evaluated for the detection of primary tumor, lymph nodes, and visceral and bone metastases. True or false positivity and negativity to detected lesions was assigned on the basis of histopathology from biopsies or surgical excision, as well as imaging validation. Results: 68Ga-FAPI PET revealed higher accuracy than 18F-FDG PET in the detection of colorectal cancer (n = 14; per-patient, 85.7% vs. 78.6%; per-region, 95.6% vs. 91.1%) and prostate cancer (n = 22; per-patient, 100% vs. 90.9%; per-region, 96.4% vs. 92.7%). 68Ga-FAPI PET and 18F-FDG PET had comparable per-patient accuracy in detecting breast cancer (n = 16, 100% for both) and head and neck cancers (n = 10, 90% for both modalities). 68Ga-FAPI PET had lower per-patient accuracy than 18F-FDG PET in cancers of the bladder (n = 12, 75% vs. 100%) and kidney (n = 10, 80% vs. 90%), as well as lymphoma (n = 9, 88.9% vs. 100%) and myeloma (n = 10, 80% vs. 90%). Conclusion: 68Ga-FAPI PET demonstrated higher diagnostic accuracy than 18F-FDG PET in the diagnosis of colorectal cancer and prostate cancer, as well as comparable diagnostic performance for cancers of the breast and head and neck. Accuracy and impact on management will be further assessed in an ongoing prospective interventional trial (NCT05160051).

Noninvasive minimal residual disease assessment in relapsed/refractory large B-cell lymphoma using digital droplet PCR.

Although several promising approaches for the treatment of relapsed/refractory diffuse large B-cell lymphoma (rrDLBCL) have been approved recently, it remains unclear which patients will ultimately achieve long-term responses. Circulating tumor (ct)DNA sequencing has emerged as a valuable tool to assess minimal residual disease (MRD). Correlations between MRD and outcomes have been shown in previously untreated DLBCL, but data on the repeated assessment of MRD in the dynamic course of rrDLBCL is limited. Here, we present an approach leveraging cost- and time-sensitivity of digital droplet (dd)PCR to repeatedly assess MRD in rrDLBCL and present proof-of-principle for its ability to predict outcomes.

Durable response after tisagenlecleucel in adults with relapsed/refractory follicular lymphoma: ELARA trial update.

ABSTRACT: Tisagenlecleucel is approved for adults with relapsed/refractory (r/r) follicular lymphoma (FL) in the third- or later-line setting. The primary analysis (median follow-up, 17 months) of the phase 2 ELARA trial reported high response rates and excellent safety profile in patients with extensively pretreated r/r FL. Here, we report longer-term efficacy, safety, pharmacokinetic, and exploratory biomarker analyses after median follow-up of 29 months (interquartile range, 22.2-37.7). As of 29 March 2022, 97 patients with r/r FL (grades 1-3A) received tisagenlecleucel infusion (0.6 × 108-6 × 108 chimeric antigen receptor-positive viable T cells). Bridging chemotherapy was allowed. Baseline clinical factors, tumor microenvironment, blood soluble factors, and circulating blood cells were correlated with clinical response. Cellular kinetics were assessed by quantitative polymerase chain reaction. Median progression-free survival (PFS), duration of response (DOR), and overall survival (OS) were not reached. Estimated 24-month PFS, DOR, and OS rates in all patients were 57.4% (95% confidence interval [CI], 46.2-67), 66.4% (95% CI, 54.3-76), and 87.7% (95% CI, 78.3-93.2), respectively. Complete response rate and overall response rate were 68.1% (95% CI, 57.7-77.3) and 86.2% (95% CI, 77.5-92.4), respectively. No new safety signals or treatment-related deaths were reported. Low levels of tumor-infiltrating LAG3+CD3+ exhausted T cells and higher baseline levels of naïve CD8+ T cells were associated with improved outcomes. Tisagenlecleucel continued to demonstrate highly durable efficacy and a favorable safety profile in this extended follow-up of 29 months in patients with r/r FL enrolled in ELARA. This trial was registered at www.clinicaltrials.gov as #NCT03568461.

CXCR4-targeted Theranostics in Hematooncology: Opportunities and Challenges.

C-X-C motif chemokine receptor 4 (CXCR4) is overexpressed in a multitude of cancers, including neoplasms of hematopoietic origin. This feature can be leveraged by a theranostic approach, which provides a read-out of the actual CXCR4 expression in vivo, followed by CXCR4-targeted radioligand therapy (RLT) exerting anti-cancer as well as myeloablative efficacy. In a recent meeting of hematooncology and nuclear medicine specialists, statements on the current clinical practice and future perspectives of this innovative concept were proposed and summarized in this opinion article. Experts concluded that i) CXCR4-directed [68Ga]Ga-PentixaFor PET/CT has the potential to improve imaging for patients with marginal zone lymphoma; ii) CXCR4-targeted RLT exerts anti-lymphoma efficacy and myeloablative effects in patients with advanced, treatment-refractory T-cell lymphomas; iii) prospective trials with CXCR4-based imaging and theranostics are warranted.

Management of Patients Undergoing CAR-T Cell Therapy in Germany.

INTRODUCTION: Chimeric antigen receptor positive T cell (CAR-T cell) treatment became standard therapy for relapsed or refractory hematologic malignancies, such as non-Hodgkin's lymphoma and multiple myeloma. Owing to the rapidly progressing field of CAR-T cell therapy and the lack of generally accepted treatment guidelines, we hypothesized significant differences between centers in the prevention, diagnosis, and management of short- and long-term complications. METHODS: To capture the current CAR-T cell management among German centers to determine the medical need and specific areas for future clinical research, the DAG-HSZT (Deutsche Arbeitsgemeinschaft für Hämatopoetische Stammzelltransplantation und Zelluläre Therapie; German Working Group for Hematopoietic Stem Cell Transplantation and Cellular Therapy) performed a survey among 26 German CAR-T cell centers. RESULTS: We received answers from 17 centers (65%). The survey documents the relevance of evidence in the CAR-T cell field with a homogeneity of practice in areas with existing clinical evidence. In contrast, in areas with no - or low quality - clinical evidence, we identified significant variety in management in between the centers: management of cytokine release syndrome, immune effector cell-related neurotoxicity syndrome, IgG substitution, autologous stem cell backups, anti-infective prophylaxis, and vaccinations. CONCLUSION: The results indicate the urgent need for better harmonization of supportive care in CAR-T cell therapies including clinical research to improve clinical outcome.

An inducible Cd79b mutation confers ibrutinib sensitivity in mouse models of Myd88-driven diffuse large B-cell lymphoma.

ABSTRACT: Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive lymphoma and constitutes a highly heterogenous disease. Recent comprehensive genomic profiling revealed the identity of numerous molecularly defined DLBCL subtypes, including a cluster which is characterized by recurrent aberrations in MYD88, CD79B, and BCL2, as well as various lesions promoting a block in plasma cell differentiation, including PRDM1, TBL1XR1, and SPIB. Here, we generated a series of autochthonous mouse models to mimic this DLBCL cluster and specifically focused on the impact of Cd79b mutations in this setting. We show that canonical Cd79b immunoreceptor tyrosine-based activation motif (ITAM) mutations do not accelerate Myd88- and BCL2-driven lymphomagenesis. Cd79b-mutant murine DLBCL were enriched for IgM surface expression, reminiscent of their human counterparts. Moreover, Cd79b-mutant lymphomas displayed a robust formation of cytoplasmic signaling complexes involving MYD88, CD79B, MALT1, and BTK. These complexes were disrupted upon pharmacological BTK inhibition. The BTK inhibitor-mediated disruption of these signaling complexes translated into a selective ibrutinib sensitivity of lymphomas harboring combined Cd79b and Myd88 mutations. Altogether, this in-depth cross-species comparison provides a framework for the development of molecularly targeted therapeutic intervention strategies in DLBCL.

Entirely noninvasive outcome prediction in central nervous system lymphomas using circulating tumor DNA.

ABSTRACT: State-of-the-art response assessment of central nervous system lymphoma (CNSL) by magnetic resonance imaging is challenging and an insufficient predictor of treatment outcomes. Accordingly, the development of novel risk stratification strategies in CNSL is a high unmet medical need. We applied ultrasensitive circulating tumor DNA (ctDNA) sequencing to 146 plasma and cerebrospinal fluid (CSF) samples from 67 patients, aiming to develop an entirely noninvasive dynamic risk model considering clinical and molecular features of CNSL. Our ultrasensitive method allowed for the detection of CNSL-derived mutations in plasma ctDNA with high concordance to CSF and tumor tissue. Undetectable plasma ctDNA at baseline was associated with favorable outcomes. We tracked tumor-specific mutations in plasma-derived ctDNA over time and developed a novel CNSL biomarker based on this information: peripheral residual disease (PRD). Persistence of PRD after treatment was highly predictive of relapse. Integrating established baseline clinical risk factors with assessment of radiographic response and PRD during treatment resulted in the development and independent validation of a novel tool for risk stratification: molecular prognostic index for CNSL (MOP-C). MOP-C proved to be highly predictive of outcomes in patients with CNSL (failure-free survival hazard ratio per risk group of 6.60; 95% confidence interval, 3.12-13.97; P < .0001) and is publicly available at www.mop-c.com. Our results highlight the role of ctDNA sequencing in CNSL. MOP-C has the potential to improve the current standard of clinical risk stratification and radiographic response assessment in patients with CNSL, ultimately paving the way toward individualized treatment.

Follow-up of the GHSG HD16 trial of PET-guided treatment in early-stage favorable Hodgkin lymphoma.

The primary analysis of the GHSG HD16 trial indicated a significant loss of tumor control with PET-guided omission of radiotherapy (RT) in patients with early-stage favorable Hodgkin lymphoma (HL). This analysis reports long-term outcomes. Overall, 1150 patients aged 18-75 years with newly diagnosed early-stage favorable HL were randomized between standard combined-modality treatment (CMT) (2x ABVD followed by PET/CT [PET-2] and 20 Gy involved-field RT) and PET-2-guided treatment omitting RT in case of PET-2 negativity (Deauville score [DS] < 3). The study aimed at excluding inferiority of PET-2-guided treatment and assessing the prognostic impact of PET-2 in patients receiving CMT. At a median follow-up of 64 months, PET-2-negative patients had a 5-year progression-free survival (PFS) of 94.2% after CMT (n = 328) and 86.7% after ABVD alone (n = 300; HR = 2.05 [1.20-3.51]; p = 0.0072). 5-year OS was 98.3% and 98.8%, respectively (p = 0.14); 4/12 documented deaths were caused by second primary malignancies and only one by HL. Among patients assigned to CMT, 5-year PFS was better in PET-2-negative (n = 353; 94.0%) than in PET-2-positive patients (n = 340; 90.3%; p = 0.012). The difference was more pronounced when using DS4 as cut-off (DS 1-3: n = 571; 94.0% vs. DS ≥ 4: n = 122; 83.6%; p < 0.0001). Taken together, CMT should be considered standard treatment for early-stage favorable HL irrespective of the PET-2-result.

Multicenter development of a PET-based risk assessment tool for product-specific outcome prediction in large B-cell lymphoma patients undergoing CAR T-cell therapy.

PURPOSE: The emergence of chimeric antigen receptor (CAR) T-cell therapy fundamentally changed the management of individuals with relapsed and refractory large B-cell lymphoma (LBCL). However, real-world data have shown divergent outcomes for the approved products. The present study therefore set out to evaluate potential risk factors in a larger cohort. METHODS: Our analysis set included 88 patients, treated in four German university hospitals and one Italian center, who had undergone 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography (PET) before CAR T-cell therapy with tisagenlecleucel or axicabtagene ciloleucel. We first determined the predictive value of conventional risk factors, treatment lines, and response to bridging therapy for progression-free survival (PFS) through forward selection based on Cox regression. In a second step, the additive potential of two common PET parameters was assessed. Their optimal dichotomizing thresholds were calculated individually for each CAR T-cell product. RESULTS: Extra-nodal involvement emerged as the most relevant of the conventional tumor and patient characteristics. Moreover, we found that inclusion of metabolic tumor volume (MTV) further improves outcome prediction. The hazard ratio for a PFS event was 1.68 per unit increase of our proposed risk score (95% confidence interval [1.20, 2.35], P = 0.003), which comprised both extra-nodal disease and lymphoma burden. While the most suitable MTV cut-off among patients receiving tisagenlecleucel was 11 mL, a markedly higher threshold of 259 mL showed optimal predictive performance in those undergoing axicabtagene ciloleucel treatment. CONCLUSION: Our analysis demonstrates that the presence of more than one extra-nodal lesion and higher MTV in LBCL are associated with inferior outcome after CAR T-cell treatment. Based on an assessment tool including these two factors, patients can be assigned to one of three risk groups. Importantly, as shown by our study, metabolic tumor burden might facilitate CAR T-cell product selection and reflect the individual need for bridging therapy.

Mouse models of diffuse large B cell lymphoma.

Diffuse large B cell lymphoma (DLBCL) is a genetically highly heterogeneous disease. Yet, to date, the vast majority of patients receive standardized frontline chemo-immune-therapy consisting of an anthracycline backbone. Using these regimens, approximately 65% of patients can be cured, whereas the remaining 35% of patients will face relapsed or refractory disease, which, even in the era of CAR-T cells, is difficult to treat. To systematically tackle this high medical need, it is important to design, generate and deploy suitable in vivo model systems that capture disease biology, heterogeneity and drug response. Recently published, large comprehensive genomic characterization studies, which defined molecular sub-groups of DLBCL, provide an ideal framework for the generation of autochthonous mouse models, as well as an ideal benchmark for cell line-derived or patient-derived mouse models of DLBCL. Here we discuss the current state of the art in the field of mouse modelling of human DLBCL, with a particular focus on disease biology and genetically defined molecular vulnerabilities, as well as potential targeting strategies.