Mediastinal B Cell Lymphoma

P1, N=78, Recruiting, Adicet Bio, Inc | Trial completion date: Mar 2024 --> Dec 2027 | Trial primary completion date: Mar 2023 --> Dec 2025

Long term safety and efficacy data from these ongoing studies are eagerly awaited. In this comprehensive review, we discuss the mechanism of immune checkpoint inhibitors, the key takeaways from the reported results of completed and ongoing studies of these therapies in the context of hematological malignancies.

P=N/A, N=592, Completed, University Hospital Southampton NHS Foundation Trust | Active, not recruiting --> Completed

P2, N=35, Recruiting, Jennifer Crombie, MD | Not yet recruiting --> Recruiting

This large-scale genomic characterization of PMBCL identified novel treatment targets and genetic lesions for refined risk stratification. DUSP2 and CD58 mutation analyses may guide treatment decisions between rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone and dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab.

We validated these results in an independent cohort of 40 patients and confirmed the significant association between PDL1high/PDL2high status and inferior PFS (HR=6.11 [1.61-23.2]). High PDL1/PDL2 gene expression defines a population with strong immune privilege and poor outcomes from standard chemotherapy who might benefit from first-line anti-PD1 immunotherapy.

Eligible patients received 6 cycles of Tislelizumab (200 mg D1), Rituximab (375 mg/m 2 D1), Cyclophosphamide (750 mg/m 2 D2), Pirarubicin (50 mg/m 2 D2), Vincristine (1. 4 mg/m 2, maximum dose 2 mg, D2), Prednisone (100 mg/d D2-6), every 21 days for 1 cycle... Tislelizumab combined with R-CHOP for the treatment of previously untreated PMBCL had good efficacy and sustained response with low toxicity. Longer follow-up is required to access the survival benefit of this regimen. Figure 1: Disease Remission in the Included Patients

ConclusionAltogether, data suggests that ruxolitinib enhances immunogenicity primarily in 9p amplified cell lines and supports the hypothesis that ruxolitinib may prime for lymphoma cell death when combined with immunotherapy. These findings provide a foundation for in vivo assessment in humanized mouse models treated with combination anti-PDL-1 and JAK1/2 inhibitor, targeting tumorigenesis driven by 9p amplification.

Like HIV associated DLBCL, these results show that PTLD is more genomically stable than IC-DLBCL, and that genomic stability is further enhanced in EBV(+)PTLD which have increased expression of UPS related genes. In contrast, EBV(-)PTLD have increased expression of DNA damage repair genes, including RAD51. In summary, monomorphic DLBCL PTLD tumors have enhanced genomic stability that appears to be mediated by two distinct mechanisms stratified by EBV status.

High plasma levels of a 9-gene signature (BECN1, PRKCB, COPA, TSC22D3, MAP2K3, UQCRHL, PTMAP4, EHD1, NAP1L1 pseudogene) and a 5-gene signature (FTH1P7, PTMAP4, ATF4, FTH1P8, ARMC7) were significantly associated with inferior progression-free and overall survival in DLBCL patients, respectively, independent of the NCCN-IPI score. Total RNA sequencing of blood plasma samples allows the analysis of the cell-free transcriptome in DLBCL and PMBCL patients and demonstrates its unexplored potential in identifying diagnostic, cell-of-origin, and prognostic cfRNA biomarkers.

Mass spectrometry demonstrates that ZNF217 acts within a histone modifier complex containing LSD1, CoREST and HDAC and interferes with H3K4 methylation and H3K27 acetylation. Concluding, our data suggest non-catalytic activity of ZNF217, which directs histone modifier complex function and controls B cell differentiation-associated patterns of chromatin structure.

Twenty-three (79.3%) pts were treated with axicabtagene ciloleucel and 6 (20.7%) with tisagenlecleucel. Imaging features extracted from pre-infusion 18F-FDG PET/CT images in combination with several clinical features could predict survival and neurotoxicity in pts with DLBCL or PMBCL treated with CAR-T cell therapy. Quantitative features extracted from the PET/CT imaging exams may be useful for patient risk stratification and neurotoxicity prediction. Validation of these classifiers in independent datasets is warranted.

In this post hoc analysis of ZUMA-1 with up to 6 years of follow-up, axi-cel had long-term LREFS in a substantial proportion of patients, with a 5-year rate of 34% (57% among patients who achieved a CR). Additionally, a CR at 12 and 24 months may be predictive of extended OS. Among patients who achieved a CR, deaths due to axi-cel–related AEs mainly occurred before Month 24.

Among them , stage III-IV accounted for 43/49 (87.8%) and GCB subtype 22/49 (44.9%),and received a median of 7 cycles(3-14)of prior treatment, previous radiotherapy was 8/49 (16.3%), and previous other target CART patients were 20/49 (40.8%).The disease status of patients before ASCT-CART was 23 patients in complete remission, 17 patients in partial remission, 3 patients with stable disease, and 6 patients with progressive disease.Patients were treated with BEAM and fludarabine before ASCT...Summary/Conclusion The ASCT-CART therapy could enhance its the remission rate and long-term efficacy in the treatment of advanced relapsed/refractory B-cell lymphoma with controllable safety. Patients who were in remission before ASCT-CART therapy achieved a longer term remission after ASCT-CART cell therapy.

Introduction Co-expression of C-MYC and BCL2 in diffuse large b-cell lymphomas (DLBCL), also termed double-expressor lymphomas (DEL), has been shown to be associated with poorer outcomes after standard R-CHOP induction therapy...Conclusion Co-expression of C-MYC/BCL2 was associated with inferior outcomes after ASCT in patients with R/R DLBCL. While ASCT has been the standard curative approach in the R/R setting, considerations for novel targeting therapies to achieve a deeper response prior to transplant or the upfront use of chimeric antigen receptor T-cell therapy at first relapse may be further explored in this high-risk subset of patients.

Lymphodepletion chemotherapy with fludarabine 30 mg/m2/day and cyclophosphamide 500 mg/m2/day was administered on Days −5 to −3 prior to CAR T-cell infusion. Moreover, CART19/20 showed robust activity in patients with R/R NHL with durable responses seen. By utilizing a bispecific CAR and enriching for TN/MEM cells, this phase 1 trial of CART19/20 demonstrates the possibility of improving outcomes through targeting common mechanisms of CAR-T cell resistance.

We found co-occurrence of inactivating events in A20 and XPO1 missense mutations impacting 15% of PMBCL evaluated cases, with consistent results seen across all studies (range: 13.8-20%). As expected, A20 mutations/del were more prevalent than XPO1 mutations across all studies (OR 2.46, 95% CI 0.84-7.18, p = 0.02). XPO1 mutated cases trended towards a greater likelihood of having co-occurring A20 mutations (OR 8.51, 95% CI 0.84-86.47, p = 0.08).

Dose-adjusted Etoposide, Prednisolone, Vincristine, Cyclophosphamide, Doxorubicin and Rituximab (DA-EPOCH-R) without radiotherapy has demonstrated excellent activity in a small phase II study but with increased chemotherapy toxicity. Key secondary endpoints include response to window phase treatment, overall survival, requirement for radiotherapy and safety of treatment including rates of early discontinuation due to treatment toxicity. Several biomarkers are also being investigated for their predictive value for treatment response including minimal residual disease status (measured by Adaptive Immunoseq and CAPP-Seq), PET-CT parameters (e.g., Metabolic tumour volume), and PD-1/PD-L1 expression and 9q24 alterations.

Blood and tissue samples will be analyzed by multi-parameter flow cytometry and hiplex imaging assays (Phenocycler-Fusion/CODEX) to identify immune signatures of response and resistance to Lonca, and to assess CAR T-cell persistence; blood samples will be analyzed by CAPP-Seq to measure minimal residual disease. Finally, total metabolic tumor volume will be assessed on pre-treatment PET-CT scans, and association with response to consolidation therapy will be analyzed.

These results demonstrate that HIV pos DLBCL tumors are less aberrant than their HIV neg counterparts irrespective of COO subtype. However, the degree of genomic stability differs by COO, with HIV pos GCB tumors being more genomically stable than HIV pos ABC tumors. Although both have enhanced expression of UPS related SCF genes (RBX1, SKP1), only HIV pos GCB tumors have enhanced expression of key DNA repair genes as well including Fanconi Anemia (BRCA2/FANCD1, FANCL) and mismatch repair (MSH2, MSH6) genes (adjusted p-values of ≤ 0.0263).

Moreover, analysis of serum proteins refines molecular classification. Altogether, joint analysis of serum proteins and ctDNA provides new tools to dismantle LBCL heterogeneity.

We could not confirm an association between COO, as determined by Hans algorithm, and outcomes in R/R aNHLs who received axi-cel at our center. Prospective analyses on larger datasets and other types of CAR-T products are needed.

In this study cohort, 106 (77.9%) patients received R-CHOP-like regimens as induction therapies, 25 (18.4%) patients received an R-EPOCH regimen, two (1.5%) patients received an R-HyperCVAD regimen, and three (2.2%) patients died before completing the first cycle of chemoimmunotherapy... A low ratio of circulating CD8+ T lymphocytes to M-MDSCs (CD8MMR) serves as a poor prognostic factor for both PFS and OS in treatment-naïve DLBCL patients. This finding warrants further investigation and highlights the possibility of risk-adapted strategies when treating DLBCL patients.

P2, N=25, Recruiting, New York Medical College | Trial primary completion date: Dec 2023 --> Dec 2024

In this secondary analysis of a phase III randomized trial of chemotherapy alone for DLBCL, initial bulk was not shown to be significantly associated with outcomes. Prospective data comparing consolidative RT versus no RT are necessary to determine optimal treatment paradigms.

CRT may be omitted in patients with a negative end of treatment PET scans; however, careful observation may also obviate the need for CRT in PET positive patients.

P1/2, N=307, Completed, Kite, A Gilead Company | Active, not recruiting --> Completed

Whereas R-CHOP or polatuzumab vedotin + R-CHP are now both standard treatments for DLBCL, in primary mediastinal B-cell lymphoma, dose adjusted EPOCH-R has become the standard of care based on prospective trials demonstrating that this treatment can obviate the need for mediastinal radiation in most patients.12,13 In the case of traditional Burkitt lymphoma, the Magrath regimen of R-CODOX-M/IVAC is frequently used for young/fit patients although there are also prospective data supporting the use of dose adjusted EPOCH-R for Burkitt lymphoma.14,15 For double/triple hit lymphoma, more intensive chemotherapy regimens are frequently recommended for fit patients including dose adjusted R-EPOCH, R-hyperCVAD, and R-CODOX-M/R-IVAC based on prospective single-arm trials and/or retrospective experience.16,17 In the case of HGBL, NOS, it is generally assumed that one of these intensive regimens should be used, as outcomes with R-CHOP are generally unsatisfactory, but comparative data are lacking. In conclusion, as outlined in the 2016 WHO classification and carried forward to updated classifications, HGBL remains an imperfectly described disease with lack of consensus diagnostic or treatment recommendations. In general, aggressive treatment regimens are recommended, if feasible, and future research is needed to study a larger number of cases with advanced molecular techniques and to prospectively assess different treatment regimens to improve outcomes for patients with these high-risk lymphomas.

STR AI in 9p24.1 and 16p13.13 and PD-L1 and HLA-DR expression are highly frequent though probably independent events relevant to immunotherapy response in PMBCL.

Standard approach (S-CIT) was defined as R-CHOP-21/CHOP-21, with or without RT...DI-CIT demonstrates a survival benefit, with significantly less radiation exposure, curtailing long-term toxicities associated with radiotherapy. As we await results of randomized prospective trials, our study supports the use of dose-intensive chemoimmunotherapy for the treatment of PMBCL.

According to data from the phase III IELSG37 trial, consolidation radiotherapy is unnecessary for patients with primary mediastinal B-cell lymphoma who respond completely to standard immunochemotherapy. Two other studies of peripheral T-cell lymphomas and adult T-cell leukemia/lymphoma, respectively, point to golidocitinib, an investigational JAK1 inhibitor, and mogamulizumab, which targets CCR4, as potential new treatment options.

The patient developing SJS was treated with corticosteroids, infliximab, and cyclosporine but ultimately died of invasive fungal infection from the extensive immunosuppression used to treat the SJS. Amongst DLBCLs, the CR and ORR was 80%/80% for PMBL and 17%/33% for non-PMBL. In conclusion, Pembrolizumab with Vorinostat was tolerable and produced responses in relapsed/refractory B-cell NHL, with particularly notable efficacy in PMBL.

Grade 3 or 4 treatment-related AEs occurred in 22.6% of patients; no grade 5 AEs occurred. After 4 years of follow-up, pembrolizumab continued to provide durable responses, with promising trends for long-term survival and acceptable safety in R/R PMBCL.

In a 2 × 2 factorial design, patients were randomized to 6× R-CHOP-14 or R-CHOP-21 (rituximab, cyclophosphamide, doxorubicin, vincristine, and prediso(lo)ne) and to consolidation radiotherapy to extralymphatic/bulky disease or observation. With the limitation of a pre-PET-era trial, the results suggest a benefit of radiotherapy only for patients responding to R-CHOP with PR. PMBCL treated with R-CHOP have a favorable prognosis with a 3-year OS of 97%.

P2, N=35, Not yet recruiting, Jennifer Crombie, MD

P1, N=30, Recruiting, Malaghan Institute of Medical Research | N=12 --> 30 | Trial completion date: Aug 2026 --> Feb 2029 | Trial primary completion date: Sep 2021 --> May 2024

Recent data has shown that incorporation of immune therapy has enhanced event free survival in advanced patients. Future studies will address the possibility of reducing the burden of chemotherapy by substitution of immune based therapies.

Numerous predictive biomarkers have been investigated in solid malignancies, such as PD-L1 expression, tumor mutational burden (TMB) and microsatellite instability (MSI), among others. This review aims to appraise the current knowledge on PD-1/PD-L1 ICB efficacy in lymphoma when used either as monotherapy or combined with other agents, and describes potential biomarkers of response in this specific setting.

Clinical development of glofitamab, as a monotherapy and in combination with other agents for the treatment of non-Hodgkin lymphomas, is continuing worldwide. This article summarizes the milestones in the development of glofitamab leading to this first approval for relapsed or refractory DLBCL.

AuthorNumber and patient population/trialMedian FUDiseaseTreatmentModelMethod of measurement and cut-offs as applicableStatistical relationship with survivalPFS/OSComments Ceriani et al.1910362 monthsPMBCL first line I-IV R-CHOP R-CHOP-like R-VACOP-B R-MACOP-B MTV + metabolic Heterogeneity (MH)MTV of hottest lesion using SUV ≥2.5 and AUC-CSH for MH cut–off 0.45ROC-AUC analysis5 years PFS 94% versus 73% in low and high MH groups, respectively (p = 0.0001) IELSG 26 Ceriani et al.20141 test64 monthsDLBCL first line I-IVR-CHOPMTV + MH MTV of hottest lesion using SUV ≥2.5 and AUC-CSH for MH Cut-off 931 cm3 PFS, 1149 cm3 OS 0.43 MH ROC-AUC analysis5 years PFS 83% versus 61% (p = 0.0005), 5 years OS 91% versus 65% (p = 0.0001), in low and high MTV respectivelyIn high MTV group, pts with high MH had higher risk of progression (HR, 5.6; 95% CI, 1.8–17) and death (HR, 9.5; 95% CI, 1.7–52) 113 validation SAKK 38/07 study Cottereau et al.219544 months DLBCL first line I-IV 60–80 R-CHOP R-ACVBP tMTV + Dmax tMTV using 41% SUVmax Cut-off >394 cm3 SDmax >58 cm ROC-AUC analysis4 years PFS 94% versus 73% versus 53% and 4 years OS 97% versus 88% versus 50% for pts with 0, 1 or 2 risk factors (p = 0.0003 PFS, p = 0.0011 OS) respectively LNH073B Cottereau et al.222905 years DLBCL first line I-IV 60–80 R-CHOPtMTV + SDmax (Dmax standardized by body surface area) tMTV using 41% SUVmax Cut-off 220 cm3 SDmax >0.32 m−1 ROC-AUC analysis4 years PFS 90% versus 63% versus 41% and 4 years OS 95% versus 79% versus 66% for pts with 0, 1 or 2 risk factors (p = 0.0001) respectively REMARC Driessen et al.276540 months HL R/R BV-DHAPsTARC + TLR using SUV peak lesion + SUV mean liver and sTARC after one cycle 1 of BV-DHAP and SUVpeak prior to ASCTsTARC cut-off 500 pg/mL baseline TLR ≥3.0 pre-ASCT TLR ≥1.0 using liver SUVmean and lesion SUVpeakROC-AUC analysis 3 years FFP 35% versus 95% for pts with high baseline sTARC and high baseline TLR versus either high risk factor 3 years FFP 0% versus 95% for 4 pts with high sTARC post c1 and high TLR pre-ASCT versus all pts BRAVE Durmo et al.53155 retrospective RW63 monthsHL I-IVABVDDmax + MTVMedian Dmax 20 cmMedian used to subdivide pts4 years PFS 90% versus 72% for pts with low and high Dmax respectivelyGene expression and cell populations differentially expressed in high and low Dmax groups Eertink et al.831792 months (parent trial)DLBCL first line I-IVR-CHOPRadiomics (MTV4, SUVpeak Dmaxbulk) clinical (IPI components and bulk >10 cm) tMTV4 Continuous scale ROC-AUC analysis2 years TTP, 28% versus 44% for high risk pts for radiomics + clinical model and IPI respectively Patient level features performed better than individual lesion analysis Simple radiomics model performed better than complex model HOVON-84 Eertink et al.4323DLBCL first line I-IVRadiomics (MTV4, Dmaxbulk, DSUVpeak, spread) + MYC status tMTV4 Continuous scale ROC-AUC analysis 2 years TTP 50% versus 70% 2 years PFS 51% versus 65% 2 years OS 57% versus 69% for high risk pts for radiomics + MYC model and IPI respectively HOVON-84 PETAL Mikhaeel et al.35124155 monthsDLBCL first line I-IVR-CHOPMTV-age-stage tMTV4 using SUV ≥4.0 and 3mls min volume Continuous scale Linear spline with 2 coefficients above and below median 310 cm33 years PFS for high risk pts 46.3% versus 58.0% and 3 years OS 51.5% versus 66.4% for IMPI and IPI respectivelySplit by scale into low risk 60% intermediate risk 30% high risk 10% 5 clinical trials from PETRA consortium Thieblemont et al.541825 PETAL + GOYA47.1–76.5 mDLBCL first line I-IVR-CHOPMTV + PStMTV using 41% SUVmax (PETAL, RW) and liver threshold (GOYA) PS ≥2COMBAT method used to harmonize tMTV measurements 4 years PFS 54% versus 59% (PETAL) 49% versus 58% (GOYA) 36% versus 55% (RW) for high risk pts for MTV + PS and IPI respectively p < 0.001 4 years OS 61% versus 70% (PETAL) 61% versus 72% (GOYA) 41% versus 59% (RW) for high risk pts for MTV + PS and IPI respectively p < 0.001 349 RW Vercellino et al.143015 years DLBCL first line I-IV 60–80 R-CHOPMTV + PS tMTV using 41% SUVmax Cut-off 220 cm3 PS ≥2 ROC-AUC analysis X-tile analysis 4 years PFS 82% versus 63% versus 41% and 4 years OS 94% versus 79% versus 59% for pts with 0, 1 or 2 risk factors (p = 0.0001) REMARC Abbreviations: ASCT, autologous stem cell transplant; DLBCL, diffuse large B-cell lymphoma; MH, metabolic heterogeneity; OS, overall survival; PFS, progression-free-survival; PMBCL, primary mediastinal B-cell lymphoma; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone; sTARC, serum thymus and activation regulated chemokine; SUV, standardized uptake value; tMTV, total metabolic tumor volume. A model including baseline tMTV ≥220 cm3 (using 41% of the maximum SUV to delineate tumors) and performance status (PS) ≥2 was also developed in a population of patients aged 60–80 with DLBCL in the REMARC study treated with R-CHOP.14 These two risk factors were the only independent variables associated with 4-year OS from tMTV, IPI, NCCN-IPI, B2 microglobulin, albumin and treatment arm (maintenance lenalidomide vs. placebo)...A new concept of “near CMR” with >90% reduction in MTV has been suggested as a more sensitive method of response to checkpoint inhibitors than CMR, given either sequentially or in combination with doxorubicin, vinblastine and darcarbazine (AVD) chemotherapy in first-line treatment of patients with HL.62, 63 The combination of emerging blood biomarkers as well as established risk factors with early PET scans, which may provide complementary information to monitor response is appealing...In another report exploring baseline and intra-treatment blood biomarkers and PET scans in HL,27 baseline serum thymus and activation regulated chemokine (sTARC), baseline SUV peak (the “hottest” 1 cm3 of tumor) and sTARC after one cycle 1 of brentuximab vedotin (BV)-dexamethasone, cytarabine, cisplatin (DHAP) and SUVpeak prior to autologous stem cell transplant were shown to predict response in 65 patients with relapsed/refractory (R/R) disease in the transplant BRAVE study, where tMTV had low prognostic value...The prognostic value of these models will need to be tested in patients treated with polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, prednisolone (R-CHP),64 which is rapidly becoming an alternative standard approach.65 Newer algorithms incorporating artificial intelligence40 are likely to allow even faster and reproducible measurement of tMTV...It is clear that evaluation of radiomic features, molecular markers and ctDNA at baseline and during treatment should be factored into current clinical trial designs using appropriate statistical models to explore the relationship of continuous variables with patient outcomes.35 Promising radiomic and circulating blood biomarkers should be assessed with established clinical risk factors in clinical decision models. Prospective collection of data and retrospective analysis of curated imaging data from clinical trials will enable the development of baseline and dynamic risk scores that could further advance the field to facilitate testing of novel treatments and personalized therapy in aggressive lymphomas.