An international analysis evaluating frontline bendamustine with rituximab in extranodal marginal zone lymphoma

: Extranodal marginal zone lymphoma (EMZL) is a heterogeneous non-Hodgkin lymphoma. No consensus exists regarding the standard-of-care in patients with advanced-stage disease. Current recommendations are largely adapted from follicular lymphoma, for which bendamustine with rituximab (BR) is an established approach. We analyzed the safety and efficacy of frontline BR in EMZL using a large international consortium. We included 237 patients with a median age of 63 years (range, 21-85). Most patients presented with Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 (n = 228; 96.2%), stage III/IV (n = 179; 75.5%), and intermediate (49.8%) or high (33.3%) Mucosa Associated Lymphoid Tissue International Prognosis Index (MALT-IPI). Patients received a median of 6 (range, 1-8) cycles of BR, and 20.3% (n = 48) received rituximab maintenance. Thirteen percent experienced infectious complications during BR therapy; herpes zoster (4%) was the most common. Overall response rate was 93.2% with 81% complete responses. Estimated 5-year progression-free survival (PFS) and overall survival (OS) were 80.5% (95% CI, 73.1% to 86%) and 89.6% (95% CI, 83.1% to 93.6%), respectively. MALT-IPI failed to predict outcomes. In the multivariable model, the presence of B symptoms was associated with shorter PFS. Rituximab maintenance was associated with longer PFS (hazard ratio = 0.16; 95% CI, 0.04-0.71; P = .016) but did not impact OS. BR is a highly effective upfront regimen in EMZL, providing durable remissions and overcoming known adverse prognosis factors. This regimen is associated with occurrence of herpes zoster; thus, prophylactic treatment may be considered

Impact of Early Relapse within 24 Months after First-Line Systemic Therapy (POD24) on Outcomes in Patients with Marginal Zone Lymphoma: A US Multisite Study

Progression of disease within 24 months (POD24) from diagnosis in marginal zone lymphoma (MZL) was shown to portend poor outcomes in prior studies. However, many patients with MZL do not require immediate therapy, and the time from diagnosis-to-treatment interval can be highly variable with no universal criteria to initiate systemic therapy. Hence, we sought to evaluate the prognostic relevance of early relapse or progression within 24 months from systemic therapy initiation in a large US cohort. The primary objective was to evaluate the overall survival (OS) in the two groups. The secondary objective included the evaluation of factors predictive of POD24 and the assessment of cumulative incidence of histologic transformation (HT) in POD24 versus non-POD24 groups. The study included 524 patients with 143 (27%) in POD24 and 381 (73%) in non-POD24 groups. Patients with POD24 had inferior OS compared to those without POD24, regardless of the type of systemic therapy received (rituximab monotherapy or immunochemotherapy) at diagnosis. After adjusting for factors associated with inferior OS in the univariate Cox model, POD24 remained associated with significantly inferior OS (HR = 2.50, 95% CI = 1.53-4.09, p = 0.0003) in multivariable analysis. The presence of monoclonal protein at diagnosis and those who received first-line rituximab monotherapy had higher odds of POD24 on logistic regression analysis. Patients with POD24 had a significantly higher risk for HT compared to those without POD24. POD24 in MZL might be associated with adverse biology and could be used as an additional information point in clinical trials and investigated as a marker for worse prognosis

A Case Report of Nongerminal Center B-Cell Type Diffuse Large B-Cell Lymphoma Treated to Complete Response with Rituximab and Ibrutinib

Diffuse large B-cell lymphoma (DLBCL) is a molecularly heterogeneous disease consisting of different subtypes with varying clinical behaviors. For example, the activated B-cell-like (ABC) type of DLBCL has lower cure rates with traditional chemotherapy regimens. The molecular pathway promoting tumorigenic growth of the ABC type includes a dependence on intracellular signaling by Bruton’s agammaglobulinemia tyrosine kinase (BTK). This specific pathway has led to the investigation of the utility of ibrutinib in treatment of this type of lymphoma at relapse or in combination with standard chemotherapy. In elderly patients stricken with this disease, standard combination chemotherapy can pose significant toxicity. Some reduced intensity regimens have activity but significantly less favorable long-term outcomes and still pose significant toxicity to elderly patients. In the following case, we demonstrate induction of complete response in an elderly patient with significant comorbidities with nongerminal center B-cell type (NGCB) DLBCL treated with rituximab, ibrutinib, and prednisone. Toxicity included atrial fibrillation that ultimately led to heart failure as well as sepsis which ultimately led to the patient’s demise. Despite this fact, the response to treatment appeared durable. This case illustrates the utility and limitations of molecularly targeted therapies to treat aggressive lymphoma in frail elderly patients

Serine 15 Phosphorylation of p53 Directs Its Interaction with B56γ and the Tumor Suppressor Activity of B56γ-Specific Protein Phosphatase 2A▿ †

Earlier studies have demonstrated a functional link between B56γ-specific protein phosphatase 2A (B56γ-PP2A) and p53 tumor suppressor activity. Upon DNA damage, a complex including B56γ-PP2A and p53 is formed which leads to Thr55 dephosphorylation of p53, induction of the p53 transcriptional target p21, and the inhibition of cell proliferation. Although an enhanced interaction between p53 and B56γ is observed after DNA damage, the underlying mechanism and its significance in PP2A tumor-suppressive function remain unclear. In this study, we show that the increased interaction between B56γ and p53 after DNA damage requires ATM-dependent phosphorylation of p53 at Ser15. In addition, we demonstrate that the B56γ3-induced inhibition of cell proliferation, induction of cell cycle arrest in G1, and blockage of anchorage-independent growth are also dependent on Ser15 phosphorylation of p53 and p53-B56γ interaction. Taken together, our results provide a mechanistic link between Ser15 phosphorylation-mediated p53-B56γ interaction and the modulation of p53 tumor suppressor activity by PP2A. We also show an important link between ATM activity and the tumor-suppressive function of B56γ-PP2A

Abstract A27: Impact of a validated composite comorbidity score on outcomes in patients treated with CAR T-cell therapy for diffuse large B cell lymphoma (DLBCL): A multicenter real-world evidence (RWE) study

Introduction: CAR T-cell therapy (CART) has dramatically improved outcomes for patients (pts) with relapsed/refractory (r/r) DLBCL, but the majority of pts still have poor outcomes due to progressive disease and toxicities. Here we used a machine learning algorithm to rank the prognostic impact of specific comorbidities measured by the Cumulative Illness Rating Scale (CIRS) in DLBCL pts indicated for CART in a multicenter learning cohort (LC) and a separate validation cohort (VC). Methods: pts with r/r DLBCL included in RWE analysis underwent leukapheresis for CART at 10 academic centers. CIRS was assessed at the time of T-cell collection (Salvi et al, 2008). Progression-free survival (PFS) and overall survival (OS) were measured from T-cell collection. Random survival forest (RSF) modeling of PFS and OS was repeatedly applied to random subsets of the LC to determine the most important CIRS categories and comorbidity levels in the presence of known prognostic factors. Cox proportional hazards models of PFS and OS were fit to both cohorts. Associations between comorbidities and CART adverse events were evaluated with Fisher’s exact test. Results: The LC comprised 577 pts, median age of 63 (range, 19-90); 90% had ECOG 0-1. Median number of prior therapies was 3 (range, 1-11). GCB subtype was found in 54% of pts, with 38% non-GCB and 8% unknown. Twenty-seven pts (4.7%) died before CART infusion. Of the 550 pts who received CART, 71% got axicabtagene ciloleucel, 22% tisagenlecleucel, and 7% lisocabtagene maraleucel. The median CIRS score was 7 (range, 0-25) with 54% having CIRS ≥7. The median PFS was 11 months (95% CI: 8 – 15) and OS 30 months (95% CI: 23 – NA), with a median follow-up time of 20 months. Although CIRS ≥7 was significantly associated with PFS (HR=1.26) and OS (HR=1.35) in univariable analysis, it did not remain significant in multivariable models. According to a RSF tree depth-weighted nodal split score, severe comorbidities in the following CIRS categories had the greatest impact on PFS: respiratory, upper GI, renal, and hepatic (denoted Severe4, 9% of pts). When accounting for other significant variables, Severe4 was independently associated with inferior PFS (HR=2.45, p\u3c0.001) and OS (HR=2.30, p\u3c0.001) in the LC. This finding was recapitulated in a single-center VC (n=218, median follow-up of 35 months, median age 61 years, median of 3 prior therapies, ECOG 0-1 in 74%, Severe4 in 16% of pts, 98% receiving axicabtagene ciloleucel) as Severe4 remained independently associated with inferior PFS (HR=1.84, p=0.003) and OS (HR=1.82, p=0.007). Pts with Severe4 also had a higher rate of grade ≥3 CRS (16% vs 6%; p=0.013), while development of grade ≥3 ICANS was associated with CIRS ≥7 (26% vs 12%; p\u3c0.001).Conclusions: In this large RWE study, we identify and validate a composite index comprising four organ systems (respiratory, upper GI, renal and hepatic; Severe4) that correlates with survival outcomes in CART recipients for r/r DLBCL. GS & AK contributed equally Citation Format: Geoffrey Shouse, Andy Kaempf, Max Gordon, David Yashar, Audrey M Sigmund, Gordon Smilnak, Steven M Bair, Agrima Mian, Lindsey Fitzgerald, Amneet Bajwa, Samantha Jaglowski, Neil Bailey, Mayzar Shadman, Krish Patel, Deborah M Stephens, Manali Kamdar, Brian T Hill, Jordon Gauthier, Reem Karmali, Loretta Nastoupil, Adam S Kittai, Alexey V Danilov. Impact of a validated composite comorbidity score on outcomes in patients treated with CAR T-cell therapy for diffuse large B cell lymphoma (DLBCL): A multicenter real-world evidence (RWE) study [abstract]. In: Proceedings of the Third AACR International Meeting: Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2022 Jun 23-26; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2022;3(5_Suppl):Abstract nr A2

Impact of Comorbidities on Outcomes and Toxicity in Patients Treated with CAR T-Cell Therapy for Diffuse Large B Cell Lymphoma (DLBCL): A Multicenter Rwe Study

Introduction: CAR T-cell therapy has dramatically improved outcomes for patients (pts) with relapsed/refractory (r/r) DLBCL, with some achieving durable response. Still, the majority of pts have poor outcomes with CAR-T due to progressive disease, while inherent characteristics may predispose pts to CAR-T toxicities. Tools quantifying frailty and comorbidities have not been verified in large patient cohorts. The Cumulative Illness Rating Scale (CIRS) is a comprehensive tool that has been found to predict outcomes in various B cell malignancies. Here we use a machine learning algorithm to rank the prognostic impact of specific comorbidities, as measured by CIRS, and then assess survival and toxicities in pts treated with commercially available CAR T-cell products for DLBCL. Methods: We conducted a retrospective RWE analysis of pts with r/r DLBCL who underwent leukapheresis for CART at 9 academic centers. CIRS was assessed at the time of T-cell collection and calculated as in Salvi et al, 2008. High comorbidity burden was defined using a published cutoff of CIRS score ≥7. Progression-free survival (PFS) and overall survival (OS) were measured from T-cell collection. Repeated subsampling and random survival forest (RSF) modeling of PFS were used to determine the most prognostic CIRS categories in the presence of covariates. Cox proportional hazards models were fit to quantify the association between survival and the following patient features: IPI at diagnosis, concurrent indolent lymphoma, age, ECOG performance status, number of prior therapies, prior transplant, number of medications, cell of origin subtype, complex karyotype, MYC rearrangement by FISH, and MYC+BCL2/BCL6 rearrangement (double-hit). Associations between comorbidities and CAR-T adverse events were evaluated with Fisher\u27s exact test. Results: We analyzed data from 577 pts, with a median age of 63 (range, 19-90); 90% had ECOG 0-1. Median number of prior therapies was 3 (range, 1-11) and 25% of pts (n=143) had prior autologous stem cell transplant. GCB subtype was found in 54% of pts (n=312), with 38% (n=218) non-GCB and 8% (n=47) unknown (Hahn\u27s algorithm). MYC gene rearrangement was present in 21% and double-hit in 16% with 9% lacking FISH. Twenty-seven pts (4.7%) died before CAR-T infusion (progressive disease in 24 and infection in 3). Of the 550 pts who received CAR-T, 71% (n=393) got axicabtagene ciloleucel, 22% (n=120) tisagenlecleucel, and 7% (n=37) lisocabtagene maraleucel. The median CIRS score was 7 (range, 0-25) with 54% (n=309) having CIRS ≥7. The most frequent comorbidities were seen in the vascular (51%), endocrine (45%), and hypertension (43%) organ system categories. PFS event was observed in 56% of pts and 41% died, while survivors had a median follow-up time of 20 months. Median survival estimates were 11 months (95% CI: 8 - 15) for PFS and 30 months (95% CI: 23 - NA) for OS. CIRS ≥7 was significantly associated with PFS (HR=1.26, Fig 1A) and OS (HR=1.35, Fig 1B) in univariable analysis. According to RSF variable importance and node splits, key CIRS categories were respiratory, upper GI, renal, and hepatic (Fig 1C). Multivariable analysis showed higher ECOG (2/3 vs 1 vs 0) and 3 or more prior lines of treatment predicted shorter PFS and OS. Non-GCB subtype was related to reduced PFS but not OS, while double-hit status did not correlate with either outcome. Interestingly, CIRS ≥7 was not a significant predictor of outcomes in multivariable models. However, a severe comorbidity in any of the above four systems (denoted Severe4 , 9% of pts) was independently associated with inferior PFS (HR=2.45, Fig 1D) and OS (HR=2.30, Fig 1E). Although CIRS ≥7 was not associated with the development of CRS, pts with Severe4 had a higher rate of grade ≥3 CRS (16% vs 6%; p=0.013). In addition, development of grade ≥3 ICANS was associated with CIRS ≥7 (26% vs 12%; p\u3c0.001). Conclusions: In this large RWE study, we demonstrate that CIRS is predictive of outcomes and identify a composite index comprising four CIRS organ systems (respiratory, upper GI, renal and hepatic; Severe4 ) that had prognostic significance in CAR-T recipients for r/r DLBCL. Severe4 is predictive of severe CRS and CIRS ≥7 is predictive of severe ICANS. The underlying mechanism leading to this observation is an area of active ongoing investigation. Given these results, CIRS evaluation and Severe4 should be considered prior to CAR-T in DLBCL. GS & AK contributed equall

Impact of a Validated Composite Comorbidity Score on Outcomes in Patients Treated with CAR T-Cell Therapy for Diffuse Large B Cell Lymphoma (DLBCL): A Multicenter Real-World Evidence (RWE) Study

Introduction: Chimeric Antigen Receptor T-cell therapy (CART) has dramatically improved outcomes for patients (pts) with relapsed/refractory (r/r) DLBCL, but the majority of pts still have poor outcomes due to progressive disease and toxicities. Tools quantifying frailty and comorbidities have not been verified in large patient cohorts. The Cumulative Illness Rating Scale (CIRS) is a comprehensive tool that has been found to predict outcomes in various B cell malignancies. We used a machine learning algorithm to rank the prognostic impact of specific comorbidities measured by CIRS on progression-free survival (PFS) in DLBCL pts undergoing leukapheresis for CART in a multicenter learning cohort (LC; Shouse et al, ASH 2021). In this study, we establish that these comorbidities also predict overall survival (OS) and verify their prognostic significance in a separate validation cohort (VC). Methods: We conducted a retrospective RWE analysis of pts with r/r DLBCL who underwent leukapheresis for CART at 10 academic centers. CIRS was assessed at the time of T-cell collection and calculated per Salvi (2008). High comorbidity burden was defined using a published cutoff of CIRS score ≥7. PFS and OS were measured from T-cell collection. Random survival forest (RSF) modeling of PFS and OS was repeatedly applied to random subsets of the LC to determine the most important CIRS categories and comorbidity levels in the presence of known prognostic factors (IPI at diagnosis, concurrent indolent lymphoma, age, ECOG performance status, number of prior therapies, prior transplant, number of medications, cell of origin subtype, complex karyotype, MYC rearrangement by FISH, and MYC+BCL2/BCL6 rearrangement). Cox proportional hazards models were fit to quantify the association between survival and significant pt features. Associations between comorbidities and CART adverse events were evaluated with Fisher\u27s exact test. Results: We analyzed data from 577 pts. The median CIRS score was 7 (range, 0-25) with 54% (n=309) having CIRS ≥7. The median PFS was 11 months (95% CI: 8 - 15) and OS 30 months (95% CI: 23 - NA), with a median follow-up of 20 months. Although CIRS ≥7 was significantly associated with inferior PFS (HR=1.26) and OS (HR=1.35) in univariable analysis, it did not remain significant in multivariable models. According to RSF variable importance and node splits, key CIRS categories which adversely impacted OS were respiratory, upper GI, renal, and hepatic. 9% of pts had a score of ≥3 in at least one of the above comorbidities, which we designated Severe4. When accounting for other significant variables, Severe4 was independently associated with inferior PFS (HR=2.45, p\u3c0.001) and OS (HR=2.30, p\u3c0.001) in the LC. This finding was recapitulated in a single-center VC of 218 patients. In this cohort, median follow-up was 35 months, median age 61 years, median 3 prior therapies, ECOG 0-1 in 74%. As in the LC, axicabtagene ciloleucel was the predominant CART (93%). A CIRS comorbidity score of ≥3 in any of the Severe4 categories was found in 16% of pts. Severe4 remained independently associated with inferior PFS (HR=1.84, p=0.003) and OS (HR=1.82, p=0.007) in the VC (Figure). Pts with Severe4 also had a higher rate of grade ≥3 CRS (16% vs 6%; p=0.013), while development of grade ≥3 ICANS was associated with CIRS ≥7 (26% vs 12%; p\u3c0.001). Conclusions: In this large RWE study, we demonstrate that the presence of comorbidity within the Severe4 composite index had prognostic significance for OS in CART recipients for r/r DLBCL. Importantly, Severe4 was validated in a separate cohort. Severe4 is predictive of severe CRS and CIRS ≥7 is predictive of severe ICANS. The underlying mechanism leading to this observation is an area of active investigation. Given these results, CIRS evaluation and Severe4 should be calculated prior to CART in DLBCL to identify those at highest risk for morbidity and mortality and to counsel pts about their expected risk. These results may be product specific given the enrichment of axi-cel patients and may need additional verification with other products

B56γ tumor-associated mutations provide new mechanisms for B56γ-PP2A tumor suppressor activity.

UNLABELLED: The hetero-trimeric PP2A serine/threonine phosphatases containing the regulatory subunit B56, and in particular B56γ, can function as tumor suppressors. In response to DNA damage, the B56γ subunit complexes with the PP2A AC core (B56γ-PP2A) and binds p53. This event promotes PP2A-mediated dephosphorylation of p53 at Thr55, which induces expression of p21, and the subsequent inhibition of cell proliferation and transformation. In addition to dephosphorylation of p53, B56γ-PP2A also inhibits cell proliferation and transformation by a second, as yet unknown, p53-independent mechanism. Here, we interrogated a panel of B56γ mutations found in human cancer samples and cell lines and showed that these mutations lost B56γ tumor-suppressive activity by two distinct mechanisms: one is by disrupting interactions with the PP2A AC core and the other with B56γ-PP2A substrates (p53 and unknown proteins). For the first mechanism, due to the absence of the C catalytic subunit in the complex, the mutants are unable to mediate dephosphorylation of any substrate and thus failed to promote both the p53-dependent and -independent tumor-suppressive functions of B56γ-PP2A. For the second mechanism, the mutants lacked specific substrate interactions and thus partially lost tumor-suppressive function, i.e., either the p53-dependent or p53-independent contingent upon which substrate binding was affected. Overall, these data provide new insight into the mechanisms of tumor suppression by B56γ. IMPLICATIONS: This study further indicates the importance of B56γ-PP2A in tumorigenesis