Okcu, Izel

Abstract Introduction: Primary mediastinal B-Cell lymphoma (PMBCL) is a rare form of large B-Cell lymphoma (LBCL) with around 90% of patients (pts) cured with first line (1L) treatment. For pts with relapsed or refractory (RR) PMBCL, the optimal treatment is unclear. Prior retrospective analysis in the rituximab (R) era have shown high response rates to platinum salvage and high-dose chemotherapy followed by autologous stem cell transplant (HDT/ASCT) in second line (2L) RR PMBCL (Bakos et al. ASH 2023 and Dumke et al. ASCO 2024). The pivotal phase III LBCL trials in early relapsing pts that compared CD19 chimeric antigen receptor-T cell (CAR-T) with HDT/ASCT as 2L treatment had few PMBCL pts: none on ZUMA-7 and 17 PMBCL on TRANSFORM, of whom only 8 were randomized to 2L CAR-T. This study aims to evaluate outcomes of 2L therapies for RR PMBCL, including pts treated with 2L CAR-T. Methods: We performed a multicenter retrospective study in pts with RR PMBCL treated between 2001 and 2025. Clinical and pathologic characteristics, treatment regimens, and efficacy outcomes were collected and analyzed. Results: 139 pts were included with 43% male, 69% Caucasian, 7.9% Black, 8.6% Asian and 79% Non-Hispanic. R-EPOCH (64%) and (32%) were the most common 1L treatments and all pts received R. Consolidative radiation was used in 21 pts (15%) as part of 1L therapy, 28% after RCHOP. Primary refractory disease with relapse ≤6 month (mo), or early relapse ≤12 mo, occurred in 83% (N = 115) and 93% (N = 129 pts), respectively. At relapse, median age was 34 years (yrs), 44% had advanced stage disease, 31% had bulky disease (≥ 7.5cm). CNS relapse occurred in 8.6% of pts. Overall and complete response rate (ORR and CR) to any 2L treatment was 44% and 27%, respectively. At median follow-up of 40 months (mo) from the start of 2L treatment, median PFS of the entire cohort was 3.2 mo with a 3 yr OS of 70%. For 2L treatment, N=93 (67%) pts were treated with platinum salvage with intention to proceed with HDT/ASCT. Most commonly used platinum salvage regimens were ICE± R (n= 53, 38%), R-DHAP (n=23, 17%), R-GemOx (n= 5, 3.6%), and GDP ± R (n= 10, 7.2%), and the majority (95%) of pts received R with 2L therapy. ORR and CR to platinum salvage was 46% and 15% respectively. With a median follow up of 30 mo from start of 2L therapy, median PFS was 2.6 mos, and 3 yr PFS and OS was 15% and 64%, respectively. Of the 93 pts treated with platinum salvage, only 25 pts (27%) proceeded with HDT/ASCT- of whom, N = 17 (68%) achieved a CR after ASCT. In patients that proceeded to ASCT, relapses occurred in 10 pts (40%) with a 3 yr PFS and OS 56% and 83%, respectively. CAR-T was used as 2L in 20 pts (14%)- most commonly either axi-cel (N =7) or liso-cel (N = 8). ORR and CR to CART was 89% and 55% respectively, median PFS and OS was NR after CAR-T infusion and 3 yr PFS and OS was 55% and 95%, respectively. Other 2L treatments included pembrolizumab (N =3), brentuximab vedotin (BV) + nivolumab (N= 4) or single agent BV (N=2). Radiation was given as part of 2L treatment in 25.9% of pts. 2L CAR-T therapy was associated with improved ORR (OR 7.60, 95% CI 1.68 – 34.55, p = 0.002), improved CR rate (OR 4.15, 95% CI 1.49 – 11.53, p = 0.008) and improved PFS (HR 0.18, 95% CI 0.06 – 0.57, p = 0.004) compared to pts treated with 2L platinum salvage. There was no difference in OS between pts treated with platinum salvage or 2L CAR-T. A total of 96 patients progressed on 2L therapy, and 92 pts (95.8%) received third-line (3L) treatment. Third line treatments included chemoimmunotherapy +/- HDT/ASCT (N= 23), CD19 CAR-T (N = 35), clinical trial (N=7), check point inhibitor-based regimen (N= 11), BV based regimen (N= 8), allogeneic stem cell transplant (N = 3) or other (N = 5), with 7 pts receiving radiation as part of 3L therapy. Median PFS and OS from start of 3L therapy was 6.7 mo and 6.4 mo, respectively. Conclusions: We report the largest cohort of pts with RR PMBCL treated in the rituximab era and the largest number of PMBCL pts treated with 2L CAR-T. This is the first analysis, to our knowledge, to show a statistically significant benefit in PFS, ORR and CR rate of CAR-T compared to platinum salvage followed by HDT/ASCT as 2L treatment in a study of exclusively RR PMBCL pts. Our dataset was largely (93%) compromised of pts with primary refractory or early relapsing disease and provides support for using CAR-T as 2L treatment in this high-risk subset of RR PMBCL patients.

Abstract Background: De novo secondary central nervous system (CNS) lymphoma (SCNSL), characterized by concurrent systemic and CNS aggressive B-cell lymphoma at diagnosis, is a rare entity with a dismal prognosis. The prognostic significance of the initial anatomical compartment of CNS involvement (parenchymal vs. leptomeningeal) is not well-defined. We sought to analyze outcomes based on CNS localization in a single-institution cohort. Methods We retrospectively reviewed 34 patients with de novo SCNSL (including diffuse large B-cell lymphoma [DLBCL], high-grade B-cell lymphoma, not otherwise specified (HGBCL NOS), and double-/triple-hit lymphoma) treated at the Mayo Clinic between 2002 and 2025. Clinicopathological features, radiologic findings, treatment details, and survival outcomes were abstracted from the medical records. Patients were categorized by the primary site of CNS involvement. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method, and groups were compared with the log-rank test. Results The study cohort had a median age of 61.5 years (range 19-79) and a median International Prognostic Index score of 3 (range 2-4). Pathological subtypes included double-/triple-hit lymphoma (n=14, 41.2%), non-germinal center B-cell like (non-GCB) DLBCL (n=11, 32.4%), germinal center B-cell like (GCB) DLBCL (n=8, 23.5%), and HGBCL NOS (n=1, 2.9%). Among patients with available data, 14 (43.8%) were positive for MYC rearrangement, 13 (54.2%) for BCL2 rearrangement, and 10 (45.5%) for BCL6 rearrangement. First-line regimens received by patients included MR-CHOP (n=18, 52.9%), DA-R-EPOCH (n=5, 14.7%), combined CODOX-M/IVAC (n=4, 11.7%), R-CHOP with intrathecal methotrexate (n=3, 8.8%), miscellaneous therapies (n=3, 8.8%), and MRT (n=1, 2.9%). The complete response rate was 58.8% (n=20). Intrathecal chemotherapy was administered to 61.8% of patients, and consolidation with autologous stem cell transplant was performed in 35.3%. Based on the CNS compartment involved, de novo SCNSL (DN-SCNSL) were classified into two subtypes: the leptomeningeal subtype, defined as leptomeningeal involvement with or without parenchymal CNS disease (LM-DN-SCNSL; n=22, 64.7%), and the parenchymal subtype, defined as parenchymal-only CNS involvement (P-DN-SCNSL; n=12, 35.3%). Parenchymal disease was multifocal in 75% of cases, supratentorial in 58.3%, and associated with a midline shift in 30%. Although no tested factors (including pathological subtype, age, sex, and bone marrow involvement) were significantly associated with the anatomical compartment, a non-significant trend was noted for BCL6 rearrangement to be more common in the leptomeningeal group (8/13, 61.5%) than the parenchymal group (2/8, 25.0%) (P = 0.18). Survival outcomes were analyzed for both anatomical and pathological classifications. For the parenchymal versus leptomeningeal cohorts, 2- and 5-year Overall Survival (OS) rates were 75.0% vs. 45.1% and 41.0% vs. 38.7%, respectively (P = 0.34). For Progression-Free Survival (PFS), the 2- and 5-year rates were 48.6% vs. 32.5% and 29.2% vs. 26.0%, respectively (P = 0.53). The 2-year OS rates by pathological subtype were 81.8% for non-GCB DLBCL, 45.8% for DHL/THL, and 37.5% for GCB DLBCL (P = 0.27). Survival outcomes (OS/PFS) were not significantly associated with patient age, sex, pathological subtype, or anatomical compartment. Conclusion DN-SCNSL can be anatomically classified into two subtypes: LM-DN-SCNSL and P-DN-SCNSL. While a prognostic trend favoring the parenchymal subtype was observed, the difference did not achieve statistical significance, a finding likely attributable to the small cohort size. This classification may hold clinical utility for guiding risk stratification, and larger studies are needed to validate these findings and identify the most optimal treatments for each subtype of DN-SCNSL.

Background Primary mediastinal large B-cell lymphoma (PMBCL) is an uncommon type of non-Hodgkin lymphoma. Clinicopathologic features are distinct from diffuse large B cell lymphoma, but it shares some clinical and biologic features with Nodular sclerosis classic Hodgkin lymphoma. Central nervous system (CNS) relapse appears to be rare in patients with PMBCL, with limited literature reporting a rate of approximately 1.5% to 4%. We examined the incidence of CNS relapse, treatment approaches and survival outcomes in patients with PMBCL. Methods Patients with newly diagnosed PMBCL seen at Mayo Clinic between 2002 and 2022 were identified using the prospective Mayo Clinic Lymphoma Database. Clinical features, treatment details and outcomes were abstracted from the medical record. Cumulative incidence of CNS relapse was analyzed with death as a competing risk. The association of CNS-IPI, systemic treatment, and CNS prophylaxis approach with CNS relapse rate was analyzed using competing risk models and descriptively. Event-free survival (EFS) for the cohort was defined as time from PMBCL diagnosis to first recorded CNS and/or systemic relapse or death from any cause. Overall survival (OS) was defined as time from PMBCL diagnosis (or CNS relapse) to death from any cause. Survival analysis was performed using the Kaplan-Meier method. Results A total of 124 PMBCL cases were identified. The median age at diagnosis was 37 years and 61% were female. The distribution of CNS-IPI was low-risk in 67 (61%), intermediate-risk in 41 (37%), and high-risk in 2 (2%). 64 patients (52%) received R-CHOP and 54 patients (44%) received R-DA-EPOCH as frontline therapy. High-dose methotrexate (HD-MTX) for CNS prophylaxis was administered to 6 patients (5%), 5 with R-CHOP and 1 with R-DA-EPOCH. 16 patients received intrathecal (IT) chemotherapy (methotrexate and/or cytarabine) for CNS prophylaxis, 3 with R-CHOP and 13 with R-DA-EPOCH. The median follow-up was 56.0 months. The 5-year EFS rate was 75.1% and the 5-year OS rate was 90.7% for the entire cohort. 20 patients had systemic relapse only and 3 had CNS relapse. The cumulative incidence of CNS relapse was 1.84% (95% CI 0.46%-7.17%) at 2 years and 2.92% (95% CI 0.50%-8.84%) at 5 years (Figure 1). No statistically significant association of CNS-IPI, systemic therapy or CNS prophylaxis regimen with CNS relapse rate was found in competing risk models; however, this analysis was limited by a small event number (n=3). Among the 3 patients with CNS relapse, 1 had high-risk CNS-IPI and 2 had intermediate risk. All 3 patients were treated initially with R-CHOP. Two patients did not receive any CNS prophylaxis and 1 patient received IT CNS prophylaxis. All three patients who had CNS relapse were female. Patient #1 was diagnosed at age 48 and had simultaneous CNS and systemic relapse 6 months later. The patient was treated with HD-MTX, temozolomide and rituximab for CNS relapse, and subsequently received multiple therapies for systemic disease including R-DHAP, R-ICE, and died 17 months after CNS relapse. Patient #2 was diagnosed at age 22 and had CNS relapse after 8.7 months, followed by systemic relapse 2 months later. The patient received HD-MTX, temozolomide and rituximab for CNS relapse, followed by systemic and whole-brain radiation therapy (RT) for both systemic and CNS relapse. Subsequently the patient received salvage chemotherapy, autologous and allogeneic stem cell transplant for systemic relapse. The patient died 26.8 months after CNS relapse. Patient #3 was diagnosed at age 24 and had systemic relapse after 20.7 months, followed by CNS relapse 5.4 months later. The patient received methotrexate and whole-brain RT following CNS relapse and died 1.2 months after CNS relapse. Besides these 3 patients, we identified 6 PMBCL patients with CNS relapse who were diagnosed at other medical centers and subsequently referred to our institution for management of refractory disease. The survival after CNS relapse was poor, with a median OS of 10.4 months (95% CI 5.6-15.2). Conclusion Our study showed that the CNS relapse rate (1.84% at 2 years and 2.92% at 5 years) was overall low in patients with PMBCL, consistent with previous reports. CNS relapse was associated with poor survival despite aggressive treatment approaches. Novel approaches utilizing biological risk factors for CNS relapse, such as circulating tumor DNA, are needed to identify patients with CNS relapse.